T H E M E DIC A L PAT I E N T
PSYCHI ATR IC CA R E OF
THE MEDICA L PATI ENT
THIR D EDITION
EDITED BY EDITED BY
BOSTON,MA
1
1
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This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in
this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate information with respect to the subject
matter covered and to be current as of the time it was written, research and knowledge about medical and health issues is constantly evolving and dose schedules for
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135798642
Printed in the United States of America
on acid-freepaper
BF:Idedicate this book to my wife Xiaoling and my children Susanna, Juliana, and WilliamJames.
DG:This book is dedicated with gratitude for my family and dear friends with a focus on
the new generation just walking.
CONT ENTS
vii
26. Pharmacologic and Other Somatic Treatments PA RT V
of Nausea and Vomiting 526
N E U RO P S YC H I AT R IC D I S OR D E R S
Danielle N.Ko and Eva H.Chittenden
27. Pharmacologic and Other Somatic Treatments 41. Delirium:Neurobiology, Characteristics,
of Dyspnea 536 and Management 823
Pedro E.Prez-Cruz and Eva H.Chittenden Jos R.Maldonado
28. Therapeutic Nutrients, Herbs, and Hormones 545 42. Dementia:Diagnosis and Treatment 908
Patricia L.Gerbarg and Richard P.Brown Scott McGinnis
43. Epilepsy and Seizures 935
W. Curt LaFrance, Jr. and Andres M.Kanner
PA RT I V 44. Diagnosis and Treatment of Headache 963
M A J OR S Y M P TOM S A N D S Y N DROM E S Elizabeth W.Loder
45. Traumatic Brain Injury:Evaluation and
29. Grief, Complicated Grief, and Management for the Psychiatric Physician 984
Bereavement-Related Depression 611 Gregory J.OShanick, George T.Moses,
Alana Iglewicz and Sidney Zisook and Nils R.Varney
30. Acute and Chronic Reactions to Trauma 620 46. Frontal Systems and Dysfunctions 999
T. H.Eric Bui, M. Alexandra Kredlow, Kimiko Domoto-Reilly, Paul Malloy,
Meredith E.Charney, Mary C.Zeng, and Deborah A.Cahn-Weiner, and
Naomi M.Simon Thomas MarkhamBrown
31. Anxiety in the MedicallyIll 635 47. Movement Disorders 1007
Richard J.Goldberg and Shreya Raj and Jeremiah M.Scharf
Donna B.Greenberg 48. Neuropsychiatric Aspects of Focal
32. Eating Disorders 656 Neurological Disease:Cerebrovascular Disease
Megan Moore Brennan, Caitlin M.Nevins, and Multiple Sclerosis 1019
and Jennifer J.Thomas Ruchi Aggarwal and Mario F.Mendez
33. Primary Sleep Disorders in Medical and 49. Brain Tumors 1034
Neurological Patients 678 Donna B.Greenberg
Amit Chopra and Jarrett W. Richardson 50. Attention-Deficit Hyperactivity Disorder
34. Medical and Psychiatric Aspects of Chronic in Medical Illness 1045
Fatigue Syndromes and Apathy 691 Anna M.Georgiopoulos and Craig B.H.Surman
Linda L. M.Worley and 51. The Psychiatric Care of Medical Patients
Donna B.Greenberg with Autism 1066
35. Sexual Dysfunction 708 Robert L.Doyle
Barry S.Fogel and
Donna B.Greenberg
36. Chronic Pain 731 PA RT V I
David Borsook
M E D I C A L S PE C I A LT I E S
37. Excessive Illness Behavior 743
James C.Hamilton, Krystal A.Hedge, and
Marc D.Feldman 52. Psychiatric Care of the Patient with Heart Disease 1083
W. Victor R. Vieweg and Mehrul Hasnain
38. Treatment of Addictions and Related
Disorders 756 53. Multidimensional Behavioral Medicine
RobertSwift Strategies:Management of Tobacco Use
and Obesity 1112
39. Evaluating and Managing Suicide Risk and Michael G.Goldstein and MargaretDundon
Violence Risk in the Medical
Setting 781 54. Psychiatric Aspects of Pulmonary Disease 1140
Phillip M.Kleespies, Douglas H.Hughes, RichardKradin
Sarah R.Weintraub, and Ashley S.Hart 55. Neuropsychiatric Manifestations of Endocrine
40. Personality Disorders in the Medical Disorders 1155
Setting 801 Erin Sterenson, Christopher L.Sola,
Barry S.Fogel and Shirlene Sampson
viii C o n t e n t s
56. Gastroenterology 1169 71. Ophthalmology 1399
Donna B.Greenberg Mary Lou Jackson and JenniferWallis
57. Psychiatric Care of the Oncology Patient 1182 72. Otolaryngology 1410
Donna B.Greenberg Harold Bronheim
58. Hematologic Disorders 1198 73. Aesthetic Surgery 1424
Madeleine Becker, David J.Axelrod, Keira Chism, David B.Sarwer and Jacqueline C.Spitzer
Tal E.Weinberger, Dimitri Markov, Lex Denysenko, 74. Transplantation 1432
Christine Marchionni, Olu Oyesanmi, Howard Field, Thomas W.Heinrich, Michael Marcangelo, and
andElisabeth J.ShakinKunkel Heidi Christianson
59. End-Stage Renal Disease and Its Treatment:Dialysis 75. Burns 1455
andTransplantation 1216 Shamim H.Nejad, Amelia Dubovsky, Kelly Irwin,
Gregory M.Gressel, Norman B.Levy, Shawn Fagan, and Jeremy Goverman
Michael J.Germain, and Lewis M.Cohen
76. Urology and Andrology 1473
60. Infectious Diseases 1231 Andrew J.Roth, Suzanne R.Karl, and
Scott R.Beach Christian J.Nelson
61. Rheumatic Disease, Autoimmune Disorders, 77. Psychosocial Aspects of Upper Extremity Illness
and Allergy 1250 and Other Orthopedic Problems 1489
ShereseAli Ana-Maria Vranceanu, David Ring, and
62. Dermatology 1279 Donna B.Greenberg
Joseph A.Locala 78. Sexual and Psychological Aspects of Rehabilitation
63. HIV and AIDS 1293 AfterSpinal Cord Injury 1504
Philip A.Bialer and JosephZ.Lux Robert M.Kohut, Allen D.Seftel,
64. Medical Genetics 1312 Stanley H.Ducharme, Barry S. Fogel, and
Kristen M.Shannon and Gayun Chan-Smutko Donald R.Bodner
PA RT I X
PA RT V I I
C H I L DR E N A N D A D O L E S C E N T S
WOM E N S H E A LT H
65. Gynecological Surgery, Pelvic Pain, and 79. Psychiatric Assessment of the Physically Ill Child 1529
Other Relevant Issues 1323 Wendy Froehlich-Santino, Hans Steiner, and
Gail Erlick Robinson and Diane de Camps Meschino Richard J.Shaw
66. Infertility, Pregnancy Loss, and Abortion 1336 80. Adaptation of Psychiatric Drug Treatments to
Gail Erlick Robinson Children and Adolescents 1551
67. Hormones and Mood 1344 Eric P.Hazen
Gail Erlick Robinson and Sophie Grigoriadis 81. Death and Grief Counseling for Children
68. Pregnancy and Postpartum 1354 and Adolescents 1564
Diane de Camps Meschino, Ariel Dalfen, and Patricia J.OMalley, Hillary G.DAmato, and
Gail Erlick Robinson Frederick J.Stoddard,Jr.
PA RT V I I I PA RT X
S U RG IC A L S PE C I A LT I E S M E D IC A L P S YC H I AT RY I N T H E
E VO LV I N G S Y S T E M OF C A R E
69. General Surgery:Basic Principles 1367
Frederick J.Stoddard, Jr., Robert L.Sheridan, 82. Second Medical Opinions in the Era of
Jeevendra Martyn, Lawrence F.Selter, and Donna Personalized Medicine 1581
B.Greenberg Mayanka Tickoo, Aditya Bardia, and
Lidia Schapira
70. Psychiatric Management of Behavioral Syndromes
inIntensive Care Units 1389 83. The Continuum of Chronic Care:Nursing
Robert J.Boland, Michael G.Goldstein, Homes, Assisted Living, Home Care 1589
Scott D.Haltzman, and Tracey M.Guthrie Hong-Phuc T.Tran and David B.Reuben
C o n t e n t s ix
84. End-of-life Issues 1603 87. Telepsychiatry 1678
John L.Shuster, Harvey Max Chochinov, and Terry Rabinowitz
Natalie L.Jacobowski 88. Practice Guidelines, Performance Measurement,
85. Capacity, Competency and Consent in andIncentives 1685
Medical Psychiatry 1619 Daniel P.Hunt
Barry S.Fogel
86. Objective Psychiatric Assessment and Management Index 1701
ofChronic Disability Syndromes 1643
C. Donald Williams
x C o n t e n t s
PR EFACE
This third edition of Psychiatric Care of the Medical Patient The patient who sees a medical psychiatrist might begin the
reflects changes in medicine, psychiatry, and the healthcare relationship with tentativeness, skepticism, or ambivalence.
system over the two decades since the first edition was pub- Ideally these feelings give way to trust and confidence. Highly
lished. Medical psychiatrythe medical subspecialty that specific knowledge of the medical issues the patient faces can
applies psychiatric knowledge and skills to the problems be an important factor in bringing about the change. It can
of patients with general medical problemsis continually be transformative when a patient sensesor concludesthat
evolving. What remains constant is the primacy of the sacred the medical psychiatrist can grasp without excessive expla-
relationship between the patient and the physician, and the nation the details of the patients symptoms and functional
psychiatrists knowledge and experience of medicine as a basis impairments, drug side effects, burdens in adhering to treat-
of that relationship. ment, difficult treatment-related decisions, andmore.
Medical psychiatrists like general psychiatrists have We believe there are many patients who need what medi-
expertise in the diagnosis and treatment of primary mental cal psychiatrists can offer and who don't get it, usually because
disorders, appreciating the relevance to health of patients' the need isn't recognized and sometimes because resources
developmental histories, family relationships, and social and don't permit it. The need is greater than ever because of spe-
occupational environments, and understanding how the cific changes and trends in medicine and the healthcare sys-
physicianpatient relationship can be an aid or an impedi- tem. We offer an illustrative and far from exhaustivelist:
ment to a favorable outcome of medical care. In addition,
medical psychiatrists have detailed knowledge of one or more 1. People are living longer and accumulating more chronic
specific general medical or surgical specialties, as well as famil- diseases and impairments. These conditions make increas-
iarity with aspects of neurology, endocrinology, and clinical ing demands for adaptation at the same time as patients
pharmacology that are particularly relevant to the interac- physical and/or mental capacity to adapt can be dimin-
tion of mental disorders with general medical conditions and ished by illness.
their respective treatments. In addition medical psychiatrists
are highly aware of healthcare system issues and relationships 2. The healthcare system demands more standardization,
among different physicians, specialties, and disciplines. care according to evidence-based practice guidelines, and
These differences can be seen as a matter of degree, as all rules-based recordkeeping that severely limits discussion
good general psychiatrists should have some of the knowl- of subjective, synthetic, speculative, and holistic perspec-
edge and skills we attribute to medical psychiatrists. General tives. At the same time we are increasingly recognizing
psychiatrists can become medical psychiatrists, beginning how different patients can be, based on their age and
by focusing their practices on patient populations with gen- gender, their genetics, their ethnic origins and fam-
eral medical issues. Even so, there really is a qualitative dif- ily environments, their personalities, their social and
ference in the attitudes and professional identity of medical economic circumstances, their personal preferences, and
psychiatrists. Medical psychiatrists view themselves as phy- their particular combination of comorbid conditions. It is
sicians above all, not as mental health professionals with a sometimes daunting challenge to respect this diversity
medical training. Their aims are not limited to diagnosing and effectively advocate for appropriate individualization
and managing primary mental disorders or differentiating of care within the current context.
between functional and organic etiologies for symptoms. 3. Electronic health records, rapidly becoming the norm,
When they evaluate patients they aim to understand patients' can be an impediment to patient care. When a physi-
adaptations to their existential predicaments, which include cians eyes and attention are focused on a screen, they
whatever diseases afflict them or threaten them, be those are not focused on the patient. When records are full of
categorized as mental or otherwise. This understanding cut-and-pasted routine information, and when medical
often is accompanied by the psychiatrists empathy and the notes are filled-in templates, auditors can check boxes
patients trust. Along these lines, a motivated physician who to ensure that coding rules are followedbut it can be
is not a psychiatrist but who is psychologically minded and difficult for physicians to see what is distinctive about a
emotionally intelligent can effectively function as a medical patient, to convey important subjective perceptions, and
psychiatrist for many of his or her own patients with the aid to effectively message their colleagues through the record.
of ongoing consultation and mentorship from a psychiatrist. Alerts about potential drugdrug and drugdisease
xi
interactions can be triggered too oftenor not often 9. Consumption of psychotropic drugsmostly by people who
enoughfor physicians to depend on them. The time have never received even an evaluation by a psychiatristis
spent dealing with the electronic record may not be offset endemic in the United States. For example, the pointnot
by the time saved or adverse events avertedwith the lifetimeprevalence of antidepressant use in a recent Mayo
patient thus losing valuable face time with the physician Clinic community survey was 13%, and among women
or the physician losing time for reflection, research, and aged 5064years the rate was 24%. By the time patients
recreation. (As information technology advances, these see psychiatrists they usually have experienced one or more
issues eventually will be resolved:better voice recognition, psychotropic drugs, or they currently are taking one or more.
better processing of free text and other unstructured data, This alters the presentation of mental disorders to psychia-
more intelligent machines, and effective deployment of trists as well as often affects the attitude a patient has when
hypertext willhelp.) anew psychotropic drug prescription is proposed.
4. The Internet has had profoundand mixedeffects on 10. Attention to pain as "the fifth vital sign" has increased,
patients' health and their adaptation to illness. Patients with mixed effects. While fewer patients are suffering from
are better informed but sometimes misinformed by what untreated severe pain, the misuse, abuse, and ineffective use
they find online. Through social media patients can of prescription opiates clearly has increased. Pain research has
find others with similar problems, but time spent online advanced, with better understanding of neuropathic pain,
is time not spent in direct face-to-face interaction. It more specific treatment for many painful conditions, greater
remains to be seen for whom online social support works recognition of unusual pain syndromes, and improved meth-
as well as the traditionalkind. odology for rehabilitation. All chronic pain is now appreci-
ated as having a neuropathic aspect. Tools for recognition of
5. Hospitalizations are shorter, and people now receive care
addiction and new treatment options such as buprenorphine
in community settings who would not have just 20years
have evolved as well. Dissemination of these advances to date
ago. Care rendered in a hospital for a serious illness
has been uneven, as is typical of medical innovations.
involves many people of different specialties and disci-
plines, whose efforts often are not optimally coordinated. 11. Cognitive impairment disorders have increased in preva-
The team of physicians and other health professionals lence with the aging of the population, and there is much
who get to know a patient in the hospital or emergency greater differentiation of the diseases that cause them. The
room is different from the team caring for the patient distinctions among dementia syndromes and their underly-
outside the hospital. The outpatient team has different ing neurodegenerative diseases are widely appreciated in
resources and a different time frame for action, and it the neurological community. Symptomatic treatments
mayhave different goals and incentives. Communication are used both for neurodegenerative diseases and for their
failures are commonand even with good communica- neuropsychiatric complications such as depression and
tion there can be failures of coordination ofcare. psychosis. Diagnostic practice, which just a few decades ago
was typically the identification of a chronic organic brain
6. Patient autonomy has become a dominant
syndrome and ruling out a treatable dementia, has moved
principleusually but not always for the best. Competent
toward broader appreciation of distinct neurodegenerative
patients are expected to give or withhold informed con-
diseases that elicit physicians intellectual interest.
sent for medical procedures and to give advance directives
for their care in hypothetical life-or-death circumstances. 12. Some highly prevalent mental disorders including depres-
Despite current pressures to get advance directives or sion, generalized anxiety, and ADHD are less stigmatized
get informed consent from patients, taking informed than they once were. Nonetheless, many disorders
consent and advance directives seriously requires much including schizophrenia, borderline personality, and drug
more than getting patients signatures on long and dependence continue to carry stigma. An unfortunate
detailed printed forms. How questions are asked, when consequence is a tendency toward diagnosis of nonstigma-
they are asked, and who asks them all will affect answers tized conditions when the diagnosis of a stigmatized con-
to the questions on thoseforms. dition, either as an alternative or as comorbidity, would be
more accurate and helpful in planning treatment.
7. While physicians have less control over what happens to
their patients, they are no less accountable for medical 13. Brain imaging has captured the publics imagination with
outcomes. Physicians must teach and persuade, suggest positive effects like broader public support for brain research.
and motivate, rather than simply order and prescribe. There are, however, some prevalent misconceptions. For
example, some patients believe that normal brain imaging
8. Patients expectations for care are greater because more
rules out neurodegenerative disease. In cases of traumatic
conditions can be treated. Because of the Internet and
brain injury, defense lawyers have essentially argued that
direct-to-patient advertising, patients know what is
normal anatomic brain imaging means that an injury will
available and may request or even demand particular
not lead to prolonged disability, while plaintiffs lawyers have
treatments. At the same time costs are escalating and
argued that abnormal functional brain imaging means that
physicians are pressed to limit the use of expensive
it will; neither inference is necessarily correct.
treatments.
xii Pr e fac e
14. Complementary and alternative medicine (CAM), getting fatter, with steadily increasing rates of over-
including the use of herbal remedies and nutritional weight and obesity and the syndromes associated
supplements, has moved toward the mainstream of with excessive weight, including Type 2 diabetes
practice, but it is not quite there. Many popular treat- and obstructive sleep apnea. Medical, surgical, and
ments have weak evidentiary support, and the use of cognitive-behavioral therapies for obesity have an
complementary and alternative treatments can delay increasing evidence base, but the majority of people
access to evidence-based conventional treatments or can with medically significant overweight and even morbid
interact adversely with them. For specific patients the obesity are not effectively treated.
consideration of evidence-based CAM treatments that
20. Sleep disturbance, sleep disorders, and sleep deficits are
are potentially superior to conventional treatments is
highly prevalent, and their pervasive impact on physical
almost random, depending on the physician's personal
and mental health is increasingly recognized. Even so,
knowledge and experience.
sleep does not yet get the attention it deserves, and thera-
15. Perceptions are changing of what is normal function pies for sleep disorders that are efficacious in controlled
later in life and what losses of function are acceptable. studies are less effective in actual practice. Principles of
More people than in the past believe that they should sleep hygiene are known to the field but not necessarily
continue in their occupations, remain as athletic as they taught to patients or followed by patients even when
were when they were younger, and have an active sexual they are known. The critical sleep-related questions
life well into their 70s and80s. are changing. Where two decades ago the question
might have been, Could this patient have obstructive
16. There are an ever-increasing number of circumstances
sleep apnea? it might now be, Is this patient using his
where medical situations that once had to be accepted
CPAPmachine, and if not, whynot?
are now potentially changeable, although often with
pain, inconvenience, and/or expense. For example, an 21. Questionnaire-based screening tests and patient-reported
aging face can be made to look younger with Botox or outcome measures have become mainstream and in some
aesthetic surgery. Apostmenopausal woman can con- contexts mandatory.
ceive and bear a healthy child with the aid of IVF, using
donor eggs or her own eggs or embryos frozen at an The editors of this volume have selected chapter authors
earlier time. Bionic devices can partially alleviate losses whom we regard as medical psychiatrists or as key members
in vision or hearing; prosthetic limbs can be attached to of medical-psychiatric teams. Many of them have training
nerves and function more like naturalones. in neurology, internal medicine, obstetrics and gynecol-
ogy, or another nonpsychiatric specialty. In our editorial
17. Long-term psychodynamic therapy is not as central to
dialogue with them we have asked them questions from our
general psychiatric practice as it once was. At the same
own medical-psychiatric perspective. This perspective, and,
time, the evidence base supporting psychodynamic
implicitly, the attitudes and identity of the medical psychia-
concepts of defense mechanisms, attachment styles, and
trist, are conveyed by the first three sections of this book,
personality organization has increased. Psychodynamic
which describe the evaluation of medical-psychiatric patients
understanding has particular value in helping patients
and a comprehensive approach to assessing major symptoms
adapt to general medical illnesses, their symptoms and
and syndromes.
impairments, and the demands of their treatments.
The potential of healthcare to prolong life and to enhance
Ironically, psychodynamic theory and practice might
the quality of life has never been greater. Yet, there often are
find broader application in medical psychiatry than in
gaps between the potential of 21st-century medicine, patients
the treatment of primary mental disorders.
expectations from their healthcare, and the reality of patients
18. Organized religion is important to a smaller propor- healthcare experiences, clinical outcomes, and health-related
tion of the population, but it is essential to the lives quality of life. Medical psychiatrists participate in efforts
of believers. Many people are spiritual but not to identify and close such gaps. In doing so they begin with
religious, and many have deeply felt ethical principles the legacy of the physicianpatient relationship; they draw
and transpersonal motivations not based on belief upon know-how and wisdom developed and articulated by
in a higher power or transcendent being. Faced with 20th-century psychiatrists, and they apply 21st-century medi-
illness-related existential challenges, patients turn to cal knowledge. The editors hope is that this third edition
their principles, but without conventional religious of Psychiatric Care of the Medical Patient will supportand
affiliations they may not have an obvious source of memorializethis effort.
assistance in applying them. Medical psychiatrists
sometimes can help patients discover and utilize their Barry S.Fogel,MD
spiritual or religious resources. Donna B.Greenberg,MD
Boston, Massachusetts
19. The population in the United Statesand in several
April2015
other upper-income and middle-income countriesis
Pr e fac e xiii
ACK NOW LEDGM ENTS
We deeply appreciate the work of our contributing authors, scholar who has lived in China, Japan, and the United States;
whose chapters reflect the time and care given to this project. she has observed the changes of the last two decades in medi-
In the academic world book chapters may not count as much cine and psychiatry from outside the medical profession and
as peer-reviewed journal articles, but in the real world the from a global perspective, deconstructing them with her usual
clinical wisdom found in a good medical textbook can stick acuity. Answering her many questions about the content of
in a physicians mind and durably improve practice. the book and my own contributions to it evoked many new
We acknowledge David DAddona, our editor at Oxford insights. She encouraged me to pursue the project and helped
University Press. Hes the best of the many editors we have me protect the time to complete it. And, she inspires me in
worked with in over 30years of writing for medical publica- general.
tions. David has a great sense of what would make someone I also would like to thank the many fellows and
want to reador even buya medical textbook when so junior faculty in neuropsychiatry and behavioral neurol-
much information is instantly and freely available online. ogy whom I have mentored over the past 17 years at the
In addition, no one could do a better job of making a tardy Brigham and Womens Hospital. Several have contributed
contributoror editorfeel guilty and understood at the chapters to this volume; all have contributed to the evolu-
sametime. tion of my thinking about how neurological, psychiatric,
We remember our late colleague Dr.Alan Stoudemire, a and general medical perspectives can be better integrated.
wonderful physician, prolific writer, and tireless proponent It has given me joy to see them succeed in their scientific
of medical psychiatry, who collaborated with us and inspired and clinicalwork.
us from the early 1980s until his death shortly after the sec- DG: Iam indebted to many of my medical and psychi-
ond edition of this book was published. We also remember atric colleagues at Massachusetts General Hospital. They set
Dr.W.Victor (Vic) Vieweg, a cardiologist-psychiatrist who a high standard of clinical reasoning, dedication, and curi-
co-wrote our cardiology chapter. Vic was an outstanding osity, and their passion for medicine is infectious! Further
teacher and scholar of both psychiatry and cardiology, whom inspiration comes from the psychiatrists and psychologists,
we were honored to have as a contributor to this volume. nationally and internationally, who express their creativity
BF: Above all I must acknowledge the contribution of at the bedside of the medically ill, challenging all of us to
my wife, Xiaoling Jiang, PhD. Xiaoling is a trilingual literary do better.
xv
CONT R I BUTOR S
xvii
Lucienne A.Cahen,MD Ariel Dalfen, MD,FRCPC
Department of Psychiatry Assistant Professor
Harvard Medical School; and Department of Psychiatry
Massachusetts General Hospitaland University of Toronto Faculty of Medicine; and
Division of Behavioral and MentalHealth Head Perinatal Mental Health Program
Spaulding Rehabilitation Hospital Mount Sinai Hospital
Boston,MA Toronto, Ontario, Canada
Deborah A.Cahn-Weiner,PhD Hillary G.DAmato
Department of Neurology Department of Psychiatry
University of California-San Francisco Harvard Medical School; and
San Francisco,CA Massachusetts General Hospital
Boston,MA
Gayun Chan-Smutko, MS,CGC
Center for Cancer Risk Assessment Diane de Camps Meschino,
Massachusetts General Hospital Cancer Center MD, BSc(H),FRCPC
Boston,MA Department of Psychiatry
University of Toronto Faculty of Medicine;and
Meredith E.Charney,PhD
Womens College Hospital
Massachusetts General Hospital; and
Toronto, Ontario,Canada
Department of Psychiatry
Harvard Medical School Lex Denysenko,MD, FAPM
Boston,MA Department of Psychiatry and Human Behavior
Thomas Jefferson University Hospital
Keira Chism,MD
Philadelphia, PA
Department of Psychiatry and
Human Behavior Kimiko Domoto-Reilly,MD
Thomas Jefferson University Hospital Department of Neurology
Philadelphia,PA University of Washington
Seattle, WA
Eva H.Chittenden,MD
Director of Education Robert L.Doyle,MD
Palliative Care Division, Department of Medicine Department of Psychiatry
Massachusetts General Hospital Massachusetts General Hospital
Assistant Professor of Medicine Boston,MA
Harvard Medical School
Amelia Dubovsky,MD
Boston,MA
Psychiatry Consultation Service
Harvey Max Chochinov, MD, PhD,FRCPC Harborview Medical Center
Distinguished Professor of Psychiatry Psychiatry and Behavioral Sciences
University of Manitoba University of Washington
Canada Research Chair in Palliative Care Washington, WA
Manitoba Palliative Care Research Unit CancerCare
Stanley H.Ducharme,PhD
Manitoba
Professor of Urology
Winnipeg, Canada
Boston University Medical Center
Amit Chopra,MD Clinical Psychologist
Department of Psychiatry Boston Medical Center
West Penn Allegheny HealthSystem Boston,MA
Pittsburgh,PA
Margaret Dundon,PhD
Heidi Christianson,PhD Veterans Health Administration
Department of Psychiatry and National Center for Health Promotion and Disease
Behavioral Medicine Prevention
Medical College of Wisconsin Durham, NC
Milwaukee,WI
Shawn Fagan,MD
Lewis M.Cohen,MD Burn and Reconstructive Surgery
Department of Medicine Critical Care Medicine
Tufts University School of Medicine;and Joseph M Still Burn Centers, Inc
Baystate MedicalCenter Boston, MA
Springfield,MA
xviii C o n t r i b u t o r s
Marc D.Feldman,MD Michael G.Goldstein,MD
Department of Psychiatry and Behavioral Medicine Veterans Health Administration National Center
The University of Alabama for Health Promotion and Disease Prevention
Tuscaloosa, AL Providence,RI
Howard Field,MD Jeffrey S.Gonzalez,PhD
Department of Psychiatry and Departments of Medicine and Epidemiology &
Human Behavior PopulationHealth
Thomas Jefferson University Hospital Albert Einstein College of Medicine
Philadelphia,PA Bronx,NY
Barry S.Fogel, MD,MBA Cheryl Gore-Felton,PhD
Department of Psychiatry Department of Psychiatry and Behavioral Sciences
Harvard Medical School;and Stanford University School of Medicine
Brigham and Womens Hospital Stanford,CA
Boston,MA
Tristan Gorrindo,MD
Gregory L.Fricchione,MD Department of Psychiatry
Assistant professor of Surgery Harvard Medical School;and
Division of Burns Surgery Massachusetts General Hospital
Massachusetts General Hospital Boston,MA
Harvard Medical School
Jeremy Goverman,MD
Boston,MA
Assistant professor of Surgery
Wendy Froehlich-Santino,MD Division of Burns Surgery
Departments of Psychiatry & Behavioral Massachusetts General Hospital
Science and Pediatrics Harvard Medical School
Stanford University School of Medicine Boston, MA
Stanford,CA
Stephen A.Green,MD
Anna M.Georgiopoulos,MD Department of Psychiatry
Department of Psychiatry Georgetown University School
Harvard Medical School; and of Medicine
Massachusetts General Hospital Washington,DC
Boston,MA
Donna B.Greenberg,MD
Patricia L.Gerbarg,MD Department of Psychiatry
Department of Psychiatry Harvard Medical School;and
NewYork Medical College Massachusetts General Hospital
Valhalla,NY Boston,MA
Michael J.Germain,MD Joseph A.Greer,PhD
Department of Medicine Center for Psychiatric Oncology &
Tufts University School of Medicine;and Behavioral Sciences,
Baystate MedicalCenter Massachusetts General Hospital Cancer Center
Springfield,MA Department of Psychiatry,
Harvard Medical School
Richard J.Goldberg,MD, MS
Boston,MA
Professor, Department of Psychiatry and Human Behavior
Warren Alpert School of Medicine at Gregory M.Gressel,MD
Brown University Department of Obstetrics
Providence,RI Gynecology & Reproductive Sciences
Yale University School of Medicine
Richard T.Goldberg,EdD
New Haven,CT
Department of Psychiatry
Harvard Medical School; and
Massachusetts General Hospitaland
Division of Behavioral and MentalHealth
Spaulding Rehabilitation Hospital
Boston,MA
C o n t r i b u t o r s xix
Sophie Grigoriadis, MD, MA, PhD,FRCPC Paul J.Helmuth,MD
Head Womens Mood and Anxiety Clinic: Valley Medical Associates
Reproductive Transitions Springfield,MA
Fellowship Director
Seth D.Herman,MD
Department of Psychiatry
Department of Physical Medicine & Rehabilitation
Sunnybrook Health Sciences Centre Scientist
Spaulding Rehabilitation Hospital;and
Sunnybrook Research Institute
Massachusetts General Hospital
Adjunct Scientist
Boston,MA
Womens College Research Institute
Associate Professor Douglas H.Hughes,MD
Department of Psychiatry Department of Psychiatry
University of Toronto Boston University School of Medicine
Toronto, Canada Boston,MA
Tracey M.Guthrie,MD Daniel P.Hunt,MD
Department of Psychiatry and Human Behavior Department of Medicine
Warren Alpert School of Medicine at Harvard Medical School;and
Brown University Massachusetts General Hospital
Providence,RI Boston,MA
Scott D.Haltzman,MD Alana Iglewicz,MD
David LawrenceCenter Department of Psychiatry
Naples,FL University of California-San Diego; and
VA San Diego Healthcare System
James C.Hamilton,PhD
San Diego, CA
Associate Professor of Psychology
Clinical Affiliate Associate Professor of Internal Medicine Kelly Irwin,MD
University of Alabama MGH Psychiatric Oncology and Behavioral Sciences
Tuscaloosa,AL MGH Cancer Center; and
MGH Schizophrenia Program
Ashley S.Hart,PhD
Harvard Medical School
Veterans Administration Boston HealthcareSystem
Boston, MA
Boston,MA
Mary Lou Jackson,MD
Mehrul Hasnain,MD
Massachusetts Eye and Ear Infirmary
Department of Psychiatry
Department of Ophthalmology
Memorial University
Harvard Medical School
Waterford Hospital
Boston,MA
St. Johns, Newfoundland,
Canada Natalie L.Jacobowski,MD
Department of Psychiatry
Eric P.Hazen,MD
Vanderbilt University School of Medicine
Department of Psychiatry
Nashville,TN
Harvard Medical School; and
Massachusetts General Hospital Andres M.Kanner,MD
Boston,MA Department of Neurology
University of Miami Miller School of Medicine
Krystal A.Hedge
Miami,FL
Department of Psychology
University of Alabama Nasser Karamouz,MD
Tuscaloosa,AL Department of Psychiatry
Harvard Medical School; and
Thomas W.Heinrich,MD
Massachusetts General Hospitaland
Department of Psychiatry and Behavioral
Division of Behavioral and MentalHealth
Medicine;and
Spaulding Rehabilitation Hospital
Department of Family and Community Medicine
Boston,MA
Medical College of Wisconsin
Milwaukee,WI
xx C o n t r i b u t o r s
Suzanne R.Karl, DO W. Curt LaFrance Jr, MD,MPH
Department of Psychiatry Departments of Psychiatry
The Zucker Hillside Hospital and Neurology
North Shore-LIJ Health System The Warren Alpert School of Medicine at
Glen Oaks, NY BrownUniversity;and
Rhode Island Hospital
Gabor I.Keitner,MD
Providence,RI
Department of Psychiatry
The Warren Alpert School of Medicine at Brown Norman B.Levy,MD
University;and Professor Emeritus
Rhode Island Hospital Psychiatry
Providence,RI SUNY, Downstate Medical Center; and
Director of Psychiatry
Shahram Khoshbin,MD
Southern California Mental Health Associates
Associate Professor of Neurology
Los Angeles, CA
Harvard Medical School
Department of Neurology Joseph A.Locala,MD
Brigham and Womens Hospital Division of Medicine and Psychiatry
Boston,MA University Hospitals Case Medical Center;and
Department of Psychiatry
Phillip M.Kleespies,PhD
Case Western Reserve University School
Department of Psychiatry
of Medicine
Boston University School of Medicine;and
Cleveland,OH
Veterans Administration Boston HealthcareSystem
Boston,MA Steven E.Locke,MD
Department of Psychiatry
Danielle N.Ko, MBBS,LLB
Harvard Medical School; and
Department of Medicine
Beth Israel Deaconess Medical Center
Harvard medical School; and
Boston, MA
Massachusetts General Hospital
Boston, MA Elizabeth W.Loder, MD,MPH
Department of Neurology
Robert M.KohutJr,MD
Harvard Medical School; and
Department of Urology
Brigham and Womens Hospital
Case Western Reserve University
Boston,MA
School of Medicine
Cleveland,OH Joseph Z.Lux,MD
Department of Psychiatry
Richard Kradin,MD
NewYork University School of Medicine;and
Director of Dyspnea Clinic
Bellevue HospitalCenter
Pulmonary and Critical Care Unit
NewYork,NY
Center for Psychoanalytical Studies
Massachusetts General Hospital and Jos R.Maldonado, MD, FAPM,FACFE
Associate Professor of Medicine and Pathology Associate Professor of Psychiatry, Internal Medicine,
Harvard MedicalSchool Surgery, Emergency Medicine & Law
Boston,MA Medical Director
M. Alexandra Kredlow Psychosomatic Medicine Service
Department of Psychiatry Stanford University School of Medicine
Massachusetts General Hospital Stanford, CA
Boston,MA Paul Malloy,PhD
Elisabeth J.Shakin Kunkel,MD Department of Psychiatry & Human Behavior
Vice Chair for Clinical Affairs The Warren Alpert Medical School of Brown University
Department of Psychiatry and Human Behavior Brown University
Thomas Jefferson University Providence, RI
Philadelphia, PA
C o n t r i b u t o r s xxi
Vaughn L.Mankey,MD Aaron P.Nelson,PhD
West Lake Hills,TX Department of Psychiatry
Harvard Medical School;
Michael Marcangelo,MD
Department of Neurology
Department of Psychiatry and
Brigham and Womens Hospital
Behavioral Neurosciences
Boston,MA
Pritzker School of Medicine at the
University of Chicago Christian J.Nelson,PhD
Chicago,IL Department of Psychiatry and Behavioral Sciences
Memorial Sloan-Kettering CancerCenter
Christine Marchionni,MD
NewYork,NY
Psychiatry
Temple University Hospital Caitlin M.Nevins
Philadelphia,PA The California School of Professional Psychology
San Francisco,CA
Dimitri Markov,MD
Department of Psychiatry and Human Behavior Patricia J.OMalley,MD
Thomas Jefferson University Hospital Assistant Professor in Pediatrics
Philadelphia,PA Department of Pediatrics primary,
Emergency Medicine secondary
Jeevendra Martyn, MD
Harvard Medical School; and
Department of Anesthesiology
Medical Director, Pediatric Palliative Care
Harvard Medical School; and
MassGeneral Hospital for Children and
Massachusetts General Hospital
Massachusetts General Hospital
Boston, MA
Boston, MA
Cynthia A.Gutierrez,PharmD
Laura Ortiz-Tern, MD,PhD
South Texas Veterans Health CareSystem
Department of Neurology
San Antonio,TX
Harvard Medical School; and
Scott McGinnis,MD Beth Israel Deaconess MedicalCenter
Department of Neurology Boston,MA
Harvard Medical School; and
Gregory J.OShanick, MD,DLFAPA
Brigham and Womens Hospital;and
Center for Neurorehabilitation Services
Massachusetts General Hospital
Richmond, VA
Boston,MA
Adjunct Clinical Professor of Psychiatry and
Mario F.Mendez, MD,PhD the Behavioral Sciences
Department of Psychiatry & Biobehavioral Sciences;and Keck School of Medicine
Department of Neurology University of Southern California
David Geffen School of Medicine Los Angeles, CA
University of California-Los Angeles
Olu Oyesanmi, MD,MPH
Los Angeles,CA
Economic Cycle Research
Cynthia W.Moore,PhD Plymouth Meeting,PA
Department of Psychiatry
Lawrence Park,MD
Harvard Medical School;and
Food and Drug Administration
Massachusetts General Hospital
Washington,DC
Boston,MA
David L.Perez,MD
George T.Moses, DO,MA, FAPA
Departments of Neurology and Psychiatry
Family Care Behavioral Health, INC.
Harvard Medical School;and
Zanesville,OH
Brigham and Womens Hospital
Shamim H.Nejad,MD Massachusetts General Hospital
Director, Burns and Trauma Psychiatry Boston,MA
Medical Director, Addiction Consultation Team
Division of Psychiatry and Medicine
Department of Psychiatry
Massachusetts General Hospital
Assistant Professor of Psychiatry,
Harvard Medical School
Boston, MA
xxii C o n t r i b u t o r s
Pedro E.Prez-Cruz, MD,MPH Fernando A.Rivera,MD, FACP
Department of Medicine Assistant Professor of Medicine, Mayo College of Medicine
Harvard Medical School; and Consultant Division of Diagnostic and
Massachusetts General Hospital Consultative Medicine
Boston, MA; and Mayo Clinic
Departamento Medicina Interna, Facultad de Medicina Jacksonville, FL
Pontificia Universidad Catlica de Chile
Gail Erlick Robinson, MD, DPsych,FRCPC
Santiago,Chile
Departments of Psychiatry and Obstetrics/Gynecology
John R.Peteet,MD University of Toronto Faculty of Medicine;and
Department of Psychiatry Womens Mental Health Program
Harvard Medical School; University Health Network
Brigham and Womens Hospital; and Toronto, Ontario,Canada
Dana Farber Cancer Institute
Andrew J.Roth,MD
Boston, MA
Department of Psychiatry and Behavioral Sciences
Donn A.Posner,PhD Memorial Sloan-Kettering Cancer Center and
Department of Psychiatry and Human Behavior Professor Clinical Psychiatry
The Warren Alpert School of Medicine at Weill Cornell Medical College
Brown University New York, NY
Providence,RI
Steven A.Safren,PhD
Terry Rabinowitz, MD,DDS Department of Psychiatry
Professor, Departments of Psychiatry and Family Medicine, Harvard Medical School; and
University of Vermont College of Medicine Massachusetts General Hospital
Medical Director, Division of Consultation Boston,MA
Psychiatry and Psychosomatic Medicine
Shirlene Sampson,MS, MD
Medical Director, Telemedicine
Associate Professor in Psychiatry
Burlington, VT
Department of Psychiatry and Psychology
Shreya Raj,MD Mayo Clinic College of Medicine
Departments of Psychiatry and Neurology Rochester, MN
Harvard Medical School; and
Rani A.Sarkis,MD, MSc
Brigham and Womens Hospital
Department of Neurology
Boston,MA
Harvard Medical School; and
David B.Reuben,MD Brigham and Womens Hospital
Multicampus Program in Geriatric Medicine and Boston, MA
Gerontology
David B.Sarwer,PhD
Director
Departments of Psychiatry and Surgery
Division of Geriatrics
The Edwin and Fannie Gray Hall Center for Human
Chief
Appearanceand
Archstone Professor of Medicine
Center for Weight and Eating Disorders;and
David Geffen School of Medicine at UCLA
Perelman School of Medicine at the University of
Los Angeles, CA
Pennsylvania
Jarrett W.Richardson,MD Philadelphia,PA
Department of Psychiatry & Psychology
Jeremiah M.Scharf, MD,PhD
Center for Sleep Medicine
Departments of Neurology and Psychiatry
Mayo Clinic College of Medicine
Harvard Medical School
Rochester, MN
Brigham and Womens Hospital; and
David Ring, MD,PhD Massachusetts General Hospital
Chief of Hand Surgery, Massachusetts Boston, MA
General Hospital
Lidia Schapira,MD
Department of Orthopaedic Surgery,
Associate Professor of Medicine
Harvard Medical School
Harvard Medical School
Massachusetts General Hospital
Associate Physician
Boston, MA
Massachusetts General Hospital Cancer Center
Boston, MA
C o n t r i b u t o r s xxiii
Allen D.Seftel,MD Jacqueline C.Spitzer,MSEd
Departments of Surgery and Urology;and Center for Weight and Eating Disorders;and
MD Anderson Cancer Center at Cooper University Department of Psychiatry
HealthCare Perelman School of Medicine at the University of
Marlton,NJ Pennsylvania
Philadelphia,PA
Lawrence F.Selter,MD
Department of Psychiatry Hans Steiner,MD
Massachusetts General Hospital Departments of Psychiatry & Behavioral Science
Boston,MA andPediatrics
Stanford University School of Medicine
Kristen M.Shannon, MS,CGC Stanford,CA
Center or Cancer Risk Assessment
Mass General Hospital Cancer Center Erin Sterenson,MD
Boston, MA Department of psychiatry and psychology
Olmsted Medical Center
Richard J.Shaw,MD Rochester, MN
Departments of Psychiatry and Behavioral
Science and Pediatrics Frederick J.Stoddard Jr.,MD
Stanford University School of Medicine Professor
Stanford,CA Harvard Medical School
Boston, MA
Robert L.Sheridan,MD
Department of Surgery Kimberly Stoner,MD
Harvard Medical School Departments of Medicine and Psychiatry
Shriners Hospital for Children;and Medical College of Wisconsin
Massachusetts General Hospital Milwaukee,WI
Boston,MA Alan Stoudemire,MD
John L.Shuster,MD Department of Psychiatry
Chief Medical Officer Emory University School of Medicine
MindCare Solutions Group, Inc.; and Atlanta,GA
Clinical Professor of Psychiatry Craig B.H. Surman,MD
Vanderbilt University School of Medicine Scientific Coordinator, Adult ADHD Research Program
Nashville, TN Massachusetts General Hospital;
David A.Silbersweig,MD Assistant Professor of Psychiatry
Department of Psychiatry and Harvard Medical School
Institute for the Neurosciences Boston, MA
Brigham and Womens Hospital; and Robert Swift, MD,PhD
Harvard Medical School Department of Psychiatry and Human Behavior
Boston, MA The Warren Alpert Medical School of Brown
Naomi M.Simon,MD University; and
Department of Psychiatry The Center for Alcohol and Addiction Studies; and
Harvard Medical School;and The Providence VA Medical Center
Massachusetts General Hospital Providence, RI
Boston,MA Jennifer J.Thomas,PhD
Christopher L.Sola,DO Department of Psychiatry
Department of Psychiatry and Psychology Harvard Medical School;and
Mayo Clinic College of Medicine Massachusetts General Hospital
Rochester,MN Boston,MA
David Spiegel,MD Mayanka Tickoo,MD
Department of Psychiatry and Department of Medicine
Behavioral Sciences Tufts University School of Medicine
Stanford University School of Medicine Boston,MA
Stanford,CA
deceased
xxiv C o n t r i b u t o r s
Lara Traeger,PhD Sarah R.Weintraub,PhD
Department of Psychiatry Veterans Administration Boston HealthcareSystem
Harvard Medical School; and Boston,MA
Massachusetts General Hospital
C. Donald Williams, MD,CGP
Boston,MA
Academy of Organizational and Occupational Psychiatry
Hong-Phuc T.Tran,MD Yakima, WA
Department of Geriatric Medicine
Linda L. M.Worley,MD
UCLA MedicalCenter
Mental Health Chief Physician Consultant,
Santa Monica,CA
VISN 16 Veterans Health Administration
Nils R.Varney, PhD,ABPP Adjunct Professor of Medicine Vanderbilt University
United States Naval Beaufort Hospital Adjunct Professor of Psychiatry University of
Port Royal,SC Arkansas for Medical Sciences
Fayetteville, AR
W. Victor R. Vieweg,MD
Department of Psychiatry and Internal Medicine Monique V.Yohanan, MD,MPH
Virginia Commonwealth University School of Medicine Milliman Care Guidelines
Richmond,VA San Francisco,CA
Ana-Maria Vranceanu,PhD Mary C.Zeng,MD
Assistant Professor in Psychology Department of Psychiatry
Department of Psychiatry Harvard Medical School; and
Harvard Medical School; and Massachusetts General Hospital
Clinical Psychologist Boston,MA
Behavioral Medicine Service
Sidney Zisook,MD
Massachusetts General Hospital
Distinguished Professor
Boston, MA
Department of Psychiatry
Jennifer Wallis,PhD University of California-San Diego and
Department of Ophthalmology San Diego VA Healthcare System
Harvard Medical School;and La Jolla, CA
Massachusetts Eye and Ear Infirmary
Boston,MA
Tal E.Weinberger,MD
Clinical Assistant Professor
Sidney Kimmel Medical Center at
Thomas Jefferson University
Department of Psychiatry and Human Behavior
Philadelphia PA
deceased
C o n t r i b u t o r s xxv
PA RT I
DI AG NO S T IC M ET HOD S
1.
PR INCIPLES OF MEDICA L PSYCHI ATRY
Donna B.Greenberg and Barry S.Fogel
3
public as a type of clinical neuroscientist. Psychiatrists train- import to the patient, sets priorities for action, weeds out erro-
ing still emphasizes the ability to listen with empathy to neous and obsolete data, and highlights what is most impor-
patients narratives, to perceive subtle emotional communica- tant going forward.
tion, and to understand patients existential predicaments as The Internet has profoundly changed medical practice
well as their diagnoses. Nonpsychiatristsboth patients and in ways that are especially relevant to medical psychiatrists.
health professionalsstill perceive psychiatrists as in some Getting information about medical conditions is now very
way different from other physicians. These perceptions may easy for patients and families. Patients and families frequently
include the attribution of esoteric skill, as well as less admi- come to visits with preformed ideas about the clinical situa-
rable attributes. tion rather than with completely open minds. In order to pro-
As more medical conditions are treatable, as life expec- vide information about treatment options, the physician often
tancy has increased, and as the cost of care escalates, the must start with correcting misinformation. Sometimes online
medical profession and the healthcare system in general have clinical information relieves patients anxiety, but often it
focused more on quality of life. Function and well-being are increases it. Specialists, including medical psychiatrists, are
more often now explicitly described and measured. Afocus on no longer gatekeepers controlling access to arcane knowledge.
the patients quality of life in the face of chronic illness or dis- Instead they are interpreters, critics, and expert users of infor-
ability fits well with the tradition of integrating humanistic mation that increasingly is available to all. Medical psychia-
and physiologic perspectives on illnesses of all kinds. The med- trists have an important role in summarizing and clarifying
ical psychiatrist asks, How can Ibe helpful to this patient? the data that exist and in using their expert communication
in the broadest sense, to increase function and quality of life skills to elicit and address patients beliefs, including those
as well as life expectancy and freedom from distressing symp- arising from online self-study.
toms. Some medical psychiatrists even venture to touch upon
the meaning of life in their interactions with patients.
Ironically, another tradition in twentieth-century psy- T H E E VOLV I N G ROL E OF T H E
chiatryone that has been codified in the Diagnostic and M E DIC A L P S YC H I AT R I S T
Statistical Manual of the American Psychiatric Association
and in the International Classification of Diseasesgives Other aspects of the contemporary environment of medical
primacy to the classification of mental disorders by charac- practice affect what medical psychiatrists do and the chal-
teristic symptoms. This allows treatment, research, and reim- lenges they face. These include (1)a trend toward institutional
bursement for care to be based on categorical diagnosis. This medical practice, with most physicians employed by hospi-
tradition of diagnostic classification by characteristic symp- tals, clinics, or group practices; (2) greater reliance on prac-
toms was motivated in part by the aim of making psychiatric tice guidelines and other explicit and usually evidence-based
diagnoses more reliable and thereby improving the quality of standards of care; (3)greater use of screening tests and rating
psychiatric research. This methodology is necessarily reduc- scales in routine practice, with quantitative measurement of
tionist; in the absence of definitive biologic markers, it can care outcomes; (4)greater legitimacy of complementary and
convey specious precision in diagnosis. Nevertheless, for- alternative medicine, with wider use of vitamins, herbs, and
mal psychiatric diagnosis by consensus criteria is essential to bodywork; and (5)devolution of most psychotherapy and psy-
evidence-based practice. It is necessary but rarely sufficient for chosocial treatments to nonmedical disciplines.
optimizing the overall outcomes of care in patients with mul- The current system of physician payment in the United
tiple comorbidities. States has complex effects on medical-psychiatric prac-
Electronic medical records, the adoption of which in the tice. The current regulatory requirement that health plans
United States has been heavily promoted by the federal gov- cover mental health and substance abuse services poten-
ernment, have increased the standardization of clinical data tially increases the supply of services. However, as long as
and have improved the availability of such data to consultants. such services are managed separately (carved out) from
These records also permit the systematic application of deci- general medical services, they create barriers to the inte-
sion support tools and predictive analytics at the point of care. gration of psychiatric and general medical care. Physician
At the same time, the use of such records for documenting payment schedules do provide more compensation for lon-
physician services for billing and compliance purposes has ger visits with patients, but the requirements for documen-
filled electronic records with content of little clinical inter- tation of longer visits bias the use of the physicians time
est or professional perceptiveness; promiscuous cutting and toward broader scope rather than greater depth of interac-
pasting can propagate errors. Decision-making prompts such tion. Medicare and some other health plans pay individual
as drug interaction warnings, if generated too frequently and physicians for coordination of care but dont usually cover
without priorities, tend to be ignored by busy clinicians. The interdisciplinary conferences. Some health plans engage in
care of patients with multiple and complex chronic conditions gain sharing with physician groups who make the care of
will generate huge volumes of data which can be opaque with- chronic diseases more efficient; the physician group receives
out systematic, intelligent data reduction and summarization. a percentage of the amount by which the total cost of caring
It frequently falls to the medical psychiatrist to put a surfeit of for a clinical population was less than expected. Integrating
data into a patient-centered context, summarizing the present medical and psychiatric care for patients with complex med-
and past history in a way that acknowledges its meaning and ical and psychiatric comorbidities can reduce overall costs
N E U ROP S YC H I AT R IC PE R S PE C T I V E S
C I RC U L A R PRO C E S S E S
Neuropsychiatry is a subspecialty distinguished both by the
In most general medical conditions, and particularly those kind of patients and conditions it treats and by its perspec-
with frequent psychiatric accompaniments, the patients tive on symptoms and conditionsone that is particularly
behavior influences the course of illness. In addition to attentive to alterations in brain function associated with
I N T RODUC T IO N PU R P O S E S A N D T Y PE S OF PH Y S IC A L
E X A M I N AT ION S
In general medical patients, the physical examination typi-
cally comprises a combination of hypothesis testing driven There are several situations in which physical examinations
by the chief complaint and medical history and screening conducted by medical psychiatristsor at their behestcan
for physical signs related to various organ systems. The lat- add special value to the care of the patient:
ter is driven by customary practice and often by the need
to comply with practice guidelines and/or billing regula- 1. Narrowing a differential diagnosis prior to ordering diag-
tions, and it may be perfunctory. In any case, it would not nostic tests and imaging procedures. For example, patients
be feasible to routinely examine each organ system at the with depression, anxiety, fatigue, multiple somatic
level of completeness and detail typical of a specialist in complaints, and weight loss frequently will have both a
that system. This is often the case with the neurological chronic general medical disease and a mood disorder. In
examination, as a complete neurological examination is this situation, characteristic physical findings suggestive
time consuming, and the level of neurological knowledge of adrenal hyperactivity or adrenal insufficiency would
and skill can vary considerably among accomplished physi- trigger the measurement of plasma cortisol and follow-up
cians who are not neurologists. Furthermore, examinations provocative tests if there were even a borderline abnor-
of other organ systems often are abbreviated when the sys- mality. In the absence of physical findings or a history
tem is outside the scope of the presenting complaint. The of endocrine disease, it is unlikely that a plasma cortisol
generalists examination of the skin often is less meticulous level would be obtained as part of a general medical
and complete than that of a dermatologist; physicians out- screen in such a patient.
side of orthopedics, physical medicine, or rheumatology
tend to be less complete and quantitative in their examina- 2. Looking for physical signs supporting the diagnosis of a
tion of joints. specific condition that often has symptoms or functional
No physician would regard a computed tomography impairment in excess of findings on a nonfocused, gen-
(CT) scan of the brain as ruling out all brain disease, though eral physical examination. Conditions ranging from
it could be definitive in ruling out hydrocephalus, or a suf- vulvodynia to many of the focal neuropathies due to
ficiently large brain tumor or intracerebral hemorrhage. If nerve entrapment or compression have characteristic
demyelinating disease were suspected, magnetic resonance physical findings that would not be detected or not
imaging (MRI) would have fewer false negatives than a be adequately characterized without a specialized
CT scan. Different types of physical examination are like examination.
different imaging procedures or different laboratory test 3. Quantifying the severity of a known physical condition
panelstheir sensitivity and specificity and ultimate diag- to better assess its relationship to the patients subjec-
nostic value depend on what conditions are to be diagnosed tive distress and functional impairments. For example,
or ruled out and on the prior probability that the patient measuring changes in vital signs and auscultating the
has one of the conditions of interest. If a physical examina- heart and the chest following mild exertion can help
tion is done purely for screening or for medical clearance the clinician understand why a patient with cardiac or
without any diagnostic hypothesis or list of conditions to be pulmonary disease might be unmotivated to exercise.
excluded, it is likely to have many false negatives if consid- Anxiety about exercise might be commensurate with
ered in the light of specific diagnostic hypotheses formed changes in vital signs and objective signs of dyspnea or
after careful consideration of the patients presenting prob- be disproportionate to them, and the approach to the
lem, its context, and findings on laboratory tests and diag- psychological dimension of rehabilitation will differ
nostic imaging. accordingly.
20
4. Getting a subjective sense of the patients condition to better the same as the examination by a primary care physician. A
understand its emotional impact. This is most obvious in patient, for example one with delirium, is thought to have
the case of skin lesions or physical deformities, or when an acute medical illness, which, if present, is likely to show
the patient is in evident distress from pain or dyspnea, manifest physical signs that will be found on examination,
but it is also helpful when the patient is asked to perform such as the signs of heart failure, pneumonia, or an acute
a task during the physical examination and does it with abdomen. Or, a homeless and medically neglected patient
unusual effort or excessive timidity. with chronic mental illness is admitted to hospital and
screened for comorbid medical conditions that, though
5. Enhancing positive transference through appropriate
apparent when a general medical history and physical are
touching of the patient. Patients who are dying, patients
done, went unrecognized because the patient was not receiv-
with a poor prognosis, patients in pain, and patients
ing regular medical care. The second type of examination is
with stigmatized conditions can in many cases be com-
performed when a patient has medically unexplained symp-
forted and reassured by the physicians touch during the
toms or an obscure diagnosis after examination by a primary
examination. Psychiatrists are well aware of the potential
care physician, examination in an emergency room, or even
problem of boundary violations and evocation of anxiety
examination by other medical specialists. In this case, spe-
or negative transference in individuals predisposed by
cialized, focused examinations of greater depth and scope than
their history or their diagnosis. Notwithstanding, even
typical of a general medical examination are needed. These
the limited touch involved in taking vital signs can have
are hypothesis-driven, based on the patients symptoms, med-
positive effects in contexts where a more extensive physi-
ical history, context, and results of prior diagnostic investi-
cal examination by the psychiatrist would be unwise.
gations and laboratory tests. This type also includes a careful
6. Communicating across disciplinary lines to stimulate a fresh redo of a screening examination that might have been done
look at a patients problem. Citing a specific physical sign rapidly and with low sensitivity in the context of medically
that is unequivocally present yet not previously noted on clearing a patient for admission to a psychiatric inpatient
another physicians examination can be an effective way service. The third type of examination is performed when
to request a second look at the patient with a fresh per- a patient has a known diseasesuch as an autoimmune
spective. Many specialists find an inquiry about a physical disease, cancer, or chronic organ failurethat is relapsing-
sign more welcome and less meddlesome than the medical remitting, progressive, or subject to recurrence, and the med-
psychiatrists expressing a concern that there might be a ical psychiatrist aims to determine whether the disease has
missed or underappreciated diagnosis. relapsed or progressed, as this will have impact on the inter-
pretation of symptoms and on treatment planning. In this
Physical examinations by medical psychiatrists are of situation the examination is focused on assessing the presence
four general types (see Table 2.1). The first type is essentially and severitythe latter sometimes quantitativelyof specific
Screening for general Identify conditions missed because Similar to a primary care Focus on acute diseases or chronic
medical diseases of lack of recent medical care or physicians comprehensive diseases depending on context and
brevity of recent medical visits examination setting
Investigating poorly Determine cause of symptoms not Focus on conditions that could Hypothesis-driven; methodology
explained symptoms well explained by diagnoses to better explain the patients similar to subspecialist
date; identify potentially missed symptoms; deep and detailed examination
diagnoses examination of relevant organ
systems
Assessing status of a known Assess current activity (e.g., Organ system focus; thorough Quantitate results using
disease exacerbation, remission, or assessment of disease-specific specialty-specific scales
relapse) and severity; screen for signs
complications of the disease and
its treatments
Functionally-focused Evaluate for disability and/or Do simultaneous physical Quantitate physical findings,
examination assess for symptom amplification examination, functional functional impairments, and
or excessive illness behavior assessment, and observation symptoms; note inconsistencies
of patient behavior during the
examination
S E T T I N G OF T H E E X A M I N AT ION G E N E R A L A PPE A R A NC E , H E IG H T
A N D DE MO G R A PH IC S A N D W E IG H T
Examination findings in hospitalized patients and other The general appearance of the patient, including how the
acutely ill patients can change from hour to hour, and patient is dressed and groomed, can give important clues
neurological symptoms, especially mental status findings, to the patients functional capacities and to whether there
can be context-dependent. These considerations are of par- is impairment of executive cognitive function due to prob-
ticular relevance in the assessment of delirium. If it will lems with the frontal lobes and/or their connections.
not be self-evident from the medical record, the examiner These clues will be absent if the patient has been dressed
should note the time and place of the examination and, and groomed by caregivers prior to the examination. Note
if applicable, whether there was anything unusual about should be taken of signs of physical abuse; often bruises
environmental conditions, such as an unusually high envi- will be covered by garments, and so the entire skin should
ronmental temperature or a particularly noisy and distract- be checked at some point in the examination. Muscle bulk
ing environment such as that of a busy emergency room or should be noted; its significance will depend on demograph-
intensive care unit (ICU). ics. Increased muscle bulk due to athletic activities will be
The age and gender of the patient will of course be indi- associated with an increased serum creatinine; this can lead
cated on every page of the medical record, but it is worth to underestimation of renal function if it is not taken into
noting whether the patient looks younger or older than his account. Disproportionately increased muscle bulk asso-
or her chronological age. Many of the diseases and impair- ciated with excessive hair and testicular atrophy raises a
ments associated with aging correlate more strongly with suspicion of anabolic steroid use. Diminished muscle bulk
biological rather than chronological age. While there is a no has a broad differential diagnosis including deconditioning
generally accepted definition for biological age, experienced due to immobility, nerve or muscle disease, and catabolic
clinicians usually will agree when a patient looks signifi- states such as those due to cancer. In addition, patients with
cantly older or younger than his or her years. The holistic diminished muscle bulk can have a serum creatinine level
perception of age by clinicians integrates diverse items within normal limits in the presence of moderate renal
including rate of movement, mental acuity, skin condi- insufficiency.
tion, and oral health. ADanish longitudinal study of 1826 The distribution of body fat should be noted. Excess
same-sex twins aged 70 or older examined the relation- abdominal fat is more strongly correlated with the meta-
ship between age as perceived by assessors of various back- bolic syndrome than excess fat in the buttocks, hips, and
grounds looking at passport-style photographs and a range thighs; a patient with a waist circumference of 40inches or
2. A cuff of adequate size must be used; given the high Respiratory rate can be accurately measured by counting
prevalence of obesity, many patients will require a large breaths over a minute or more; in the authors experience
adult cuff for an accurate reading. Using a cuff that is this is not consistently done by clinicians, despite evidence
too small is a common cause of erroneously high blood that in adults an abnormally high respiratory rate (over
pressure measurements. Specifically, if the arm circumfer- 20 breaths per minute) is a valid indicator of illness sever-
ence is 35 cm or greater the standard adult size cuff is too ity and poor prognosis (Cretikos etal., 2008; Bianchi etal.,
small; in this situation a large adult cuff should be used if 2013). Periodic breathingbreathing that cyclically oscil-
the arm circumference is between 35 cm and 44 cm, and lates between shallow and deep with a cycle length of 12
an adult thigh cuff should be used if the arm circumfer- minutesshould be noted; it can reflect a primary problem
ence is 45 cm or greater. either in the cardiovascular system or in the central nervous
system (CNS). Its most severe form is Cheyne-Stokes respira-
3. The cuff must be deflated slowlynot faster than tion, in which there is actual apnea at the nadir of the cycle.
2mmHg per second. If the cuff is deflated too rapidly the Periodic breathing is worse with exercise in patients with
systolic blood pressure will be underestimated and the heart failure. In heart failure patients, periodic breathing
diastolic blood pressure will be overestimated. both correlates with severity of disease and carries indepen-
4. Blood pressure is influenced by the patients position. dent weight as an indicator of poor prognosis (Dhakal etal.,
Diastolic pressure is approximately 5mmHg higher 2012; McGee, 2013).
sitting as opposed to supine; systolic pressure is approxi- Patients with recurrent functional hyperventilation
mately 8mmHg higher supine as opposed to standing. with or without associated panic attacksdo not necessarily
Sitting with the back unsupportedas on an examining have tachypnea; their breathing may be deeper than normal
tablecan increase the diastolic pressure by approxi- rather than more rapid than normal; this pattern is com-
mately 6mmHg. mon in younger patients (Han et al., 1997). Thus, a normal
respiratory rate, even during a panic attack, does not rule out
5. Ambulatory patients typically have higher blood episodic functional hyperventilation as the basis of somatic
pressures when measured by the physician than when symptoms of anxiety.
Median nerve at the wrist Pain in wrist radiating Thumb weakness and/or atrophy Sensory loss on palmar side of
(carpal tunnel) proximally; paresthesias in of thenar muscles (later than medial 3.5 fingers; palm is
thumb and index finger symptoms and sensory signs) spared
Ulnar nerve at the elbow Deep ache around the elbow; Grip weakness and/or Sensory loss on both palmar and
(cubital tunnel) tingling in ring and little hypothenar atrophy (later than dorsal sides of ulnar 1.5 fingers;
fingers symptoms and sensory signs) palm is spared
Ulnar nerve at the wrist Pain and numbness of ulnar Hypothenar and interosseous Sensory loss on palmar side of
(compression in Guyons 1.5 fingers, or painless atrophy weakness and/or atrophy ulnar 1.5 fingers
canal) of hypothenar and interosseous
muscles
Radial nerve in proximal Dull aching pain over front Weakness of extension of third None
forearm (posterior ofelbow and fourth fingers early; weak
interosseous nerve ness of extension of all fingers
syndrome) and of thumb adduction later
Common peroneal nerve Pain radiating from knee to Foot drop (may come later than Sensory loss on dorsum of foot
entrapment dorsal foot; sensory loss on sensory symptoms)
dorsum of foot
Tarsal tunnel syndrome Burning pain and tingling of Weak flexors of great toe; Sensory loss over one or both
plantar region; pain triggered clawing of other toes due to sides of the plantar surface of
by pressing or rubbing plantar weak flexors (later than sensory the foot, depending on site of
surface of foot symptoms) entrapment
Lower trunk of brachial Pain and paresthesia of ulnar Usually none; rarely atrophy None
plexus (thoracic outlet aspect of forearm, hand, and and weakness of intrinsic hand
syndrome) ulnar two fingers muscles
56
from Europe with life-altering brain injuries. Assessing the be useful, each test must be constructed according to sound
cognitive consequences of such injuries spurred the growth of psychometric principles and possess adequate validity and
early assessment methodologies. The aftermath of World War reliability. In addition, there must be appropriate normative
II marked the establishment of modern clinical psychology, data with which to compare a single patients performance.
with an emphasis on the special skill of psychological testing. The neuropsychologist relies on a comprehensive under-
Measurement of intelligence was the venue in which early standing of test construction and standardization in order to
testing applications were most significant. select and interpret measures for a given clinical context. This
The earliest codification of neuropsychological exami- includes choosing tests with normative data derived from sub-
nation methods can be attributed to Dr. Ralph Reitan. jects of similar age, education, and nationality to the patient
A pioneering neuropsychologist, Reitan and his colleagues currently being tested (Attix et al., 2009).
assembled a battery of test measures in which specific pat- The interpretation of test results depends on an under-
terns of scores were linked to dysfunction of associated brain standing of the component processes involved in any given
regions (Reitan & Wolfson, 1993). Later approaches diverged test response. For example, the ability to name an object to
from a reliance on a set battery of tests and instead used a more visual confrontation depends on multiple processes that are
dynamic method, the process approach to neuropsychologi- mediated by different brain systems. The individual must first
cal assessment developed by Dr. Edith Kaplan in her work orient and attend to the stimulus. Second, the stimulus must
at the Boston Veterans Administration Hospital (Kaplan, be accurately registered at the level of visual perception. Third,
1990). This technique entails ongoing in situ hypothesis test- the neural pathway that links the visual percept to meaning-
ing in which particular attention is paid to the qualitative ful recognition must be patent. Fourth, the ability to assign a
aspects of a patients test response. Although quantitative phonemic/lexical label to the object must be intact. Finally,
data are also important, the patients route to solving a par- the individual must be able to convey a response through
ticular cognitive problem often reveals an underlying process speech. Because a complex cognitive action, such as naming
that can be reflective of spared and affected brain regions. In a simple object, can be undermined by perturbation at any
contemporary practice, both of these methods rely on a vast point within the network linking multiple functions, a neu-
body of knowledge about characteristic syndromes that are ropsychologist must understand the component processes
associated with underlying disease states. involved in each behavior. By examining the patients func-
The current practice of clinical neuropsychology concerns tion in multiple domains with multiple measures, the neuro-
itself with assessment of cognitive functions, through the use psychologist can determine which processes and associated
of test instruments, for the purpose of understanding the neural circuits are functioning abnormally.
functional integrity of the brain. By relying on knowledge of Performance on a single test is not sufficient to make a
brainbehavior relationships and characteristic syndromes, diagnostic inference. Acommon misconception is that a poor
the results of assessment are useful for diagnosis and treat- score on a particular test denotes an impairment in the domain
ment of brain-related injuries and illness. that the test is nominally designed to assess. For example, if
a patient performs poorly on a memory test, this does not
necessarily signify impairment in memory but could indicate
F U N DA M E N TA L A S S U M P T IO N S difficulties with attention or language. A neuropsychologist
will evaluate a profile of test results in a dynamic, interactive
The study of clinical neuropsychology is firmly rooted in the fashion in order to arrive at a diagnostic formulation.
larger field of neuroscience and therefore rests on the assump- Neuropsychological testing is simply one means of obtain-
tion that the nervous system impacts behavior and cognition. ing a sample of behavior. Aneuropsychologist must proceed
Conversely, inferences can be made about the integrity of the with caution in using test data to predict behavior. The testing
brain based on observable behavior. The ability to make accu- environment is, by necessity, contrived to promote a standard
rate and meaningful inferences is predicated on a thorough approach to test administration. This contrivance constitutes
understanding of two streams of knowledge: (a) the neu- a challenge in understanding how test performance cor-
ral infrastructure underlying normal human cognition and responds to real life behavior. For example, a patient who
behavior, and (b)the characteristic profiles of neurocognitive complains of difficulty with concentration and memory at
and neurobehavioral syndromes. work may perform quite normally in the context of the quiet,
Observable behavior is frequently the most sensitive man- distraction-free examination room. Discrepancy between
ifestation of brain pathology. Such behavior can range from test behavior and real-life behavior is the source of ongo-
subtleties of social comportment to performance on a specific ing challenge for the design of an ecologically valid assessment
neuropsychological test. Acompetent neuropsychologist will environment.
sample multiple domains of behavior. Observable behavior,
including test behavior, reflects an interaction between the
domains of person and environment. Variables from each C L I N IC A L A PPL IC AT ION S
domain must be considered in order to arrive at an under-
standing of the clinical significance of a given behavior. The overall purpose of the neuropsychological evaluation is
Individual tests used in neuropsychological practice focus the creation of a dynamic portrait of the patient in cogni-
on measurement of particular cognitive processes. In order to tive, psychological, and functional terms. Characterizing
Wechsler Intelligence The Wechsler Adult Intelligence Scale (WAIS-IV) is composed of 13 individual subtests.
Scales Administration of all subtests generates Full-Scale IQ and four different performance indices:
Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index, and Processing
Speed Index.
The Wechsler Abbreviated Scale of Intelligence (WASI) is designed to be a short and reliable measure of
intelligence that produces Indices that are similar to those obtained with the WAIS-IV.
The Wechsler Intelligence Scale for Children (WISC-IV) is used for testing children and adolescents
ranging in age from 617 years.
The Wechsler Preschool and Primary Scale of Intelligence (WPPSI) is used for testing children ranging
in age from 46.5years.
Wechsler Test of Adult The WTAR is a measure of recognition vocabulary requiring oral reading of 50 phonetically irregular
Reading (WTAR) words. It is used to estimate premorbid baseline intellectual ability in patients with known or suspected
dementia. Similar measures include the NART, NART-Revised and ANART. Errors consist of word
mispronunciations.
Ravens Standard and These are standardized measures of nonverbal analogical reasoning widely used both within and
Colored Progressive Matrices outside the United States as a culture fair measure of general intellectual ability. Both tests require
the patient to demonstrate an understanding of the logic underlying visual patterns by selecting the
missing component of the pattern from a series of choices. The Standard Matrices contain 60 black and
white items ranging from simple to extremely difficult, while the Colored Matrices consist of 36 colored
items that span a limited range of complexity. Errors consist of incorrect identification of the missing
component of the visual pattern.
ATTENTION SPAN Digit Span The examiner reads increasingly long strings of numbers aloud. The
examinee must repeat the numbers aloud in the same order, first forward
andthen in the reverse order.
Spatial Span The examiner taps a series of blocks in fixed locations. The examinee must
repeat this series in the same order, and then in the reverse order.
SUSTAINED Auditory & Visual Continuous Basic auditory vigilance is tested by having the patient listen to a series of
ATTENTION & Performance Test (CPT) letters read serially and responding to a single target letter or series of letter
VIGILANCE configurations. Visual vigilance can be tested by showing a series of single
numbers on a computer screen and requires responding to a target stimulus,
but not to nontarget stimuli.
Paced Auditory The patient hears a tape-recorded voice reading numbers at various rates,
Serial Addition Test(PASAT) ranging from every 2.4 seconds to every 1.2 seconds. The objective of the
task is to sum the last two numbers heard and voice the sum aloud (e.g., if the
numbers from the tape were 5, 2, 8, 4, the patients responses would be the
following (in italics):5, 2, 7, 8, 10, 4, 12, etc.). The process of voicing the
sum aloud serves as interference, which must be overcome in order to attend
to the following number. In total, 60 numbers are read in each of the four
trials and every subsequent trial is faster than the one preceding it.
SET-SHIFTING Trail Making This measures of visual scanning, visuomotor tracking, and response set
Test A& B flexibility. Trails Ainvolves connecting consecutively numbered circles,
from 1 to 25. Trails B requires the patient to continually shift set, alternating
between letters and numbers (i.e., 1, A, 2, B, etc.). Both tasks must be
performed as quickly as possible and without lifting the writing utensil from
the paper.
Wisconsin Card Sorting Test A measure of nonverbal concept formation, response set flexibility, sustained
attention, and ability to integrate corrective feedback. The patient must sort
cards according to underlying principles (color, form, number), which must
be deduced and which are shifted at set intervals.
Luria Graphomotor Involves using a pencil to copy a series of patterns (i.e., m-n-m-n, peaks and
Sequencing plateaus, and multiple loops) without lifting the pencil. Errors consist of
failing to alternate (i.e., m-n-m-m-m-m)
Luria Motor Sequences Involves performing repeated sequences of hand movements. Errors consist
of failure to maintain the order of movements within each sequence.
RESPONSE Stroop Composed of 3 parts that require (1)reading a series of black and white
INHIBITION Color-Word color words (red, blue, green), (2)identifying the color of red, blue and green
Interference Test Xs, and (3)identifying the ink color of incongruent color words (i.e., the
correct response to the word red printed in blue ink would be blue). In all
conditions the patient is asked to perform as quickly as possible.
Motor Involves responding to a target signal (1 loud knock) by lifting a finger, but
Go-No-Go not to a second signal (2 loud knocks). The tendency to respond to the second
signal must be inhibited. The examiner produces a series of 1 or 2 knocks and
observes the patients responses. Each hand is tested separately.
PLANNING Delis-Kaplan Executive Involves ordering 4 colored beads within a set of constraints. Only one
Function System (DKEFS) beadmay be moved at a time, and beads moved from their initial placement
Tower Test may not be returned. Similar tests include Tower of Hanoi and Tower of
London.
PERSEVERANCE Verbal & Design Letters:the examinee must recite as many words as possible that start
Fluency with a particular letter, with the exception of proper nouns, numbers, and
more than one iteration of the same root word. This is repeated with three
different letters in total. Categories:the examinee must recite as many words
as possible from a particular category. This is repeated with three different
categories in total. Design:the examinee must create as many unique designs
as possible by connecting lines between dots laid out in a grid.
AT T E N T ION A N D E X E C U T I V E F U NC T ION to sustain a particular course of action, even in the absence
of an external prompt. Measurement of perseverance often
Attention
begins with both examiner and subject performing the
Many cognitive capacities are inherently predicated on a fun- same task, but involves the subject continuing the task even
damental ability to attend to the surrounding environment. after the examiner has stopped (see Luria Motor Sequences,
For example, an individual cannot effectively name an object Verbal and Design Fluency). Initiation refers to the ability to
if the object is not first attended to and visually processed. spontaneously commence an action in the absence of a direct
Because attention is a prerequisite for other aspects of cogni- prompt from the external environment. This function is mea-
tive function, disruption of attention can generally skew the sured with presentation of a task followed by a period of time
results of a neuropsychological assessment. Early assessment during which the subject is expected to respond indepen-
of attention is vital for informing the scope of the examina- dently (see Verbal Fluency, Go-No-Go). Reasoning involves
tion and the analysis of test data (Table 3.2). using a system of logic to solve a particular problem or task.
Attention is a general term that encompasses a number of This can be measured in a variety of ways, including using
different component processes. Attention span refers to the visual puzzles and verbal analogies (see Ravens Progressive
number of unrelated bits of information that can be held Matrices, WAIS-IV Comprehension). Abstraction is the
on line at a given moment in time. Assessment of attention ability to articulate shared attributes of dissimilar objects
span is typically accomplished through the recall of progres- (e.g., WAIS-IV Similarities, Wisconsin Card Sorting Test)
sively longer series of information bits, such as numbers (digit (Table 3.2).
span) or spatial locations (spatial span). Sustained attention,
also called vigilance, refers to the capacity to maintain active
C OM P ORT M E N T, I N S IG H T, A N D J U D G M E N T
attention over time. The most common method of assessing
vigilance utilizes a target detection paradigm. Here the patient Although few tests probe these functions in a formal manner,
is instructed to respond to an infrequently occurring target they are important components of neuropsychological func-
stimulus. For example, on a measure of auditory vigilance, the tion and are frequently disturbed in cases of neurological and
patient hears a series of letters of the alphabet and must sig- neuropsychiatric illness. Comportment refers to the ability to
nal by pressing a response key each time a particular target is behave in a contextually appropriate manner. Disturbances
presented (see CPT, PASAT). Selective attention is similar to often manifest as socially inappropriate behaviors that sug-
sustained attention, but requires a response only to a particular gest insensitivity to accepted cultural norms. Examples might
class of stimuli and not other stimuli. Set-shifting refers to the include making offensive comments, crossing interpersonal
capacity to relinquish an existing procedural strategy in favor boundaries, interrupting during conversation, or failing to
of a new response, based on recognition of a change in reward attend to personal hygiene. In the context of neuropsycho-
contingencies. It is typically measured with tasks requiring the logical assessment, insight involves an accurate perception of
patient to shift focus among stimulus features of a test display ones mental and physical condition as well as appreciation of
(see Trail Making A and B, Wisconsin Card Sorting Test, the impact of ones behavior on others. Cognitively impaired
Luria Graphomotor Sequences). Resistance to interference, individuals often lack one or both of these components of
also called response inhibition, refers to the ability to sustain a insight. Judgment involves the capacity to perceive and assess
given response even in the face of a salient distraction designed ones environment accurately and to make decisions that
to undermine the target response. This is assessed with tasks reflect sensitivity to preserving the safety and integrity of one-
requiring the patient to inhibit overlearned responses or other self, ones resources, and ones environment.
distractions that could undermine a desired response (see A neuropsychologist can assess these functions infor-
Stroop Interference Test, Trail Making Test). mally through naturalistic observation, reports from
individuals familiar with the patient, and also by inquir-
ing about any accidents or legal infractions involving the
Executive Functioning patient. Formal measures of these functions exist primar-
Executive functions require the capacity to process informa- ily in the form of questionnaires that quantify the degree
tion in a planful, organized, and contextually appropriate to which the patient manifests disturbances in these general
manner. Formal tests of executive function assess a number areas. The Frontal Systems Behavior Scale (FrSBe) comprises
of different capacities including some functions mentioned descriptions of various behaviors that are characteristic of
above (set-shifting, overcoming interference, response inhi- patients with frontal lobe damage. Each behavior is assigned
bition) and also planning, perseverance, initiation, reason- a severity rating by the patient and by a family member, and
ing, and abstraction. Planning involves thinking several the overall severity rating is thought to reflect the degree
steps ahead of ones current circumstances for the purpose of behavioral disturbance present. The Neuropsychiatric
of informing and altering a course of action. Tests measur- Inventory (NPI) is another self-report rating scale that is
ing planning ability often require subjects to determine the completed by a family member or caregiver. Both the extent
correct series of steps needed to successfully reach a particu- of the patients behavior and the degree of subsequent famil-
lar goal (see DKEFS Tower Test). Perseverance is the ability ial distress are rated.
WORKING MEMORY Tests of Mental Control The examinee is asked to recite familiar sequences such as the alphabet, days
of the week, months of the year, and numbers from 120 as quickly as possible.
The examinee then must recite all sequences, except the alphabet, in reverse
order. Serial subtractions involve subtracting a particular number until a
predetermined point is reached.
WAIS-IV Letter-Number The patient hears a series of alternating numbers and letters and is required
Sequencing to reconfigure them so that all of the numbers are recited first, in ascending
order, and then letters in alphabetical order.
WAIS-IV Arithmetic Involves mental calculation of aurally presented arithmetic problems of
increasing difficulty.
See also Digit Span Forward and PASAT in Table3.2.
RETROGRADE Boston Retrograde Involves showing a series of black and white photos of famous persons from
MEMORY Memory Test the 1920s to the 1980s. If the patient cannot spontaneously generate the
correct name, the examiner can give a semantic cue (i.e., he was a singer in the
1920s) and then a phonemic cue (i.e., first name). This test assumes that the
patient has been exposed to the information in the first place.
Transient Events Test This is a measure of memory for popular news events from the 1950s through
(TET) the 1990s. Items were selected by way of the NewYork Times index according
to the criteria that they were mentioned at least 250 times during a particular
year and less than five times over the subsequent 2years. Hence, all items
were of transient notoriety thereby minimizing confounding effects of
overexposure. Free recall and recognition are tested.
(continued)
ANTEROGRADE Wechsler Memory Scale This is a composite battery of tests assessing orientation, attention, learning,
MEMORY (WMS-IV) and memory for verbal and visual information across immediate and delayed
intervals. It yields a series of index scores.
Rey Auditory Verbal This measure of verbal encoding, learning, and retention involves drilling
Learning Test theexaminee on a series of 15 unrelated words over five successive trials.
Learning is followed by an interference trial, immediate recall, and
30-minute delayed recall and recognition. Various comparisons yield
information regarding sensitivity to proactive and retroactive interference
andrate of forgetting.
Bushke Selective This is a special type of list-learning test that is most helpful in cases where
Reminding Test encoding is intact, but there may be a question of impairment at the level of
consolidation or storage. Alist of 12 words is read, and the patient must repeat
as many words as possible. However, different from the previous list-learning
tasks, the examiner then reads only the words that the patient did not recall.
This continues across 6 trials, and each time the patient must try to recite as
many words as possible but only hears the words not recalled on the preceding
trial. There are immediate and delayed recall trials followed by visual multiple
choice recognition paradigms.
Three Words Three The patient is instructed to copy three words and three shapes, after which
Shapes Memory Test incidental recall is tested. The patient is drilled on the words and shapes until
criterion is reached, and recall is tested after intervals of 5, 15, and 30 minutes.
Recognition is tested using distracter shapes and words.
Warrington Involves the visual presentation of single words and faces at the rate of
Recognition one every 3 seconds. The patient is instructed to reach each word silently
Memory Test and makeand report a judgment regarding his association (pleasant or
unpleasant)to it. Immediately afterward, the patient is shown a pair of
words,each containing a target word and a distracter, with the instruction
to identify the one presented previously. Memory for faces is tested in the
sameway.
informal index of receptive language ability or comprehen- locales on a blank map. Graphic reproduction of designs
sion. Visual confrontation naming is carefully assessed so and assembly of patterns using sticks, blocks, or other media
that word-finding problems and paraphasic errors may be are used to assess visual organization and constructional
elicited. Repetition is measured with phrases of varying abilities. Facial recognition represents a special component
length and phonemic complexity. Auditory comprehen- perceptual process and can be measured using Bentons
sion is evaluated by asking the patient questions that range Facial Recognition Test. The Judgment of Line Orientation
in length and grammatical complexity. Reading measures Test assesses perceptual accuracy in judging the angular
include identification of individual letters, common words, displacement of lines. Warringtons Visual Object Space
irregularly spelled words, and nonwords, as well as mea- Perception Battery is an example of a collection of measures
sures of reading speed and comprehension. Spelling can be designed to assess various aspects of perceptual function
assessed in both visual and auditory modalities. A narra- (see Table 3.5).
tive handwriting sample can be obtained by instructing the
patient to describe a standard stimulus scene.
MOTOR F U NC T ION S
V I S UO S PAT I A L F U NC T ION S
Naturalistic observations of the patients gait and upper
After establishing the integrity of basic visual acuity, the and lower extremity coordination are an important part
spatial distribution of visual attention is evaluated. The of the motor examination. Hand preference should be
presence of visual neglect is assessed through the use of assessed either through direct inquiry or a formal handed-
tasks that require scanning across all quadrants of visual ness questionnaire (Table 3.6). Motor speed, dexterity, and
space. Assessment of left/right orientation involves direct- programming are tested with timed tasks, some of which
ing patients to point to specific body parts, either on them- involve repetition of a specific motor act (e.g., finger tap-
selves or the examiner. Topographical orientation can be ping, peg placement) and others that involve more complex
tested by instructing the patient to indicate well-known motor movements (e.g., finger sequencing, sequential hand
Boston Diagnostic Aphasia This is composed of measures that assess all aspects of expressive and receptive
Examination (BDAE) language function including naming, comprehension, repetition, reading,
writing, praxis, and prosody.
Boston Naming Test One component of the BDAE, this measure of confrontation naming is often
administered independently. It consists of a series of 60 black and white line
drawings of objects. Naming difficulty increases as the objects progress from high
frequency to low frequency. Stimulus cues are provided in the event of perceptual
difficulty. Phonemic cues are used to distinguish between retrieval difficulties and
lack of knowledge of a particular object name.
Nelson Denny Reading Test This test contains two multiple-choice measures that assess vocabulary
and reading comprehension. Reading speed is also computed. Reading
comprehensioncan be scored on the basis of both a standard and extended
lengthof time.
Wide Range Achievement Test This standardized battery of acquired scholastic skills includes measures of
(WRAT-4) spelling, written arithmetic, and single word reading.
Wechsler Individual Achievement This Wechsler test assesses the academic achievement of children, adolescents, and
Test (WIAT-II) adults, aged 4 through 85years. The test enables the assessment of a broad range
of academic skills or only a particular area of need within the areas of reading,
written language, oral language, and math.
Benton Facial Recognition Test This task is composed of two parts. The first involves matching a target face with
one of six faces. The target stimulus is always identical to the correct answer. The
second part of the task involves choosing the three photographs, out of the array of
six, that contain the same face as the target photograph. Increasing use of camera
angle and shadow contribute to the progressive difficulty of the task.
Benton Line Orientation Test This task involves judging the spatial orientation of sets of line segments by
comparing them to a grid composed of 11 radii. It is sensitive to visuoperceptual
deficits associated with posterior right hemisphere lesions.
Visual Object Space Perception This battery contains eight individual tests that each probe a specific
Battery component of object or space perception. Individual subtests are untimed and
can be given in isolation or within the context of the full battery. Normative
data are based on healthy control subjects as well as patients with right- and
left-hemisphere lesions.
Visual Cancellation The objective of this task is to circle each instance of a target letter or symbol from
among a field of similar stimuli. There are a total of 60 targets evenly distributed
among the four quadrants of the 8-1/2 11inch page. Errors of omission involve
failing to respond to the target stimulus. Errors of commission involve responding
to stimuli other than the target stimulus.
Hooper Visual Organization Test This task involves examining line drawings of objects that have been broken
into fragments and rotated. The objective is to mentally reorganize each set of
fragments and subsequently identify the corresponding coherent whole.
Complex Figure Drawing This task involves copying a complex line drawing, usually the Rey-Osterreith
complex figure or Taylor complex figure. Ability to reproduce the gestalt as well
as the internal details of the design facilitate the detection of various perceptual
deficits. Significant distortion of or failure to copy one side of the figure can
indicate the presence of hemispatial neglect.
Table3.6MOTOR FUNCTIONING
Finger Oscillation Test Finger tapping speed is measured by having the patient tap a key as quickly as possible
over a period of 10 seconds, using the index finger. Each hand is tested a number of
times and trial totals are averaged. Poor performance consists of slow tapping speed.
Unilateral motor weakness can be assessed by comparing tapping speeds of each hand.
Bilateral weakness is assessed through comparison with age-matched norms.
Hand Dynamometer Grip strength is measured in each hand by having the patient squeeze a
pressure-calibrated instrument. Unilateral motor weakness can be assessed by
comparing performance with each hand. Bilateral weakness is assessed through
comparison with age-matched norms.
Grooved Pegboard Measures of fine motor speed and dexterity, entailing placement of pegs in a pegboard,
are obtained with each hand separately. Poor performance consists of difficulty grasping
and manipulating the pegs, resulting in slowed performance.
Reitan-Klove Collection of measures of tactile, auditory, and visual perception using unilateral and
Sensory-Perceptual double simultaneous stimulation. Fingertip number writing, visual fields, and tactile
Examination finger recognition are tested.
positions). Manual grasp strength can be assessed with a syndromes and proceed with caution when evaluating psy-
hand dynamometer. chiatric symptoms in the presence of neurological or medical
illness.
A F F E C T, MO OD, A N D P S YCHOL O G IC A L
F U NC T ION I NG DE M E N T I A S C R E E N I NG TO OL S
Standardized measures of mood, personality, and psychopa- Because detection of age-related cognitive impairment and
thology can be used to assess the contribution of psychiatric dementia plays a significant role in neuropsychological evalua-
illness to the patients presentation and diagnosis (Table 3.7). tion, a number of specific screening tools have been developed
However, it is important to understand that many neurologi- (Table 3.8). Many of these measures are designed to quickly
cal illnesses can cause disorders of affect and mood. In addi- assess gross level of functioning in major cognitive domains
tion, certain neurological illnesses can produce symptoms that and can be administered in a matter of minutes (see Blessed
overlap with particular psychiatric disorders. Therefore, neu- Dementia Scale, MMSE). The Mattis Dementia Rating Scale
ropsychologists must possess a thorough understanding of the is a more comprehensive set of items designed to stage severity
psychiatric profiles associated with various neurobehavioral of impairment in patients with known dementia.
Beck Depression Inventory This instrument is used to assess depression severity based on self-reported ratings of
a number of different relevant symptoms. Higher scores indicate greater severity of
symptoms.
Beck Anxiety Inventory This instrument is used to assess anxiety severity based on self-reported ratings of a
variety of somatic, cognitive, and psychological symptoms of anxiety. Higher scores
indicate greater severity of symptoms.
Personality Assessment This test contains 344 questions with a scale ranging from false, not at all true, to
Inventory (PAI) very true. It consists of 22 non-overlapping scales that assess constructs relevant to
personality and psychopathology. Validity, treatment, and interpersonal scales are also
included.
This series of 537 true/false questions load on to a number of different subscales that
Minnesota Multiphasic correspond to various personality traits or types of psychopathology. Scores on each
Personality Inventory-2 subscale are standardized. Combinations of high and low scores on individual subscales
(MMPI-2) correspond differentially to the presence or absence of various psychopathologies.
Careful interpretation of subscale scores is crucial to the accurate use of this measure.
71
W H AT M E DIC A L-P S YC H I AT R IC R AT I N G of synthesizing clinical data, and in some situations the stan-
S C A LE S M E A S U R E dardized approach is superior. Once a diagnosis is made, rat-
ing scalesif they are sufficiently sensitive to changescan
General psychiatric rating scales measure mental and behav- be used to track the course of illness and measure the patients
ioral symptoms and syndromes. In medical-psychiatric set- response to treatment.
tings, general psychiatric rating scales have their placebut
they are complemented by scales relevant to the relationship
and interaction of psychiatric and general medical conditions. T Y PE S OF R AT I N G S C A LE S
These include (1)scales for rating specific symptoms and syn-
dromes like pain, sleep disturbance, or sexual dysfunction Rating scales measure the severity of a disease, syndrome, con-
that can reflect either primary mental disorders, general medi- dition, symptom, functional impairment, or disability. They
cal disorders, or the combination of the two; (2)scales that are quantitative and usually ordinal rather than truly continu-
directly assess cognitive function; (3)scales that measure gen- ous. Points on an ordinal scale can be represented as words
eral health status; (4)scales of functional performance; and and/or pictures; the 010 rating scale for pain (Fig. 5.1) is a
(5)scales for quantifying the psychosocial impact of general familiar example. Rating scales can be have a single factor
medical illness. or dimension, or can be multifactorial. The score on a single
In acute medical-psychiatric contexts, scales for dimension is the sum of a specific subset of item scores.
risk assessmentspecifically of the risks of suicide or Rating scales are completed by the patient, by a caregiver
violencehave a special place. In the care of chronic general or other collateral source, by a trained rater who is not a clini-
medical conditions, scales that measure impediments to treat- cian, or by a clinician who might or might not require spe-
ment adherence or to optimal treatment outcomes are espe- cialized training on the scale. Some patient-completed scales
cially relevant. require only that the patient answer specific factual ques-
tions, while others require the patient to make judgments or
self-assessments. The latter type of scale will be insensitive
R EL AT IO N S H I P OF R AT I NG S C A LE S in the face of impaired metacognition or denial of illness.
TO S C R EE N I NG T E S T S Patient-completed scales that refer to a time other than the
immediate present rely on the patients memory, and if they
Rating scales can be used as screening tests for specific diag- ask the patient to count events or summarize experiences dur-
noses. Based on a rating scale score, a patient is identified as ing an interval, some degree of executive function is required
probably having a particular disease, disorder, syndrome, or as well. For this reason the validity of such scales decreases
condition. The actual diagnosis is made by a clinician, who in the face of cognitive impairment. Note in this connection
combines the data from the rating scale (often the items and that scales of binary items like symptom checklists impose
not just the score) with some combination of elements from less cognitive demand than scales with ordinal items, and
the medical history, clinical examination, and diagnostic frequency-based ordinal items impose a greater cognitive
tests. Psychometric properties like sensitivity and specificity demand on the patient than severity-basedones.
are applied to the concept that patients with scores above a Some clinician-rated scales require the clinician to have
threshold have the diagnosis, and all others do not. In prac- specialized training in psychology or psychiatry. Clinician-
tice, patients with scores near the cutoff score often are viewed rated scales that draw heavily on clinical expertise will be less
probabilisticallymore likely than not to have the diagno- reliable with less experienced clinicians. All of the above issues
sis, but not as certainly as those well above the threshold (or deserve consideration when determining whether a published
well below it, when the diagnostic criterion is a low score on measure of scales reliability is applicable in a specific clinical
the rating scale). Less commonly, a rating scale is made into situation.
a screening test by applying Boolean logic, a regression equa- When there are self-rated, caregiver-rated, and clini-
tion, a decision tree, or a neural net algorithm, using individ- cian-rated versions of the same scale, agreement of scores
ual item scores as the independent variables. among the versions strengthens confidence in the rating.
In the context of general medical illness, psychiatric rat- On the other hand, disagreement between self-ratings and
ing scale items that are typical of a particular primary mental caregiver/family ratings and/or clinician ratings is diag-
disorder might instead be attributable to a general medical ill- nostically valuable information. Disagreement between
ness. The diagnosis of a syndrome (e.g., clinical depression) is self-ratings and clinician ratings can represent impaired
independent of the attribution of specific symptoms, but the metacognition, unawareness of deficits or denial of illness,
diagnosis of a primary mental disorder (e.g., major depressive symptom amplification by the patient, clinician underes-
disorder) is not. The attribution issue reduces the certainty of timation of the patients distress, or, if the self and clini-
a diagnosis of a primary mental disorder made using a rating cian ratings are done at different times, fluctuation of the
scale criterion. Nonetheless, using rating-scale item responses condition. When ratings of symptoms by family members
as a point of departure in a psychiatric interview can make or other caregivers are more severe than patients self-rat-
the interview more productive. Furthermore, summing scale ings, the discrepancy can reflect patients denial or families
items, or applying a validated algorithm for combining rel- distress. Discrepancies between family/caregiver ratings
evant items, complements the more subjective clinical process and clinician ratings have implications similar to those of
2. The bidirectional, symmetric ordinal scale (aka Likert 1. Framework for structuring a clinical assessment;
scales, after the psychologist Rensis Likert, who
2. Screening test;
described them). There are several items, usually eight
or more. Items are ordinal, bidirectional, and typically 3. Support for a diagnosis;
expressed in words: for example, patients are given a
4. A id to treatment-related decisions;
statement and is asked whether they strongly agree,
agree, neither agree nor disagree (or are not sure), dis- 5. A id to prognosis;
agree, or strongly disagree. Positive or negative numerical
6. Measurement of clinical course;
scores are assigned to each item; the assignment of scores
to responses can differ by item. The sum of the numerical 7. Measurement of treatment response;
item scores is the scale score. Likert scales in which item
scores have five options and those in which item scores 8. A id to prediction of future course or treatment response;
have seven options are the most common. One species 9. R igorous measurement of an area of function that is
of Likert scale utilizes items with an even number of important to the understanding of medical-psychiatric
response choices, forcing patients to choose to either conditions but is poorly covered by routine medi-
agree or disagree with each item, even if their agreement cal and psychiatric histories (e.g., measurement of
or disagreement is mild. sleepiness/wakefulness and measurement of apathy/
3. The visual analog scale. In this scale, the patient is asked motivation);
to mark on a line segment a place corresponding to the 10. Communication between clinicians, including com-
severity of the symptom being assessed. The line segment munication across disciplines and standardization of
can be either horizontal or vertical. If the segment is medical records;
horizontal, the left end means the symptom is absent; the
right end means the symptom is present with maximum 11. Broadening the scope of patient assessment within
possible severity. If the segment is vertical, the bottom practical time constraints, by facilitating reliable and
means the symptom is absent and the top means the structured input from patients, family caregivers, and
symptom is present with maximum severity. A common clinicians of various disciplines; and
set of anchoring examples make scores more comparable 12. Inquiring via patient questionnaires about areas patients
between patients. The visual analog scale can be converted might be reluctant to discuss in face-to-face interviews,
into a numerical 0100 scale by measuring the distance including sexuality and substance use.
SpecificityIssues 0 2 4 6 8 10
The considerations mirror those for sensitivity. When a No Hurts Hurts Hurts Hurts Hurts
screening test is based on reaching a threshold score on a rat- Hurt Little Bit Little More Even More Whole Lot Worst
ing scale, raising the threshold will increase the tests specific-
ity at the expense of its sensitivity. High specificity is desirable
in situations where being wrong about calling a patient a Figure4.1 Wong-Baker FACES Pain RatingScale.
case entails unnecessary cost, risk, or stigma. The diagnosis
of psychogenic non-epileptic seizures (PNES) offers a useful R E C E I V E R OPE R AT I NG CH A R AC T E R I S T IC
medical-psychiatric example; the diagnosis of HIV infection The receiver operating characteristic (ROC) is a curve that
is a good general medical one. A common approach to clini- illustrates the tradeoff of sensitivity and specificity for a
cal situations where both high sensitivity and high specificity screening test that is based on a rating scale with various
are needed is a two stage screening approach, where a highly options for the cutoff score (criterion level) for determining
sensitive and moderately specific test is given first, and those that a patient has the condition of interest. The ROC curve is
who screen positive are given a more specific test to vali- drawn within a box where the x-axis is the rate of false posi-
date the diagnosisoften one that is more expensive or less tives and the y-axis is the rate of true positives. Each point on
convenient. the curve is determined by a cutoff score for the test on the
underlying rating scale. Note that the cutoff scores themselves
PR E DIC T I V EVA LU E do not appear on either the x-axis or the y-axis. It sometimes
makes an ROC curve more comprehensible to label a few
Positive Predictive Value (PPV) is the proportion of patients points on the curve that correspond to specific cutoff scores.
who test positive that actually have the condition of interest. Figure 4.3, from an article on diagnostic test interpretation
Expressed as a formula, PPV=TP/(TP+FP). (Tape, 2013) illustrates the ROC curve for serum T4 as a screen-
Negative Predictive Value (NPV) is the proportion of ing test for hypothyroidism, the latter diagnosed clinically. The
patients who test negative test that in fact not have the three points on the curve represent three different cutoff points
condition of interest. Expressed as a formula, NPV = TN/ for the serum concentration of thyroxine (T4): 5, 7, and 9 g/dL.
(TN+FN). The ROC curve for a test with no predictive value would
be a line with slope 1the diagonal of the square in which
Predictive ValueIssues the ROC curve is drawn. When a test has such a ROC
curve, higher sensitivity can only be had by reducing speci-
Like sensitivity and specificity, PPV and NPV are attri- ficity. The ROC curve for an ideal test would be a vertical
butes of a test and a population, not attributes of a test in line along the y-axis plus a horizontal line at y = 100%. With
itself. A test with high sensitivity and high specificity can an ideal test there is a cutoff score at which false positives are
have a low PPV if the condition of interest is very rare in zero and true positives are 100%. With a very good but not
the population tested. For, example, suppose a test is 99% ideal test the rate of true positives will approach 100% at a
sensitive and 95% specific for a condition with a prevalence cutoff score that implies only a very small number of false
of 1% in the population tested. Its PPV will be approxi- positives.
mately 20%, since out of every 100 people in the popu-
lation approximately 1 will be a true positive and 4 will
be false positives (that is, negatives to which the test was ROCIssues
insensitive). In this situation five patients who screened A test of no value whatever would have an ROC of 50%; a test
in would have to undergo further evaluation to identify with an ROC of 90% or higher would have outstanding value;
one patient who truly had the condition of interest. When
the implications of a diagnosis are weighty and the con-
dition of interest is relatively rare in the population to be Condition
(as determined by Gold standard)
tested, a test must have very high specificity to be clinically Condition Positive Condition Negative
useful. Test Positive predictive value =
Like PPV, NPV is always relative to a specific population, Outcome True Positive
False Positive
(Type I error)
True Positive
Positive
and the considerations for NPV mirror those for PPV, just as Test
Outcome
Test Outcome Positive
Negative predictive value =
the considerations for specificity mirror those for sensitivity. Test
Outcome
False Negative
True Negative True Negative
(Type II error)
Avery high prevalence of the condition of interest in the test Negative Test Outcome Negative
population will imply a low NPV unless a test is extremely Sensitivity = Sensitivity =
True Positive True Negative
sensitive. Condition Positive Condition Negative
The relationship of sensitivity, specificity, PPV and NPV is
illustrated in Figure4.1. Figure4.2 Relationship of Test Attributes.
COGNITIVE FUNCTION
OR TEST FEATUR E MMSE MOCA
Attention and Serial 7s or spelling world backwards Repeating 5 digits forward and 3 digits backward,
Concentration signaling to the letter A, serial 7s
Language Naming a pencil and a watch; repeat no ifs, ands, or Naming of three pictured animals; listing words
buts; following a 3-stage spoken command; following a starting with f in 60 seconds (verbal fluency);
1-step written command repetition of two sentences
Orientation Date, day, season, state, county, town, hospital, floor Date, day, place, city
Memory 3-word list presented, immediate recall scored, list 5-word list presented twice for immediate recall;
presented up to six times until learned, then delayed recall delayed recall at end of test
after an intervening test item
Alternate Forms Examiner can change the three words for the memory test Original plus two alternates
Copyright status Publisher expects fees for clinical or research Free for clinical use; license needed for commercial
research
toxic-metabolic encephalopathy, medication side effects, and familiar verse. Either type of error shows impairment in
major primary mental disorders including bipolar disorder working memorythe ability to keep an instruction in mind
and schizophrenia. Establishing that executive cognitive func- despite a distracting stimulus. Executive functions like work-
tion is impaired can be particularly useful when the medical ing memory are provably important to self-care and occu-
psychiatrist is called upon to explain why instrumental func- pational function, yet are not directly tested by typical brief
tion is much worse than physical function in a patient who cognitive screens.
otherwise has grossly intact memory, orientation, and so on. The CDT has both literal and figurative face validity
Two practical and empirically validated bedside scales when a caregiver or clinician sees a grossly disorganized clock
for executive cognitive function are the Clock Drawing Test face produced by an educated adult, it is not hard to con-
(CDT; described in Chapter 2, with additional comments vince the person that there is an issue with brain function.
below; see also Royall et al., 1999) and the Executive Interview Moreover, neglect of the left half or one of the left quadrants
Test (EXIT; see Royall et al., 1992). The EXIT gives a score of of the clock strongly suggests a structural lesion of the right
050 based on a 25-item structured clinical examination that hemisphere. Though they perhaps communicate less than an
takes about 15 minutes. Each item is an ordinal item scored 0 image of the drawing, there are over 20 different ordinal rat-
if the response is normal and scored 1 or 2 if the item is abnor- ing scales for clock drawings that measure just how bad the
mal, according to severity of abnormality. The examination drawing is. No specific scoring system has become a de facto
is designed to elicit signs of executive dysfunction including standard. Royall, the co-developer of the EXIT, devised a
perseveration, imitation behavior, intrusions, lack of sponta- scoring system for the clock drawing, the CLOX (Royall et
neity, disinhibited behaviors, and utilization behavior; it also al., 1998) that is especially focused on errors due to executive
checks for the presence of a grasp reflex and a snout reflex. dysfunction. The CLOX comprises two tasks: CLOX1 is a
Mentioning which items were responsible for a high EXIT free drawing of a clock, and CLOX2 is a copy of a clock drawn
score adds to its value as a tool for communicating with other in front of the patient by the examiner. CLOX1 is highly sen-
clinicians. sitive to executive cognitive dysfunction; both CLOX1 and
The unique value of the EXIT to the medical psychiatrist CLOX2 will be impaired in cases of constructional apraxia
is that it contains itemsand tests for signsthat are not or global dementia.
usually included in other bedside examinations. For exam- The patients score on CLOX1 ranges from 015, with 15
ple, one item presents the patient with anomalous sentences representing a perfect performance and a score less than 10 sug-
(e.g., Mary fed a little lamb) and asks the patient to repeat gesting executive cognitive dysfunction. The clock drawing task
them. The mildly impaired patient will spontaneously cor- is presented in a way that increases the likelihood of failure if the
rect the phrase despite the examiners instructions; a grossly patient has impaired executive function. The patient is shown
impaired one might continue with the second phrase in the a blank sheet of paper and is asked by the examiner to Draw
10 Moribund; fatal
Summary measures of the overall functional impact of physi- processes progressing
cal or mental illness have been used in treatment outcome rapidly
studies for decades. Such measures can be one-dimensional or
0 Dead
multidimensional, clinician-rated or self-rated.
Curiously, the MDS does not include a sleep history apart Over the years since many currently-used questionnaire-
from the item on the PHQ-9 relating to changes in sleep based rating scales were developed there have been sub-
pattern. stantial advances in psychometric theory and technology.
The OASIS provides a much smaller number of neuropsy- The National Institutes of Health (NIH) in 2002 began
chiatric items, with the effect that it is a relatively nonspecific an initiative to develop new methods for patient-reported
screen for psychiatric conditions not yet explicitly diagnosed. healthcare outcome measurementone that emphasized
This is in contrast to the MDS, which actually can be used to a rigorous and methodical approach to developing and
make reasonably confident new diagnoses of depression, delir- validating new measures and that took full advantage of
ium, or cognitive impairment. OASIS item responses are clinical computerized adaptive testing. Computerized adaptive
judgments based on all data available to the clinician, including testing permits the patients responses to current ques-
medical records, interviews of the patient, observations of the tions to determine the choice of future questions. This
patient, communications from other clinicians, and interviews enables a scale to be simultaneously broader in scope and
of caregivers. The relevant content comprises the following: richer in detail, without compromising efficiency and user-
friendliness. All scales developed under the initiative are
1. Acomposite rating of level of consciousness, attention, in the public domain, though private entities are involved
orientation, comprehension, and immediate memory on in developing related software and in providing fee-based
the day of the evaluation, using a single-item 5-point scale services to users. Extensive information about the Patient-
ranging from 0 (intact) to 4 (totally dependent due to Reported Outcome Measurement System (PROMIS) ini-
delirium, persistent vegetative state, stupor, orcoma). tiative and the scales developed under it are available from
the NIH website www.nihpromis.org.
2. Asingle-item 5-point scale rating the temporal pattern of Areas tested by PROMIS instruments include the
a patients confusion over the last 14days, ranging from 0 following:
(not confused) to 1 (confused in new situations only) to 4
(constantly confused).
Emotional distress:anger, anxiety, and depression
3. Asingle-item 5-point scale rating the frequency with
Applied cognition:abilities and general concerns
which a patient has felt anxious (or shown signs of anxi-
ety) during the past 14days. Psychosocial illness impact:positive and negative
4. Acomplex item concerning depression screening. The Alcohol:positive effects, negative effects, positive expec-
item asks if the patient has been screened for depression tancies, and negative expectancies
by the agency using a standardized instrumentone
that has been validated for use in a community-dwelling Fatigue:general and cancer-specific
home care populationand if so, whether the instrument Pain:behavior, interference, and intensity, general and
indicated a need for further evaluation for depression. cancer-specific
One option is to complete the PHQ-2, a two-item version
of the PHQ-9 with questions about the frequency of low Physical function:mobility and upper extremity, general
mood and the frequency of loss of pleasure or interest in and cancer-specific
the last 14days. Sleep:sleep disturbance and sleep-related impairment
5. Achecklist of six behavioral symptoms; items are checked Sexual function:satisfaction, interest, lubrication,
if they occurred at least once in the prior week. The items vaginal pain, erectile function, orgasm, therapeutic aids,
are memory deficit, impaired decision making, verbal sexual activities, anal discomfort, and interfering factors
disruption, physical aggression, disruptive, infantile, or
socially inappropriate behavior, and delusional, halluci- Social roles:satisfaction with social roles, ability to
natory, or paranoid behavior. participate in them and actual participation in them;
satisfaction with discretionary social activities; compan-
6. A6-point scale rating the frequency of disruptive or dan- ionship, instrumental support, informational support,
gerous behavior. and emotional support; and social isolation
While the medical-psychiatric content of the OASIS is much PROMIS is a source of forms for paper-based administration,
less rich than that of the MDS, it is still valuable in several ways. items for constructing customized scales, and Web-based
It is helpful in setting the context of the first encounter with testing with automated scoring. It remains to be seen when
a patient currently receiving home care. And, when a patient and how the PROMIS resources will replace well-established
receiving home care has a change in mental, behavioral, or func- scales. The familiarity of a scale can trump its psychometric
tional status, the scales of the OASIS provide a standardized properties, especially if one of the purposes of the scale is com-
way for the nursing staff to communicate what has changed. munication across specialties and disciplines.
10 5
result that falls within the reference range may still be clini- occur in the preanalytical phase (Bonini, Plebani, Ceriotti, &
cally important. Patients who have a baseline creatinine of 0.6 Rubboli, 2002). Errors can also occur during specimen analy-
mg/dl have acute kidney injury warranting intervention when sis, if reagents are degraded or a machine is improperly cali-
their creatinine rises to a level of 1.2 mg/dl, but both of these brated. Postanalytical errors occur after specimen analysis,
values may fall within the normal reference range. Reference such as the test result being entered with a missing decimal
ranges themselves may vary in difference patient popula- point or into a different patients chart. These preanalytic,
tions. Most reference ranges are established by sampling analytic, and postanalytic sources of error have been the focus
healthy 2040-year-olds (Edwards & Baird, 2005)and may of attention for personnel working in clinical labs. Pre-pre
not represent the true normal range for patients of different and post-post analytical errors have also been described
ages, gender, or ethnicity. Furthermore, what is statistically (Laposata & Dighe, 2007) and are of concern to the order-
normal may not be physiologically normal. If there is a high ing physician. Pre-pre analytical errors occur when a physi-
prevalence of iron deficiency in a population, the reference cian decides to order the wrong test for the clinical question
range for mean corpuscular volume (MCV) in asymptomatic at hand. Post-post analytical errors occur when the accurate
patients may be low relative to that in a typical Western popu- test results are misinterpreted.
lation in which iron deficiency is less common. One reason patients see medical psychiatrists is that they
have physical symptoms and a negative work-up for organic
causes. Sometimes the psychiatrist must function as an advo-
PAT I E N T S A F E T Y A N D S OU RC E S OF
cate to reopen consideration of a missed medical diagnosis.
L A B OR ATORY E R ROR
When the normal lab test results do not fit with the history,
Sometimes abnormal lab values are statistically and clini- it is time to reconsider whether there is laboratory error using
cally significant but go unnoticed by providers. By con- the framework above to distinguish different types of poten-
vention, abnormal values are usually highlighted in some tial errors. One particularly common error of interpretation
manner when documented. Despite efforts to flag abnormal is to regard a single normal test result as ruling out a disease
lab results, it has been reported that physicians do not always that tends to fluctuatewhere lab values sometimes are nor-
note or respond appropriately to important laboratory find- mal and sometimes are not. This is the case, for example, in
ings (Nykanen etal., 1993). This may be due to an increasing prediabetes or early type 2 diabetes, where the fasting plasma
amount of laboratory data generated by more efficient meth- glucose may be normal but the postprandial glucose is not. In
odology and computer automation, without a corresponding Hashimotos thyroiditis, there may be euthyroid periods alter-
increase in medical professionals abilities to sort through a nating with periods of clinical hypothyroidism (see chapter6
barrage of test results (Mayer etal., 1998). Abnormal labora- on endocrine testing).
tory results fail to elicit an appropriate clinical response in
up to 30% of cases (Altshuler, 1994). Some laboratories have
BIO S TAT I S T IC A L T E R M S US E D I N
instituted reporting policies mandating that extremely abnor-
E VA LUAT I NG DI AG NO S T IC T E S T S
mal values must be communicated directly to a care provider
to decrease the risk of their being overlooked. However, the Characterization of test performance is helpful in interpret-
manner in which abnormal lab results are flagged continues ing test results. Standard terminology has evolved to describe
to be potentially problematic. Avalue that is 20 units outside the performance of tests utilized to make a yes/no decision
of the normal range may be highlighted no differently than a about the presence of a disease or condition. This terminology
value that is 1 unit outside of the normal range. For tests such is applicable to laboratory tests, physiological tests, imaging
as gamma-glutamyl-transferase (GGT), an abnormally low procedures, and psychological tests. Table 5.1 offers defini-
value has no clinical significance, but the results are flagged tions of terms frequently used to describe the properties of
in the same manner as an abnormally high value. By chance diagnostic tests.
alone, 5% of laboratory test results will be abnormal, implying All test characteristics are a function of both the test and
that a physician with a large patient panel who orders many the clinical context in which it is applied. When the test
tests will be overwhelmed with abnormal test flags. Many involves converting a continuous quantity into a binary deci-
laboratories have responded to the problem with protocols sion, the cut point for diagnosis may also affect test charac-
for directly notifying physicians of abnormal test results that teristics. Sensitivity and specificity are the best known test
may imply serious short-term medical consequences, such as a characteristics. 100% sensitivity means that every patient in
potassium level >6 mEq/mL. the population examined who tests negative will not have
Laboratory errors are responsible wholly or in part for the disease. 100% specificity means that every patient in the
a significant proportion of diagnostic errors in medicine population examined who tests positive will have the disease.
(Graber, 2005). Laboratory errors can be divided into pre- Typically, a test will approach 100% sensitivity only by sac-
analytical, analytical and postanalytical errors. Preanalytical rificing specificity, and conversely. For this reason a single
errors occur prior to the sample being analyzed and include laboratory test seldom suffices to make a definitive diagnosis.
the timing of the phlebotomy, improper filling of the speci- Likelihood ratios are an extension of the sensitivity and speci-
men tube, patient hydration status, duration of tourniquet ficity concepts that specifically concern how test results mod-
application, and elapsed time before analysis of the specimen ify diagnostic impressions formed without them (Lawrence &
(Ritchie, Ledue, & Craig, 2007). Studies suggest most errors Gyorkos, 1996). By definition, likelihood ratios describe how
Anxiety Hgb & Hct, TSH and free T4, blood and urine toxicology screen, glucose, ABG, sodium, See chapter33
calcium, magnesium, phosphate, urine catecholamines
Delirium Glucose, ABG, sodium, phosphate, calcium, BUN, magnesium, urinalysis, blood and urine See chapter31
toxicology screen, electroencephalogram, brain imaging, liver function tests including
ammonia, WBC, albumin and prealbumin
Depression Hgb & Hct, liver function tests, TSH and free T4, sodium, BUN, creatinine, urinalysis, cortisol See chapter29
Fatigue WBC, Hgb & Hct, calcium, sodium, BUN, creatinine, potassium, phosphate, TSH and free See chapter36
T4, liver function,
Mania/Psychosis TSH and free T4, sodium, vitamin B12, ceruloplasmin and urine copper, RPR, HIV, blood and
urine toxicology screen, WBC, BUN, creatinine, iron, liver function tests, urinalysis, calcium,
phosphate, glucose, folate, cortisol
Alcohol abuse ALT, AST, CDT, MCV, GGT, blood alcohol level, albumin, lipase, glucose, bilirubin direct and
and dependence total
Dementia ABG, blood & urine toxicology screens, Hgb & Hct, WBC, glucose, BUN, calcium, magnesium, See chapter32
TSH and free T4, vitamin B12, folate, urinalysis, RPR, heavy metal in 24 hour urine, sodium,
liver function test, brain imaging, lumbar puncture, phosphate, creatinine
Eating Disorders Hgb & Hct, WBC, platelet, glucose, BUN, creatinine, calcium, magnesium, TSH and See chapter34
free T4, vitamin B12, folate, sodium, liver function test, cholesterol profile, FSH and LH,
DEXA scan, amylase, potassium, bicarbonate, phosphate
Astatistical approach will identify 95% of test results as Altshuler, C. H. (1994). Data utilization, not data acquisition, is the
being normal, with 2.5% of highest values and 2.5% of main problem. Clinical Chemistry, 40, 16161620.
American Diabetes Association. (2013). Diagnosis and classifications of
lowest values deemed abnormal. However, statistical diabetes mellitus. Diabetes Care, 36(Suppl 1), S67S74.
significance does not always portend clinical significance. Antony, A. C. (2007). Megaloblastic anemias. In L. Goldman &
D. Ausiello (Eds.) Cecils Medicine. (23rd ed.) (pp. 12311240).
Pre-pre analytical errors occur when a physician decides Philadelphia, PA:Saunders Elsevier.
to order the wrong test for the clinical question at hand. Arbuckle, M. R., McClain, M. T., Rubertone, M. V., Scofield, R. H.,
etal. (2003). Development of autoantibodies before the clinical onset
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120
to too much or too little thyroid hormone, in combination T S H I N MON I TOR I NG T H Y ROI D HOR MON E
with typical physical symptoms or signs on physical examina- R E PL AC E M E N T FOR H Y P OT H Y ROI DI S M
tion. The neuropsychiatric and general somatic symptoms and
TSH Is Elevated, Free T4 Is Low
signs of hypothyroidism and thyrotoxicosis are summarized
in Table 6.1. TSH is elevated in primary hypothyroidism. Free T4 is low.
Like other pituitary hormones, TSH is released in a pul- After treatment for clinical hypothyroidism is initiated, the
satile manner, but its serum level varies smoothly because the dose of levothyroxine is adjusted to bring TSH levels into the
serum half-life of TSH is 50 minutes. In normal individuals lower half of the normal range.
the serum level of TSH has a circadian rhythm, with a peak TSH responses to levothyroxine replacement are gradual
level at 2 a.m. to 4 a.m. and a nadir between 4p.m. and 8p.m. and should be measured at about 2months after initiating treat-
The recommended time for drawing a diagnostic TSH level ment and a similar period after any subsequent change in dosage.
is first thing in the morning (Sviridonova, Fadeyev, Sych, & Data from recent studies, including the National Health
Melnichenko, 2013). A spot TSH level drawn in the late and Nutrition Examination Survey of the Centers for
afternoon can be in the normal range, slightly higher than Disease Control (NHANES III, 2013), are challenging the
the morning readinga false negative in patients with mild validity of the traditional TSH reference range of 0.5U/mL
hypothyroidism. Apart from the circadian rhythm, changes to 5.0 U/mL (0.55.0 mU/L). When patients with a fam-
in TSH from hour to hour and from day to day are relatively ily history of thyroid disease or the presence of thyroid anti-
small, so that a single serum TSH drawn in the morning is bodies are excluded from the reference population, the TSH
sufficient for diagnostic purposes. normal range appears to be more narrow (0.52.5 U/mL
Table6.1 CLINICAL SIGNS AND SYMPTOMS OF THYROID HOR MONE EXCESS AND DEFICIENCY
SOURCES:Brent, 2008; Nayak & Hodak, 2007; DeGroot etal. (2009) in Endocrinology, 2007.
T S H I N S E C ON DA RY OR T E RT I A RY
Subclinical Hyperthyroidism
H Y P OT H Y ROI DI S M TSH Low, Free T4 Normal, Free T3 Normal
Subclinical hyperthyroidism is defined as the presence of a
TSH Is Normal, Free T4 Is Low
below-normal serum TSH with simultaneous free T4 and free
With rare exceptions a normal TSH rules out a primary T3 levels in the normal range. Specifically, a patient with a
abnormality of thyroid function. ATSH level with a free T4 TSH <0.1 mIU/L would be treated for hyperthyroidism even
level should be done when the clinical context and the com- if the free T4 and free T3 were normal and the patient did not
bination of neuropsychiatric and other somatic symptoms show the typical clinical syndrome of thyrotoxicosis.
increases the probability that secondary thyroid dysfunc-
tion is present; for instance, when there is a history of head
AU TOA N T I B ODI E S A N D
trauma or brain radiation. The addition of a free T4 to TSH
AU TOI M M U N EDI S E A S E
level will improve diagnostic sensitivity. When the TSH is
normal or below the normal range and the free T4 level is There are two common autoimmune thyroid diseases:
low, the patient is diagnosed with hypothyroidism due to Hashimotos disease, which usually causes hypothyroidism,
pituitary (secondary) or hypothalamic (tertiary) dysfunction and Graves disease, which usually causes hyperthyroidism
While neuropsychiatric symptoms as the sole mani fes- Weakness Weight loss
tation of adrenal disorders is a rare occurrence, excess or
deficiency of glucocorticoids usually entails mental and Fatigue Abdominal pain
behavioral symptoms. When patients present with a com- Anorexia Nausea, vomiting
bination of neuropsychiatric symptoms and general somatic
Diarrhea, constipation
symptoms and signs compatible with excess or deficiency
of adrenal hormones, the laboratory evaluation of adrenal Hyperpigmentation
function is indicated. Measurement of serum cortisol is not, Salt craving (palmar creases, extensor surfaces
however, part of the routine laboratory screening of patients inside of cheeks)
who present with changes in mood, behavior, or cognition;
Vitiligo
the presence of general somatic symptoms or physical signs
characteristic of an adrenal disorder is the prompt for labora- Postural dizziness postural hypotension
tory investigation. If a serum cortisol level has been recently Hyponatremia
measured, and it is known that it was drawn between 8 a.m. Hypoglycemia
and 9 a.m., it can be compared with a normal range of 7g/
Anemia
mL to 25g/mL. Values <7g/mL suggest adrenal insuffi-
ciency, and values >25g/mL raise a concern of glucocorti- Eosinophilia
coid excess. Table 6.2 lists the neuropsychiatric and general Adrenal Hyperfunction (Schneider,2012)
somatic manifestations of glucocorticoid excess and of adre-
nal insufficiency. Depression Central obesity
Buffalo hump
Hypercalcemia
ionized calcium samples must be drawn under anaerobic con- calcium level is usually adequate; ionized calcium samples
ditions and kept on ice for accurate results. Additionally, the must be drawn under anaerobic conditions and kept on ice for
availability and cost of this test somewhat limit this decision. accurate results.
Low Calcium, High Phosphate, Low PTH, Hypoglycemia is a syndrome best defined by the following
Normal Albumin triad of clinical findings (Whipples triad): (1) characteristic
symptoms, (2) plasma or serum glucose concentration <50
Hypoparathyroidism occurs most commonly due to surgical mg/dL, and (3) reversal of symptoms by glucose administra-
damage to the parathyroids during surgery for head and neck tion. As a general rule, this means glucose levels <55 mg/dL
cancer or thyroid surgery, or neck irradiation. Other causes (3.0 mmol/L) with clinical symptomatology that is relieved
are rare and include parathyroid aplasia; infiltration by amy- promptly after the glucose level is raised (Cryer et al., 2009).
loid, sarcoid, or hemochromatosis; and autoimmune disease. The symptoms of hypoglycemia are described in Table 6.4.
PH E O C H ROMO C Y TOM A E N D O C R I N E S C R E E N I NG I N
PAT I E N T S W I T H W E IG H T L O S S A N D
Pheochromocytomas are rare catecholamine-secreting FA I LU R E TO T H R I V E
tumors that arise most often from chromaffin tissue of the
adrenal medulla. While most patients with pheochromocyto- Weight loss in hyperthyroidism is due primarily to increased
mas are hypertensive, hypertension is endemic and pheochro- catabolism, but other causes include increased intestinal
mocytomas are rare; routine testing of hypertensive patients motility and malabsorption. Most patients have hyperpha-
for pheochromocytoma is not warranted. Patients with gia. In older patients, however, hyperthyroidism often causes
hypertension should have a laboratory evaluation for pheo- anorexia with accelerated weight loss. The average weight loss
chromocytoma if they have one or more conditions that raise in a patient with hyperthyroidism is 16% of usual body weight
the likelihood of their having the condition well above the (Hoogwerf & Nuttall, 1984). Weight gain occurs quickly
population base rate. These conditions are (1) hypertension with treatment.
refractory to standard, stepped antihypertensive drug therapy Uncontrolled diabetes mellitus is a common cause of
and not explained by renal artery stenosis or by another endo- weight loss with increased appetite, particularly with
crine disorder; (2)paroxysmal hypertension accompanied by new-onset type 1 diabetes mellitus. There is a loss in lean
headache, sweating, tremor, and other signs of sympathetic body mass as well as loss of extracellular and cellular water
overactivity; (3)hypertension associated with hypermetabo- due to the osmotic diuresis from glucosuria. The etiology
lism (e.g., weight loss despite increased caloric intake); (4) a of weight loss in uncontrolled diabetes is likely multifac-
personal history of associated disorders such as neurofibroma- toriala combination of anorexia, depression, pain, mal-
tosis, tuberous sclerosis, Sturge-Weber syndrome, or multiple absorption, gastroparesis, and enteropathy. Some reports
endocrine neoplasia; or (5)pheochromocytoma or an associ- describe persons who intentionally undertreat their dia-
ated condition in a first-degree relative. About 10% of patients betes in order to lose weight (Rodin & Daneman, 1992).
with pheochromocytomas do not have hypertension at all but Although patients with poorly controlled or undiagnosed
do have discrete episodes of symptoms of sympathetic overac- type 2 diabetes can occasionally present with weight
tivity, including paroxysmal sweating and paroxysmal atrial loss, weight gain is much more common. However, some
tachycardia or fibrillation or ventricular tachycardia. patients with type 2 diabetes can occasionally present
The most sensitive test for pheochromocytoma is a ran- with diabetic neuropathic cachexia, an unusual and poorly
dom plasma free metanephrine level. Because it is less spe- understood syndrome characterized by profound weight
cific than 24-hour urine studies, it is best done in patients loss (as much as 60% of body weight) and often severe
where the clinical suspicion is already high. Aless sensitive neuropathic pain of the anterior thighs (Neal, 2009). The
but more specific test should be used when clinical suspicion pathophysiology is not clear, especially since there is no
is low, or to confirm the diagnosis when the plasma meta- strong relationship between glucose control and resolution
nephrine level is somewhat elevated but is inconclusive. That of weight loss, which usually happens spontaneously after
test is a 24-hour urine for catecholamines and metabolites months or years.
(Pacak etal., 2007). Chronic primary adrenal insufficiency often presents
with significant weight loss, although other associated signs
and symptoms are more prominent:dehydration, anorexia,
Table6.5 NEUROPSYCHIATR IC AND SOMATIC lassitude, fatigue, and weakness. Adrenal insufficiency that
SYMPTOMS OF PHEOCHROMOCYTOMA is acute or due to hypothalamic or pituitary dysfunction is
usually not associated with weight loss (Dorin, Qualls, &
NEUROPSYCHI ATR IC
SYMPTOMS SOM ATIC SIGNS
Crapo, 2003).
Anorexia, nausea, constipation, and polyuria may account
Panic attacks Refractory hypertension for weight loss in patients with the classic clinical manifes-
tations of hyperparathyroidism. However, the majority of
Headaches Orthostatic hypertension
patients with primary hyperparathyroidism are asymptom-
Palpitations Paroxysmal hypertension atic and do not have weight loss (Bolland, Grey, Gamble, &
Reid, 2005).
Visual blurring Pallor and flushing
The hyperadrenergic state among patients with pheochro
Especially as episodes (Spells) mocytoma would theoretically cause weight loss with increased
appetite, but only 5% of patients with pheochromocytomas
Atrial tachycardia or fibrillation
report weight loss (Goldstein etal., 1999).
TSH X X X X X
Calcium X X X X X
PTH X X X
Cortisol X X X X X
ACTH X X X X X
Glucose X X X
IGF-1 X X X
Prolactin X
Testosterone X
CT T1 T2 DW I FLAIR
Blood (hyperacute <7 hours) white dark gray light graywhite white light graywhite
Blood (acute 772 hours) white dark gray-gray dark gray dark gray dark gray
Blood (subacute >72 hours) light graygray light graywhite dark gray dark gray dark gray
Gray Matter gray gray light gray light gray light gray
White Matter dark gray white dark gray gray dark gray
Infarction hyperacute (06 hours) * gray light gray white light gray
Infarction acute (6 hours4days) dark gray dark gray white white white
Infarction subacute (414days) dark grayblack dark gray white light graywhite white
Infarction chronic black black dark grayblack gray dark grayblack
DWI indicates diffusion weighted image; FLAIR, fluid attenuated inversion recovery.
*Indirect signs of infarction such as hyperdense arteries and loss of gray/white differentiation.
**indicates not consistently appreciated.
The appearance of the brain on MRI is dependent on ordering a clinical MRI, while there are variations across insti-
acquisition properties that are described using parameters tutions, standard brain MRI orders will almost always include
such as echo times and time repetition. These parameters cre- T1, T2, and FLAIR sequences; however, the use of contrast,
ate different sequences referred as T1 and T2 (see Table 7.2). SWI, or diffusion sequences (discussed below) should be spe-
On T1 sequences, white matter consisting mainly of fat-rich cifically requested based on the differential diagnosis.
myelinated axons appears white; gray matter structures such Clinical radiologists, neurologists, and neuropsychiatrists
as cerebral cortex and the nuclei of the brainstem and dien- mainly rely on visual inspection to identify pathology on CT
cephalon appear gray. T2 sequences display as white brain or MRI brain scans. However, quantitative techniques for
regions with a high water content; a normal brain will show a MRI interpretation originally devised for research are begin-
pattern of gray and white inverse to that seen on T1 sequences. ning to be used in clinical practice. Manual volumetry is a
Fluid attenuated inversion recovery (FLAIR) is a T2-based technique that combines manual tracing of regions of interest
image that uses an inversion recovery pulse sequence to block (ROIs) with calculations that estimate the volume of struc-
cerebrospinal fluid signal. While T2-based sequences are use- tures based on cross-sectional areas. While this technique is
ful at detecting parenchymal pathology such as prior infarcts, widely available, it is time consuming, operator dependent,
mass lesions, edema, and white matter demyelinating plaques, and requires that operators have an exquisite familiarity with
FLAIR images particularly aid the detection of periventricu- the neuroanatomy of the region(s) being imaged. A more
lar abnormalities that may be obscured by cerebrospinal fluid convenient, automated approach is Voxel-based morphom-
signal on T2 images. T1 sequences are most useful in delin- etry (VBM). In VBM, T1-based MRI sequences for a given
eating brain anatomy (i.e., regional atrophy). The addition of cohort of subjects are spatially normalized to the same ste-
gadolinium, a paramagnetic heavy metal that decreases the reotactic space. During spatial normalization, distinct brains
T1 relaxation times of tissues when injected intravenously as a are deformed to correspond regionally to one another and
contrast agent, enhances lesions that disrupt the bloodbrain enable cross-subject comparisons. Following normalization,
barrier including acute demyelinating white matter lesions, an automated segmentation procedure subdivides the ROIs
vascular lesions, and high-grade glial tumors. In addition, sus- into voxels (cubes of brain tissue) and characterizes each voxel
ceptibility weighted imaging (SWI) is an magnetic resonance as comprised of gray or white matter. Thereafter, voxel-wise
technique that employs a gradient echo pulse sequence that is statistical parametric mapping (SPM) techniques are applied
particularly sensitive to venous blood, hemorrhage, and iron across groups to detect group differences (Ashburner &
deposition (although insensitive to hyperacute blood). When Friston, 2000). Analyses that label all of the voxels within a
M AG N E T IC R E S ON A NC E S PE C T RO S C OP Y
Magnetic resonance spectroscopy (MRS) is used to measure
the average amount of distinct metabolites in brain tissue over 4 3 2 1 0
the duration of an approximately 15-minute scan. It detects ppm
and quantifies resonance signals of molecules present at much Figure7.1
Magnetic resonance spectroscopy illustration. The number of
lower concentrations and differentiates molecules based on signals represented corresponds to the number of different metabolites
their magnetic resonance properties. This technique relies sampled within a specified voxel. The position of distinct peaks on the
in part on chemical-shift imaging which takes into account horizontal axis is proportional to the intensity of the magnetic field,
the effect of the local chemical environment on particu- normally called chemical-shift, and measured in parts per million (ppm).
The area under the curve for each signal provides a relative concentra-
lar nuclei. The metabolic profile of a region can be obtained tion of each metabolite. ml indicates Myoinositol; Cho, Choline;
through single voxel MRS (SVMRS) or multivoxel MRS Cr, Creatine; NAA, N-Acetyl-Aspartate.
imaging. SVMRS provides a metabolic average score within
the selected voxel, while multivoxel MRS provides, within a
unique image acquisition, various molecular images indicat- cell membrane synthesis; and creatine (Cr), associated with
ing the spatial distribution of different metabolites. The major cellular energy metabolism. MRS, thus far, is the only read-
limitation of SVMRS is the lack of spatial information due to ily available technique enabling in vivo sampling of metabolic
limited sampling, although voxel size across single voxel and information and is used clinically to aid diagnosis of meta-
multivoxel MRS is typically similar. bolic disorders (i.e., leukodystrophies), distinguish neoplasms
The central nervous system metabolites measured with from other abnormal brain signals (high-grade brain tumors
MRS are outlined in Table 7.3 and Figure 7.1. Commonly characterized by high Cho and low NAA), and assess the
detected metabolites include N-acetyl aspartate (NAA), a effects of chemotherapeutics on brain tumors by helping to
marker of neuronal integrity; choline (Cho), an indicator of distinguish between necrosis and neoplasm recurrence.
Figure7.2
Functional activation pattern in a patient with schizophrenia experiencing dual auditory and visual hallucinations, recorded using a symp-
tom capture paradigm with the patient also utilized as his own control. Reprinted by permission from Macmillan Publishers Ltd:Nature. Silbersweig DA, Stern E, Frith C, Cahill C,
Holmes A, Grootoonk S, etal. Afunctional neuroanatomy of hallucinations in schizophrenia. 1995;378:1769.
Infection
Herpes Simplex Virus, Fever, meningeal irritation, MRI:High T2WI signal in the temporal lobe(s). Restricted
Varicella Zoster Virus delirium, seizures diffusion/gyriform edema. Meningeal enhancement.
Human Immunodeficiency Virus Opportunistic infections, MRI:Generalized atrophy. Nonspecific T2WI WM lesions.
(HIV) Dementia subcortical cognitive deficits CT:Generalized atrophy.
Cerebrovascular
Large Vessel Strokes Cortical deficits:aphasia, neglect, MRI:T2WI hyperintensities. Mass effect. DWI high, ADC low.
visual field loss CT:Hypoattenuation.
Lacunar Strokes Motor/somatosensory deficits MRI:T2WI hyperintensities. DWI high, ADC low.
CT:Punctate hypoattenuation.
Oncologic
Malignant Primary CNS Tumor Headache, focal deficits, seizures MRI (preferred) and CT:Mass effect +/- post-contrast
enhancement.
Benign CNS Tumor Seizures, cognitive/affective deficits MRI (preferred) and CT:Variable mass effect and post-contrast
(i.e. orbital groove meningioma) enhancement.
Metastatic CNS Tumor Focal deficits, headache, known MRI (preferred) and CT:Enhancing mass lesions at the
malignancy gray-white junction.
Limbic Paraneoplastic
Anti-NR1/NR2 of Ovarian teratoma MRI:High signal mainly in the temporal lobe(s) in T2WI.
N-methyl-D-aspartate (NMDA) Restricted diffusion, gyriform edema.
receptor
Anti-Hu (ANNA-1) Small cell lung cancer MRI:High signal mainly in the temporal lobe(s) in T2WI.
Restricted diffusion, gyriform edema.
Anti-Voltage-Gated Potassium Thymoma, small cell lung cancer MRI:High signal mainly in the temporal lobe(s) in T2WI.
Channels (VGKC) Restricted diffusion, gyriform edema.
Demyelinating
Multiple Sclerosis Optic neuritis, relapsing-remitting MRI:T2WI WM hyperintense lesions, enhancing acute WM
deficits lesions.
Neurodegenerative
Alzheimers Disease Progressive amnesia, anomia MRI (preferred) and CT:Medial temporal lobe atrophy.
Frontal Temporal Dementia Progressive impulsivity, apathy, MRI (preferred) and CT:Frontotemporal atrophy.
Behavioral Variant personality change
(continued)
Table7.4(CONTINUED)
Diffuse Lewy Body Disease Visual hallucinations, fluctuating MRI:Brain stem, substantia nigra, and cortical atrophy on
delirium, parkinsonism T1WI.
Sporadic Creutzfeldt-Jakob Myoclonus, ataxia, rapidly MRI:High signal on T2WI and DWI in the striatum and
Disease (CJD) progressive cognitive decline posterior cortical ribbon.
Inflammatory
Systemic Lupus Erythematosus Rash, arthritis, headache, MRI:High T2WI signal in WM, non specific.
constitutional symptoms
Primary Angitis of the CNS Headache, focal neurologic deficits MRI:Restricted diffusion on DWI and ADC. High intensity
T2WI lesions.
Diffuse Axonal Injury Variable deficits but includes coma MRI:High intensity T2WI lesions +/- hemorrhage on SWI.
CT:Focal high density with surrounding low-density edema.
Acute Subdural Hemorrhage Brief lucid period prior to loss of CT (preferred):Crescent-shaped high density fluid collection.
consciousness, herniation MRI:Isointense on T1WI, hypointense on T2WI.
Other
Thiamine Deficiency: Alcoholism, nystagmus, ataxia, MRI:mammillary body atrophy on T1WI, hyperintensity on
Wernicke-Korsacoff Syndrome confabulation, amnesia T2WI. Enhancement.
Normal Pressure Hydrocephalus Magnetic gait, urinary incontinence, MRI:Hydrocephalus, periventricular T2WI hyperintensities.
subcortical dementia CT:Hydrocephalus and periventricular hypoattenuation.
NOTE :CT scan abnormalities are delineated based on changes in density while MRI-based abnormalities are described by delineating lesional intensity.
Gadolinium may be used as an intravenous contrast for T1WIs and iodinated contrast is available for use in CT scans. Also, similar findings are typically denoted
in both T2WIs and FLAIR sequences with the except that FLAIR sequences improve delineation of periventricular pathologies. T2WI indicates T2-weighted
image; WM, white matter; DWI, diffusion weighted image; SWI, susceptibility weighted image; CSF, cerebrospinal fluid; CT, computed tomography.
acute-subacute mental status change, fever, and meningeal performed, an anterior cerebral artery stroke could be mis-
irritation (photophobia, nuchal rigidity). The additional pres- taken for a hypoactive delirium.
ence of focal neurologic signs, including papilledema or lat- Increasing characterized paraneoplastic phenomena may
eralizing weakness, numbness or cortical deficits including present with prominent limbic symptoms, and can be inves-
aphasia, neglect, or visual field deficits, suggest parenchymal tigated using cerebral spinal fluid sampling, antibody test-
involvement and warrant a CT brain scan prior to cerebral ing, oncologic screening, and MRI brain imaging (Dalmau
spinal fluid sampling. FLAIR/T2 and T1 post-gadolinium & Rosenfeld, 2008). Awell characterized example is the case
MRI sequences can also help confirm if an infection extends of anti-N-methyl-D-aspartate (NMDA) receptor antibodies
to the brain parenchyma, as in a meningoencephalitis, or aid presenting with psychosis, memory deficits, altered mental
the diagnosis of a limbic encephalitis (i.e., herpes simplex status, seizures, dyskinesias, and autonomic disturbances in
virus) presenting with fever and mental status change without young women with undetected ovarian teratomas. FLAIR,
definitive meningeal irritation. T2, and T1post-gadolinium sequences may identify medial
Patients with cerebrovascular disease may also present temporal lobe and prefrontal cortical inflammation support-
with underrecognized affective and behavioral symptoms. ive of limbic encephalitis.
One such example is apathy in patients with an anterior Screening for vascular disease, and particularly small ves-
cerebral artery stroke. If a detailed neurologic examination sel (microangiopathic) white matter disease, is an important
screening for corticospinal tract involvement (i.e., leg weak- component of the diagnostic work-up for geriatric patients
ness, numbness, Babinski sign, increased reflexes) along with presenting with progressive subcortical cognitive impairments
either a CT scan or DWI and ADC MRI sequences are not (diminished processing speed, retrieval deficits with relatively
E F G H
Sample diagnoses aided by radiographic findings. A. Computed tomography (CT) scan of an elderly man with impulsivity and disinhibition
Figure7.4
revealing hypoattenuation in the left frontal region consistent with a prior stroke. B. Noncontrast CT scan of a young woman with recent blunt head
trauma demonstrating a right frontotemporal subacute subdural hemorrhage. C. Diffusion weighted image (DWI) of a woman with mood labiality
and myoclonus showing bilateral caudate and putamen restricted diffusion consistent with prion disease. D. Fluid attenuated inversion recovery
(FLAIR) scan in an elderly woman with medically refractory seizures demonstrating increased left hippocampal FLAIR signal related to anti-HU
paraneoplastic antibodies. E. T1 post-gadolinium scan of a woman with marked apathy demonstrating a heterogeneously enhancing intraparenchy-
mal mass lesion consistent with a high-grade glioma. F. T1post-gadolinium scan of a young man presenting with right-sided weakness found to have
multifocal periventricular and subcortical enhancing white matter lesions consistent with an acute multiple sclerosis flare. G. T1 post-gadolinium
scan of a middle-aged woman with alcohol dependence presenting with gait instability, amnesia, nystagmus, and bilateral gaze palsy, demonstrating
bilateral mamillary body enhancement consistent with Wernicke-Korsakoff syndrome. H. T1 MRI of a man with progressive personality change and
apathy revealing bilateral frontal, anterior temporal, and peri-insular atrophy with sulcal widening, consistent with frontotemporal dementia.Adapted
from Perez DL, Larvie M, Acar D, Daffner K.Teaching NeuroImage:Apathetic variant of frontotemporal dementia, Neurology 2011;77(20):e117. Note:all images are displayed using radiographic conventions (i.e., right
hemisphere displayed on the left side of the scan).
preserved retention/recognition on memory testing) and/or unfortunately there are not yet well-accepted guidelines to
late-onset mood disturbance. Extensive hypoattenuation of assist clinicians in these determinations. Despite this, com-
the periventricular and subcortical white matter on CT scan, parative analyses show that the aging brain loses volume in
or T2/FLAIR hyperintensity on MRI, would support cere- nonlinear and region-dependent fashion, and prefrontal cor-
brovascular disease, particularly in patients with a known his- tical volume decreases more rapidly than other brain regions.
tory of hypertension, hyperlipidemia, and/or diabetes mellitus. Reductions in cortical volume, particularly in prefrontal and
Structural and functional imaging also aids in the diagnosis of temporal regions, have been estimated to be approximately
neurodegenerative disorders through detection of lobar pat- 0.5% per year in patients over 60years of age (Fjell etal., 2009).
terns of atrophy with associated sulcal widening (i.e., medial Furthermore, volumetric reductions in aging populations are
temporal or frontal) and focal hypometabolism (temporal/ thought to reflect reductions in synaptic spine density rather
parietal or frontal/anterior temporal/insular) as present in than actual neuronal loss. Physical exercise and cognitively
Alzheimers disease and frontotemporal dementia. Ventricular stimulating activities may also modulate the trajectory of nor-
enlargement frequently accompanies neurodegenerative disease mal age-related brain changes by promoting successful cog-
(hydrocephalus ex vacuo) and can be discerned from other forms nitive aging and enhanced neuroplasticity (Daffner, 2010).
of hydrocephalus, including normal pressure hydrocephalus, by Thus, patient age is an important, heterogeneously presenting
concurrently detecting sulcal widening and a lack of periven- variable to consider when evaluating neuroimaging findings.
tricular signal abnormality suggestive of transependymal flow. In general, a common problem in daily clinical practice is
When evaluating potentially abnormal structural neu- the extent to which brain imaging findings may be overinter-
roimaging findings, it is also useful to consider the effects of preted or underinterpreted. Radiographic misinterpretation
normal aging (Fox & Schott, 2004). Assessing the extent to can be partially avoided by familiarizing ordering physicians
which atrophic changes are within the normal limits for age is with the limitations of the individual neuroimaging techniques
a sophisticated clinical judgment, with the potential for differ- as previously discussed. Examples of this include the limitation
ences of opinion even among experienced neuroradiologists; of CT scans to appreciate even subtle ischemic stroke changes
Obsessive Compulsive
Disturbances
Sensory Cortex
Amygdala
Brainstem/Periaqueductal
Gray
Ventral Striatum
Hypothalamus
Hippocampus Memory
Fornix
Mammillary Bodies
Orbitofrontal Cortex
(continued)
Table7.5(CONTINUED)
Default Mode Network Ventral and Dorsal Medial Self Referential Processing Under Investigation
PFC
Precuneus
Hippocampal Formation
OFC indicates orbitofrontal cortex; VM, ventral medial; MDM, medial dorsomedial; MD, mediodorsal; VA, ventral anterior; ACC, anterior cingulate cortex;
NA, nucleus accumbens; DLPFC, dorsolateral prefrontal cortex; DL, dorsolateral; LDM, lateral dorsomedial; PFC, prefrontal cortex.
dlPFC
ACC
Orbitofrontal
Cortex
Caudate Nucleus
Caudate Nucleus
Globus Pallidus Putamen
DL NA/VM
VM
LDM Caudate Nucleus MDM
V
Globus Pallidus
MD Globus Pallidus MD
MD
VA VA VA Thalamus
Thalamus Thalamus
Figure7.5 Graphic depiction of dorsolateral, orbitofrontal, and anterior cingulate prefrontalsubcortical circuits. dlPFC indicates dorsolateral prefrontal cortex; DL,
dorsolateral; LDM, lateral dorsomedial; MD, mediodorsal; VA, ventral anterior; VM, ventromedial; MDM, medial dorsomedial; NA, nucleus accumbens; V, ventral; ACC, anterior cingulate cortex. Adapted from
Perez DL, Catenaccio E, Epstein J (2011) Confusion, hyperactive delirium, and secondary mania in right hemispheric strokes:Afocused review of neuroanatomical correlates. Journal of Neurology and Neurophysiology
S1. doi:10.4172/2155-9562. S1-003.
Schizophrenia Total brain volume Prefrontal (i.e., dlPFC) activity dlPFC activity during a working
during rest and cognitive challenge memory task atypical
Ventricular size studies antipsychotic response
Hippocampal volume Temporal lobe dysfunctionduring dlPFC activity during a working
rest and cognitive challenge studies memory task CBT response
Reversal of cerebral asymmetry
Frontal structural asymmetry
STG, IPL, dlPFC atypical antipsychotic response
Basal Ganglia (related to typical
antipsychotic drugs)
MDD Prefrontal (sgACC, OFC) sgACC ACC activity (during rest and
affective challenge studies) and
Hippocampal volume AMG volume antidepressant response
Striatum Mediodorsal thalamus Hippocampal volume
antidepressant response
dorsal ACC
dlPFC
Insular dysfunction
PTSD Hippocampal Hippocampus AMG and ventral ACC activity
during an affective challenge task
volume Medial prefrontal (ACC, OFC) CBT response
ACC AMG Rostral ACC volume
CBT response
Preliminary structural and functional predictors of treatment response are also highlighted. Also, unless otherwise specified, functional findings reflect primarily
task-driven abnormalities.
STG indicates superior temporal gyrus; IPL, inferior parietal lobule; dlPFC, dorsolateral prefrontal cortex; sgACC, subgenual anterior cingulate cortex;
OFC,orbitofrontal cortex, ACC, anterior cingulate cortex; AMG, amygdala; CBT, cognitive behavioral therapy.
help identify potential targets for neuromodulatory interven- across psychiatric diseases. Furthermore, additional novel tar-
tions. Two of the more targeted neuromodulatory approaches gets will be identified for neuromodulation and biofeedback
are transcranial magnetic stimulation (TMS) and deep brain techniques such as real-time fMRI. Overall, this endeavor will
stimulation (DBS). Medication-resistant MDD has been the help clarify final common pathways through which medical/
most well studied condition, with hypoactivity of the dorso- neurological disorders and primary psychiatric disorders pro-
lateral prefrontal cortex and hyperactivity of the subgenual duce behavioral, affective, perceptual, and cognitive symptoms.
cingulate cortex targeted using TMS and DBS respectively In summary, physicians treating psychiatric disorders will
(Mayberg et al., 2005; Pascual-Leone, Rubio, Pallardo, & increasingly make use of structural and functional neuroim-
Catala, 1996). Ongoing research will likely broaden the use aging techniques. Proficiency in the use and interpretation
of these techniques for the treatment of additional affective of neuroimaging findings will become the norm for psychia-
and psychotic disorders. trists, and a working knowledge of functionstructure rela-
tionships will enable future advancement in the field.
S U M M A RY
C L I N IC A L PE A R L S
This chapter has outlined the emerging role for neuroimaging
in the diagnosis and management of patients with psychiat- Computed tomography (CT) scans are relatively insensi-
ric and neuropsychiatric conditions. Ongoing translational tive to acute ischemic stroke detection; a well visualized
research endeavors will help link neuroimaging advances with hypodensity may not be appreciable until more than 24
genetic and epigenetic information to clarify endophenotypes hours after symptom onset. Subtle ischemic changes such
C
linical neurophysiology comprises electroencepha- The electrical activity is then measured between 2 elec-
lography (EEG), evoked potential (EP) studies, trode pairs as a voltage difference. The electrodes can be
electromyography (EMG), nerve conduction stud- paired in two different ways (montages) and then amplified.
ies, and specialized investigations such as electrical testing In the referential montage, all the electrodes are referred to
of specific reflex arcs (e.g., the blink reflex). It can be critical the same electrode, for example, one attached to an earlobe.
in the differentiation of neurological conditions with simi- In contrast, the bipolar montage consists of pairs of succes-
lar phenomenology but different brain mechanisms, and its sively numbered electrodes:electrode 1 linked to electrode 2,
objective nature gives it a special place in the investigation electrode 2 to 3, and so forth. With the current digital tech-
of somatoform neurological symptoms. This chapter will nology the EEG reviewer can easily switch between montages
describe the most commonly used procedures of clinical neu- to better assess the brain activity in question.
rophysiology and highlight points of special interest to medi- The electrical activity once recorded can be characterized
cal psychiatrists. by its amplitude in microvolts (5-200 V) and its frequency.
Surface EEG frequencies include Delta (04 Hz), Theta
(48Hz), alpha (813 Hz), and beta (>13 Hz) (Table 8.1). By
E L E C T RO E NC E PH A L O G R A PH Y (E E G) convention, any upward deflection on EEG is termed negative
and any downward deflection is termed positive.
The surface electroencephalogram is a neurophysiological tool
which measures brain activity with the aid of surface scalp
T H E NOR M A L E E G DU R I NG
electrodes. The exact source of this brain activity is the result
WA K E F U L N E S SA N D S L E E P
of a complex interplay of large populations of neurons and
surrounding glia, with the majority of the activity generated The normal adult EEG consists of a prominent alpha
by dendritic synaptic potentials in gray matter pyramidal cells rhythm predominantly located in the posterior head regions,
(Schaul, 1998). On a larger scale, the corticocortical and thal- and low voltage faster frequencies (LVF) in the frontal
amocortical connections are also an important contributor regions (Figure 8.2). Alpha rhythm and posterior dominant
to the EEG signal. For example, the thalamocortical connec- rhythm are sometimes used interchangeably; however, under
tions are known to be essential in the generation of a num- certain circumstances a persons posterior dominant rhythm
ber of sleep rhythms such as the sleep spindle (Speckmann & may consist of lower frequencies. When the posterior domi-
Caspers, 1979). nant rhythm attenuates with eye opening and reappears with
The standard EEG consists of electrodes placed according eye closure, it is considered reactive. The normal 813 Hz
to the 10-20 international electrode system (Jasper, 1958). posterior background rhythm/alpha rhythm is achieved in
The 10 and 20 refer to the percentage of the distance, used to the majority of cases at the age of 3years. The normal alpha
guide placement, from nasion (the craniometric point at the rhythm is reactive to eye opening and is maintained through-
bridge of the nose where the frontal and nasal bones of the out life in healthy individuals. However, 10% of normal
skull meet) to inion (the projecting part of the occipital bone individuals do not have an appreciable posterior dominant
at the base of the skull) anteroposteriorly, and then left to rhythm on standard EEG, due to its having a very low ampli-
right preauricular points (Figure 8.1). In total, 19 electrodes tude when measured at the scalp (<15uV). The frequency of
are placed in addition to a ground and reference electrode. the rhythm seems to be closely related to cerebral blood flow.
Electrode nomenclature consists of the following:C for cen- As the person transitions to drowsiness (stage Isleep), slow
tral, F for frontal, Fp for frontopolar, O for occipital, P for roving eye movements are noted on EEG, the posterior alpha
parietal, T for temporal. Odd numbers refer to electrodes on rhythm gradually disappears, and the brain activity consists
the left and even numbers on the right. All central electrodes of fronto-centro-temporal theta activity alongside prominent
have a z subscript. frontocentral beta activity (Figure 8.3). With deeper levels of
155
Figure8.1
EEG electrode set up. Scalp EEG electrodes are placed according to the 1020 system. Occasionally, extra electrodes are placed for moni-
toring of eye movements.
Alpha 813 Hz
Beta >13 Hz
Theta 48 Hz
Delta 04 Hz
Figure8.2
Normal adult EEG. Adouble banana montage is used with the left temporal chain on top, then left parasagittal chain, then midline electrodes,
then right parasagittal chain, then the right temporal chain. A10-second EEG sample is shown with the distance between each bar representing 1 sec-
ond. The prominent positive deflections (downward) are due to artifact from the eye blink. During the first 2 seconds the patient has the eyes open, then
upon eye closure an 11 Hz posterior alpha rhythm is seen; indicating that it is reactive. Lower voltage faster activity is noted in the anterior electrodes.
sleep, vertex waves appear. These waves are prominent nega- negativity, a slow positivity, and then another negativity seen
tive waves, best appreciated in the midline electrodes, and prominently in the frontal or midline regions. Stages III and
can occur in isolation or in trains. Stage II sleep is character- IV sleep are lumped together and termed slow-wave sleep and
ized by the persistence of vertex waves and the appearance consist of higher voltage theta and delta activity. REM (rapid
of 1214 Hz frontocentral, sinusoidal rhythms termed sleep eye movement sleep) is characterized by rapid eye movements,
spindles (Figure 8.4). In addition to the sleep spindles, K com- intermittent alpha activity, and the appearance of sawtooth
plexes can also be seen, which are characterized by an initial waves over the central regions.
Figure8.4
EEG during stage II sleep. The record consists of bilateral slowing predominantly in the theta range. In this EEG sample several vertex
waves and sleep spindles can be seen, which are most prominent in the midline electrodes.
E E G A B NOR M A L I T I E S
is usually abnormal. Based on the location of the slowing on
EEG abnormalities can be broadly divided into slow-wave EEG, it can further be classified into focal or generalized.
abnormalities and epileptiform abnormalities. Slow-wave Other descriptors of the slowing also include whether it is
abnormalities are documented when activity in the theta and continuous or intermittent. In general, focal cerebral abnor-
delta range is seen (Figure 8.5) beyond what is expected for a malities cause focal slowing on EEG, while more diffuse pro-
normal EEG. For example, any slowing during wakefulness cesses such as metabolic derangements cause diffuse slowing
on EEG. Certain slowing patterns can be readily distinguish- more prominent during this stage. Slow-wave sleep and REM
able. Continuous polymorphic delta activity is a pattern sug- sleep are rarely seen during the routine EEG.
gestive of a structural cerebral lesion with disruption of white Other activation procedures are also performed depend-
matter tracts in the majority of the cases. In the absence of any ing on the circumstances. The purpose of the activation pro-
structural lesion on imaging, continuous slowing may repre- cedures is to bring out focal or epileptiform activity not
sent a postictal state and should resolve with time. Frontal apparent in the record. During the hyperventilation pro-
intermittent delta activity (FIRDA) is a nonspecific pattern cedure, the patient is asked to hyperventilate for 3 minutes.
seen in metabolic encephalopathy and raised intracranial Hyperventilation is of higher yield in young adults, and is con-
pressure. FIRDA can also be seen in normal drowsy individu- traindicated during pregnancy and in patients with asthma,
als, and as a result is not necessarily pathological (Accolla, cardiovascular disease, or cerebrovascular disease, due to the-
Kaplan, Maeder-Ingvar, Jukopila, & Rossetti, 2011). oretical concerns regarding bronchospasm or ischemia. Photic
Epileptiform abnormalities include spikes and sharp waves. stimulation is another activation procedure, where flickering
Aspike is defined as a transient (i.e., transient wave) that is dis- lights of variable frequencies are shined into the patients eyes.
tinguishable from the background activity, with duration of In rare circumstances, the activation procedures themselves
20 to less than 70 milliseconds (Chatrian etal., 1974). Asharp may trigger a nonepileptic seizure. In the inpatient setting,
wave is similar, but its duration is 70 to 200 milliseconds the activation procedures may not be performed unless spe-
(Figure 8.6). Spikes and sharp waves are often followed by a cifically requested by the ordering physician. When dealing
slow wave, and can also be classified as focal or generalized. with a comatose individual, verbal and noxious stimuli are
When the spikes or sharp waves are periodic and lateral- often given by the technologist to assess for reactivity on EEG.
ized to one hemisphere, they are termed PLEDs: periodic
lateralized epileptiform discharges (Figure 8.7). PLEDs are T H E E E G R E P ORT
seen under different circumstances; they can represent an
injury pattern seen with an acute insult (Garcia-Morales etal., A complete report should include the following:
2002)and resolve with time, or ongoing ictal activity (there The patients posterior background and whether it is reactive
are cases where clinical findings are correlated with each dis-
charge, such as clonic movements), or a postictal state. Adescription and characterization of beta activity
Stages of sleep noted
T H E ROU T I N E I N PAT I E N T A N D
Response to activation methods
OU T PAT I E N TE E G
Single lead EKG rhythm
The standard routine EEG consists of 2040 minutes of
recording with the EEG technologist at bedside. During the Presence of any asymmetries
procedure the patient is asked to open and close the eyes to
Documentation of any slowing or epileptiform discharges
assess for reactivity. Ideally, stage II sleep should be captured
during the recording, as abnormalities may arise or become Acomparison of the current EEG to any prior EEGs
Figure8.7
EEG with PLEDs (periodic lateralized epileptiform discharges). EEG of a 72-year-old man with a history of head trauma, a left subdural
hematoma, and altered mental status. The EEG shows periodic sharp waves (arrows) in the left hemisphere at a frequency of ~1Hz.
As can be clearly seen above, the EEG report includes impor- Comparisons to prior EEGs are invaluable, as it may show
tant information not limited to epileptiform activity. The new epileptiform activity or may establish the progression
body of the report should always be scrutinized by the treating of an encephalopathy or degenerative brain disease. Finally,
physician and not rely solely on the electroencephalographers there are certain EEG waveforms that are suspicious but do
conclusions. For example, REM sleep noted on a routine EEG not fulfill criteria for epileptiform activity; these may be
is suggestive of medication effect or possibly narcolepsy. Due labeled as sharply contoured discharges. When these are
to the complexities involved in EEG interpretation, it is always reported and the clinical suspicion of epileptic seizures is
advisable to consult with the EEG reader when in doubt. high, a repeat routine EEG, a more prolonged study, and/or
It also has to be kept in mind that an EEG is always inter- a provocative procedure such as sleep deprivation is advised.
preted in the context of the patients age. Certain degrees of In addition, a spike/sharp wave noted on EEG does not
temporal slowing, for example, are allowed in the elderly. automatically mean a patient has epilepsy. In fact, studies
Figure 8.9
EEG with triphasic waves. EEG of a 30-year-old patient with meningitis, renal failure, and agitation. The EEG sample during wakefulness
shows bilateral, frontally predominant theta waves which have a triphasic morphology (arrow), commonly referred to as triphasic waves. The
record also shows bilateral slowing in the theta>delta range.
patients with uremia, electrolyte imbalances, anoxic brain where characteristic EEG findings can be seen. The virus has
injury, and medication intoxications (Kaplan, 2004). a predilection for the temporal lobes, and subsequently after
The EEG in chronic alcoholics is also nonspecific; how- a few days of clinical symptoms; characteristic PLEDs are
ever, a higher percentage of these patients have a low voltage noted in the temporal regions, sometimes independently, a
EEG as compared to the normal population. phenomenon termed bi-PLEDs. The PLEDs are transient in
nature and resolve within 34 days (Lai & Gragasin, 1988).
Similarly characteristic EEG findings are also seen in sub-
EEG in Autoimmune and Infectious Encephalopathies
acute sclerosing panencephalitis (SSPE) and Creutzfeld-Jakob
Other important causes of alterations in mental status include disease (CJD). SSPE is the result of chronic measles infection
the autoimmune and infectious encephalopathies. With acute and is characterized by the appearance of high voltage spike
viral or bacterial encephalitis, the EEG changes are nonspe- and wave discharges occurring every 415 seconds. In CJD
cific with diffuse slowing. Herpes encephalitis is an exception early changes on EEG are nonspecific, while later stages of the
may be seen over the posterior head regions. In frontotempo- clinical suspicion should drive more extensive neuroimaging
ral dementia, the alpha seems to be preserved and frontotem- and electrophysiologic testing.
poral slowing is expected (Jenssen, 2005). The EEG in a patient with a history of diagnosed epilepsy
The EEG can be useful in a patient who is exhibit- who is presenting with new psychotic symptoms is useful in
ing apparently severe cognitive deficits and has a history or corroborating the clinical impression of the relationship of
examination atypical for dementia. In this setting a normal the psychosis to the seizure disorder. If discrete, repetitive, ste-
EEG would be evidence against the diagnosis of a dement- reotypic mental or behavioral symptoms are ictal, one would
ing process (Holschneider & Leuchter, 1999). However, an expect the EEG to show seizure discharges coincident with the
EEG with a posterior background rhythm of 88.5 Hzat symptoms; video recording with EEG telemetry can demon-
the lower end of the normal rangecould represent signifi- strate such a relationship. Psychotic symptoms occurring as
cant change from the patients baseline. As such, it would be part of recurrent episodes of delirium lasting minutes to hours
weaker evidence against a dementing process than one with at a time would most likely be postictal, and the EEG usually
an alpha rhythm between 10 Hz and 12 Hz. will show focal or diffuse slowing coincident with the symp-
toms. A persistent psychosis with gradual onset in a patient
with several years history of limbic epilepsy is likely to be an
E E G I N PAT I E N T S W I T H A N X I E T Y DI S OR DE R S
interictal psychosisone related to the patients persistent
A N D P S YCHO S I S
abnormal brain electrical activity, but with symptoms not syn-
Differentiating panic attacks from simple partial seizures can chronous with seizures or postictal states. In this case the EEG
be difficult on clinical grounds due to the common symp- in the symptomatic patient usually shows temporal sharp wave
tomatology and similar brain regions involved (Hurley et al., or spike activity but not frank seizure discharges or focal slow-
2006). The two conditions may also exist within the same ing. On the other hand, EEG is not routinely recommended
patient (Mintzer & Lopez, 2002). There are also a few case in the assessment of a patient with first-episode schizophrenia
reports of patients incorrectly diagnosed with panic disorder and no known history of epilepsy. Some studies have shown
who in fact had a new onset of focal epilepsy (Gallinat, Stotz- that patients with normal EEG were more likely to remit after
Ingenlath, Lang, & Hegerl, 2003; Scalise, Placidi, Diomedi, one year of treatment (Freudenreich etal., 2007).
De Simone, & Gigli, 2006); the latter diagnosis would not
only influence treatment but would be an indication to work
E E G I N E PI L E P S Y A N D P S YCHO G E N IC
up the patient to exclude a focal lesion such as a tumor. EEG
NON E PI L E P T IC S E I Z U R E S
in this clinical situation is most valuable when it shows an ictal
pattern simultaneous with the patient experiencing his or her Psychogenic nonepileptic seizures (PNES) are characterized
typical symptoms. Interictal epileptiform discharges sugges- by involuntary repetitive episodes of movement, behavior, and/
tive of epilepsy are less diagnostically specific, but would sup- or alteration of consciousness, sensation, or memory (Alsaadi
port a trial of antiepileptic drugs. The caveat is that in some & Marquez, 2005)without ictal or postictal changes on EEG
patients with only simple partial seizures, the scalp EEG may consistent with the pattern of symptoms seen (Figures 8.11
be negative both ictally and interictally; in these cases a high and 8.12). Patients may present with generalized or unilateral
Figure8.12
EEG in PNES (psychogenic nonepileptic seizures). A30-year-old patient with spells of generalized shaking. At the beginning of the
recording there is a lot of EEG artifact due to the shaking. Afew seconds afterwards, a posterior alpha rhythm is appreciated after an eye blink.
shaking, unresponsiveness, bizarre behavior, weeping, pelvic complex but stereotyped and repetitive behavior, without
thrusting, or forceful eye closure, among others. PNES is dis- major alteration of consciousness, can result from seizure
cussed in detail in chapter43. discharges deep in the frontal lobe that do not spread to the
Patients with PNES frequently have genuine epilepsy as brain surface. Seizures of this type can yield a video EEG sug-
well. In this patient population, video EEG is the gold stan- gestive of PNESshowing the typical symptomatic behavior
dard for diagnosis, as it is the best way to determine whether with no coincident EEG change. Clinical suspicion should be
the mental and behavioral symptoms are simultaneous with high if the spells are stereotypic in nature, cluster, and tend to
seizure discharges or immediately follow them. Video EEG occur out of sleep. In rare circumstances, invasive electrode
is definitive when the suspected PNES include loss or altera- placements may be necessary to definitively settle the issue.
tion of consciousness or bilateral tonicclonic movements, They are undertaken when clinical suspicion of frontal lobe
as alterations in the EEG at the brain surface are inevitably epilepsy is high because of the patients history or findings of
present during epileptic seizures with such symptoms. More anatomic or functional brain imaging.
Figure8.14
Examples of arm and leg somatosensory evoked potentials. Several stimulations of the median nerve (above), or posterior fibular (nerve
below) are averaged between a pair of electrodes (C7S= 7th cervical spine, EP=Erbs point, T12:12th thoracic spine, PF=popliteal fossa). The
signals obtained are labeled P for positive and N for negative.
latency of the VEP. VEPs can be abnormal early in the course cortex in the contralateral superior temporal lobe. In this
of MS at a time when the MRI is normal or nondiagnostic. test, a patient is presented with an auditory stimulus consist-
The test should be considered when the patient is suspected of ing of brief clicks. A complex signal of 6 waveforms is gen-
MS on clinical grounds, has a history of visual symptoms, and erated as the signal travels from the cochlear nerve, up the
has a normal or nondiagnostic MRI. brainstem, and then reaches the cortex. Each wave represents
AEPs, also known as brainstem auditory evoked potentials a location on the way from the inner ear to the auditory cor-
(BAEPs) assess the integrity of the auditory pathways, which tex (Figure8.15). If the time between one wave and the next
connect the cochlea on each side with its primary auditory is prolonged over the normal interval, there is demyelination
of the auditory pathway between the two corresponding loca- the median nerve) and at the lumbar spine (for the posterior
tions, a partial lesion of the pathway. or anatomic impinge- tibial or peroneal nerve), the cervical spine, and the contralat-
ment on the pathway. eral cerebral cortex. Delayed latency of the SSEP is evidence
As with VEPs, the AEPs may provide evidence of demye- for demyelination of the sensory pathway; the differential
lination in a patient clinically suspected of MS at a time when diagnosis includes demyelinating neuropathies and myelopa-
the MRI is normal or nondiagnostic. It would be particularly thies as well as encephalopathies. Completely normal SSEPs
sensitive in this setting if the patient had complaints of ver- would suggest a diagnosis of conversion in a patient complain-
tigo or impaired balance, or if the neurological examination ing of severe sensory loss in a limb. An SSEP study would be
showed nystagmus or unsteady gait. appropriate when MS is suspected in a patient with promi-
Just as the VEPs can be used to assess alleged loss of visual nent sensory symptoms but a normal MRI. Both the AEP and
acuity, the AEPs can be used to assess the magnitude of genu- the SSEP can be used in confirmingor disconfirminga
ine hearing loss. The stimulus for the AEP is a series of clicks. diagnosis of brain death in a patient who might conceivably
If the clicks are above the threshold for hearing they will pro- be locked inalive and conscious but unable to respond to
duce an AEP; if they are below the threshold they will not. If stimuli because of motor system damage. If a cortical poten-
a patient has a normal AEP at a volume at which they deny tial can be evoked by an auditory or somatosensory stimulus,
hearing, it can be concluded that the patients deafness is of the patient is alive.
cerebral origindue either to conversion, malingering, or
a disorder of higher cortical function. In the last case there
would always be evidence of cerebral cortical damage on an E L E C T ROM YO G R A PH Y A N D N E RV E
anatomic image. C ON DUC T ION S T U DI E S
Somatosensory evoked potentials (SSEPs) assess the trans-
mission of a sensory signal from peripheral nerves to the Electromyography (EMG) is the study of the electrical activity
contralateral somatosensory cortex (Figure 8.16). The three of muscle fibers. This is typically done using a needle inserted
nerves stimulated in a standard SSEP test are the median into the muscle of interest, though the EMG is recorded
nerves and, in the lower extremities, either the posterior tibial on the surface of the skin in some contexts. It is useful in
nerves (at the ankles), or the peroneal nerves at the fibular diagnosing three types of problems: (1) intrinsic diseases of
heads. The signal is then measured at the brachial plexus (for muscle; (2) disturbances in the nerve supply to muscle;
(3)disorders of the neuromuscular junction; and (4)distur- patient has polyneuropathy. This may be valuable when the
bances in motor control. Electromyography requires a skilled patients neuropsychiatric symptoms may be due to a drug or
operator and can involve technical subtleties, depending on toxin that is known to affect the peripheral nerves as well as
the muscles of interest. Amedical psychiatrist would be most the brain. A patient with significant cerebral problems may
likely to initiate an EMG study in a patient with a complaint not complain of neuropathic symptoms like numbness and
of weakness that is ascribed by the patient and/or other phy- tingling but may nonetheless have polyneuropathy, and the
sicians to either systemic illness or depression, but might presence of the polyneuropathy may be useful in the differ-
actually involve primary disease of muscle (e.g., polymyosi- ential diagnosis. For example, a patient with mental-status
tis) or the neuromuscular junction (e.g., myasthenia gravis or changes potentially due to heavy metal exposure would be
Lambert-Eaton syndrome). Disproportionate involvement of expected to show polyneuropathy as well, if the heavy metal
proximal muscles is a clue to myopathy; dramatic decline in exposure were severe enough to explain their neuropsychiatric
strength with continued exertion of a single muscle group is symptoms. Atest proving neuropathy may be useful in con-
typical of myasthenia. Neither of these is typical of the general fronting a patient who abuses alcohol or drugs; some patients
weakness and asthenia of systemic disease nor of the anergia are more effectively motivated by test results they find more
and fatigability of depression. objective than a psychological or psychiatric examination.
Nerve conduction studies involve the application of a The second special use of nerve conduction tests in medi-
discrete, standardized electrical stimulus to a specific nerve cal psychiatry is in establishing the diagnosis of an entrapment
distally and measuring the voltage over a specified proximal neuropathy with severe symptomsusually of painthat has
part of the nerve. There are well-established normal ranges been underappreciated or misdiagnosed by the patients other
for the amplitude of the proximal signal and for the interval physicians, leading to the patients experiencing significant
between the distal stimulus and the proximal responseor, emotional distress. Entrapment neuropathies, which include
considering the distance as well as the time, the nerve con- the common carpal tunnel syndrome as well as some unusual
duction velocity. Nerve conduction tests can establish damage entrapments, such as that of the infrascapular nerve associ-
to specific nerves, as from trauma, demyelination, ischemia, ated with holding an infant when breastfeeding, can cause
compression, or entrapment, as well as polyneuropathydif- pain and dysesthesia disproportionate to any obvious physi-
fuse damage to nerves throughout the body with the greatest cal sign. In such cases the nerve conduction study is virtually
effect on the long nerves to the extremities. always abnormal, often markedly so. Specific treatment to
The second special use of nerve conduction tests in medi- decompress the nerve usually follows the nerve conduction
cal psychiatry is in establishing the diagnosis of an entrapment study, frequently leading to relief of both physical and mental
neuropathy with severe symptomsusually of painthat has distress.
been underappreciated or misdiagnosed by the patients other Special EMG techniques using repetitive nerve stimula-
physicians. In the medical-psychiatric context, nerve conduc- tion may also be used to assess the neuromuscular junction
tion studies have two special uses. One is to establish that and diagnose myasthenia gravis. These patients may complain
171
psychiatric history with a particular emphasis on sleep com- sleep-disordered breathing. Detailed mental state exami-
plaints. Acute and chronic pain should be assessed in the nation should be done to rule out psychiatric issues such as
medically ill, as they are important causes of sleep distur- mood and anxiety disorders.
bances. Questionnaires such as the Stanford Sleepiness Scale
and Epworth Sleepiness scale should be used in patients to
assess the severity of daytime somnolence. Box 9.1 lists the I N V E S T IG AT ION S
important areas of assessment for thorough evaluation and
diagnosis of underlying sleep disorders.
OV E R N IG H T PU L S E OX I M E T RY
Patients are often unaware of their nighttime breath-
ing complaints, such as snoring, apneic spells, or behavioral Overnight pulse oximetry can be a useful initial screening
events such as dream enactment behaviors. Therefore, col- tool to detect repetitive oxygen desaturations >4% in patients
lateral history from a bed partner is vital to gain informa- at risk of sleep-disordered breathing. It measures only one
tion about nighttime respiratory and behavioral events. It is variable; without other data the clinician cannot correlate the
not uncommon for bed partners to have moved out of the oxygen saturation with the corresponding sleep stage, heart
bedroom because of intolerable snoring or dream-enactment rhythm, or body position (Svanborg etal., 1990); therefore, it
behaviors, so collateral information may not be available. should not be used as a definitive diagnostic method. Normal
Further laboratory investigation should likely be pur- findings on oximetry do not rule out sleep apnea, as younger
sued for adequate evaluation of sleep complaints in these patients may not have significant oxyhemoglobin desatura-
circumstances. tions with apneic episodes or, alternatively, the patient may
The physical examination should focus on body mass not have slept during the oximetry study. Patients with posi-
index, neck circumference, nasal and oropharyngeal abnor- tional (supine-dependent) apnea who happen to sleep on their
malities, cervical/supraclavicular lymphadenopathy, and sides may have normal oximetry study results.
thyroid examination. Thorough pulmonary and cardiovas-
cular examination allows assessment of the cardiopulmonary
P OLY S OM NO G R A PH Y
sequelae of sleep-disordered breathing. Neurological exami-
nation should be done to assess level of alertness, cognition, At present, the overnight polysomnographic (PSG) study
and to rule out neuromuscular disorders that may lead to conducted in an accredited sleep disorders center remains the
state of the art diagnostic procedure for evaluation of sleep
disorders. The standard procedure involves multiple monitors
Box 9.1 ESSENTIAL ISSUES IN A SLEEP DIAGNOSTIC including electroencephalogram, surface electromyogram,
INTERVIEW OF PATIENTS AND BED PARTNERS electro-oculogram, electrocardiogram, pulse oximetry, respi-
ratory airflow, and respiratory effort (Phillipson & Remmers,
Presenting complaint 1989). Continuous videotaping is helpful for assessing pos-
Previous sleep evaluations sible parasomnias or unusual nocturnal movements. Sleep
Sleep scheduleparenting issues? technologists can record body position and describe snoring
Work schedulerotating shifts? intensity. Under these circumstances patients are observed to
Nap schedulefrequent? prolonged? sleep for at least one sleep cycle with NREM and REM sleep
Exercise schedulelate in evening? in the supine and nonsupine positions.
Sleep environmentbright light? noisy? too hot/cold? PSG is the gold standard for diagnostic investigations for
Initial/middle/insomnia assessment of sleep-disordered breathing (SDB) including
Nocturnal movements obstructive or central sleep apnea syndromes. PSG is con-
Sleepwalking/somnambulism/enuresis ducted in a split-night fashion where the first half of the night
Excessive daytime somnolence is utilized to assess the nature and severity of SDB and, dur-
Motor vehicle accidents ing second half of the night, a positive airway pressure (PAP)
Cataplexy/sleep paralysis/ hallucinogenic experiences trial is applied to determine optimal PAP pressure settings for
Snoring adequate control of SDB. Other indications for PSG study
Observed apneas include excessive daytime somnolence, parasomnias, and peri-
Sleep position odic limb movements of sleep. PSG is not indicated for diag-
GI refluxdiagnosed? partially treated? nosis of restless legs syndrome.
Painchronic? acute? medications wear off? Portable monitoring can be used to assess obstructive
Erectile problems sleep apnea, and it is usually performed in the home with-
Alcohol/street drug/caffeine use/abuse/dependence out a sleep technician in attendance. Portable monitoring
Depression/mania/panic attacks includes overnight oximetry, partial cardiorespiratory stud-
Vivid dreams/nightmares ies, and a fully portable PSG with monitoring of EEG, EOG,
Prescription drug use/abuse/dependence and EMG. Portable equipment that monitors EEG is often
Family sleep history prone to malfunction due to displacement during sleep with-
Childhood sleep history.
out sleep technologists available to rectify a faulty signal. The
American Academy of Sleep Medicine recommends that
C L I N IC A L F E AT U R E S
S L E E P R E L AT E D B R E AT H I NG
DI S OR DE R S Obstructive sleep apnea (OSA) is the most common
sleep-disordered breathing disorder. It is characterized by the
Sleep related breathing disorders (SRBD) describes a group of repetitive collapse or partial collapse of the pharyngeal airway
disorders characterized by apneas (complete cessation of air- during sleep and the need to arouse to resume ventilation.
flow), hypopneas (partial cessation of airflow), or the quantity Sleep apnea is defined as a period of 10 seconds or more with no
respiratory movement. Hypopnea is a similar period of abnor-
Box 9.3 CAUSES OF INSOMNIA mally slow or shallow respiration, insufficient for normal gas
exchange. OSA can occur at any age, with a greater prevalence
Primarily Medical in males than in females (4% vs. 2%). The steepest prevalence
increase is in the transition from middle to old age. At younger
Obstructive sleep apnea (less common than hypersomnia) ages it is more common in African-American patients.
Central sleep apnea High-risk patients for OSA include those who are
COPD obese or being considered for bariatric surgery, those with
Asthma treatment-resistant hypertension, diabetes mellitus type II,
Gastroesophageal reflux atrial fibrillation, pulmonary hypertension, congestive heart
Peptic ulcer disease failure, and stroke (Epstein etal., 2009). Box 9.4 summarizes
Hyperthyroidism
Cardiac
Arrhythmias P O S I T I V E A I RWAY PR E S S U R E T H E R A PY
Hypertension PAP therapy is the treatment of choice for mild, moderate,
Right heart failure and severe OSA and should be offered as an option for all
patients. PAP may be delivered in continuous (CPAP), bilevel
Gastrointestinal (BPAP), and auto (APAP) modes. PAP is applied through
Gastroesophageal reflux nasal, oral, and oronasal interface. The treatment for OSA
has been revolutionized by the use of CPAP therapy in the
Renal last few decades. This treatment involves delivering pressur-
ized air (ranging typically from 5 to 20cm of water pressure)
Nocturia to the sites of upper airway blockage (generally oropharynx,
less commonly nasopharynx) and forcing the airway open.
Apneas and snoring are eliminated, allowing the patient to
sleep continuously without arousals. The CPAP device is gen-
the diagnostic criteria of this common disorder. Box 9.5 out- erally introduced during overnight polysomnography (PSG)
lines the medical complications of OSA. study in the sleep lab, where staff can adjust the CPAP pres-
sures appropriately.
Bilevel (BPAP) therapy represents a modification of
DI AG NO S I S
CPAP where the positive pressure fluctuates depending on
Comprehensive sleep history in a suspected OSA patient whether airflow is inspiratory or expiratory (Hillberg &
includes assessment of symptoms including snoring, wit- Johnson, 1997). Bilevel pressure is considerably more expen-
nessed apneas, gasping/choking episodes, and daytime drows- sive and is reserved for patients who cannot tolerate CPAP.
iness. Subjective assessment of daytime sleepiness can be done Automated positive airway pressure(APAP)devices, which
by using scales including the Epworth sleepiness scale and can continually optimize positive airway pressure, can be
the Stanford sleepiness scale. Physical examination findings used in self-adjusting mode for unattended treatment of mod-
in OSA patients include increased neck circumference, BMI erate to severe OSA in the absence of medical comorbidities
>30 kg/m2, modified Mallampati score on the oropharyn- (Morgenthaler et al., 2006). Supplemental oxygen alone is
geal exam of 3 or 4, presence of retrognathia, macroglossia, inadequate for OSA, and patients with both OSA and intrin-
enlarged tonsils, elongated/enlarged uvula, and nasal abnor- sic lung disease who have persisting hypoxia despite CPAP
malities (polyps, septum deviation). may benefit from supplemental oxygen delivered via the
The accepted objective measures of OSA diagnosis CPAP mask.
include in-laboratory polysomnography (PSG) and home PAP treatment ideally involves a multidisciplinary care
testing with portable monitors (PM). PM is not indicated team including a sleep specialist, referring physician, nursing
in patients with major medical comorbidities including, but staff, sleep technologist, and respiratory specialist. Patients
not limited to, congestive heart failure, moderate to severe should be educated about the function and the benefits of
pulmonary disease, neuromuscular disease, and those with PAP treatment, care of the equipment, and potential prob-
a comorbid sleep disorder such as narcolepsy or nocturnal lems including leakage through the PAP interface, claustro-
myoclonus (Collop etal., 2007). Respiratory events in OSA phobia due to the PAP interface, and dry mouth or nasal
comprise primarily obstructive apneas and hypopneas, which congestion which may lead to PAP noncompliance. Close
are characterized by cessation or reduction in airflow with follow-up in the first few weeks with trained healthcare
ongoing respiratory effort. Based on the apnea/hypopnea providers is indicated to establish effective PAP usage pat-
index (AHI) derived from diagnostic study, OSA is divided terns and remediate problems if needed. After initial PAP
into categories of severity:mild (AHI=515 events per hour), set up, long-term follow-up is recommended on a yearly basis
moderate (AHI=1530 events per hour) and severe (AHI>30 and as needed to troubleshoot PAP-related issues (Kushida
events per hour). etal., 2006a).
Essential Signs/Symptoms
R E S T L E S S L E G S S Y N DROM E A N D
PE R IODIC L I M B MOV E M E N T S 1. Unpleasant nocturnal sensation in the legs or difficulty fall-
ing asleep.
Conditions
Barbiturate withdrawal
Box 9.6 DIAGNOSTIC CRITERIA:PERIODIC LIMB
Anticonvulsant withdrawal
MOVEMENT DISORDER
Benzodiazepine withdrawal
Iron deficiency anemia
1. Insomnia or excessive sleepiness. The patient can be symp-
tomatic with the movements noted by an observer.
Medications
2. Repetitive, highly stereotyped movements usually involving
Tricyclic antidepressants
extension of the big toe with partial flexion of the ankle,
Caffeine
knee, and sometimes hip.
Lithium
Adapted from American Sleep Disorders Association (1997), The Phenothiazines
International Classification of Sleep Disorders, Revised:Diagnostic and coding
manual. Rochester, MN. Selective serotonin reuptake inhibitors.
T H E R A PEU T IC MODA L I T I E S
10.
PSYCHOTHER A PEUTIC PR INCIPLES A ND TECHNIQUES
PR I NC I PL E S OF M E DIC A L P S YCHOT H E R A PY
Stephen A.Green
191
According to the biopsychosocial model, pathologic social environment. This determines how, and to what extent,
mood states that exist concurrently with medical illness may they react affectively to a particular loss of health.
be predominantly biological or psychological in origin. For Whether illness is experienced in the literal sense, as a
example, the biological model advocates that depression is result of concrete physical restrictions, or more symbolically,
the symptomatic and behavioral expression of abnormalities due to implied or anticipated limitations, it promotes the same
associated with central nervous system biogenic amines, and psychological responsea grief reaction during which patients
that appropriate treatment requires use of pharmacological mourn the loss of their previous state of health. The process is
agents that influence neurotransmission. The psychological akin to bereavement. Illness obliges one to acknowledge and
paradigm suggests that dynamic interaction of unconscious, confront a diminished level of functioning, causing indi-
preconscious, and conscious thoughts and feelings produce viduals to progress through a series of feeling statesdenial,
psychic conflict that may result in depression, and that treat- anxiety, anger, depression, helplessnessbefore resolving the
ment rests heavily on a comprehensive study of the patients various emotions precipitated by their loss.
illness dynamics (Green, 1985)that is, the varied psycho- This is most obvious during a medical emergency, such as
social factors affecting, and affected by, the patients organic an acute appendicitis. The gravity of the initial pain caused by
pathologyinformation which is then incorporated into an an inflamed appendix, which may be quite severe, is often dis-
individualized psychotherapeutic approach. missed as indigestion or the effects of an enterovirus. Other
As this chapter discusses, psychotherapy is generally clas- feelings supplant the early denial as the significance of the
sified as a supportive or introspective treatment. The former symptoms becomes clearer. Anxiety emerges as patients rumi-
attempts to minimize emotional distress; one such treatment nate about the morbidity (and possible mortality) of surgery,
is a patient support group. Introspective therapy, on the other as well as their need to abdicate considerable responsibility for
hand, seeks to compel patients to actively confront and grap- their well-being and comfort to anonymous caretakers. This
ple with disturbing feelings in an effort to gain better affec- anxiety can persist during the recuperative period, focused
tive control; insight-oriented psychotherapy is the prototype on such issues as the restrictions and length of convalescence;
intervention. There are many variants of these therapeutic however, emerging resentments usually predominate during
approaches (American Psychiatric Association, 1996), each this stage, prompting patients to discharge their anger on
emphasizing different methods for resolving distressing psy- family members, friends, and even medical personnel who
chological states. For example, cognitive therapy attempts to provide succor and support. These feelings eventually give way
modify irrational beliefs and distorted perceptions toward the to a period of helplessness and overt depression, characterized
self and the environment, while interpersonal therapy seeks to by mood, behavioral, and cognitive changes, when one is most
define and explore specific stressors, such as social isolation, in aware of the losses brought on by a surgical emergency that
order to minimize their regressive impact. However, all psy- has relegated all other activities (e.g., professional and social
chotherapies ultimately are based in a supportive or introspec- responsibilities) to positions of secondary importance. Most
tive orientation, which can be administered on an individual patients emerge from this phase, progressively reestablishing
basis or in broader settings such as couples, family, or group an emotional equilibrium by working through all of the feel-
therapy. How individuals react emotionally to their illness ings precipitated by illness. This requires their appropriate
determines whether supportive or introspective psychother- assessment of the specific limitations caused by their disease,
apy is indicated for the treatment of pathologic mood states as well as a general acknowledgment of their vulnerabilities
that exist concurrently with a medical illness. and ultimate mortality.
An abnormal emotional response to illness occurs when one
is unable to effectively grieve the losses caused by ill health. For a
R E S P ON S E S TO I L L N E S S variety of reasons idiosyncratic to a particular individual dur-
ing a particular period of life, the patient may be unable to rec-
Impaired health, whether it takes the form of a mild upper ognize, experience, and put into proper perspective some or
respiratory infection or a life-threatening cerebrovascular all of the feelings precipitated by illness. That individual may
accident, is a universal condition that precipitates a predict- completely deny all emotions, or, more commonly, experience
able emotional response: illness is experienced as a lossspe- a specific mood to the relative exclusion of all others. In effect,
cifically, the loss of healthbecause it diminishes ones level the patient becomes mired in some phase of the grief process,
of functioning. This is most obvious when serious ailments preoccupied with the feelings characteristic of that stage. This
permanently and profoundly change an individuals physi- forestalls attainment of an emotional resolution regarding the
cal status, such as the severe restrictions caused by blindness. loss of health, a situation that can evolve into an emotional
However, even a limited illness may precipitate considerable state similar to pathological grief whose symptomatic expres-
feelings of loss due to the symbolic significance to the patient. sion may take the form of a mood disturbance (e.g., excessive
In addition to challenging omnipotent wisheshighlighting anxiety and/or depression), a behavioral disturbance (e.g.,
ones vulnerability to physical ailments whose onset, course, compulsive eating or substance abuse), or impaired object rela-
and response to treatment are often unexplainable and unpre- tionships (Brown & Stoudemire, 1983). Subsequent effects on
dictablean episode of ill health conveys specific symbolic somatic functioningwhich may aggravate the initial organic
meaning that derives from the highly personalized interplay pathologyderive from mind-body interactions. Because of
between patients physical pathology, intrapsychic life, and this interdependence, affective resolution of the loss of health is
A
dvances in healthcare technology, more medical treat- Research on families and health has led to the following
ment options, and more choices for improved lifestyle general conclusions: (1) family relationships have a power-
have contributed to longevity and more patients liv- ful influence on health, as great as that of well-known bio-
ing with chronic illness and disability. The extended period medical risk factors; (2)marriage is the family relationship
of time spent with disability or chronic illness has profound with the greatest impact on health for adults; (3)the most
effects on the lives of loved ones caring for and living with important type of support provided by families is emotional
such patients (Schulz & Beach, 1999). The ways in which a support; and (4) the adverse effects on health of critical or
patients family of caregivers, in turn, deal with illness has hostile family relationships are of greater magnitude than
a significant impact on the course and outcome of that ill- the beneficial effects of positive or supportive relationships
ness. It is important to understand this reciprocal relation- (Campbell, 2003).
ship between illness and family coping in order to assess the Families influence health by a variety of different path-
patient and social situation and to provide appropriate family ways. In addition to sharing genes that are risk factors for dis-
interventions. eases or influences on the effectiveness of treatment, families
The goals of this chapter are to provide an overview of the that live together share exposure to infectious agents, noxious
impact of illness on families, to provide evidence for the benefit environments, or toxic substances. Behavioral patterns rel-
of family intervention for medially ill patients and families, to evant to health such as smoking, eating habits, exercise, and
describe a model of family assessment that can guide relevant adherence to prescribed medical treatments tend to be shared
treatment options, and to present a family intervention approach within families. Finally, family relationships also can affect
that is applicable in a wide range of clinical circumstances. physical health via neuroendocrine and psychoimmunologic
mechanisms (Campbell, 2003).
There are a wide variety of responses by family members
T H E I M PAC T OF I L L N E S S to chronic illness in their loved ones, ranging from functional
ON T H E FA M I LY adaptation to significant dysfunction. More than one-half
of families caring for the chronically ill manage the bur-
Numerous studies have evaluated the impact of a wide range den effectively (Rabins, Fitting, Eastham, & Fetting, 1990).
of illnesses on families and caregivers. These include car- Such families are able to adapt to changing circumstances
diovascular disease (Coyne et al., 2001; Gallo et al., 2003; and are able to balance the needs of individuals and the fam-
Rohrbaugh, Shoham, & Coyne, 2006), diabetes (Fisher, ily system so as to ensure the familys well being. Afamilys
Chesla, Skaff, Mullen, & Kanter, 2002) cancer (Cliff & response to the illness of a member depends more on that
MacDonagh, 2000; Manne, Norton, Winkel, Ostroff, & familys functioning than on the nature of the illness. In gen-
Fox, 2007; Northouse, Mood, Templin, Mellon, & George, eral, the perceived impact of the illness on significant others
2000; Rolland, 2003; KL Weihs, Enright, T., & Simmens, is not dependent on the type of chronic disease (Baanders &
2008), gastrointestinal disorders (Baanders & Heijmans, Heijmans, 2007). More important is the adequacy of the fit
2007), fibromyalgia (Bigatti & Cronan, 2002), neurological between the psychosocial demands of the illness, the familys
disorders (De Ridder, Schreurs, & Bensing, 1998; Helder coping style, and the availability of adequate resources.
etal., 2002), rheumatoid arthritis (Riemama, Taal, & Rasker, A biopsychosocial perspective of the familys situation
1999), chronic pain (Margolis, Merkel, Tait, & Richardson, ensures that the biological, psychological, and social com-
1991), hemodialysis (Kimmel et al., 2000), and dementia ponents impacting the family are sufficiently evaluated.
(Vitaliano etal., 2001). Biological parameters include the nature of the illness, physi-
Instead of detailing the unique problems associated with cal limitations, and current pharmacological treatments.
each of such a wide range of disorders, it is more useful to find Psychological parameters include the meaning of the illness
common factors that most families experience while deal- and its specific symptoms to the patient and to the family,
ing with illness. Understanding the nature of such general habitual ways of coping with difficulties, personality styles,
stresses should allow for thinking of commonalities in family frustration tolerance and impulse control, intellectual func-
treatment approaches. tioning, insight, and spirituality. Social parameters include
205
interpersonal and family relationships, social connections categories:psycho-educational and relationship-focused. The
and support systems, work functioning, and other situational goals of psycho-educational interventions are to increase
stresses. Such a comprehensive evaluation leads to a biopsy- knowledge about the illness and to teach patients and family
chosocial formulation that is shared with the patient and members more effective ways of managing it. Skills training
family as a foundation for developing an appropriate treat- includes lifestyle modifications relating to diet and exercise,
ment plan. learning skills to monitor the illness such as blood pressure
A basic task for families dealing with chronic disorders monitoring, and supporting adherence to prescribed medi-
is to create ways of understanding the illness that allows the cal treatment (DiMatteo, 2004). Relationship-focused inter-
family to retain a sense of competence and mastery (Rolland, ventions attempt to directly improve family functioning
2003). Rolland (2003) has described a family systems health by helping families to communicate more effectively, solve
model for the assessment of and intervention with families problems, resolve conflicts, and develop a greater sense of
facing chronic and life-threatening disorders. This model cohesiveness. These interventions also include some degree of
identifies three dimensions: psychosocial types of disorders, education about the illness and discussion of more effective
major phases in the natural history of the illness, and key fam- illness-related coping skills.
ily system variables. Two meta-analyses of family/psychosocial interventions
Psychosocial types of illness refer to the demands on the for adult patients with chronic illnesses have been published
family made by the varying nature of disorders. Some illnesses (Hartmann, Bazner, Wild, Eisler, & Herzog, 2010; Martire,
have an acute or gradual onset. Illnesses can be progressive, Lustig, Schultz, & Miller, 2004). Martire etal. (2004) used
constant, or relapsing -remitting. Outcomes can be hopeful meta- analysis to focus on the benefits of interventions that
or terminal. Different phases of illness (crisis, chronic, termi- involved a family member, for patients and for family mem-
nal) also impose their own demands on the family requiring bers. Patient outcomes examined included depressive symp-
different adaptations. Key family variables that impact on the toms, anxiety, relationship satisfaction, physical disability,
familys capacity to cope effectively include the family and and mortality. Family member outcomes included depressive
individual life cycle, multigenerational legacies related to ill- symptoms, anxiety, relationship satisfaction, and caregiving
ness and loss, and belief systems. burden. Family psychosocial interventions were defined as
A family is best understood and helped by utilizing such nonmedical interventions that were psychologically, socially,
a broad conceptual framework, which takes into consider- or behaviorally oriented and that involved a member of an
ation the demands of the illness and the coping capacities adult patients family or both the patient and the family mem-
of the family. ber. All studies had to be randomized controlled trials and
A number of family characteristics have been demon- all had to include a comparison of the family intervention
strated by multiple studies to influence illness outcomes. with a usual medical treatment. Of 235 studies identified,
Protective factors include good communication, adaptability, 70 met criteria for inclusion in this analysis. The majority of
clear roles, achieving family development tasks, support for the family interventions consisted of a combination of differ-
individual members, expression of appreciation, commitment ent types of psychosocial and behavioral approaches. Most
to the family, social connectedness, spending time together, commonly these included education with emotional support
and religious/spiritual orientation (Weihs et al., 2002). or emotional support with skills training. Family members
Conversely, many risk factors for detrimental illness outcome included spouses, children, or siblings. The most common ill-
have also been identified. These include low cohesion/close- ness groups studied were individuals suffering from demen-
ness, poor family organization, inconsistent structure, poor tia, cardiovascular disease, osteoarthritis, pulmonary disease,
conflict resolution, lack of agreement about disease beliefs Parkinsons, and cancer.
and expectations, low relationship satisfaction, high conflict, Overall results showed the strongest evidence of efficacy
high criticalness, poor problem solving, and high hostility for benefits to family members, with lesser evidence for an
(Fisher, 2006). effect on the outcome of the patients disease. Family inter-
It is helpful to understand such protective and risk fac- ventions led to family members feeling less depressed and
tors in order to develop and implement family treatment less burdened. The interventions also led to reduced anxiety
approaches that modify the risk factors and enhance those in family members when the therapeutic focus was on rela-
that are effective. tionship issues between the patient and the family member.
Interestingly, the interventions did not appear to enhance the
family members satisfaction in his or her relationship with
E V I DE N C E F OR B E N E F I T OF FA M I LY the patient. The family interventions led to a reduction in
I N T E RV E N T ION S I N M E DIC A L I L L N E S S depressive symptoms in the patient only when the interven-
tions focused on spouses or couples. Family interventions also
A wide variety of family interventions have been developed enhanced patients survival, particularly for patients with car-
and tested for many medical illnesses, including dementia, diovascular disease. This was more likely to happen when the
cardiovascular diseases, cancer, diabetes, arthritis, stroke, interventions did not address relationship issues. There was
chronic pain, traumatic brain injury, systemic lupus erythe- no evidence that the family interventions reduced anxiety
matosis, and AIDS (Chesla et al., 2004). In spite of differ- or disability in patients or that they increased their relation-
ences, most family approaches can be divided into two broad ship satisfaction. Changes in patients were not dependent on
a) Problem-solving
Box 11.2 COMPONENTS OF FAMILY ASSESSMENT
b) Communications
A. Orientation c) Roles
B. Data Gathering d) Affective responsiveness
C. Problem Description e) Affective involvement
D. Problem Clarification f) Behavioral control
C L I N IC A L PE A R L S DI S C L O S U R E S TAT E M E N T
Abasic task for families dealing with chronic disorders Dr.Keitner has no conflicts to disclose.
is to create ways of understanding the illness that allows
the family to retain a sense of competence and mastery
(Rolland, 2003). R E F E R E NC E S
The key to effective family treatments is a comprehensive Baanders, A., & Heijmans, M. (2007). The impact of chronic diseases.
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Beavers, R., & Hampson, R.B. (1990). Successful families:Assessment and
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healthcare use, and psychological wellbeing of spouses of people with
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K. (2004). Family and disease management in African-American
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weaknesses. and quality of life of chronically ill patients. The case of Parkinsons
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often therapeutic in and of themselves. Care, 43(3), 200209.
Epstein, N.B., Baldwin, L.M., & Bishop, D.S. (1983). The McMaster
The therapist should not try to persuade or entice the family assessment device. Journal of Marital and Family Therapy,
family into treatment. 9(2), 171180.
Fisher, L. (2006). Research on the family and chronic disease among
It is useful to limit, to two or three at a time, the number adults: Major trends and directions. Families, Systems, and Health,
of changes that any family member expects from others. 24(4), 373380.
I N T RODUC T IO N 23.5 million adults over 20 years of age that have diabetes
in the United States alone. If we subtract the 12.2 million
The challenges experienced as a result of a serious illness are U.S.adults over 60years old with diabetes we see that roughly
usually not isolated to the individual with the illness alone. 11.3million U.S.adults between the ages of 20 and 60 have
Often the innermost sphere of relationships is very much diabetes. This age group includes the most common ages
affected in both emotional and practical ways, typically for having and raising children. According to Halle (2002)
including the nuclear family. Mounting evidence documents and collaborators, data from the National Health Interview
the distress that both adult family members and dependent Survey of 2000 indicates that 84% of males and 86% of
children experience when a loved one is sick and/or going females over 45years old have had at least one biological child.
through rigorous treatment (Armistead, Klein, & Forehand, Although these numbers are not specific to males/females
1995; Braun, Mikulincer, Rydall, Walsh, & Rodin, 2007; with diabetes, it is safe to assume that there are millions of
Northouse etal., 2007). parents with diabetes in the U.S.
A number of serious, sometimes fatal, conditions can
affect individuals in their childbearing and child-rearing
H I V/A I D S
years, and parents may actually experience greater distress
than nonparents with the same conditions (Bloom & Kessler, Schuster etal. (2000) also describe that an estimated 28% of
1994; Rauch & Moore, 2010). After all, parents must con- US adults with HIV have dependent children. An even larger
tend with the stress of the illness and treatment as well as the proportion of adults with HIV are parents generally speak-
ongoing responsibilities of caring for dependent children. By ing, as this estimate does not include parents who have young
considering the number of serious illnesses that afflict adult adult children.
patients at child-rearing age, the scale of illness impact on Looking only at these three illness categories quickly
families is more clearly seen. Examining a few illnesses and demonstrates that a significant number of parents and their
some associated statistics helps bring the issue to life more families are affected by serious illnesses. If all serious illnesses
concretely. were to be considered, the number of parents whose families
must contend with the challenges of illness is certainly in the
millionsjust in the United States alone. Clearly this is a
C A NC E R
large public health issue, as the effects on parents, children,
At least 18% of recently diagnosed cancer patients, and 14% of and family units can be several and severe at times.
all cancer survivors, are parenting minor children. This trans-
lates to more than 1.5million cancer survivors having close
to 3million children at home (Weaver, Rowland, Alfano, & C L I N IC A L GU I DA N C E F OR T H E PA R E N T
McNeel, 2010). Over half a million of these children are liv-
ing with a parent in the early stages of cancer treatment and Parents with serious illnesses often worry about how their
recovery. These data underestimate the numbers of affected children could be affected by their illness almost immediately
children, most notably by omitting noncustodial parents after diagnosis. In fact, for some ill parents, worries about
and children who have already experienced a parents death their children are pronounced, distressing, and may even
from cancer. Furthermore, the cutoff of 18years that defines affect treatment decisions (Duric & Stockler, 2001; Yellen &
minors does not reflect the ongoing need for substantial par- Cella, 1995; Muriel etal., 2010).
enting support for older adolescents and young adults (Rauch As healthcare providers, learning more about these paren-
& Moore, 2010). tal concerns is the first step to caring for this aspect of a
patients psychosocial needs. Providers can begin by routinely
asking all adult patients if they are parents and, if so, learning a
DI A BE T E S
bit about each of their children in terms of age, temperament,
The Center for Disease Control and Preventions most recent functioning, coping abilities, specific challenges, and so forth.
National Diabetes Fact Sheet (2007) reports that there are Parents usually like discussing their children. A providers
218
open-ended inquiry, such as, Tell me about your children, art classes. Jason is the star soccer player of his team, generally
can often enhance the relationship between provider and active, athletic, and a doer instead of a talker. Davids diabe-
patient while eliciting important information. Asking parents tes was of insidious onset and was discovered by his primary
directly if they have any concerns about how their illness may care provider (PCP) after presenting with polyuria. David tried
affect their children can elicit the parents primary concerns to check his blood sugars regularly from the beginning, and
and can potentially identify children at risk of needing addi- usually did so at least once a day. Despite some small improve-
tional support. Once the parents concerns are understood, ments in diet and beginning intermittent exercise a few times
customized interventions can be designed and implemented. a week, his sugars remained fairly high. He had frequent
Clinical experience suggests that there is no simple formula follow-up appointments with his PCP, and about 12years ago
to predict the effects of an individuals illness on loved ones; he was placed on Metformin, which he took regularly twice a
therefore, there is no one-size-fits-all intervention that can be day. However, his blood glucose levels tended to remain high.
broadly applied. However, some of the variables that influence About 10years ago he was referred to an endocrinologist
and mitigate the effects of an illness within a family can be who specializes in diabetes, and he was started on insulin
considered for each family, allowing for personally relevant injections 3 times a day. He has had a number of appoint-
assistance. Some of these variables relate to features of the ments with other specialists over the years for monitoring of
illness itself, and others to the families and family members other possible sequelae of diabetes. He sees an ophthalmolo-
affected. Many of these variables are discussed in this chapter, gist regularly, and more recently he had several appointments
as are ways in which the healthcare team can consider them with a podiatrist after a small foot ulcer was slow to heal. He
when providing personalized assistance. often has low energy and feels sluggish. He recently had a sei-
zure that was witnessed by both children after he took insulin
before breakfast, which was then unexpectedly delayed.
C A S E E X A M PL E S It can be helpful to have an organizing framework when
considering the impact of a parents serious illness on the fam-
Throughout this chapter, two case examples will be used to ily system and the children. The same framework can also guide
illustrate many of the illness and family variables, along with interventions with parents to support family functioning and
the guiding principles for clinicians. The basic histories of the childrens normal development. Rollands Family Systems illness
two patients and their families are described below, and addi- model (1999), which emphasizes the goodness of fit between the
tional information will be provided throughout the chapter psychosocial demands of the disorder and the strengths and vul-
as relevant. nerabilities of the family, provides such a framework and will
guide the following discussion. Rolland describes three lenses
through which families facing medical illness can be helpfully
PA NC R E AT IC C A NC E R
assessed:the developmental stage of the family, the developmen-
Kelly OBrien is a 45-year-old female diagnosed 2months ago tal phase of the illness, and the psychosocial aspects of the ill-
with unresectable stage III pancreatic cancer after evaluation ness. The developmental stage of the family refers to the relative
for back pain and a 15-pound unintended weight loss. She age of the familyfrom pre-parenthood, through the ascend-
and her husband Jim have three children:an 8-year-old son, ing ages of children, into their young adulthood. The develop-
Connor; a 6-year-old daughter, Brianna; and a 3-year-old son, mental phase of the illness is delineated into the crisis, chronic,
Michael. Kelly has received two rounds of chemotherapy with terminal, and survivorship phases. Psychosocial aspects of the
gemcitabine and experienced some nausea, fatigue, and thin- illness include acuity of onset; a progressive, constant, or relaps-
ning hair. She knows that her lowered white blood cell count ing course; the degree of incapacitation; the illness outcome; and
leaves her particularly susceptible to infections. the predictability of the illness. Each lens interacts with the oth-
Kelly works part-time as a bookkeeper for Jims business ers and, considered together, they create a nuanced description
from home, but she sees caring for their children as her pri- of the familys challenges.
mary job. She notes that Connor has had challenges in
school since kindergarten, and was recently diagnosed with
ADHD and a reading disorder at the beginning of this school DE V E L OPM E N TA L S TAG E
year, making him eligible to receive supportive services at OF T H E FA M I LY
school. Brianna is like a little mother sometimes, both boss-
ing her brothers around and looking for ways to make Mom Parent guidance is most helpful when the uniqueness of a
feel better. Michael is all boy, loud, active, exuberant, and familys identity is considered. The familys current stage
increasingly difficult for Kelly to manage. along the life cycle affects the developmental tasks and impor-
tant issues the family faces. For example, some stages require
intense bonding and high cohesion, while others call for loos-
DI A BE T E S
ening the external family boundary as personal identity and
David is a 50-year-old male with a 15-year history of diabe- autonomy become more important (McGoldrick & Carter,
tes. He and his wife Irene have two children: a 17-year-old 2003). In all stages, family cohesion, open communication
daughter, Monica, and a 13-year-old son, Jason. Monica is among all family members, and a clear family identity apart
creative, expressive, and involved in drama club and advanced from the illness are markers of good functioning.
CR ISIS PHASE CHRONIC AND SURVIVOR SHIP PHASES TER MINAL PHASE
Parent of: Focus on maintaining childrens sense of safety and Promote a sense of the family as a team, with more in Focus on making the most of the time together for
security. common than just the illness. as long as possible, and on leaving children tangible
Consistent rules and routines when possible Be mindful of how role changes impact each persons reminders of the parents love.
Identify readily available supports development. Consider setting of end-of-life care from both adult
and child perspectives.
Toddler (13) Familiar caregivers Honest assessment of what additional help with Preverbal, will have few memories of the parent
Consistent routines and micro-environment child may be required, how often, and who is Consider letters, videotaping, annotated photos
(portable crib and blankets) available from parent
Transitional objects available (blankie, stuffed Written routines for caregivers Identify people who can tell stories about the
rabbit) Prepare for toddler distress with parental absence parent as child gets older
Be patient with regression
Pre-schooler (35) Provide basic information (who and what) Be understanding about egocentric concerns and Consider letters, videotaping, annotated photos
Confirm the childs lack of responsibility for the requests from parent
illness Emerging anxieties about the world (e.g., fear of Provide notice of an imminent death, when
Specify immediate impact on child the dark, monsters) are developmentally normal known, so child has the option of a last visit
Minimize displays of strong parental emotion to but may be heightened; be prepared to seek help if Many strangers in the home may be upsetting
child they are very distressing or long-lived Be clear that adult distress is not the childs fault
Name childs emotions Be patient with regression but keep expectations
Familiar caregivers, the fewer the better consistent (e.g., use your words, not your hands)
Encourage teachers to maintain preschools
normalcy
Correct misperceptions and self blame about
parents mood or functioning
Grade-schooler (612) Provide simple, age-appropriate information Separate treatment side effects from illness Begin to discuss the idea that the parent will not
about diagnosis and treatment progression get better
Clarify risk of contagion Clarify risk of contagion Plan how to answer, Will you die?
Specify short-term impact on child Childs distress will often be unrelated to parental Help child express love, in ways that are
Ask what has been noticed and explain childs illness; remember to inquire about childs own comfortable to child
observations individual challenges Consider impact of setting of parents care on
Minimize displays of strong parental emotion to Consider what the ill parent uniquely provides the childs access to parent and exposure to suffering
child child and save time and energy for those functions As above, consider leaving a written legacy to
Elicit, discuss, normalize childs emotions Maintain consistent school routine and child
Emphasize areas of control expectations If death is imminent, may discuss how child wants
Protect family time not focused on the illness to be notified
Adolescent (1318) Provide age-appropriate information about who, Include adolescent in discussions about role Suggestions for grade-schoolers apply
what, when, where and why changes and new responsibilities; find a fair Acknowledge the love underlying conflictual
Specify impact on child balance relationships
Ask what has been noticed and explain childs Monitor teens, watch for risk- taking behavior Demonstrate that surviving parent has ample
observations Provide enough information about expected support from other adults
Elicit, discuss, normalize childs emotions while changes so teens can make informed decisions Help adolescent make choices that will minimize
respecting privacy about the future regrets, without suggesting that they will or
Emphasize areas of control Protect family time not focused on the illness, should have regrets
Encourage reliance on friends, trusted adults for while respecting the adolescents need for time
additional support with peers
C L I N IC A L PE A R L S DI S C L O S U R E S TAT E M E N T S
243
fatigue and insomnia may then interfere with the ability to reviewing the impact of missed or delayed doses on pain con-
appraise accurately and problem-solve current stressors. This trol. Among adults with asthma, a review of optimal inhaler
case formulation highlights potential treatment targets for use and education about associations of anxiety with asthma
symptom reduction. The next section describes the basic char- physiology may improve both disease knowledge and com-
acteristics of CBT and the key interventions that may be inte- mitment to specific symptom management goals. Finally,
grated into CBT treatment plans. given the goal-oriented and active nature of CBT, therapists
must often employ treatment motivation strategies, which we
further address in the next section.
E L E M E N T S OF C O G N I T I V E
B E H AV IOR A L I N T E RV E N T IO N S
MOT I VAT ION A L E N H A NC E M E N T
CBT interventions reflect a problem-oriented, skills-based Throughout treatment, CBT therapists commonly incorpo-
approach to therapeutic change. The first one to two sessions rate techniques for monitoring and enhancing motivation
may be dedicated to collecting information about a patients for therapeutic change. Motivation is a key element in com-
presenting problems, sharing and revising the CBT case for- plex health behavior change, such as cessation of tobacco use,
mulation, and using this formulation to establish tailored changes in physical activity and dietary patterns, and improve-
treatment goals. At each subsequent therapy session, the ments in medical treatment adherence. Ambivalence may be
therapist and patient review progress via informal feedback prominent in patients who are experiencing depression-related
and relevant symptom inventories (e.g., Hospital Anxiety and anhedonia or hopelessness, or anxiety-related avoidance.
Depression Scale [Zigmond & Snaith,1983]), and set the cur- Patients also may be relying on health risk behaviors (e.g.,
rent session agenda. smoking or overeating) to cope with negative affect. Examples
Throughout treatment, the therapist encourages active of motivational techniques include collaborative treatment
collaboration with the patient serving as cotherapist. Socratic goal-setting, information provision, encouragement, feed-
questioning is used to guide patients in their own discovery back on goal progress, and treatment contracting.
of problematic patterns in thoughts and behaviors. Sessions In comparison to basic techniques, motivational interview-
typically focus on building skills that address these patterns. ing (MI) is a brief (generally 12 sessions) evidence-based com-
Patient self-efficacy is a critical concept in CBT, particularly munication method that was developed to enhance personal
for medical patients who may be facing some uncontrollable commitment to behavior change (Miller & Rollnick, 2002).
aspects of a disease or its treatment. Between-session assign- This method is based on assumptions of personal autonomy.
ments are used to practice and problem-solve the skills in A variety of strategies may be used to elicit a patients own
real-life situations. Most interventions are time-limited, with intrinsic arguments for change and to use these arguments
the intention for patients to become increasingly independent as the source of motivation. MI is goal-oriented but does not
in their use and application of CBT skills. Interventions typi- involve teaching specific skills (Miller & Rollnick, 2009). In
cally conclude with a focus on relapse prevention by anticipat- practice, MI is sometimes combined with CBT or used to
ing and problem-solving potential obstacles to the ongoing enhance entry into an intensive behavior change program. For
use of CBT skills. instance, Safren and colleagues include MI communication
In the following sections, we describe common CBT strat- strategies as a prelude to their CBT intervention for improv-
egies and other methods that may be combined with CBT. ing depression and adherence to medical treatments in adults
Rather than simply strung together, strategies are selectively with a chronic illness (Safren, Gonzalez, & Soroudi, 2008).
integrated into a cohesive treatment plan that is directly
informed by the CBT case formulation. We also provide rec-
BE H AV IOR A L AC T I VAT ION
ommendations throughout this chapter for adapting treat-
ment plans to incorporate factors associated with medical Behavioral activation (BA [Martell, Addis, & Jacobson,2001])
conditions. is a straightforward, empirically supported intervention that
was developed for depression treatment and relapse preven-
tion, which is also a core component of CBT. BA does not
P S YCHOE DUC AT ION
simply encourage patients to become more active. Rather,
Psychoeducation is a core feature of CBT interventions. At the intervention represents a collaborative effort between the
the start of treatment, a critical aim for the therapist is to therapist and patient to identify specific activities that may be
engage patients in understanding the CBT model and col- personally rewarding and that may interrupt current behav-
laborating to identify how the model applies specifically to ior/environment contingencies (e.g., impact of a patients
them. The model is an important road map to help patients social avoidance on sadness and sense of isolation). The patient
discover and evaluate associations between their thoughts, is encouraged to schedule meaningful and achievable activi-
feelings, and behaviors that may be impacting health and ties and then monitor progress throughout each week. When
quality of life. Additionally, the model may be a tool for rein- working with medical patients, therapists must consider com-
forcing areas in which patients may have personal responsibil- plicating factors such as medication regimens, functional
ity or control over chronic disease management. For instance, status, symptoms (e.g., dyspnea, pain), and daily fatigue pat-
a patient on long-acting pain medications may benefit from terns in order to plan and adapt rewarding activities. Activity
All-or-nothing thinking Placing experiences in one of two opposite categories I missed my medication dose this morning. Isimply
cant take care of myself.
Discounting the positives Deciding that if a good thing has happened, then it Ive been so fatigued since Istarted chemotherapy.
couldnt have been very important Being able to play with my nieces today without
feeling exhausted was just an aberration.
Jumping to conclusions Focusing on one aspect of a situation in deciding The reason my doctor hasnt yet returned my call is
how to understand it because she has bad news to tell me.
Mind reading Believing one knows what another person is That person is staring at me because they can tell
thinking, with very little evidence that Im sick.
Fortune telling Believing one knows what the future holds, while I am never going to be able to change my eating
ignoring other possibilities habits.
Magnifying/minimizing Evaluating the importance of a negative event, or the Being diagnosed with diabetes has limited my
lack of importance of a positive event, in a distorted whole life.
manner
Making should statements Telling oneself that one should door should have My surgery was weeks ago. Ishould be back to work
donesomething, when it is more accurate to say by now.
that one would like to door wishes one had done
the preferred thing
Labeling Using a label to describe a behavior, then imputing I cant seem to push myself to go to physical
all the meanings the label carries therapy. Imust be lazy.
Inappropriate blaming Using hindsight to determine what one should have I should have had my cough checked by a doctor a
done long time ago.
Adapted from DeRubeis, R.J., Webb, C.A., Tang, T.Z., & Beck, A.T. (2010). Cognitive therapy. In K.S. Dobson (Ed.), Handbook of cognitive-behavioral
therapies. NewYork, NY:The Guilford Press.
253
as the increased pharmacy costs for treating chronic condi- diabetes, and coronary artery disease. During a routine visit, Ms.
tions are easily offset by savings related to decreased healthcare Rs blood pressure readings were higher than normal, and her blood
expenditures (Sokol, McGuigan, Verbrugge, & Epstein, 2005). sugar was also elevated. The patient became tearful during the clini-
For most clinicians, the dramatic association between cal interview, noting that she had been feeling very stressed recently
poor prescription medication adherence and adverse medi- due to assuming the care of her grandchildren when her daughter
cal outcomes creates even greater concern than the substan- had an accident. Initially, Ms. R attributed the elevated blood pres-
tial costs to the healthcare system. In general, patients who sure readings to her increased psychosocial stress. However, upon
have low adherence to medical treatment recommendations further probing, the primary care physician learned that the patient
(both prescription and nonprescription) experience 26% was unable to provide the names and doses of her prescribed antihy-
worse outcomes, according to a meta-analysis of the scholarly pertensive medications. Moreover, although Ms. R had been regu-
literature over the past three decades (DiMatteo, Giordani, larly refilling her insulin and diabetic supplies, her prescriptions for
Lepper, & Croghan, 2002). Patients with hypertension or antihypertensive medications had lapsed for more than 2months.
coronary artery disease, for example, who are adherent to Patient Factors. To understand the reasons for nonadherence, a
prescription medications experience decreased risk of stroke, clinician working with a patient such as Ms. R may want to begin
heart failure, and cardiovascular events, as well as all-cause with an assessment of factors that are potentially within the patients
mortality (Bailey, Wan, Tang, Ghani, & Cushman, 2010; control. Indeed, researchers have observed that common barriers
Dragomir, etal., 2010; Ho, Magid, Shetterly, Olson, Maddox, to adherence include issues ranging from simple forgetfulness and
etal., 2008; Jackevicius, Li, & Tu, 2008). In fact, increasing concerns about possible side effects to more subtle, underlying atti-
adherence to a daily antihypertensive drug regimen by one tudes and beliefs regarding the severity of illness, effectiveness of the
pill per week appears to decrease stroke risk by 8%9% and medication, need for ongoing therapy, and ones confidence in fol-
mortality by 7% over a 5-year period (Bailey, et al., 2010). lowing through with complex regimens (Bartlett, 2002; National
Additionally, medication nonadherence helps to account Council on Patient Information and Education, 2007; Osterberg &
for failures of patients to achieve lower blood pressures after Blaschke, 2005). Moreover, Ms. Rs comorbid psychiatric problems
physicians prescribe increased intensity of the antihyperten- may be contributing to her difficulty in adhering to prescribed regi-
sive regimens (Ho, Magid, Shetterly, Olson, Peterson, etal., mens. Several meta-analyses have documented the strong association
2008)and may in part explain the differential survival among between depression and poor treatment adherence in patients with
African-American patients with heart failure as compared various chronic conditions, including hypertension, diabetes, and
to Caucasians (J. R.Wu etal., 2010). Similarly, a number of HIV, both at clinical and subthreshold levels for mood symptoms
adverse clinical outcomes are associated with nonadherence (J. S.Gonzalez, Batchelder, Psaros, & Safren, 2011; J.S. Gonzalez
to antiviral medications among patients with HIV, such as etal., 2008; Grenard etal., 2011). Compounding these potential bar-
disease progression, treatment resistance, and worse sur- riers are concerns about English language skills and health literacy.
vival (Bangsberg et al., 2001; Harrigan et al., 2005; Hogg Many patients with chronic medical conditions may lack the abil-
etal., 2002; Lima etal., 2007; Nachega etal., 2007). Taken ity to comprehend information and instructions regarding the fre-
together, these data underscore the importance of optimiz- quency, dosing, side effects, and course of therapy (Kalichman, Pope,
ing adherence to prescribed regimens as clinicians consider etal., 2008; Osborn etal., 2011).
salient factors to reduce the risk of morbidity, and in some
cases mortality, for patients with chronic conditions. Provider Factors. The providerpatient relationship has the poten-
tial to mitigate or exacerbate problems with medication nonadher-
ence. Arecent meta-analysis showed that patients whose physicians
B A R R I E R S TO M E DIC AT ION communicate poorly have a 19% higher risk of nonadherence than
A DH E R E NC E those whose physicians communicate well (Zolnierek & Dimatteo,
2009). Time pressures during clinic encounters, lack of expressed
A variety of patient, provider, and system-level factors poten- empathy and inclusion of patients in the decision-making process,
tially compromise adherence to medications. Given the com- as well as overestimation of adherence are key issues that may impair
plex underlying causes of nonadherence, clinicians ideally communication about prescription medications. In particular, phy-
would want to assess and consider the different types of bar- sicians often fail to consider the complexity and costs of regimens
riers patients experience in order to tailor their interventions or sufficiently describe the benefits and risks of therapy, potential
accordingly (Sabat & World Health Organization, 2003). side effects, and relevant dosing information (Choudhry et al.,
Using the case example below, we illustrate some of the vari- 2011; Ingersoll & Heckman, 2005; Osterberg & Blaschke, 2005).
ous obstacles to medication adherence that patients experi- Writing instructions down on paper, while helpful, is simply not
ence and present strategies for identifying these barriers. enough to ensure proper adherence. In the case of Ms. R, had her
physician accepted the patients explanation for the elevated blood
pressure reading without pursuing follow-up questions about the
CASE STUDY
names and doses for the antihypertensive agents or calling the phar-
Ms. R is a 61-year-old, divorced woman of Puerto Rican descent who macy, Ms. Rs nonadherence would likely have been overlooked.
receives federal disability benefits for psychiatric reasons (depression Patient-centered approaches to care that solicit individual patients
and anxiety). She meets with her primary care physician quarterly reasons for missing doses, as well as motivations and supports for
to manage her chronic medical problems, including hypertension, maximizing adherence, not only improve communication but also
Accurate assessment of adherence to drug therapy is the first Self-reported Inaccuracies relating to patient memory
step in reducing the medical risks and associated costs result- adherence Report bias (patient may purposely
(patient overestimate adherence)
ing from prescription medication nonadherence. However, interviews, Characteristics of the question and how
no single gold standard exists to evaluate this health behav- diariesand they are administered (e.g., interview vs.
ior in either clinical or research contexts, with all forms of self-report questionnaire) may affect how patients
assessment possessing various biases or errors in measurement measures) respond
Incomplete recording is common for
(J. S.Gonzalez & Schneider, 2011; Hansen etal., 2009). Even
diaries
the most reliable and direct assessments, such as patient obser- Numeracy and literacy issues could
vation or laboratory measurements of drug metabolites in body influence reporting
fluids, are imperfect. In the case of directly observed therapy,
patients may hold pills in their mouths without ingesting. Adapted from Gonzalez & Schneider, 2011.
Patient completes
initial online ACT
266
scientific exploration and the development of various hyp- DI S S O C I AT ION
notizability scales (e.g., Stanford Hypnotic Susceptibility
Dissociation refers to the ability to separate mental pro-
Scales (Hilgard, 1965; Weitzenhoffer & Hilgard, 1959;
cesses so they seem to occur independently from each other.
Weitzenhoffer, 1962)in an attempt to measure the presence
The process of dissociation is complementary to absorption.
and depth of the hypnotic experience. Later on, shorter hyp-
During hypnosis, the intense absorption characteristic of the
notizability scales were developed for use in clinical settings.
hypnotic state permits keeping out of conscious awareness
Investigations included studies of the relationships among
many routine experiences that would ordinarily be conscious,
hypnotizability, placebo response, and acupuncture, studies
by the process of nonpathological dissociation. When work-
of the differential hypnotizability of patients with psychosis
ing properly in our daily lives, dissociation allows us to carry
and other psychiatric disorders, and investigations used in
out several complex tasks simultaneously. There are a wide
determining neurophysiological correlates of the hypnotic
variety of dissociated states that range from the normal ability
state and hypnotic capacity.
to carry out simultaneous tasks to a number of psychiatric dis-
It was not until the second part of the 20th century,
orders. An example of a rather common form of dissociation
though, that the various professional associations in
is the ability to perform a high-complexity task (i.e., a surgical
Europe and North America officially recognized hypnosis
procedure) while carrying out a conversation regarding ones
as a valuable therapeutic intervention (i.e., British Medical
political views or a recent sport event. In fact, not only motor
Association, 1955; American Medical Association, 1958;
activities can be dissociated but also rather complex emotional
American Psychological Association, 1960; American
states and sensory experiences aswell.
Psychiatric Association, 1960). Since then, two professional
Dissociated affect and memories can elicit complex motor
hypnosis societies have emerged in North America: the
or pseudoneurologic dysfunction, as in the case of conversion
Society for Clinical and Experimental Hypnosis (SECH,
disorder (Maldonado & Spiegel, 2000; Maldonado, 2007).
1949), which emphasizes research in the field, and the
Complex forms of dissociation can prevent access to memory,
American Society for Clinical Hypnosis (ASCH, 1957).
resulting in dissociative amnesia, dissociative fugue, or disso-
A division of the American Psychological Association
ciative identity disorder (Maldonado, Butler,& Spiegel,2000).
(Division 30, 1968; also known as the Society of Psychological
Another, more common, example of how dissociated mem-
Hypnosis) is devoted to the study of hypnosis in the field of
ories affect patients is the hyperemesis experienced by some
psychology. In 1959 the International Society for Clinical
chemotherapy patients who experience nausea and vomiting
and Experimental Hypnosis was founded. Amore detailed
just with the sight, or sometimes the thought, of the hospi-
account of the history of hypnosis is beyond the scope of
tal (conditioned nausea and emesis). Memories that are dis-
this chapter and may be found elsewhere (Maldonado &
sociated at the time of the traumatic experience may reemerge
Spiegel,2008)
when they are triggered by external cues, as in flashbacks asso-
ciated with posttraumatic stress disorder that are often seen in
cases of traumatic experiences such as motor vehicle accidents
C OMP O N E N T S OF T H E H YPNO T IC
or traumatic surgical procedures or interventions.
PRO C ESS
I N T RODUC T IO N some people will feel attracted by the religious aspects they
are not essential for therapeutic effect. Throughout this chap-
The National Center for Complementary and Alternative ter we will attempt to show how recent research is providing
Medicine defines mindbody medicine as an approach that evidence for the effectiveness of these treatments, establish-
focuses on the interactions among the brain, mind, body ing their scientific value and facilitating their integration into
and behavior, and on the powerful ways in which emotional, mainstream medicine. There is already enough evidence of
mental, social, spiritual, and behavioral factors can directly the clinical efficacy of the mindbody techniques to make
affect health (NCCAM, 2007). Mindbody medicine may them viable options for patients who want to improve their
also be conceptualized as the scientifically based dimension of self-care.
what was once named complementary and alternative medi- The approaches of mindbody medicine will be mainly
cine (CAM). In 2007 close to 40% of Americans were using complementary to current allopathic therapies, but for some
CAM therapies and spending close to 34 billion dollars in conditions they may also be efficacious when used alone. These
out-of-pocket expenses to pay for them (Barnes, Bloom, & approaches reflect a unitary concept of mindbody integra-
Nahin, 2008; Nahin, Barnes, Stussman, & Bloom, 2009). tion and the more modern terms integrative medicine and
Mindbody therapies accounted for 17% of this CAM usage whole person medicine focus attention on caring for the person
(Bertisch, Wee, Phillips, & McCarthy, 2009). However, interpenetrating with the organism. Within this framework
mindbody medicine was never really alternative in the mindbody medicine takes center stage as it stresses a multi-
sense of the unresearched use of herbs, folk remedies, and rit- system integrative model that best comports with the organic
uals. Mindbody medicine uses the evidence-based effects of unity that is the human being.
thoughts, beliefs, emotions, and behaviors to positively influ- Perhaps mindbody medicine is best described in what
ence physical health. Francis Peabody said to graduating medical students some
The field of medicine may be thought of as having three 75yearsago:
component areasmedications, procedures, and self-care
(Benson, 1975). This has been called the three-legged stool The good physician knows his patients through and
model. In this schema mindbody medicine may be concep- through, and his knowledge is bought dearly. Time,
tualized as the self-care leg, comprising information derived sympathy and understanding must be lavishly dis-
from the subspecialty of psychosomatic medicine. To pro- pensed, but the reward is to be found in that personal
mote healing it employs an array of heterogeneous, researched bond, which forms the greatest satisfaction of the practice
techniques including relaxation exercises, meditation, bio- of medicine. One of the essential qualities of the clinician
feedback, guided imagery, hypnosis, yoga, tai chi, qi gong, is interest in humanity, for the secret of the caring of the
and autogenic training. In this chapter we will point out the patient is in the caring for the patient. (Peabody, 1927)
common elements of these techniques and the core elements
of the mindbody approach, which can all elicit the relax- It is essential for the physician to be interested in and to form
ation response (RR). The focus on a repetitive activitysuch a bond with the whole person as patient if true caring is to
as breathing, or a phrase, word, or prayerand disruption of take place.
the train of everyday thoughts and concerns are the two main
features of eliciting the RR:a physiological state of decreased
stress characterized by diminished heart rate, blood pressure, S T R E S S PH Y S IOL O G Y
respiratory rate, and oxygen consumption, along with periph-
eral vasodilatation (Benson, 1975).
DE F I N I T ION OF S T R E S S A N D DI S T R E S S
Mindbody medicine is often seen as a philosophical con-
ception of healing and health as well as a group of techniques. Being alive involves stress as a stimulus; stress requires bio-
Many techniques originated in ancient Eastern cultural tradi- logical, psychological, and social adaptations. Eustress can be
tions and may have a religious foundation based on a particu- thought of as the normal physiological workings of the liv-
lar conceptualization of human life. However, even though ing organism. It consists of homeostatic mechanisms called
305
eustasis, which can be visualized as a U-shaped curve with The efferent pathways from the central nucleus of the
suboptimal responsivity on each side of the curve leading to amygdala travel to a multiplicity of critical brain structures,
poor adaptation (Chrousos, 2009). Pathogenic stress or distress including the parabrachial nucleus (resulting in dyspnea and
occurs when homeostasis is threatened, or perceived to be hyperventilation), the dorsomedial nucleus of the vagus nerve
so, in the setting of overwhelming or sustained external and and nucleus ambiguous (activating the parasympathetic ner-
internal stressors. vous system/PNS), and the lateral hypothalamus (resulting in
Stress as distress can thus be defined as a state of dishar- SNS activation). Through reciprocal neuronal pathways con-
mony or of threatened homeostasis (Chrousos & Gold, necting the amygdala to the medial prefrontal cortex, the spe-
1992). It refers to a disruption of the dynamic equilibrium cific cognitive experience of the specific anxiety disorder will
among the persons physiological, psychological, and social differ, although fear symptoms may overlap. During panic
dimensions as a result of the perceived presence of an exter- attacks the fear is of imminent death; in social phobia, the
nal or internal threat. Alterations in the environment may fear is of embarrassment; in posttraumatic stress disorder, the
provoke a physiological response mediated by several inter- traumatic memory is remembered or reexperienced; in obses-
connected physiological networks constituting the so-called sive compulsive disorder, obsessional ideas recur and intrude;
stress response system. The stress response system is com- and in generalized anxiety disorder, anxiety is free-floating
posed of elements of the central nervous system (CNS), the (i.e., not conditioned to specific situations or triggers).
hypothalamus-pituitary-adrenal (HPA) axis, and the immune The CNS as stated above plays an essential role in the
system. Stressors, the stress system, and the stress response are regulation of the stress response. The ANS controls a wide
the three key elements in this process. array of functionscardiovascular, respiratory, gastrointesti-
Distress is accompanied by overactivity of the stress nal, renal, endocrine, immune, and othersthat are affected
response system mediated primarily by hypothalamic under conditions of stress (Chrousos, 2007). While the SNS
corticotrophin-releasing hormone (CRH), originally known activates the stress response, the PNS can dampen this effect
as corticotrophin releasing factor (CRF), and locus coeruleus and restore balance in the autonomic response.
A1-A2 derived norepinephrine (NE). Walter Cannon in The SNS efferent output flows down the intermediolat-
the early 1900s did groundbreaking work on one axis of the eral cell column in preganglionic fibers to synapse in a bilat-
stress response system, the autonomic nervous system (ANS; eral chain of sympathetic ganglia from whence postganglionic
Cannon, 1929). He focused on the sympathetic nervous system mostly NE fibers proceed to enervate vascular smooth mus-
(SNS) and its production of the flightfight response and was cle, the heart, the gut, the kidney and other organs. The SNS
first to use the term homeostasis. Hans Selye, another 20th cen- through its enervation of the adrenal medulla has a humoral
tury stress researcher, focused on the HPA axis (Selye, 1946). component resulting in the secretion of circulating epineph-
rine. The great vagus nerve is the major PNS cholinergic out-
flow tract. The ANS also contains SNS and PNS subdivisions
AU TONOM IC N E RVOUS S Y S T E M
with neuronal subpopulations that co-locate special peptide
The CNS and the peripheral ANS have sympathetic and para- transmitters. CRH, Neuropeptide Y (NPY), somatostatin, and
sympathetic components. All these systems constitute a com- galanin are co-localized in NE neurons of this type. Vasoactive
plex matrix with overlapping boundaries under the ultimate intestinal peptide, substance P, and calcitonin gene-related pep-
top-down control of the brain. This interconnected system tide co-localize within cholinergic neurons (Chrousos, 2007).
maintains homeostasis by modulating different bodily func-
tions and controlling the administration, distribution, and
H Y P OT H A L A M IC- PI T U I TA RY-A DR E N A L A X I S
use of energy. In this way the brain adapts the level of func-
tioning of different organs to global bodily demands under Activation of the HPA axis results in secretion of glucocorti-
each specific circumstance. It is constantly functioning at coids, hormones that act at many levels to modulate the bodys
varying levels of intensity, autoregulated by negative feedback energy resources and restore the body to homeostasis after acute
and feed-forward mechanisms. It can also be overactivated by disruption (Herman et al., 2003). The medial parvocellular
persistent or overwhelming stressors that make adaptation division of the paraventricular hypothalamic nucleus (PVN)
difficult. It is at this point that we talk about distress, which houses CRH neurons that release the CRH required for
can be acute in the face of an enormous stressor or chronic in adrenocorticotrophin (ACTH) secretion from the pituitary,
the setting of persistent unrelenting ones. along with arginine vasopressin (AVP). CRH is also expressed
When the stress response is activated, some functions can outside of the hypothalamus in the hippocampus, amygdala,
be stimulated, such as metabolism, cardiac output, vascular nucleus accumbens, bed nucleus of the stria terminalis (BNST),
tone, respiration, and muscle contraction. Other functions thalamus, hypothalamus, cerebral cortex cerebellum, and hind-
can be suppressed, such as the excretory system and gastroin- brain (Denver, 2009). There are at least two G-protein-coupled
testinal and reproductive activity (Tsigos & Chrousos, 2002). receptors (CRF 1 and CRF 2) that mediate CRH function-
The acute stress response is characterized by an increased heart ing. CRH binds to CRF 1 receptors in the pituitary, where
rate, increased breathing rate, increased metabolism, increased signal transduction involving protein kinase A (PKA) and pro-
oxygen consumption, and increased beta and reduced alpha tein kinase C (PKC) leads to ACTH synthesis and secretion.
brain wave activity. Chronic stress may lead to hypertension, ACTH moves through the systemic circulation, arriving at
depression, and prolonged inflammatory response. the adrenal cortex where it promotes synthesis and secretion of
Cognitive and emotional appraisal of a stressor is accomplished 2. The posterior subregions of the BST provide a prominent
as an amalgam by the brain (Lewis, 2005). Astressor is most forebrain inhibition of HPA responses.
distressing when it is perceived as such. Certain events or expe-
(Adapted from Ulrich-Lai and Herman, 2009, p.401)
riences are universally threatening, but there is a lot of room
for personification of particular threats. Depending on our
Box 17.1 CNS R EGULATION OF THE AUTONOMIC
appraisal, the mediators of the stress response may or may not
STR ESS R ESPONSE
emerge (Lazarus & Folkman, 1984). In fact, it has recently been
shown that anticipatory cognitive appraisal is an important
SNS Activation: infralimbic cortex (IL), the central amygdala
determinant of the cortisol stress response (Gaab, Rohleder,
(CeA), locus coeruleus (LC) and the ventrolateral medulla (VLM)
Nater, & Ehlert, 2005). On the other hand, the brain also
PNS Activation: anterior bed nucleus of stria terminalis
determines the physiological and behavioral responses to stress.
(aBST), prelimbic cortex (PL), dorsal motor nucleus of the vagus
The limbic system is a set of structures related to the control
nerve (DMX), nucleus ambiguus (NA)
of emotional responses, behavior, and long-term memory. Key
SNS and PNS Interactivity: nucleus of the solitary tract
structures involved include the hippocampus and the amygdala.
(NTS), paraventricular nucleus of the hypothalamus (PVN),
The amygdala, which is responsible for fear conditioning, serves
dorsomedial hypothalamus (DMH),
as a tripwire for the stress response. It has connections with
Mediation: Sympathetic outflow to preganglionic SNS in the
the prefrontal cortex (PFC), which is related to attention and
intermediolateral cell column occurs via direct innervation from
motivation and can inhibit amygdalar tone, and with the hypo-
the rostral VLM, LC and PVN, which are thought to initiate sym-
thalamus, which regulates endocrine and autonomic system
pathetic responses. The NTS in turn receives direct input from neu-
functioning. The hippocampus is a target of stress hormones,
rons in the IL, the CeA, and the PVN. Other hypothalamic regions,
and chronically increased levels of cortisol induce a structural
most notably the DMH, modulate ANS activation through con-
remodeling associated with selective atrophy and altered behav-
nections with the PVN (and possibly other descending pathways).
ioral and physiological responses (McEwen, 1999).
Parasympathetic outflow to postganglionic PNS occurs via
effector organs mediated largely by descending outputs from the
DMX and the NA and is under the direct influence of the PL, the T H E V IC IOUS C YC L E
PVN, and possibly other descending relays. The PFC regions (dorsolateral/ DLPFC, dorsomedial/
(Adapted from Ulrich-Lai and Herman, 2009, p.400)
DMPFC, ventromedial/ vmPFC, and inferior/iPFC) cooperate
to help us plan for the future and manage higher order decision
322
in humanity, for the secret of the care of the patient is in car- one another and caring for this planet (Olsen, 1996). For
ing for the patient. Visitors to the Massachusetts General Steindl-Rast the act of the spirit is caring. Spirituality in this
Hospital see these famous words etched in the lobbys marble sense is the lifeblood at the heart of medicine as well as reli-
wall. Alongside it is another famous quote of Dr. Edward gion. It attaches physicians and all of us to that spark of life
Churchill, speaking over 50years ago:Charity in the broad that can be felt, to that Ground of Being, to that breath of
spiritual sense, that is our desire to relieve suffering, is the all life one might call the Holy Spirit.
most prized possession of medicine. So a major contention Several years ago, the Swiss theologian Hans Kung gave
of this chapter is this:that clinicians and patients meet in the the annual Oskar Pfister lecture at an American Psychiatric
most spiritual of all earthly placesthe bedside. Association meeting. He implored the audience to attend to
Healing is a product not only of curing but of caring, a car- spiritual life and religious heritage in patient care. Several psy-
ing that is spiritually inspired. The word heal comes from the chiatrists have since written on the subject. One such psychia-
old English word haelen. It means not only to restore to health trist was the late Irving M. Rosen, working at the interface
by way of a cure but also to set right; to amend (American of medicine and psychiatry, who came to view spirituality as
Heritage Dictionary, 1978), as in the phrase to heal a rift a domain, a level of development of the mature and respon-
between us. In addition, to heal can mean to restore a per- sible person (Rosen, 1993). He came to the conclusion that
son to spiritual wholeness (American Heritage Dictionary, religion is man acting as the inclusive scientist searching for
1993). This form of healing is the major goal of religion. It is what is most real and lastingly valuable (Rosen, 1993). He
of interest that the root meaning of the word religion comes went on tosay:
from the Latin word religio, which can be translated as to
bind back; that is, to reattach or to restore. The whole person is one . . . who can find meaning;
This theme of restoration and reattachment is at the core come through suffering, commit to trust and love
of human spiritualitya uniquely human capacity for con- and deal effectively with stress and the stress emo-
solation in response to the awareness of separation and loss. tions of anxiety, anger, guilt, shame, and grief. From
Both religion and medicine are formal human structures this matrix there emerges the Witnessing Self able
within which human spirituality can be given expression by to apply the powers of meditation and finally to reach
offering care and consolation. a sense of compassion and unity with the universe,
Paul Tillich and T.S. Eliot characterized the 20th century the ultimate goal of meditation. We can help our
as an Age of Anxiety, and so far there is little evidence that patients by seeing and affirming these issues or helping
the 21st century will become anxiety free. Tillich believed the patients to grow in them. The cognitive aspect of
modern humanity was marked by a sense of disconnection, of spirituality is accessible to our understanding and use.
separation from a spiritual source of lifes meaning and pur- There is also an energy aspect, the Spirit or spark of
pose, from what he called our Ground of Being, a term he life that can be felt, but Ithink we need to learn more
essentially used for God (Tillich, 1951). Nevertheless, most about it if it is to be controlled and used in helping
Americans believe in a Ground of Being. This percentage (Rosen, 1993p.77).
has remained steady in polls taken over many years at 92%
to 96%. While the percentage of Americans who believe In an effort to integrate spirituality into medical care,
institutional religion is essential to their lives has dropped a recent consensus conference, Improving the Quality of
from 75% to 58%, the percentage reporting that spirituality Spiritual Care as a Dimension of Palliative Care, recom-
is essential has risen from 58% to 76%. The clear message is mended the following definition of spirituality:
that God, spirituality, and even religion remain important
sources of understanding and solace for most patients in the Spirituality is the aspect of humanity that refers to the
United States. way individuals seek and express meaning and pur-
pose and the way they experience their connectedness
to the moment, to self, to others, to nature, and to the
DE F I N I T ION S OF S PI R I T UAL I T Y significant or sacred (Puchalski etal., 2009, p.887).
One of the obstacles to bringing religious and medical healing This definition includes the critical elements of connect-
together has been the challenge of defining spirituality. One edness, meaning, and the search for the significant and the
consensus, from the Fetzer Foundations 2003 conference on sacred in life. These elements have theological, philosophical,
Spirituality in Palliative Medicine, has focused on spirituality empirical, and clinical dimensions. From the clinical and pub-
as a connection to something larger than oneself that gives lic health points of view, it is important to realize that spiritu-
meaning to ones life (Fetzer Institute, 2003). ality thus understood will intersect with modern concepts of
The word spirituality comes from the Latin word spiritus, health-promoting human resiliency, which emerges from neu-
meaning breath. The Benedictine monk and psychologist robiological substrates in the brain, motivation and reward
Steindl-Rast defined spirituality as alivenesssuper alive- circuitries, and paralimbic cortices that have the capacity to
ness. . . . Its the breath of all of creation. Whenever we are inhibit amygdalar fear conditioning.
alive, on every level, we are spiritual, and we are fully spiri- The Consensus Conference recommended implementa-
tual when we come alive on the highest level of our caring for tion of an inpatient spiritual care model that would include
Community
providers; Family
& Friends
Re-evaluate
Treatment
Plan
Key
Patient process Transformative Interprofessional
interaction collaboration
BCC: Board certified Chaplain
Clinicians: Chaplains, physicians, nurses, social workers
Community providers: community religious leaders, spiritual director, pastotal and community
counselors, faith community nurses, physical therapists, occupational therapists, and others
Figure18.1 Proposed Spiritual Care Implementation Model. (From Puchalski etal., 2009)
A. Substance Abuse
Desmond, 1981 248 males with opiate religiously Those enrolled in long-term based treatment-significantly more
abstinence (45% vs. 5%) from addiction to opiates over a year of
Dependence follow-up, religiosity predicted lower alcohol and tobacco use
Adlaf & Smart, 1985 2066 High school students More religious, less alcohol use
Amoateng & Bahr, 1986 16,130 High school students More religious, less alcohol use
Moore etal., 1990 1014 Male med students Lack of religious affiliation-strongest predictor of subsequent
alcoholism in subsequent 16years
Koenig etal., 1994a 2969 ECA participants Weekly church attendance led to 29% of the risk of alcoholism
during 6months compared with less frequent attenders
Kendler etal., 1997 1902 White female twins Religiosity predicted lower alcohol and tobacco use
Craig etal., 1997 101 Male VA patients 85% of those with no religious preference or non-mainstream
preference had poor outcomes in a 12-step alcohol rehab program
at 1year follow-up while 63.3% (Protestants) and 70.1% (Catholics)
had good outcomes
B. Illness Coping and Life Adjustment
Cook & Wimberley, 1983 145 Parents of child cancer victims 80% comforted by religion:40% with Religious commitment.
Better physiologic and emotional adjustment
Conway, 19851986 200 Elderly families 91% used prayer to cope with medical illness; 86% thought of God
or religiousbeliefs to cope
Kaczorowski, 1989 114 Advanced cancer State and trait anxiety correlated with (c/w) patients spiritual
well being (sex, age, use of support groups controlled for)
Burgener, 1994 135 Dementia caregivers (1)Religious attendance significantly c/w general well-being
and social functioning;
(2)When spiritual needs met, mental health improved and
caregiver stress decreased
(continued)
C. Psychiatric Illness
Williams etal., 1991 720 Adults Psychological distress inversely c/w religious attendance (age, sex,
education, marital status, gender, race controlled for)
Koenig etal., 1992 850 Hospitalized veterans Religious coping inversely c/w both self reported and observer
measured baseline depression (p<.001) and depression risk at
future hospitalization
Koenig etal., 1994b 2679 ECA participants Church attendance c/w rates of psycho-pathology
Kendler etal., 1997 1902 White female twins Religiosity predicted a lower risk of current or lifetime depression
Koenig etal., 1998 94 Elderly medical ill Intrinsic religiosity (religious belief or experience) but not
church attendance or private religious activities significantly and
independently predicted shorter time to remission of mild to
moderate depressive disorder
D. Medical Illness
Hannay, 1980 1344 Outpatients Monthly religious activity significantly c/w reduced medical
(p<.001) mental (p<.001) and social (p<.001) symptoms
Byrd, 1988 393 CCU Patients 192 patients received intercessory prayer from prayer groups; 201
patients were un-prayed-for controls, prayed-for patients had better
outcomes withless
(1) Cardiac arrest (3 vs. 14, p<.02)
(2) CHF (8 vs. 20, p<.03)
(3)Pneumonia (3 vs. 13, p<.03)
(4)Antibiotics need (3 vs. 17, p<.005)
(5) Intubation need (0 vs 12, p<.002)
Idler & Kasl, 1992 2812 Elderly Religiosity was inversely c/W subsequent disability (p<.0013) and
c/w improved function (p<.0014) in this prospective study
Benson etal., 2006 post- CABG: In? of prayer group, complications in 52%
E. Mortality
Comstock & Partridge, 1972 91,909 Individuals At least weekly church attendancec/w:
(1) 50% fewer deaths from coronary artery disease (CAD)
(2) 56% fewer deaths from emphysema
(3) 75% fewer deaths from cirrhosis
(4) 53% fewer suicides
(continued)
Table18.1(CONTINUED)
Enstrom, 1989 Mormon men Mormons had half the cancer and heart disease rates of control
populations
Gardner & Lyon, 1982 Mormon men Highly observant Mormons had half the rates of cancer and heart
disease as less observant Mormons
Berkel & de Waard, 1983 Seventh Day Adventists Adventist men lived 9years and women
4years longer than general population.
Adventists had 50% fewer neoplasms,
41% fewer episodes of cardiac disease
Zuckerman etal., 1984 225 Elderly, forced to move In a 2-year prospective study religiously committed had twice the
survival rate
Schoenbach etal., 1986 2059 In church Participants c/w lower mortality risk from cardiac disease in
persons 60years of age
Goldbourt etal., 1993 Jews In a 23-year study, Orthodox Jews had a 20% lower mortality from
coronary artery disease than did other Jews
Oxman etal., 1995 232 Elderly patients Those with strong religious coping leading to comfort more likely
to survive 6months post- operative. Mortality rate three times as
high in those without religious strength. Mortality rate 12 times
higher in those without religious strength who are also socially
isolated
Strawbridge etal., 1997 5286 Individuals Weekly church attendance over 28years of study c/w improved
survival (demographic, social, health factors controlled for)
Ironson etal., 2002 279 patients w/HIV/AIDS High scores on a Spirituality/Religiousness Index c/w long-term
survival, health behaviors, less distress and lowering urinary
cortisol levels
Levin and Schiller (1987) also concluded from their spirituality in these studies is not specific. The lack of consis-
review that religiosity does confer beneficial health effects. tency in the findings suggests that there is no easy way to oper-
This benefit was seen across a wide range of disease and condi- ationalize religiosity. Subjects who want to present themselves
tions. When comparing religious denominations, a relatively as religious may be prone to embellish their activity level in
lower risk for cardiovascular disease, high blood pressure, interviews. Sloan also takes exception to the host of outcome
stroke, certain cancers, inflammatory bowel disease, and variables used in many studies because the number of vari-
for overall and specific cause mortality appears to occur in ables makes the study vulnerable to the sharpshooters fal-
more behaviorally demanding groups such as Seventh Day lacyshoot your bullets into the side of a barn and then draw
Adventists, Mormons, Orthodox Jews, and the clergy of all the bulls-eye. He concludes that there is no empirical basis for
faiths (Levin & Schiller, 1987). And, when individual char- the assertions that religious involvement is associated with
acteristics of religious commitment such as religious service health benefits (Sloan & Bagiella, 2002; Sloan, 2005; Sloan,
attendance are studied, there is a trend toward health benefit Bagiella & Powell, 1999). This is certainly most clear with
and reduced morbidity and mortality in those with greater intercessory prayer (prayers of others on behalf of the patient),
religiosity. Studies of specific diseases support both of these which has not been shown effective in any well-designed
observations. Levin guardedly concludes that there is an asso- study. For example, Benson etal. (2006) found no benefit of
ciation between religion and health. such prayers for cardiac surgery patients. In this study, some
Some researchers, however, find no association. (Sloan, subjects were unaware they were being prayed for after bypass
Bagiella, & Powell, 1999)Sloan and Bagiella (2002) feel many surgery. There was no significant difference between health
articles cited to support an association between religion and outcomes in those who actually were being prayed for versus
health are methodologically flawed or irrelevant to the associ- those who were not prayed for. Furthermore, those subjects
ation. For example, religiosity and spirituality are value-laden who knew they were being prayed for showed a slight trend
factors usually measured by self-report questionnaires, which toward more complications.
are subject to a variety of subjective variables. In the 266 stud- Most recently, the epidemiologist Lynda H. Powell and
ies they reviewed, 83% included nonpertinent health benefits; her colleagues at Rush-Presbyterian-St. Lukes Medical
for example, those related to lifestyle and not to anything Center reviewed 150 papers, eliminating those with meth-
specifically religious. Overlap with community activity and odological flaws (Powell etal., 2003). Sloan sees this paper as
social engagement confounds the religious attendance litera- the most thorough review of the empirical evidence to date
ture (Sloan, 2005). What is meant by religious behavior and (Sloan, 2005). Powell and her colleagues conclude that there
8 CINGULUM BUNDLE
9
23
24
CC
FORNIX
ATR
SCR ST
AT
25 HAB
10 UM SM
PT
SE MTT
HPT
12 13
DB MFB
14
HYP IP
UB LOT MB
PIT
IN AMYG
S
OB
HIPPOCAMPUS CG
LMA
PRESUBICULUM G
HIPPOCAMPAL GYRUS
SOMATIC AND
VISCERAL
AFFERENTS
Figure18.2 ACandidate Neurocircuitry for Spiritual Connectedness. (Adapted from Ballantine HT, Cassidy WL, Flanagan NB, & Marino N.(1967). Stereotaxic anterior cingulotomy
for neuropsychiatric illness and intractable pain. Journal of Neurosurgery, 26, 488495, p.491; see also Fricchione, 2011a, p.123).
While the ACC/MOFC loop refines brain reward cir- association cortices, the network from memory of the
cuitry and its emotional valencing to form a memory of the past to the now-situation to memory of the future is
past as it pertains to mammalian behavioral attachment, the set (Fricchione, 2011a). The memory of past attachment
dorsolateral prefrontal cortical (DLPFC) loop also makes a serves as an attractant in the formation of our memory of
major contribution (Fricchione, 2011a). The DLPFC was an the future. Humans tend to long for relationships that are
outcropping, to a large extent, from both the ACC, which associated with attachment security and solace. Once mam-
itself developed from the hippocampal moiety, and the insu- mals who have adopted an attachment strategy for survival
lar cortex from the piriform moiety. As such, the DLPFC become conscious of their memory of the past in relation to
provides increasingly complex versions of the where and memory of their mortal future, paradise is lost. Conscious
what questions as they relate to the separation/attachment mammals will always be beset by the knowledge of the tree
process. Where am I? the organism asks, in relation to an of good and evil, namely that what they face is separation
object of attraction/attachment or repulsion/separation. Am from those they love.
Iclose enough to receive the positive reinforcement of ACC Thus, humans with their PFC expansion, which remains
pleasure, or am Itoo far away, and as a consequence do Ifeel intimately connected with the past evolutionary loops associ-
the negative valence of the pain of separation? Furthermore, ated with amygdala food status (LeDoux, 1996) and sexual
what is the object to which Iam attracted or repulsed? Is it reproductive attachment, and moreover with cingulate mater-
truly an object to be attached to, or should Iseparate from it? nal, familial, and social attachment, can think into the future
These essential separation/attachment questions, which even and gain survival advantage. Humans can also anticipate their
the simplest of organisms must address in terms of sensorimo- exquisitely painful future separations and, by extension, plan
tor behavior, become enhanced and refined in the complex- how to avoid them.
ity of the newly evolved basal ganglia thalamocortical loops However, in this evolutionary development a bargain has
(Fricchione, 2011a). been joined. The price paid for anticipatory abilities that pro-
The human PFC maintains the future action programs mote attainment of high attachments is the knowledge that
for cognition and behavior (Ingvar, 1985). Because these there exists a seemingly final separation:death.
action programs can be stored and retrieved for future The person suffering with illness feels this archetypal sepa-
use, Ingvar terms them memories of the future (Ingvar, ration anxiety (Fricchione, 2011a,b). Ironically, the birth of
1985, p.127). In the extensive connections of the DLPFC our spiritual drives derives from our unique ability to con-
to the ACC and the connection of them both to the template and affectively experience the meaning of separation
medial temporal lobe memory system (hippocampus) and and attachment.
Patient: Well, my boyfriend made me come here. the white letters as they spelled out questions:Are you sit-
Computer: YOUR BOYFRIEND MADE YOU COME ting down? Using the keyboard of the PDP-9 computer, he
HERE? typed, No. The screen flashed, Why dont you pull up a
Patient: He says Im depressed much of the time. chair and make yourself comfortable. Using a script prepared
Computer: I AM SORRY TO HEAR YOU ARE by Dr.Slack, the computer inquired about symptoms and the
DEPRESSED. patient responded, mimicking a clinicianpatient interview.
Patient: Its true. Iam unhappy And so the field of patientcomputer dialogue was born.
Computer: DO YOU THINK COMING HERE WILL The introduction of technology into the doctorpatient
HELP YOU NOT TO BE UNHAPPY? relationship has always been ambivalently received as an
Patient: I need some help, that much seems certain. intrusion. Although Laennecs invention of the stethoscope
Computer: WHAT WOULD IT MEAN TO YOU IF YOU improved the physicians ability to make accurate cardiac
GOT SOME HELP? diagnoses, this disruptive innovation introduced a lasting
Patient: Perhaps Icould learn to getalong with my mother. change in the doctorpatient relationship. Today a doctor
Excerpts from a patientcomputer psychotherapy ses- no longer places his ear on the patients chest to listen to the
sionconducted with ELIZA in 1966 heart, but performs the auscultative exam in a brief, often
perfunctory fashion in anticipation of detailed information
captured by modern diagnostic technologies. How has psy-
I N T RODUC T IO N chiatric practice fared during the transformative onslaught of
technology in the era of information-age medicine? Perhaps
Psychiatry is no stranger to technology. When ELIZA, the unsurprisingly, adoption of technology has occurred more
computer-based therapist, was unveiled in 1966, many felt slowly in psychiatry than in other specialties. In this chap-
that this was the beginning of a new revolution in psychiatry ter we will describe a variety of ways that technology has
(Weizenbaum, 1966). And while ELIZAs inventor, Joseph appeared in psychiatric care, both at the psychiatry/general
Weizenbaum, never meant for it to be a formal treatment medicine interface and in behavioral health in other settings.
tool, computer-assisted therapy would not become widely
available for another four decades. C OM PU T E R-BA S E D PAT I E N T A S S E S S M E N T
In a specialty devoted to interpersonal relationships,
self-awareness, and the human condition, patients and pro- Medical History Taking
viders have been skeptical about the role of technology in Four years after the publication of Warner Slacks semi-
psychiatry. For many, technology doesnt seem a natural fit in nal paper on computerpatient dialogue, the computer-
psychiatry. And while many providers are now seeing the use- assisted medical history was first implemented in clinical
fulness of electronic medical records and computer-assisted care around 1970 by Morris Collen, director of research at
treatments, technologys greatest influence on psychiatry may Kaiser-Permanente (KP) in Oakland, California. Patients
actually be the way in which it has influenced the patient completed a paper history form that was designed to be
physician relationship. machine-readable, producing an electronic record that
became part of the patients electronic medical record. The
KP standardized history had the advantage of thoroughness
T E C H N OL O G Y A S T R E AT M E N T and increased the likelihood that often overlooked psycho-
social factors and habits would be investigated. Around the
same time, Slack and Maultsby programmed a computer to
I N T RODUC T ION A N D OV E RV I E W
take a psychiatric history from a patient (Maultsby & Slack,
In 1965, a man walked into a laboratory at the University of 1971). Soon after, John Greist and his colleagues developed
Wisconsin and, without understanding the significance of his a computer-administered psychiatric symptom checklist that
contribution, opened a new chapter in the history of medicine. measured change in clinical condition by tracking a patients
Sitting in front of a 3 4 sapphire blue screen, he watched symptoms over time (Greist, Klein, & Van Cura, 1973). These
340
early pioneers and their collaborators spawned a generation of CAD patients are not screened. Automated, computerized
clinical researchers dedicated to studying the use of comput- screening for depression could address this deficit. It is not
ers in psychiatry and mental health. known why this obvious solution isnt utilized; one possible
explanation is that while the direct cost of automated screen-
ing is low, the indirect costs and systems problems related to
Mental Health Screening and Assessment of Behavior
following up the patients who screen in for depression dis-
The development of computer-based screening tools for courage its adoption.
behavioral symptoms and mental disorders in the 1970s was Obviously, interactions with machines are not, in general,
soon followed by the introduction of the personal computer substitutes for human contact and communicationbut
(PC). The PC made it possible to not only automate the use of there are ways and contexts in which computer-based inter-
standardized measures of psychopathology for use in mental views have advantages over conventional clinical interviews.
health screening, but also to efficiently disseminate these tools Computers are more reliable than human interviewers, they
more widely. The exponential growth of Internet access and pursue questions inexorably without finding it tedious, and
broadband availability in recent years has led to the migration the extent of their queries is limited only by patient fatigue.
of computer-assisted assessment of signs and symptoms of They easily accommodate multiple languages and can be avail-
mental disorders, from the personal computer to the Internet. able 24 7 in diverse locations, and computerized services can
Currently, the widespread availability of Software-as-a-Service quickly be scaled to serve large populations at a low incremen-
(SaaS) providers has made it possible for these assessment tal cost. Computerized systems can offer information and
programs and their data to be stored in the Cloudsecure education using interactive multimedia in a way that continu-
servers accessible from any Internet-connected device includ- ally checks patients understanding of the material presented;
ing tablet computers and smartphones. While such programs human clinicians are encouraged to verify patients under-
offer many advantages, including scalability, access, and the standing of their illnesses and treatment, but often do not have
potential for linkage with institutional and personal elec- the time to do so. Finally, computerpatient dialogue may be
tronic health records as well as use from the medical home of extraordinary value in contexts where patients are asked to
of the future, remaining questions about privacy, confiden- disclose information of a sensitive, personal nature that might
tiality, and security must be resolved before adoption can be cause them shame or embarrassment if expressed to a human
widespread. interviewer. Patients preferences to make disclosures during
Lee Baer, John Greist, and their collaborators conducted a computerized interview have been shown regarding ques-
computer-assisted screening for mental disorders beginning tions about substance abuse, sexual behavior, and sexually
in the 1980s using automated telephone interviews to query transmitted diseases such as HIV (Locke etal., 1992; Richens
people about their experience of a standardized list of psychi- et al., 2010), suggesting that computers are experienced as
atric symptoms, with the goal of identifying those individu- less judgmental. For these reasons there is growing interest
als who might likely benefit from psychiatric evaluation and in systems that augment traditional clinical care by adding
treatment(Baer etal., 1995). Since then, the use of automated well-designed and clinically effective computer-based behav-
methods for screening large populations for a variety of men- ioral technologies, in the belief that such systems will increase
tal disorders including depression, alcohol abuse, and eating access to behavioral healthcare in a variety of resource-poor
disorders has become widespread and is used in community, settings, as well as improve quality and reduce health costs.
military, college health, and workplace settings (www.men- One website, PsychCentral (www.psychcentral.com) is a fre-
talhealthscreening.org). Increasingly, automated screening quently updated source of self-assessment tools that can be
for depression, alcohol and substance abuse, and other behav- used with patients. Other websites are emerging, and a search
ioral conditions is being deployed by healthcare organizations, at www.nimh.gov, nida.gov, or va.gov will lead to other useful
insurers, employers, and student health services (Farzanfar validated tools that are available online and downloadable for
etal., 2011). use in clinical practice.
Computer-assisted assessment of patient behavior can sup- One approach to reach underserved populations without
plement the evaluations done in primary care and specialty access to computers or the Internet is the use of interactive
care settings, where clinicians are pressed for time and assess- voice response telephony, or IVR. Robert Friedman and his
ment of behavioral and psychosocial issues often is neglected colleagues at Boston Medical Center have been studying the
in favor of other priorities. Mental health measures can be use of IVR telephony at the intersection of primary care and
completed easily using tablet computers in waiting rooms, psychiatry for two decades. Friedman and his team have based
secure patient Internet portals, or commercially available their work on the concept of a virtual visit in which a com-
automated telephone screening services. Unfortunately, these puter-based telehealth system (which they call Technology
screening tools are underutilized relative to the scope of the Linked Care or TLC) guides a patient through an inter-
problem of psychiatric comorbidity in general medical illness. active interview that (1) collects information via an auto-
Despite the well-established relationship between depres- mated interview, (2) uses algorithms and expert systems to
sion and poorer clinical outcomes in coronary artery disease make clinical inferences, and (3) provides automated psycho-
(CAD), and the recommendation by the American College education, care management, and health coaching to guide
of Cardiology that CAD patients be screened for depression patients to manage their symptoms or improve health behav-
routinely (American College of Cardiology, 2010), many ior between office visits. This procedure takes place with no
L E G A L , R E GU L ATORY, A N D
PR E M A R K E T R E V I E W E D PRODUC T S
LI A BILIT YISSUES
The answer to the question of whether the FDA will require
Computer software delivered via desktop computers, the premarket review is a moving target. Experts anticipate that
Internet, or mobile platforms will transform healthcare. The the FDA will provide greater clarity in their forthcoming
programs, services, and devices have the potential for causing guidance document. Software functions likely to require
356
Table20.1 WOR LD HEALTH ORGANIZATION E MOT ION A L I M PAC T OF I L L N E S S OR I N J U RY
(WHO)DEFINITIONS
Most of the rehabilitation programs provide help for the fol-
TER M DEFINITION lowing conditions:
Impairment Any loss or abnormality of body structure or of Amputations
physiologic or psychologic function
Stroke and other Neurological Disorders
Disability Any restriction or lack resulting from an
impairment of the ability to perform an activity Burn Injuries
inthe manner or within range considered normal
for the human being Traumatic Brain Injury
Handicap A disadvantage for a given individual, resulting Spinal Cord Injuries
from an impairment or a disability, that limits or
prevents the fulfillment of a role that is normal for Pediatric Rehabilitation
that individual
Therapeutic Recreation (TR) Specialists evaluate During the active phase of rehabilitation, the patient usu-
a patients premorbid leisure interests and lifestyle. ally receives different levels of counseling from various mem-
Once identified, these interests are combined with bers of the rehabilitation team. As mentioned earlier, some
basic therapy goals that focus on education, skills patients minimize their problems and some have a tendency
teaching, and community reentry. Treatment programs to exaggerate them. The consultant who is trying to help the
are designed to give patients an opportunity to enjoy patient to deal with deficits should have a good understand-
activities of choice such as adaptive sports, games, crafts, ing of the actual degree of the patients impairment and pos-
horticulture, pet therapy, community outings, and, when sible prognosis. For instance, if the patient has emotional
available, music therapy. The focus of many sessions may struggles regarding lack of mobility the physical therapist is
be improving specific physical and/or cognitive therapy the most appropriate counselor to help the patient to express
PH A R M AC OL O GIC A N D OT H E R
S OM AT IC T R E AT M E N T S
21.
PSYCHOPHAR M ACOLOGY INTHE MEDICA L PATIENT
Thomas Markham Brown, Alan Stoudemire, Barry S.Fogel, and Michael G.Moran
3 81
Table21.1 SIDE EFFECT PROFILES OFTHECYAD*
Maprotiline + ++ ++ + ++ 150200
Trimipramine + + ++ ++ ++ 50300
Bupropion + 150450
* Relative potencies (some ratings are approximated) based partly on affinities for brain receptors in competitive binding studies; none; + slight or indeterminate;
++ moderate; +++ marked; ++++ pronounced.
Dose ranges are for treatment of major depression in healthy young adults. Lower doses may be appropriate for other therapeutic uses, and for use in the elderly and
medicallyill.
Available in injectableform.
0.11 seconds) than it was in patients with normal pretreat- channel blocker combination therapy was being considered in
ment ECGs (9% versus 0.7%). However, more than 90% of a patient with cardiac conduction disease.
patients with preexisting conduction disease did not develop Right and left bundle-branch blocks may be seen as a part
second-degree heart block (Roose etal., 1987a). of underlying cardiovascular disease but are not in them-
Certain types of heart block present particularly high risks selves a contraindication for TCA treatment. When treating
with TCAs. In patients with preexisting bundle-branch block patients with these cardiac conduction defects, the psychia-
(especially those with second-degree heart block), dissociative trist and cardiologist should jointly establish a schedule for
(third-degree) AV heart block may develop. If type 1 antiar- monitoring cardiac effects when TCA treatment is pursued.
rhythmic medications (quinidine, disopyramide, procain- In almost all cases, the SSRIs and newer antidepressants now
amide) are concurrently administered with tricyclics, additive represent the drugs of choice in patients with cardiovascular
prolongation on cardiac conduction are possible (Levenson, disease.
1985). It is now suspected, but not proven, that TCAs might
increase cardiac morbidity and mortality in depressed post-MI
Prolonged QT Syndromes andTCAs
patients (Roose & Miyazaki, 2005). Certain calcium chan-
nel blockers may prolong AV conduction and could, at least One of the quinidine-like effects of TCAs on the electro-
theoretically, interact with TCAs in this regard. Diltiazem cardiogram can be prolongation of the QT interval. This
and verapamil both may slow AV conduction; nifedipine, in involves inhibition of the human ether-a-go-go (hERG)
contrast, generally does not affect AV conduction, and this channel by TCAs. The hERG channel is a potassium chan-
calcium channel blocker may be preferred if TCA/calcium nel critical in repolarizing cardiac myocytes. Inhibition of
Lurasidone
AT Y PIC A L N EU ROL E P T IC S
Lurasidone is among the newest of the atypical antipsychot-
Aripiprazole ics. It has a low oral bioavailability of about 10% to 20%.
Aripiprazoles oral bioavailability is nearly 90%. There also Serum protein binding is 99%. Lurasidone is metabolized
exists an intramuscular version. Serum protein binding is 99%. mainly through CyP450-3A4, and produces an active metab-
The elimination half-life of aripiprazole is about 75 hours, and olite. The elimination half-life of lurasidone is 18 hours,
that of its active metabolite dehydroaripiprazole is 94 hours. while that of its active metabolite is 8 to 10 hours. No dos-
Among slow metabolizers through CyP450-2D6, the elimina- age adjustment is needed in either renal or hepatic impair-
tion half-life of aripiprazole may double. About 55% of a dose ment. Lurasidone is complicated by dose-dependent EPS that
of aripiprazole is eliminated in the feces and 25% in the urine. may be seen in as many as 10% of patients, and akathisia in
Aripiprazole appears to be well tolerated among those with as many as 20% (Yasui-Furukori, 2012). There appears to be
renal or hepatic impairment (Mallikaarjun etal.,2008). no significant effects on weight, lipids or the QTc with lurasi-
Among the main advantages claimed for aripiprazole done (Kantrowitz et al., 2012).
when compared to other atypical antipsychotics is a reduced
tendency to weight gain and an associated reduction in the risk Risperidone
of developing the metabolic syndrome (Khanna etal., 2013).
The main limitation of aripiprazole is usually dose-related Table 21.5 contrasts the differences between typical and atyp-
EPS, which is more common among children and adolescents ical neuroleptics. Risperidone in low doses embraces many
than adults. The rate of EPS with aripiprazole appears to be of the benefits of the atypical antipsychotics. It is effective
more than that of most other atypical antipsychotics, but less against negative symptoms of chronic psychosis and has a
than that of risperidone and of haloperidol (De Fazio etal.,
2010; Rummel-Kluge etal.,2012). Table21.5 DIFFER ENCES BET W EENTR ADITIONAL
(TYPICAL) AND ATYPICAL NEUROLEPTICS
Asenapine
Traditional Neuroleptics Atypical neuroleptics
Asenapine is among the newest of the atypical antipsychot-
ics. The bioavailability of asenapine is less than 2% if swal- Are associated with a high Are associated with a low
lowed, but rises to 35% when given sublingually. It is 95% incidence of EPS (extrapyramidal incidence of EPS
symptoms)
bound to serum proteins. Its elimination half-life is about 24
hours. About 50% of a dose is excreted in the urine and 40% May cause tardive dyskinesia May not cause tardive
in the feces. Inducers of CyP1A2 may speed the elimination dyskinesia
of asenapine (Minassian & Young, 2010). Side effects include Increase serum prolactin levels Show minimal or no increase
somnolence in 24%, significant weight gain in nearly 20%, in serum prolactin levels
akathisia in 2%, and other EPS in 5% (McIntyre,2011).
Treat mainly positive Treat both positive and
symptoms of psychosis (such as negative symptoms of
Iloperidone hallucinations), but not negative psychosis
ones (such as social withdrawal)
Iloperidone is another of the newest atypical antipsychot-
ics. It appears to be well absorbed. Iloperidone is metabo- Cause catalepsy in animals Do not cause catalepsy in
animals
lized through CyP4502D6 and 3A4 and has two active
M E L ATON I N
Buspirone and Other Conditions
Many case reports and studies indicate clinical efficacy for Melatonin spares psychomotor performance, unlike agents
buspirone in a variety of conditions other than anxiety dis- such as zaleplon, zopiclone and temazepam (Paul, Gray,
orders. Buspirone has been used to treat autism (Brahm, Kenny, & Pigeau, 2003). Melatonin easily crosses the
Fast, & Brown, 2008; Realmuto, August, & Garfinkel, bloodbrain barrier and stimulates endogenous recep-
1989), for the suppression of neuroleptic-induced akathi- tors, promoting sleep. Melatonin indirectly also promotes
sia (DMello, McNeil, & Harris, 1989), as an augmenting the release of GABA and inhibits the release of glutamate
agent in antidepressant treatment (Robinson etal., 1989), (Banach, Gurdziel, Jdrych, & Borowicz, 2011). Melatonin
and for ADHD in children. Antidepressant-induced brux- lacks known toxicity in acute settings. It is not a mutagen
ism is often effectively treated with buspirone (Albayrak& in the Ames test (Anisimov, 2003). Endogenous melatonin
Ekinci, 2011). Buspirone can counteract SSRI-induced is metabolized through CyP450 1A (Rifkind, 2006). Oral
sexual dysfunction in some patients. It does not, however, melatonin doses of 0.10.3 mg achieve serum levels that
appear to increase libido (Moll & Brown, 2011). Buspirone are similar to those normally seen at night. Sleep latency is
can help reduce anxiety and agitation in brain-injured reduced, and sleep duration is prolonged (Dollins, Zhdanova,
patients and in patients with dementia (Colenda, 1988; Wurtman, Lynch, & Deng, 1994). Because of its relative
Levine, 1988; Loane & Politis, 2012; Tiller, Dakis, & Shaw, benignity, as well as its potent antioxidant effects, melatonin
1988). Typically, relatively low doses are needed for this use has been recommended for a variety of disorders includ-
antiagitation effect (510 mg tid). Buspirone also may be ing Alzheimers disease, myocardial infarction, and diabetes
helpful in smoking cessation (Carro, Moreira, & Fuchs, (Korkmaz etal., 2012; Snchez-Barcel etal., 2010). Doses
2007; Gawin, Compton, & Byck, 1989)and in luteal phase of melatonin higher than 0.3 mg can cause protracted eleva-
dysphoric disorder (Rickels, Freeman, & Sondheimer, tions of serum melatonin, and hence persistent daytime seda-
1989; Yatham, Barr, & Dinan, 1989). Current studies are tion. In some cases, while melatonin reduces the time it takes
investigating high doses of buspirone for the treatment of to fall asleep it does not prolong sleep, and patients wind up
tardive dyskinesia. In this role, buspirone may help both sleeping the same total amount of time and waking up earlier
by stimulating normal dopamine activity in the brain (Gringras etal.,2012).
The bioavailability of oral ramelteon is about 2%. Its elimina- Among the agents used for insomnia, zolpidem has a rela-
tion half-life is 13 hours, and that of its active metabolite is tively strong association with falls and fractures. Among
25 hours. Over 80% of the drug is excreted as metabolites 1,508 patients with fractures and insomnia, Kang and col-
in the urine. Metabolism is primarily through CyP450s 1A2 leagues noted a relative risk of 1.72 (95% CI: 1.37 to 2.16)
and 2C19, with a small contribution from 3A4 (Obach & of having a fracture among patients taking zolpidem. The
Ryder, 2010). Ramelteon is an agonist at melatonin MT1 relative risk among patients taking a benzodiazepine was 1.00
and MT2 receptors. Although its active metabolite has some (Kang etal., 2012). Zolpidem overdose has the same general
affinity for the serotonin 5HT2b receptor, there is no sig- presentation as overdose with zaleplon, although zolpidem is
nificant activity at other receptors including the GABA-A more likely to cause side effects requiring medical attention
receptor. Significantly less impairment of cognition and of (Forrester, 2006). Zolpidem appears to be safe for patients
psychomotor performance is expected with ramelteon com- with stable mild to moderate chronic obstructive pulmonary
pared to those agents active through the GABA-A receptor disease and for patients with treated sleep apnea (Estivill etal.,
(Mets etal., 2011). Ramelteon does not have significant with- 2003). Zolpidem is available both as an immediate-release
drawal effects or lead to rebound insomnia on discontinua- agent and as an extended-release agent. The extended-release
tion. There are no significant effects on respiration among formulation permits 60% of the active agent to be taken up
patients with pulmonary problems placed on ramelteon immediately, while the remaining 40% is released slowly. This
(Greenberg & Goss, 2009). Somnolence is the most com- reduces peak serum concentrations and extends the duration
mon side effect with ramelteon and may affect 5% of patients of action by 3 hours. Two important differences between the
(Kohsaka etal.,2011). indications of immediate-release and sustained-release zol-
pidem are that the latter is indicated for sleep maintenance,
not just sleep promotion, and also can be used chronically
E S Z OPIC L O N E (Lieberman,2007).
Zolpidem use has also been linked to cancer. The hazard
Eszopiclone is the s-enantiomer of zopiclone, a nonbenzodi- ratio for oral cancer among patients taking more than 300
azepine agent that is an allosteric modulator of the GABA-A mg of zolpidem in a year was reported by Kao and colleagues
channel. Its elimination half-life is 6 hours. The drug is 50% (2012) to be 2.36 (95% CI: 1.57 to 3.56).
to 60% protein-bound. Over 75% is eliminated in the urine as
metabolites; less than 10% is recovered in the urine as the par-
ent compound. Eszopiclone is metabolized through CyP450 Z OPIC L ON E
3A4. Inhibitors of CyP450 3A4, as well as advancing age and
liver disease prolongs the elimination half-life (Greenblatt & The bioavailability of oral zopiclone is generally 70%80%.
Zammit, 2012). While sedation and dizziness do occur in a The elimination half-life normally ranges from 3.56.5 hours.
minority of patients, dose-dependent dysgeusia is the most Plasma protein binding ranges from 45%80% (Drover,
common adverse event. Between 20% and 60% of patients 2004; Fernandez, Martin, Gimenez, & Farinotti, 1995).
prescribed eszopiclone will experience dysgeusia (Uchimura, Potent inducers of CyP450 3A4, such as carbamazepine, phe-
Kamijo, & Takase, 2012). There is an elevated risk ratio of nytoin and rifampicin, speed the elimination and reduce the
1.4 for developing an infection during treatment with zopi- effects of zopiclone (Villikka, Kivist Lamberg, Kantola, &
clone or eszopiclone. These are usually mild. The reasons for Neuvonen, 1997). Zopiclone resembles zolpidem in being
this association are unclear (Joya, Kripke, Loving, Dawson, & relatively safe for patients with pulmonary disease. Neither
Kline,2009). agent significantly impairs respiratory drive when used in rec-
ommended dosages (Estivill etal.,2003).
As discussed for eszopiclone, there is an increased risk of
Z A L E PL ON infection with zopiclone (Joya etal.,2009).
Phenytoin Bioavailable phenytoin and Aspirin Can displace valproate from protein
carbamazepine increased binding sites and increase serum free
valproate levels several-fold
Carbamazepine by valproate by displacing these
drugs from their serum protein Carbapenem Serum levels of valproic acid decreased
binding sites by 90%
Carbamazepine and Serum levels of carbamazepine decreased
10,11-epoxide metabolite This metabolites levels of
by 17%.
CBZ increased by valproate of
carbamazepine 10,11-epoxide of CBZ Levels of carbamazepine-10,11-epoxide
increased by 45% in patients with
Tricyclic antidepressants TCA levels increased by valproate epilepsy taking valproate and
(TCAs) carbamazepine
Chlorpromazine Increased levels of valproate Cimetidine Slows the elimination of valproate, and
Cimetidine increases serum valproate levels
Salicylates Cisplatin Valproate may enhance sensitivity of
Guanfacine tumor cells to cisplatin
Anticoagulants (warfarin) Increased prothrombin times Clonazepam Concomitant use with valproic acid may
(valproate also inhibits secondary induce absence status in patients
phase of platelet aggregation)
with a history of absence-type seizures.
Clozapine Valproate significantly lowers serum
clozapine levels.
2008; Luszczki, Sawicka, Kozinska, Borowicz, & Czuczwar,
2007; Kim, Hwang, Jeon, & Do, 2012; Michaelis, Ha, Doerr, & Diazepam Valproate displaced diazepam
Cinatl, 2008; Perucca, 2006; Pisani, 1992; Sandson, Marcucci, from plasma albumin-binding
Bourke, & Smith-Lamacchia, 2006; Stewart, Nesmith, & sites and inhibited its metabolism.
Coadministration of valproate 1500
Mattox, 2012; Taha, Hammond, & Sheth, 2013; Unterecker, mg/day to healthy volunteers increased
Burger, Hohage, Deckert, & Pfuhlmann, 2013; Unterecker, the free fraction of diazepam (10 mg)
Reif, et al., 2013; Yoon & Kim, 2013). by 90%; diazepam plasma clearance
More recently, the effect of valproic acid on medications decreased by 25% and volume of
intended for HIV and other infections have been explored. distribution by 20%. Elimination
half-life of diazepam did not change.
Valproic acid may raise serum levels of agents such as lopina-
vir and zidovudine but not atazanavir, ritonavir, or efavirenz Doxepin Valproate can double serum levels of
(Birbeck etal., 2012). On the other hand, meropenem lowers doxepin plus N-doxepin
serum valproic acid levels and can result in therapeutic fail- Ethosuximide Valproate inhibited ethosuximide
ure of the anticonvulsant. Seizures may result (Coves-Orts metabolism. Administration of a single
et al., 2005). This appears to be a class effect of the carbo- 500 mg dose of ethosuximide with
penems on valproic acid (Mancl & Gidal, 2009). This phar- valproate (800-1600 mg/day) to healthy
volunteers increased ethosuximide
macokinetic interaction may be exacerbated by the tendency elimination half-life by 25% and
of penicillins to antagonize the GABA-A receptor. Valproic decreased its total clearance by 15%.
acid also appears to potentiate the replication of human Serum levels of both drugs should
cytomegalovirus, while undermining the antiviral effects of be monitored in patients receiving
cidofovir, foscarnet, and ganciclovir (Michaelis, Ha, Doerr, & valproate and ethosuximide, especially
with other anticonvulsants.
Cinatl,2008).
While adverse drug interactions abound with valproic Ertapenem May decrease serum valproate
acid, there is also evidence that it may be helpful in settings concentrations
(continued)
Serotonergic agents Serotonin syndrome (ataxia, antiparkinson drugs such as bromocriptine would presum-
SSRIs nystagmus, confusion, fever, ably be safer if a patient with Parkinsons disease required
Tryptophan
tremor) MAOI therapy at antidepressant doses. The use of selegiline
in antiparkinson doses of 10 mg/day is, of course, compatible
Sumatriptan
with L-dopa or carbidopa-levodopa.
Zolmitriptan
Direct-acting sympathomimetics can be used if
Caffeine Mild increase in blood pressure necessaryfor example, as bronchodilators for the treat-
Theophylline ment of asthma. Inhalers are safer than systemic drugs.
Aminophylline Furthermore, a challenge with the inhaled drug, with blood
pressure determination before and after, provides even greater
Hypoglycemic agents Lowers blood glucose further security that a particular drug is safe in the face of MAOI
Anticoagulants Prolonged PT therapy.
The second major type of drug interaction with MAOIs
concerns their combination with serotonin drugs such as the
Succinylcholine Phenelzine prolongs
action SSRIs or buspirone. The interaction with meperidine may
have a similar mechanism, since meperidine blocks serotonin
Diuretics Increased hypotensive effect reuptake (Guo etal.,2009).
Propranolol Clinical symptoms of the serotonin syndrome include
Prazosin myoclonus, ataxia, fever, and confusion. Neuromuscular
Calcium channel blockers symptoms range from tremor to lead-pipe rigidity.
Other monoamine oxidase Neurologic examination shows hyperreflexia, some-
inhibitors times with clonus; nystagmus; altered mental status; and,
I N T RODUC T IO N level, but at the gross level they are simultaneous; one process
can influence another, as when the action of a drug on the
Pharmacokinetics provides details of the relationship between intestine influences the absorption of drugs still present there.
the dose of drug administered and the alterations in drug
concentration in the body over time (Varghese, Roberts, &
Lipman, 2010). In patients with general medical illness, the PH A R M AC OK I N E T IC S V E R S US
pharmacokinetic parameters of many psychotropic agents can PH A R M AC ODY N A M IC S
be altered, at times drastically. Chronic disease states, acute
medical problems, surgery and other procedures, and con- Brain effects do not correspond directly to the blood con-
comitant nonpsychotropic medications all play a role. In addi- centrations of a drug for several reasons. First, the level of
tion to the influence of impaired hepatic or renal function, the drug in the blood can differ greatly from the level of the
other factors relevant to pharmacokinetics include changes drug in the central nervous system (CNS) because of the
in protein binding and altered gastrointestinal function such bloodbrain barrier. The difference in concentrations can
as delayed gastric emptying or altered gastrointestinal transit be as great as two orders of magnitude; it is related to the
time. Alternate nonenteral routes of administration and spe- lipophilicity of the drug, whether its entry into the brain is
cialized oral formulations can have special relevance in the facilitated by its interaction with a transporter, and whether
context of diseases that interfere with swallowing or gastro- the drug is actively transported into or out of the cerebrospi-
intestinal function. Changes in drug levels due to pharmaco- nal fluid (CSF). Second, the drugs mechanism of action may
kinetic factors can lead to toxicity or to lack of efficacy, and not require that the drug be continuously present; it may, for
the influence of psychotropic drugs on the pharmacokinetics example, induce RNA transcription leading to the synthesis
of general medical drugs can cause toxicity or lack of efficacy of a protein that will persist for hours or days. And third, the
of those medications. Therapeutic drug monitoringand changes in neuronal function initially produced by the drug
sometimes pharmacogenetic testingcan reduce risk in many can cause secondary changes in the same neurons or con-
cases, while in others the best risk mitigation strategy is to use nected neurons that produce clinically relevant effects. For
a different drug or different dose. General advice such as start example, if a drug blocks a neurons dopamine receptors that
low and go slow is nave and in some cases actually is coun- neuron will synthesize additional receptors; also, activity in
terproductive; when mental and behavioral symptoms are the related glutamatergic neurons will increase. This in turn may
greatest and most immediate threat to patients function and have effects on the targets of those neurons axons.
well-being, it is far better to make the right choice of psycho-
tropic drug and dosage as soon as possible.
Pharmacokinetics specifically deals with all of the steps T H E PH A R M AC OK I N E T IC C U RV E
between the administration of a dosage form and the elimi-
nation of the drug from the body (Shargel, Wu-Pong, & Yu, The pharmacokinetic (PK) curve, or time-concentration
2005). This includes the delivery of the drug to its ultimate curve, is a plot showing time since drug administration on the
site of actionthe brain in the case of psychotropic drugs. x-axis and the drugs blood concentration (typically its plasma
Pharmacodynamics characterizes the relationship between level) on the y-axis. It is illustrated in Figure 22.1. Three essen-
the drug concentration at the site of action and the drugs tial parameters of the PK curve, which do not totally define
clinical effects, both therapeutic and adverse. In other words, it but are critical to the drugs clinical effects, are the maxi-
pharmacokinetics is what the body does to the drug, and mum concentration attained (Cmax), the time needed to reach
pharmacodynamics is what the drug does to the body. The the maximum concentration (Tmax), and the total area under
relevant steps in pharmacokinetics are summarized by the the PK curve (AUC) (Shargel, Wu-Pong, & Yu, 2005). The
acronym ADME: Absorption, Distribution, Metabolism, AUC is based on extrapolation of the PK curve to infinity
and Excretion. These processes are sequential at the molecular from the last actual measurement of concentration (Shargel,
448
Pharmacokinetic curve (linear plot) drug (Center for Drug Evaluation and Research, 2003). Note
that formulations that are bioequivalent are not necessarily
2000 identical in their pharmacokinetic properties, because (1)the
Cmax (maximum concentration) Tmax and exact shape of the PK curve are not required to
Plasma concentration
Maximum concentration (Cmax) Peak plasma concentration of a drug after administration mg/L, g/ml
Minimum concentration (Cmin) Lowest (trough) concentration that a drug reaches before mg/L, g/ml
the next dose is administered.
Volume of distribution (Vd) Apparent volume in which a drug is distributed (i.e., the parameter liters
relating drug concentration to drug amount in the body)
Concentration (C) Amount of drug in a given volume of fluid, usually plasma mg/L, ng/ml, g/ml
Elimination half-life (T1/2) Time required for the concentration of the drug to reach hours
halfofitsoriginal value
Elimination rate constant (ke) Rate at which a drug is removed from the body hours1
Area under the curve (AUC) Integral of the concentration-time curve (after a single dose (mg/L) * hours
orinsteady state)
Clearance (CL) Volume of plasma cleared of the drug per unit time L/hour
Bioavailability (F) Systemically available fraction of a drug percentage 100%
DeVane, 1990.
Antiepileptic Drugs Most psychotropic drugs are lipophilic; this property facili-
tates their crossing the bloodbrain barrier. Psychotropic
Carbamazepine 90% drugs that are not lipophilic either are effective despite rela-
Phenytoin 95%
Tiagabine 96% tively low brain levels or have their access to the brain facili-
Valproic acid 90% tated by transporters. In their unaltered form, lipophilic
compounds are poorly excreted by the kidneys because they
Antipsychotic Agents will be reabsorbed into the systemic circulation in the renal
Aripiprazole 99% tubules. To terminate drug action and to allow for elimina-
Asenapine 95% tion from the body, drugs are transformed by metabolism to
Chlorpromazine 97% more polar, hydrophilic compounds. Hydrophilic metabolites
Clozapine 97%* usually are inactive, but some have useful therapeutic activity
Fluphenazine 99%
Haloperidol 90%
and have even been developed as drugs in their own right
Iloperidone 95% for example, 9-hydroxyrisperidone (paliperidone).
Lurasidone 99% Prodrugs are pharmaceuticals that are biologically inac-
Olanzapine 93% tive until they are metabolized; one or more of the metabo-
Quetiapine 83% lites has the desired therapeutic effect. Prodrugs are developed
Risperidone 90%
Ziprasidone 94%
to address poor bioavailability and/or other pharmacokinetic
challenges. Medical psychiatrists should be aware when a
Autonomic Agents patient has a medical condition that can interfere with the
metabolism of a prodrug into its active metabolite(s).
Propranolol 90%
Biotransformation reactions can be classified as Phase I
Analgesics (oxidative) or Phase II (conjugative). Phase I oxidative reac-
tions usually involve an enzyme of CYP (aka cytochrome
Fentanyl 86%
Methadone 90%
P450) system. Phase II conjugation reactions, which bind the
Buprenorphine 95% drug to be eliminated with a polar moiety such as glucuronic
acid, a sulfate group, or glutathione, often involve the uridine
Most of the listed drugs are primarily bound to albumin. Those with significant 5-diphosphate glucuronosyltransferase (UGT) enzymatic sys-
binding to AAG are indicated with an asterisk. PK issues related to protein
binding of albumin-bound drugs usually arise because of low serum albumin, tem. The liver is the most important site of action of both the
typically due to liver disease, malnutrition or proteinuria. PK issues related to CYP and the UGT enzymes, though both classes of enzymes
protein binding of AAG-bound drugs usually arise because of an increase in are found in the gut wall and to a lesser extent in other tissues.
AAG with infection and with inflammatory or autoimmune disease.
Typically, drugs undergo Phase I metabolism followed
by Phase II metabolism (Sandson, Armstrong, & Cozza,
the bloodbrain barrier can be large and clinically important 2005). For most psychotropic drugs, Phase I metabolism is
(Lin & Yamazaki, 2003). Drugs with clinically significant Pgp most important for terminating the drugs action; even for
transport at the bloodbrain barrier include the antidepres- prodrugs that initially are activated by Phase I metabolism,
sants fluvoxamine, citalopram and escitalopram, venlafaxine subsequent Phase I metabolism of the active metabolite
and desvenlafaxine; and the antipsychotic drugs haloperidol, yields an inactive molecule. Changes in Phase II metabolism
risperidone, and paliperidone. The pharmacokinetic and phar- have particular clinical significance when the drug or active
macodynamic effects of Pgp will go in the same direction; when metabolite does not undergo Phase Imetabolism (or when its
induction of Pgp decreases a drugs blood level by decreasing its Phase Imetabolism is impaired). In this situation, an active
net intestinal absorption, it will also decrease the drugs brain molecule can accumulate to potentially toxic levels.
Antipsychotics
Aripiprazole
Chlorpromazine
Haloperidol
Iloperidone
Perphenazine
Risperidone
Thioridazine
Stimulants
Atomoxetine
Amphetamine
Autonomic agents
Clonidine
Propranolol
Analgesics
Codeine *
Oxycodone
Tramadol*
Lidocaine
Cognitive enhancers
Donepezil
Hypnotics
Zolpidem
Zaleplon
Eszopiclone
Antipsychotics
Aripiprazole
Haloperidol
Iloperidone
Lurasidone
Risperidone
Ziprasidone
Antiepileptic drugs
Carbamazepine
Stimulants
Modafinil
Armodafinil
Analgesics
Buprenorphine
Codeine
Fentanyl
Methadone
4. Apatient has a known reason for having PK for a given For each psychotropic drug there are several PK consider-
drug differing from the general population. This could ations that together can help the medical psychiatrist antici-
be having a genotype associated with poor metabolism or pate issues that might necessitate dosage adjustments or even
ultrarapid metabolism of the drug, having liver or kidney contraindicate the drug in particular patients. Theyare:
disease, being morbidly obese, or taking other medica-
tions that induce or inhibit the metabolism of the drug 1. Hepatic metabolism
in question. In this situation a prospective dosage adjust- a. Is it necessary to activate the drug?
ment typically will be made based on an estimate of the b. Is it necessary to inactivate the drug?
patients PK profile for the drug. Checking the blood level c. Are there active metabolites, and, if so, do they require
after one or several doses of the drug can inform a more further hepatic metabolism to inactivate them?
accurate and patient-specific dosage adjustment. d. Are there active metabolites that can accumulate and
cause toxicity?
5. Apatient is taking a drug that does not have first-order e. What enzymes are involved, and which are primary?
kinetics and its therapeutic index is sufficiently low f. Does the drug induce or inhibit its own metabolism?
that there is a danger of toxicity during initial dosing g. Is the drugs metabolism affected by drugs commonly
adjustments. prescribed together with it?
Most psychotropic drugs follow first-order kinetics, in which 2. Renal elimination
the steady-state concentration of the drug is proportional to a. Is elimination by the kidney necessary to terminate
the total dose (Bauer, 2011). Exceptions are important, because action of the drug?
when drugs do not have first-order kinetics small increments b. Are there toxic metabolites that must be eliminated by
of dosage can produce large increases in blood levels, or, alter- the kidney?
natively, large increments in dosage produce small increases c. Is elimination of the drug and its metabolites depen-
in blood levels. Two antiepileptic drugs offer classic examples. dent only on glomerular filtration, or is there a signifi-
In the case of phenytoin there is a maximum amount of drug cant role for renal tubular function?
that can be metabolized per day. If, for example, a dosage of d. To what extent is the drug eliminated by hemodialysis?
300 mg per day saturated the metabolic enzymes, a dosage of 3. Protein binding
350 mg per day might double the blood level of the drug. In a. Is the drug highly protein bound?
the case of carbamazepine, the drug induces CYP3A4the b. Is the drug bound to albumin, AAG, or both?
enzyme that is the principal enzyme in its own metabolism. c. Is there significant binding to any other proteins?
When a patient is initiating therapy with carbamazepine, d. Is the difference between serum and plasma levels big
increases in dosage can be necessary just to maintain a con- enough to impact TDM?
stant blood level. Nonfirst-order kinetics are an especially
relevant concern when a standard dosage increment (e.g., one 4. Interindividual variability
pill per day) can alter a patients blood level from a subthera- a. Is there large variability in the PK of the drug in the
peutic to a toxic one, or when autoinduction of metabolism general population?
can lead to a loss of the drugs therapeutic effect. b. Are there known associations with age, gender, race, or
ethnicity of the patient?
c. Are there well-established genetic issues affecting the
PL A S M A OR S E RU M , TOTA L OR drugs PK?
F R E EC ONC E N T R AT ION S
5. Nonlinear kinetics
When physicians order blood levels of a drug, the clinical labora- a. Does the drug have nonlinear kinetics over some part
tory typically makes the decision about whether serum or plasma of its usual dosage range?
will be assayed for the drug. The difference between serum and b. Is the effect to increase or decrease the increase in
plasma is the presence of clotting factors (proteins) in the latter blood concentration for a given dosage increase?
Concentration (ng/ml)
tion of an antipsychotic drugor any other drug. IM Average
injections can be problematic in severely malnourished 8
or cachectic patients with markedly decreased muscle 6
bulk. In these patients the trauma to muscle can be 4
clinically significant, while blood levels can rise more
rapidly than in patients with normal muscle bulk. 2
c. SC injections are seldom used to administer psychotro- 0
pic drugs. 0 28 56 84 112 140 168
d. Although not approved for intravenous use, haloperi- Time (Days)
dol given IV for delirium can be effective. However, Figure22.2 Pharmacokinetic Curve of Haloperidol Decanoate.
there is a higher risk of QTc prolongation and torsades
de pointes with IV administration compared with
oral. The FDA issued a safety alert in September 2007 While medical psychiatrists would be unlikely to start
detailing this information. The alert recommends an LAI antipsychotic drug in a person with an unstable
ECG monitoring, should haloperidol be given IV medical condition, they are likely to encounter patients
(Food and Drug Administration, 2007). The anti- already receiving LAI antipsychotic drug therapy who
emetic droperidol is sometimes provided in lieu of need to start a general medical drug that might interact
haloperidol, but it also carries the risk of QTc prolon- with the antipsychotic drug already on board. While the
gation and torsades de pointes, with the FDA issuing a new drug likely wont affect absorption, it can effect dis-
black box warning for the risk of sudden cardiac death tribution, metabolism, and excretion of the antipsychotic
in 2001 (Gan, 2004). Other parenteral antipsychotics agent. For example, a patient on an LAI formulation of
are designed to be given as intramuscular injections paliperidone might develop sedation or dystonia if started
and should not be given IV. on cyclosporine, a potent inhibitor of Pgp. Or, a patient
e. Benzodiazepinesspecifically lorazepam, diazepam, with schizoaffective disorder in remission on LAI olan-
and midazolammay be administered IV. Because zapine might experience an exacerbation of symptoms
of increased lipophilicity compared to lorazepam, after the initiation of insulin for new-onset Type II diabe-
diazepam and midazolam more easily cross the blood tes, because insulin can induce CYP1A2.
brain barrier and thus have a much more rapid onset of
3. Rectal gels and suppositories. Rectal administration may
action.
be considered if oral or parenteral routes are not viable
options. However, absorption following rectal adminis-
2. Depot intramuscular injections, also known as long-
tration is erratic and often incomplete. Bioavailability is
acting injectable (LAI) formulations, mitigate problems
affected by drug placement:absorption in the lower rectal
of medication nonadherence in outpatients. However,
region bypasses first pass metabolism, while medication
once a depot injection has been given it is not feasible to
absorbed in the upper region passes through the portal
remove it, so if a patient has an adverse reaction to the
vein. In general, 50% of drug absorbed rectally will bypass
medication it may last a long time. When depot injec-
first-pass metabolism. These formulations have a limited
tions of antipsychotic drugs cause adverse neurological
role in the administration of psychotropic drugs. One
effects, these can persist for weeks or months. Depot
exception is the use of rectal diazepam for the treatment
injections of narcotic antagonists can complicate anal-
of status epilepticus or delirium tremens in patients in
gesic therapy if the patient develops a painful medical
which IV access is difficult to establish. In fact, diazepam
condition, has severe trauma, or requires major surgery
is more rapidly absorbed as a rectal solution than either
while the drug is still on board. In general, depot injec-
oral or IM administration, although rectal suppository
tions are not a good choice for patients with multiple
results in decreased bioavailability and slower rate of
medical comorbidities.
absorption (Moolenaar, Bakker, Visser, & Huizinga,
The pharmacokinetics of LAI antipsychotic drugs
1980). Diazepam is also commercially available as a rectal
exhibit the flip-flop phenomenon, where the drugs half-
gel, which has 90% bioavailability with Tmax at 1.5 hours
life is determined by its absorption rate rather than by its
(Diastat Product Information).
elimination (Ereshefsky etal., 1983). Flip-flop kinetics
occur when a drugs elimination rate is substantially 4. Transdermal patches. Transdermal administration allows
shorter than the rate of absorption. The PK curve of for a drug to be delivered into the systemic circulation
haloperidol, a typical LAI antipsychotic drug, is shown via the skin. Transdermal patches are the most common
in Figure 22.2. When a change in metabolism occurs, the formulation. Depending on the product, drug may
plasma concentration changes but the terminal elimina- be released immediately or over a prolonged period of
tion half-life does not. time. Most formulations deliver drug at a constant rate
Antidepressants
Tricyclic Antidepressants
Amitriptyline Tablet
Clomipramine Capsule
Desipramine Tablet
Doxepin Capsule, oral solution
Imipramine Tablet, capsule
Nortriptyline Capsule, oral solution
(continued)
Antipsychotics
First Generation Agents
Haloperidol Tablet, oral solution, long-acting decanoate, short-acting IM solution
Fluphenazine Tablet, oral elixir, long-acting decanoate, short-acting IM solution
Chlorpromazine Oral tablet, injectable solution
Perphenazine Tablet
Loxapine Capsule, oral inhaler
(continued)
Table22 .5(CONTINUED)
Stimulants
Dexedrine Tablet, extended release capsule, oral solution
Dextroamphetamine/Amphetamine Tablet, extended release capsule
Methylphenidate Tablet, extended release tablet, chewable tablet, extended release
capsule, oral solution, oral suspension, transdermal patch
Lisdexamfetamine Capsule
Atomoxetine Capsule
Modafinil Tablet
Armodafinil Tablet
due to its narrow therapeutic index and significant risk of lithium dosage, and usually a lower ultimate dose of the drug.
severe toxicity. The renal clearance of lithium is proportional The complexity of giving lithium to patients with medical
to creatinine clearance down to a creatinine clearance of 30 comorbidities has led many psychiatrists to avoid lithium in
ml/minute. Below this point, tubular reabsorption of lith- favor of other mood stabilizing agents, but this is not nec-
ium has a larger role, so the clearance of lithium decreases essarily wise. Many patients with bipolar disorder attain a
more rapidly than creatinine clearance. An essential point full remission on lithium but have only partial remissions on
is that lithium is reabsorbed in the proximal tubules in pro- alternative agents. Furthermore, a full response to lithium
portion to sodium reabsorption, so lithium reabsorption makes neuroleptic drugs unnecessary; patients thus avoid
is increased when aldosterone is increased, when patients the significant metabolic side effects of the latter drugs.
are on thiazide diuretics, or when the patient has another Finally, there is some suggestion from recent research that
clinical condition (e.g., heart failure) or is taking another consistent use of lithium can have a neuroprotective effect,
drug associated with sodium retention. Hypokalemia can preventing the loss of executive cognitive function that fre-
be an indicator of such conditions and should be a trigger quently complicates the long-term course of bipolar disorder
for closer monitoring of lithium levels, slower titration of (Diniz, Machado-Vieira, & Forlenza, 2013).
Antidepressants
Tricyclic Antidepressants
Amitriptyline None None None
Clomipramine None None None
Desipramine None None None
Doxepin None None None
Imipramine None None None
Nortriptyline None None None
(continued)
Sedative Hypnotics
Estazolam None None No data
Flurazepam None None None
Quazepam None None None
Temazepam None None None
Triazolam None None None
Eszopiclone None None No data
Zaleplon None None None
Zolpidem None None None
Ramelteon None None None
Autonomic Agents
Propranolol None None None
Clonidine None Consider lower initial dose None
Guanfacine None Consider lower initial dose None
Antiepileptics and Lithium
Valproic acid and derivatives None None None
Carbamazepine None None None
Oxcarbazepine None None No data
Lamotrigine None None No data
Levetiracetam 250750 mg q12h 250500 mg q12h Dialyzable; XR use not
recommended;
IR:5001000 mg daily,
then 250500 mg after
hemodialysis
Gabapentin 400 mg tid 300 mg q12h to q2h4 Dialyzable; 100300 mg
daily, then 125350 mg
after hemodialysis
Topiramate Reduce dose by 50% Reduce dose by 75% 30% dialyzable;
supplemental dose may
be needed
Lithium Reduce dose by 25%50% Reduce dose by 50%75% 50%100% dialyzable;
dose after dialysis
Stimulants
Dexedrine No data No data No data
Dextroamphetamine/Amphetamine No data No data No data
Methylphenidate No data No data No data
Lisdexamfetamine No data No data No data
Atomoxetine None None No data
Modafinil None No data No data
Armodafinil None No data No data
Cognition Enhancing Drugs
Donepazil None None No data
Rivastigmine None None No data
Galantamine Maximum 16 mg/day Maximum 16 mg/day Do not use
Memantine None Maximum 5 mg bid Do not use
(continued)
Table22 .6(CONTINUED)
Antidepressants
hypoxia can lead to decreased biotransformation of drugs Increased plasma concentrations of drug can occur, along with
with decreased hepatic extraction ratios, thus decreasing rates toxicity. Decreased Pgp expression leads to greater penetra-
of elimination (Taburet, Tollier, & Richard, 1990). In mild tion into the CNS for psychoactive drugs, increasing the risk
to moderate hypercapnia, an initial stress response leads to for serious toxicity. Alternatively, use of targeted therapeutic
increased cardiac output and pulmonary pressure; however, proteins such as antitumor necrosis factor alpha or monoclo-
as severity increases, cardiac output and vascular resistance nal antibody targeting IL-6 to treat chronic inflammatory
decreases (Devlin, 2014). Mechanical ventilation and subse- diseases can cause an upregulation in metabolic enzymes and
quent decreases in both cardiac output and hepatic blood flow transporters, leading to increased clearance and decreased
can lead to increased plasma concentrations of drugs with high exposure to therapeutic medications and, ultimately, decreased
hepatic extraction ratios (Taburet, Tollier, & Richard, 1990), therapeutic effect (Morgan, 2009). Alterations in pharmaco-
including certain antidepressants and antipsychotics such as kinetics of existing medications should be taken into account
amitriptyline and chlorpromazine, as well as propranolol. The when therapy is initiated.
benzodiazepine midazolam displays an extended elimination Infectious and inflammatory diseases can cause an increase
half-life when administered to those on mechanical ventila- in synthesis and release of acute phase proteins, including
tion (Byatt, Lewis, Dawling, & Cochrane, 1984). C-reactive protein and AAG (Morgan, 2009). Increased con-
centrations of AAG protein can lead to decreased free frac-
tions of highly bound medications, including clozapine (as
I N F E C T IOUS A N D I N F L A M M ATORY DI S E A S E S
described above), and the synthetic opioid methadone (Kapur,
Infection and inflammatory processes can significantly impact Hutson, Chibber, Luk, & Selby, 2011).
both drug distribution to site of action as well as drug metabo-
lism (Aitken, Richardson, & Morgan, 2006). Inflammation
as seen with acute infection, cancer, or chronic inflammatory MOR B I D OB E S I T Y A N D G A S T R IC
disease such as rheumatoid arthritiscan lead to decreased BY PA S S S U RG E RY
expression of metabolic enzymes, including CYP enzymes,
and drug transporters via proinflammatory cytokines includ- As noted above, morbid obesity has complex effects on the
ing IL-6. Decreased metabolic enzyme activity is seen in both pharmacokinetics of many medications, and predictions for
the liver and the gut (Xu, Wang, Sun, Chen, & Wei, 2006). dosing adjustments can be difficult to make. Alterations in Vd
479
Box 23.1 CRITERIA FOR DIAGNOSIS OF THE Patients undergoing acute medical illness, surgery, or
SEROTONIN SYNDROME trauma are overall at increased risk of SS because acute stress
causes serotonin release.
Treatment with a serotonergic agent and one or more of the
following: T R E AT M E N T
clonus (preferred finding)
agitation Treatment of SS involves removing potentially offending
autonomic disturbance agents (to the extent medically feasible) and providing sup-
tremor portive care. More specific treatment options involve either
hyperreflexia augmenting endogenous serotonergic regulatory processes or
blocking serotonin receptors with a drug. The magnitude of
treatment response will depend on syndrome severity. Mild
cases of SS will resolve within 72 hours of discontinuing the
Obviously, these criteria are sensitive but nonspecific; offending drug. Severe cases of SS may involve dehydration,
many patients with delirium have one or more of these signs, hyperthermia, and rhabdomyolysis similar to that seen in neu-
and many may be on selective serotonin reuptake inhibitors roleptic malignant syndrome (see below). In such cases inten-
(SSRIs) for treatment of depression or anxiety comorbid sive care is needed, which may include neuromuscular paralysis
with or secondary to their primary medical problems. Many and assisted ventilation (Brubacher, Hoffman, & Lurin, 1996;
patients with delirium may have hyperreflexia and a few beats Zand, Hoffman, & Nyman, 2010; Ables & Nagubilli, 2010).
of clonus; what is distinctive about SS is the prominent and Endogenous regulation of serotonin release can be
sustained clonus disproportionate to other signs of encepha- enhanced by administering nitroglycerin. This will stimulate
lopathy. The concurrence of gastrointestinal symptoms helps the synthesis and release of nitric oxide and thus shut off sero-
with the diagnosis, but the most useful point is a history of tonin release. Case series report its rapid effectiveness in severe
simultaneous onset of the CNS, autonomic, and GI symp- and refractory cases of SS; the theoretical argument for its use
toms in relation to a change in medications with serotonergic is solid, but evidence from controlled trials is lacking (Brown,
effects, or a change in medications that interact with a seroto- 2004). The authors suggest that nitroglycerin be considered
nergic medication to increase its level or its effect. in severe SS where the symptoms are a threat to the patients
life and health, and in cases of SS that show no improvement
in the first 24 hours after discontinuation of offending medi-
W HO I S AT R I S K ?
cations and provision of symptomatic treatment with ben-
SS is caused by increased activity of neurons stimulated by zodiazepines and/or cyproheptadine. A necessary caution is
serotonin. Thus drugs or medical conditions that increase to avoid nitroglycerin in a patient who has recently taken a
serotonin release, drugs that impair the neuronal reuptake PDE5 inhibitor, particularly the long-acting PDE5 inhibitor
or systemic clearance of serotonin, and drugs that directly tadalafil (Cialis). Because of the frequent occurrence of sexual
stimulate serotonin receptors all can contribute. Moreover, dysfunction as an SSRI side effect, it is not uncommon to find
the neuromodulator nitric oxide shuts off serotonin release, so patients on a combination of SSRIs and PDE5 inhibitors.
agents that reduce nitric oxide levels may indirectly increase Other drug treatments of SS include drugs that block
serotonergic activity. The onset of SS usually is provoked by a serotonin receptors. Cyproheptadine, an antihistamine that
change in one or more of these three factors. blocks all types of serotonin receptors, has a relatively benign
Circumstances and substances that increase serotonin side-effect profile, with sedation being the most common
release include the following: acute stress, trauma, surgery, reaction; however, it also has anticholinergic effects that
hypoxia, hypoglycemia, alcohol, opiates, cocaine, MDMA, can be problematic in some medically fragile patients. It is
amphetamines and other sympathomimetic agents, lith- formulated as 4mg tablets; treatment can start with one or
ium, and the nutritional supplement 5-hydroxytryptophan two tablets, and this dose of 4 mg or 8 mg of cyproheptadine
(5-HTP), which is the immediate precursor of serotonin. may be repeated every 1 to 4 hours until symptoms of SS
Drugs directly stimulating serotonin receptors are resolved. Other reported treatments include benzodiaz-
include:triptans, buspirone, lithium, and LSD. epines, ondansetron (a 5HT3 blocker), chlorpromazine, and
Drugs inhibiting neuronal reuptake of serotonin include olanzapine (which blocks 5HT2 receptors). Benzodiazepines
SSRIs, selective noradrenaline reuptake inhibitors (SNRIs), are most helpful for agitation and hyperreflexia but may not
tricyclic antidepressants (TCAs), monoamine oxidase inhibi- be effective for the full syndrome. Chlorpromazine can be
tors (MAOIs) and linezolid. helpful for agitation and the GI symptoms but may exacer-
Drugs that inhibit nitric oxide (NO) synthesis include bate tremors and autonomic disturbances, and it has substan-
paroxetine, fluoxetine, and methylene blue (Ng & Cameron, tial anticholinergic effects. Ondansetron is highly effective
2010). It is thought that the former two SSRIs may carry for nausea and vomiting, but its relatively selective inhibi-
increased risk of SS because of their dual effect on NO syn- tion of 5HT3 receptors may actually disinhibit serotonin
thase and on serotonin reuptake. release in some brain regions. Similar considerations apply
SS is more common in smokers. Diabetes and hyperten- to olanzapine, with its relatively selective 5HT2 blocking
sion are both associated with increased risk of the condition. action. Benzodiazepines, often the first choice for managing
NMS Usual; often>104 F Rigidity is usual; typically Cognition usually Creatine kinase (CK)
severe and tremulous impaired; mutism usually high, often
common extremely; myoglobinuria
in severe cases
Tetanus Fever in most cases but Muscle spasms but Confusion is sometimes Positive culture for
not usually over 104 F not tremulous rigidity present Clostridium tetani
typicalof neuroleptic-
induced EPS
Serotonin syndrome Inconsistently present Hyperreflexia and Confusion is sometimes No specific finding; mild
clonus but not rigidity; present but not severe elevation of
sometimes tremor CK in some cases
Malignant catatonia Often present but not Catatonia (waxy Usually confused, often No specific finding; CK
essential flexibility); not severe mute may be mildly elevated
rigidity; no tremor
Malignant hyperthermia Fever over 104 F Rigidity usual but not Often confused but not CK elevated, sometimes
necessarily extreme; not necessarily extremely; myoglobinuria
tremulous in severe cases
Heat stroke Fever is usual Not rigid Sometimes confused No specific findings
ATROPINE DOSE
(MILLIGR A MS) CENTR AL EFFECTS PER IPHER AL EFFECTS
1.0 Increased effects on arousal. Some short-term memory Cardiac: slight tachycardia
impairment. Pupillary: dilatation
Gut: increased oral dryness
5.0 Restlessness and fatigue. Onset of confusion and Cardiac: marked tachycardia
agitation. Visual hallucinations may occur. Pupillary: worsening of above
Gut: swallowing difficult; constipation
Other: urinary retention, skin dry
10 Delirium may progress to seizures, coma and death. Cardiac: tachycardia may be complicated by reduced
cardiac output
Pupillary: pupils maximally dilated; paralysis of
accommodation
Gut: skin red, hot, dry
Time to occurrence after Typically days Typically days Gradual accumulation of cases
medication discontinuation over 12years
Systemic findings May or may not be seen Usually present, and often Usually absent
accompanied by dyskinesias
Mental status changes Typical psychosis Non-specific with agitation or Typical psychosis
confusion
Effect of resuming discontinued Gradual improvement Swift resolution of systemic and Gradual improvement
medication mental status findings
Effect of not resuming Gradual improvement may Gradual improvement occurs No improvement without
medication occurover weeks, but is not over weeks intervention
assured, and may be less likely
with less anticholinergic agents
Fasting insulin level An elevated serum level suggests Not every clinic has this study available.
insulinresistance
Fasting glucose A normal level is <100 mg/dL Elevations may reflect a late stage of insulin resistance
HgbA1C Normal values are 4% to 5.6% Elevations may reflect a late stage of insulin resistance.
Triglyceride/HDL A ratio <3 suggests low risk for the The poor mans insulin sensitivity assay. Lipoprotein lipase is
(fasting) MS,while a ratio >6 indicates a under the control of insulin, and affected by insulin resistance. An
>50%risk of having the MS. independent disorder of lipid metabolism, or treatment for a lipid
disorder, may skew results and reduce the value of this ratio as a
measure of insulin sensitivity.
Waist circumference Men:> 40inches Increases the likelihood of metabolic syndrome, but overall
Women:> 35inches contribution is only about 25%.
Body mass index > 25:overweight Highly correlated with waist circumference and obesity, with same
> 30:obese limitation as for waist circumference
> 40:morbid obesity
White cell count Elevations are a well-established An elevated white cell count is very nonspecific.
featureof the MS.
Benefits with these agents are not as consistent as with and toxic epidermal necrolysis (TEN). Acute hypersensitivity
metformin (Fiedorowicz et al., 2012). Topiramate 250 mg reactions may be difficult to anticipate. The clinician should,
daily has been effective for some patients (Ko, Joe, Jung,& however, be aware of a few important points.
Kim, 2005). The FDA has approved Qysmia for weight Many drugs can cause rashes: among the most common
reduction. This is a combination of low-dose phentermine offenders are aromatic anticonvulsants; other psychotropics
and controlled-release topiramate (Garvey et al., 2012). are less frequent offenders. The aromatic anticonvulsants
Concerns about cardiovascular and pulmonary toxicity include carbamazepine, lamotrigine, phenobarbital, phenyt-
with phentermine are somewhat assuaged by the low-dose oin, and trileptal. Their metabolism rarely yields arene oxides,
use in Qysmia as well as toxicity studies for the combina- which are often implicated in the anticonvulsant hypersen-
tion agent. Topiramate has well described unwanted cog- sitivity syndrome (AHS). AHS may also be an immune-
nitive effects. These are dose-dependent. However, because mediated (or allergic) response. As many as 8% of all persons
the serum levels achieved by a single dose of topiramate may exposed to medications will develop some form of cutaneous
vary by a factor of over 50 times among individuals, it is dif- side effect. Perhaps 3% of all patients prescribed carbamaze-
ficult to predict the impact of a single dose (Cirulli et al., pine will develop a drug eruption (Elias, Madhusoodanan,
2012). Amantadine 200 mg daily when added to olanzapine Pudukkadan, & Antony, 2006). In one retrospective study
separates from placebo in reducing weight gain (Hoffmann, of patients started in lamotrigine, 13% developed a nonseri-
Case, & Jacobson,2012). ous rash of some kind (Ginsberg, 2006). Most of these rashes
An inquiry should also be made into sleep quality and are benign. A rash that spreads widely, is intensely pruritic,
characteristics. If obstructive sleep apnea suggests itself in the involves the mucous membranes of the eye or mouth, or has
patients history, a sleep study should be considered to make other systemic findings such as fever or lymphadenopathy,
a definitive diagnosis (Rajagopalan, 2011). For some patients, should raise alarm and lead to treatment of the rash and
bariatric surgery may be significantly helpful in treating obe- discontinuation of any medication suspected of causing it.
sity and, as a result, the MS (Giugliano, Ceriello, & Esposito, Leukocytosis, especially with eosinophilia, and elevation of
2008; Madan, Orth, Ternovits, & Tichansky, 2006). hepatic enzymes are also indicative of a more severe systemic
reaction. But devastating hypersenstivity reactions to anticon-
vulsants, or AHS, are rare. First described in 1950 by Chaiken
DE R M ATOL O G IC AL R E AC T ION S and colleagues, AHS typically occurs with older anticonvul-
sants such as carbamazepine, phenobarbital, phenytoinbut,
as noted, it may occur with lamotrigine. Because of the rela-
C L I N IC A L F E AT U R E S
tively high incidence of seizures in the first decade of life, chil-
The skin holds a special distinction among drug side effects as dren may present relatively frequently with AHS (Chaiken,
being the site of some of the drug reactions that are the most Goldberg, & Segal, 1950; Scaparrotta et al., 2011). The cli-
visible, violent, and difficult to diagnose. Among these reac- nician must be concerned when an extensive rash develops
tions are the Stevens Johnson syndrome (SJS), drug rash with that is complicated by fever, eosinophilia, lymphadenopathy,
eosinophilia and systemic symptoms (DRESS) syndrome, nephritis, or hepatitis (Cacoub et al., 2011).
(1) Check serum osmolality (1)Agents and factors that promote sodium loss:
If serum is hypoosmolar, then: Renal:
hypoaldosteronemia
(a)Obtain urine osmolality to determine:
hypocortisolism
if urine is appropriately dilute (<100 mOsm/kg) or inap-
cerebral salt-wasting syndrome
propriately concentrated (>100 mOsm/kg).
Medications:
(b)Check urine sodium and urea to assess whether these
thiazide diruetics
are being retained or inappropriately excreted.
Gastrointestinal:
If serum osmolality is normal, consider
diarrhea, vomiting
pseudohyponatremia.
Burns
(2)If possible, determine whether hyponatremia is of acute
(2) Agents and factors that promote volume expansion:
onset (48 hours or less) or is chronic.
Intravenous fluids
Symptomatic hyponatremia of acute onset should be cor-
Parenteral nutrition
rected quickly.
Congestive heart failure
Hyponatremia of prolonged duration should be corrected
Cirrhosis
slowly.
Hypothyroidism
(3)Next, identify signs and symptoms suggestive of cerebral
(3)Agents and factors that enhance the release or activity of
edema.
antidiuretic hormone:
(4) Initiate treatment as indicated. Stimulate ADH release:
Determine rate of correction:do not exceed 12 mEq/L per Cerebral disease
day to avoid demyelination. infections, multiple sclerosis, malignancies
Identify any conditions or medications that may promote Medications
hyponatremia. SSRIs may be the most common cause of drug-induced
SIADH
Other
requires clinical action. Box 23.5 outlines a clinical approach pulmonary diseases, including asthma, bacterial pneu-
to hyponatremia (Chubb, 2009; Esposito, Piotti, Bianzina, monia, tuberculosis
Malul, & Dal Canton, 2011; Josiassen et al., 2012; Vaidya, Tumors
Ho, & Freda, 2010). small cell lung cancer, less commonly lymphoma, pan-
A host of medications and conditions can cause, or encour- creatic cancer
age the development, of hyponatremia. Box 23.6 outlines the Enhance sensitivity to ADH:
general categories of these agents and treatments. Medications
SSRIs, carbamazepine, cyclophosphamide
ADH analogues
W HO I S AT R I S K ? desmopressin, oxytocin, vasopressin
Many factors increase the risk of developing hyponatremia.
Being female, advancing age, commonly used medications
such as thiazide diruetics and SSRIs, a variety of common etal., 2002), Fisher and colleagues (2002) found that the vast
medical problems including hypothyroidism, and a history of majority of patients with symptomatic hyponatremia due to
having hyponatremia are among the risk factors for develop- citalopram were at least 70years old and that three in four were
ing it (Musham, Jarathi, & Pedraza, 2010). The syndrome of women. It appears that the SSRIs increase the expression of
inappropriate antidiuretic hormone (SIADH) activity is the aquaporin 2 in the inner medullary collecting duct of the kid-
most common cause of hyponatremia (Hannon & Thompson, ney (Moyses, Nakandakari, & Magaldi, 2008). This enhances
2010). Patients with SIADH cannot dilute their urine despite the renal response to ADH and leads to hyponatremia.
hypoosmolar serum. Among medications, the SSRIs appear It is sometimes argued that other classes of antidepressant
to be a common precipitant of SIADH. may pose less risk of hyponatremia and studies have found
Certainly SSRI-induced SIADH is not common:perhaps a that the risk of hyponatremia with mirtazapine and venlafax-
few cases per thousand occur. And yet the SSRIs are prescribed ine was significantly less than with SSRIs (Jung, Jun, Kim, &
so widely that the problem has become well known. Typically, Bahk, 2011). However, case reports of hyponatremia have been
SSRI-induced SIADH develops within 2 to 4 weeks of initiat- linked to essentially every class of antidepressant. Roxanas and
ing treatment. Dosage does not appear to be a risk factor. But colleagues reported in a prospective study that 10 of 58 patients
hyponatremia may develop 3 months or more after starting over 65years old started on venlafaxine developed hyponatre-
treatment with an SSRI (Liu et al., 1996; Madhusoodanan mia within weeks (Roxanas, Hibbert, & Field, 2007).
Urine osmolality Low, and sometimes profoundly low. Not low given serum osmolality:
<100 mOsm/L >100 mOsm/L
500
(for seasonal affective disorder; Terman etal., 1989), focal elec-
trically administered seizure therapy (Spellman, Peterchev, &
Lisanby, 2009), magnetic seizure therapy (Lisanby, Schlaepfer,
Fisch, & Sackeim, 2001), low intensity pulsed ultrasound
(Tyler etal., 2008), near infrared light therapy (Hamblin &
Demidova, 2006), low field magnetic stimulation (Rohan
et al., 2004) and optogenetic stimulation (in animals; see
Yizhar etal., 2011). Each varies in the type of energy utilized
and in the methods of application. Moreover, while each of
these technologies is at a different stage of development, none
have been approved or cleared for use by the FDA. These treat-
ments remain investigational, and in the clinical setting they
would only be encountered in patients participating in clini-
cal trials studying their use.
This chapter will focus on neurostimulation treatments
that have been approved or cleared for neurological and/or psy-
chiatric indications. These treatments include well-established Figure24.1 Electroconvulsive therapy (ECT)
treatments such as ECT, which has a long history of use, as
well as more recently developed interventions such as VNS, such as psychotic depression, mania, and schizophrenia
rTMS and DBS. These technologies are being used or inves- (U.S. Department of Health and Human Services, 1999).
tigated to treat a growing number of neuropsychiatric condi- While a significant amount of research has been conducted
tions such as seizure disorder, Parkinsons disease, essential on ECT for various indications, recent systematic reviews
tremor, dystonia, catatonia, obsessive compulsive disorder, and meta-analyses of the literature support effectiveness only
and depression, and are currently being studied for numerous for depression, and only in the acute period within the first
other diseases. We will examine the historical development month after the course of treatment (Greenhalgh, Knight,
and theoretical foundation of each treatment, the indications Hind, Beverley, & Walters, 2005). For depression, ECT is
for use, potential associated adverse events, typical clinical generally considered after failure of multiple antidepres-
management, and settings where these treatments may be sant trials and/or deterioration of the patients psychiatric
encountered in the care of the medical patient. or medical condition creating a need for a rapid, definitive
response (i.e., acutely suicidal, medically unstable; American
Psychiatric Association, 2001). Because of the lack of other
ECT effective treatments, and the high mortality rate associated
with treatment-resistant catatonia, in the clinical setting ECT
Considered by many to be one of the most effective treat- is considered in treatment resistant catatonia (i.e., refrac-
ments for depression, ECT is also one of the oldest treatments tory to adequate trialsat least 2 mg parenteral lorazepam
still used for psychiatric conditions. The application of elec- or equivalentof benzodiazepine; Bush et al., 1996) as an
tricity to the scalp with the intention of causing a seizure was off-label treatment.
first conducted by two Italian physicians, Cerletti and Bini, in Of all the treatment modalities discussed in this chapter,
1938 (Bini, 1995). Since that time, ECT has had a varied his- ECT is the most likely treatment intervention to be encoun-
tory with periods of significant use and relative disuse. In the tered in clinical practice. Treatment-resistant depression has
1940s and 1950s, given the relative lack of effective pharma- been a growing concern (Rush et al., 2006) and individuals
cotherapy and used in association with psychosurgical tech- who have adequately responded to multiple antidepressant
niques, ECT was used quite widely. At this time, ECT was medication trials and suffer from severe symptomatology may
administered without modern medical and anesthetic man- be encountered in both the outpatient and inpatient setting.
agement. In the 1960s through the 1980s pharmacotherapy The catatonic syndrome, though uncommon, should be antic-
became more effective, while there was increasing public con- ipated in the general hospital setting, given that the etiology
cern about coercive treatment and the stigmatization of men- may be medical, neurological, or psychiatric in nature, and
tally ill people. In this context the usage of ECT waned, even the presentation may masquerade as a variety of related condi-
for the treatment of patient populations in which it is remark- tions. The typical course of ECT consists of 612 treatments,
ably effective. From the 1990s through the present, with the administered 23 times per week. Catatonic symptoms may
development of modern anesthesia (general anesthesia, mus- be more persistent and may require longer courses of treat-
cle relaxation, cardiovascular and pulmonary management), ment. As previously noted, the effectiveness of ECT has been
modifications in the ECT technique, and increasing con- demonstrated in the acute period; symptom relapse after a suc-
cern about treatment-resistant disease, ECT has once again cessful course of ECT is a clinical concern. Clinical practice
become an important option in the treatment algorithm of strategies that are intended to decrease the relapse rate include
severe, treatment-resistant depression. continuation pharmacotherapy using post-ECT administra-
Currently, ECT is used to treat depression (both unipo- tion of antidepressants, such as nortriptyline and lithium car-
lar and bipolar) and catatonia, as well as other conditions bonate (Sackeim et al., 2001), or maintenance ECT (a tapered
Cardiovascular Hypertension, hypotension, arrhythmias, Pre-ECT assessment (e.g., BP, EKG, echocardiogram,
ischemia,embolic or hemorrhagic strokes holter, neuroimaging, neurovascular studies)
Frequency:BP changes common, CV Appropriate procedure monitoring (e.g., BP and
uncommon,stroke rare. rate control, anticoagulation for patients with atrial
fibrillation)
Severity:mildsevere Appropriate clinical management
Physical Fractures, soft tissue injury, dental fractures, Pre-ECT dental assessment
dislocations, oral lacerations, prosthetic damage, Removal of prostheses
corneal abrasions, burns at electrode site Use of general anesthetic agents and neuromuscular
Frequency:uncommon blocking agents
Use of mouth protection (bite blocks)
Severity:mildsevere Skin preparation and electrode contact
Use of conductivity gel
Anesthesia-related Adverse reaction or prolonged reaction to Pre-ECT assessment (medical, family history)
anestheticagents, neuromuscular blocking agents Appropriate procedure monitoring
Frequency:rare Appropriate clinical management
Severity:severe
Death Resulting from other pathophysiological processes Appropriate workup and management of specific
Frequency:rare medicaland psychiatric risks
Severity:severe
Psychiatric
Cognition Disorientation generally occurs posttreatment, Use of square wave, direct current, brief pulse
but typically resolves minutes after completion of waveform stimulus (not sine wave)
treatment. Use of unilateral nondominant electrode placement
Frequency:common Use of ultra-brief pulse (0.3 msec) stimulus
Frequency of treatment no greater than twice weekly
Severity:mild during a course of ECT
Memory Anterograde memory impairmentappears to Exclusive use of square wave, direct current, brief pulse
resolve within 3months posttreatment. Retrograde waveform stimulus
autobiographical memory impairmentdata out Use of unilateral nondominant electrode placement
to 6months do not demonstrate full resolution of Frequency of treatment no greater than twice weekly
impairment. during a course of ECT
Frequency:common Use of ultra-brief pulse (0.3 msec) stimulus
Severity:mildsevere
evaluation, and special observation and management (if ECT initiating ECT. Other conditions that warrant additional eval-
is pursued). In particular, individuals with cardiac valve dis- uation and management include pregnancy, space-occupying
ease (e.g., aortic stenosis) may require cardiac outflow studies intracranial lesions, cerebral aneurysms, neurovascular mal-
and correction of the underlying structural anomaly prior to formations, and recent TIAs/strokes.
INTENSITY (%MT)
FR EQ
(HZ) 90 100 110 120 130
Figure24.3 Repetitive transcranial megnetic stimulation (rTMS) number of pulses). Maximum safe stimulation criteria have
been established, originally published by Wassermann (1998)
electrical stimulation (though, however, transcranial direct and later updated by Rossi etal. (2009; see Table 24.3). rTMS
current stimulation with low current is feasible and is under is generally conducted in the outpatient setting, with a typi-
exploration as a therapy for depression and other conditions). cal course of treatment comprising one-hour stimulation ses-
Through the use of shaped coils, the magnetic flux may be sions five days a week for 4 to 6 weeks. Potential adverse events
focused on specific cortical anatomical targets. While mag- include seizures, induction of mania, pain over the stimula-
netic stimulation utilizing different characteristics has been tion site, headache, visual changes, dental pain, facial numb-
investigated (i.e., single pulse vs. repetitive, alternating vs. ness or twitching, temporary or permanent hearing loss, and,
direct current), repetitive stimulationrTMS, utilizing in children and adolescents, neurocardiogenic syncope. The
alternating currenthas received the most attention. rTMS risk of a seizure can be minimized by adherence to safe stimu-
devices have been investigated in a number of different con- lation criteria. EEG monitoring and appropriate antiepilep-
ditions. However, they are approved for only one condition, tic management should be available in the event that seizures
which is major depression. In 2008, an rTMS device was occur in the course of treatment. Induction of hypomania
cleared for the treatment of major depressive disorder in adult or mania is also a rare complication of rTMS, and should be
patients who have failed to achieve satisfactory improve- managed by cessation of rTMS treatments and/or appropri-
ment from one prior antidepressant medication at or above ate mood stabilizing interventions. Given the loudness of the
the minimal effective dose and duration in the current epi- rTMS device and the potential for permanent hearing loss,
sode.2 The pivotal randomized controlled trial demonstrated earplugs should be worn at all times by all patients and treat-
a p-value of 0.057 for the prespecified primary effective- ers. If rTMS is off-label for a child or adolescent the patients
ness endpoint (difference between active and sham baseline blood pressure and pulse should be monitored because of the
to 4-week endpoint change on the Montgomery-Asberg risk of neurocardiogenic syncope. Overall, however, the inci-
Depression Rating Scale; see OReardon et al., 2007). Based dence of serious adverse events with rTMS is very low and the
on the evidence available, rTMS was cleared by the FDA for treatment should be regarded as relatively safe, as compared
use in individuals with major depression who had failed one with ECT, multi-drug regimens and other treatment options
prior antidepressant trial. for treatment-refractory depression. Contraindications to
While rTMS has not been cleared or approved for other rTMS include any metal in the head (except in the oral cav-
indications, current investigations are examining its use for var- ity), increased intracranial pressure, cardiac pacemakers,
ious conditions including schizophrenic hallucinations, PTSD, implanted neurostimulators, medication pumps, and intra-
obsessive compulsive disorder, Parkinsons disease, Alzheimers cardiac lines. Other conditions that may preclude rTMS
disease, neurorehabilitation, migraine headache, chronic pain, treatment or require additional monitoring and management
and tinnitus (Wassermann & Zimmermann, 2012). include significant cardiac disease, pregnancy, history of bipo-
The system includes a wrapped wire coil, a console (includ- lar disorder, stroke, brain lesions, suicide attempts, and per-
ing energy source), and a patient chair. Coils are of various sonal or family history of seizure disorders.
shapes (a common shape is figure 8) to create an optimal
magnetic field (Marangell, Martinez, Jurdi, & Zboyan, 2007).
For depression, stimulation is localized over the left dorsolat- DEE P B R A I N S T I M U LAT ION
eral prefrontal cortex. Certain parameters are then set for
the treatment, such as frequency of pulses, and intensity (as a Deep brain stimulation (DBS) is an invasive brain stimula-
percentage of motor threshold-MT, train duration, and total tion technique which involves direct electrical stimulation
of cortical and subcortical brain structures through the
2. www.accessdata.fda.gov/cdrh_docs/pdf8/K083538.pdf precisely-localized implantation of an electrode into deep
obsessive compulsive disorder (OCD). Dystonia and OCD Output current 02.25 mA
were approved by the FDA under a Humanitarian Device
Exemption, which allows for a maximum annual number Frequency <185 Hz
of patients treated of 4,000. In clinical practice, given the Amplitude <3.5 V
increased use and experience of DBS for movement disor-
ders, patients with implanted DBS devices are most likely to Pulse width <210sec
be encountered by medical psychiatrists when they consult to Charge density 30 C/cm2/phase
neurology services. On occasion medical psychiatrists are asked
to do pre-implantation assessments of candidates for DBS. Duty cycle
Table24.4 outlines the indications and anatomical targets. Stimulation ON 60 sec
In addition, DBS is currently being investigated at Stimulation OFF 0.3180 min
various locations for a number of other disorders. These
disorders include major depression, epilepsy, Tourette From Kuncel & Grill, 2004.
511
treatment with opioids and antiinflammatory agents. Patients PA I N F ROM A P S YCH I AT R IC PE R S PE C T I V E
may use words such as sharp, dull, aching, or throbbing when
The various editions of the American Psychiatric Associations
asked to describe this type pain. While radiation may be pres-
Diagnostic and Statistical Manual contain diagnoses related
ent, it is less common, and when it is noted it often does not
to pain; however, these all apply to chronic pain and con-
follow a distinct nerve distribution.
tinue to wrestle with the problem of whether pain can be
Neuropathic pain reflects an abnormal functioning of the
subdivided into subtypes that are primarily psychological
central or peripheral nervous system, which may be triggered
and primarily medical. In the fifth edition of the manual,
by a direct nerve injury or systemic illness. Severe pain may
the work group responsible for this disorder recommended
occur with trivial stimuli, such as a light touch or a breeze
that these distinctions be dropped and the category of Pain
on a patients skin. Opiates are less helpful in alleviating neu-
Disorder be subsumed into a new, more general somatoform
ropathic pain, and when they are used they tend to require
disorder (currently referred to as Somatic Symptom Disorder).
higher doses to provide adequate analgesia. Patients may
Many individuals currently diagnosed with Pain Disorder
describe the pain as electric or burning. Radiation is common
would fit into this category, whereas for others, psychological
and tends to follow a typical nerve distribution.
factors affecting other medical conditions or an adjustment
The experience of pain in a particular patient may not
disorder would be more appropriate.
always fit neatly into these categories. Patients may have
In clinical practice, the majority of pain patientspar-
acute surgical pain but a complicated postoperative course
ticularly acute pain patientswill not have a somatoform
that ultimately leads to a chronic pain syndrome. Despite
disorder. However, even short-term pain symptoms can pre-
the limitations of the acute/chronic, nociceptive/neuropathic
dispose a patient to other psychiatric disorders, particularly
framework, it may be a useful starting point in developing a
depressive and anxiety disorders. In addition, even in the
management approach.
absence of a formal psychiatric disorder it should be remem-
In addition to categorizing pain in terms of its time
bered that all pain is, in part, a psychological phenomenon
course and mechanism, a common next step is to rate pain
(Lavandhomme, 2011). The Institute of Medicine under-
intensity. Since many patients will have more than one area
scored this point in its description of the nature of pain:The
of pain at any given time, rating pain is usually preceded
experience of pain is more than a simple sensory process. It is
by a determination of the total number of pain problems
a complex perception that involves higher levels of the central
(and where they are located), and then describing and rat-
nervous system, emotional status, and higher order mental
ing each. Various instruments are available to assess pain,
processes (Osterweis, 1988).
including visual analog and numeric scales. Despite the
limitations of numeric scales, they are commonly used and
practical for bedside assessment. They are easily adminis-
PH A R M AC OL O G IC T R E AT M E N T FOR PA I N
tered, require no special forms, and can be used to track
changes over time (Hawker, Mian, Kendzerska, & French, While nonpharmacologic approaches may have an important
2011). Typically, the person administering the scale asks the role in acute pain management (and are addressed later in this
patient to rate his/her pain intensity from 1 to 10, 1 being chapter), most patients treated for acute pain will be medi-
no pain and 10 being the worst pain imaginable. In addi- cated. The choice of analgesic therapy is based on the type and
tion to asking the patient to provide a number to rate his/ severity of pain, individual patient concerns and preferences,
her current pain level, it also can be helpful to ask, What and knowledge of the clinical pharmacology of the drug pre-
number would you like it to be? Once this assessment scribed, including its half-life and common drugdrug inter-
has been performed, a common starting dose for patients actions. Attention to all these factors increases the likelihood
who are opiate-nave would be 510 mg of oral morphine of providing successful analgesia at any stage of treatment.
equivalent every 4 hours. The lower dose range should be There are some instances of acute pain when correcting
considered for patients who are older and who have renal the underlying problem will immediately resolve severe pain
or hepatic insufficiency, which may affect drug metabolism symptoms. For example, while a patient with an acute hip
and effective half-life. dislocation may present with excruciating pain that warrants
In addition to assessing the experience of pain itself, a opiate medication prior to definitive therapy, when reduction
thorough evaluation also should include an investigation for is performed it may lead to immediate resolution of pain. This
the presence of other associated non-pain symptoms that may speaks to the idea of pattern matching. Appropriate pharma-
be present. These include but are not limited to physical symp- cological treatment of pain provides medication that addresses
toms, such as dyspnea and nausea, and also an evaluation for both the severity and likely time course of the pain condition.
psychiatric comorbidities or complications. Determining the Medication choice also will depend on patient-specific fac-
degree to which a patient is suffering is essential. Suffering has tors. If the patient has a previous history of using pain medica-
been described as a state of severe distress associated with tion, the response to specific agents may be useful in guiding
events that threaten the intactness of the person (Cassel, current therapy. The presence of renal and/or hepatic impair-
1982). While suffering may be difficult to quantify, it has a ment will impact the choice of agent. If a patient has more
significant impact on quality of life. If it is not addressed, it is than one symptomfor example, back pain and debilitating
unlikely that even the most thoughtfully chosen pain regimen cougha regimen that includes an opioid could reasonably
will provide adequate palliation. be expected to palliate both symptoms.
Although regimens should be individualized, general guid- The most common cause of inadequate acute pain manage-
ing principles are available. The World Health Organization ment is the underuse of opioid analgesics. In fact, many doc-
(WHO) ladder (Ventafridda, Saita, Ripamonti, & De Conno, tors prescribe less than half the effective analgesic dose for
1985)provides a step-wise approach for the treatment of can- their patients with pain (Marks et al., 2009). In addition to
cer pain, which also may provide guidance for the manage- doses that are inadequate, opioids often are prescribed at time
ment of noncancer pain (Figure 25.1). Step 1 addresses the intervals that extend beyond the effective half-life of the drug.
management of mild to moderate pain and advises the use of The use of suboptimal doses and excessive time between dose
non-opioid agents (e.g., nonsteroidal antiinflammatory drugs intervals may result from physician orders, nursing administra-
or paracetamol). Adjuvant agents may be used at any of the tion, or patient bias. Some patients attempt to endure pain and
steps and include (but are not limited to) antidepressants, earn the respect of the nurses and doctors as good patients.
anticonvulsants, steroids, muscle relaxants, and behavioral When patients start to complain of severe pain before their
therapy. When pain persists or increases, Step 2 suggests con- next dose is due, they often are thought of as addicted or
tinuing the non-opioid drug and adding a low potency opioid excessively preoccupied with medication. In fact, such patients
(e.g., codeine). For pain that persists or increases despite this may only be expressing the fact that their pain has reemerged
regimen, Step 3 recommends more potent opioids (e.g., mor- because their dose time has gone beyond the effective duration
phine) as first-line therapy. of the opioid. Table 25.1 lists usual dose ranges for commonly
Minimizing polypharmacy is a preferred treatment strat- prescribed opioids and their average duration of action.
egy. This is in part because single agents may be more care- The consultant dealing with a pain patient who contin-
fully titrated and have more predictable side effect profiles. In ues to complain despite usually adequate treatment should
addition, the benefits of adding adjuvant medications, such as first look at the dose and frequency of analgesic delivered. Ask
antidepressants, should be weighed against the potential for patients what level of relief they get within the first hour after
drugdrug interactions. The use of codeine illustrates this con- their dose. If relief during that time is inadequate, the dose
cern. The analgesic effect of codeine is dependent on conversion is too low. If pain relief is complete but reemerges before the
to an active metabolite by the CYP 450 2D6 substrate (Eissing, next dose, the duration between doses is too long. It is essen-
Lippert, & Willmann, 2012). Approximately 7% of the popula- tial to look directly at the drug administration record, not at
tion lacks the 2D6 enzyme and are not benefited by this medi- orders or progress notes, to confirm what has actually been
cation. The enzyme can also be blocked by many commonly given to the patient and on what schedule. Opioids should be
prescribed medications, such as selective serotonin reuptake given on a schedule corresponding to their analgesic half-life
inhibitors (SSRIs) (Sindrup & Brosen, 1995) like paroxetine (see Table 25.1).
and fluoxetine that significantly inhibit the 2D6 enzyme. Pain symptom palliation always should take into account
the balance between opioid analgesic benefit and the suffering
E F F E C T I V E US E OF OPIOI D S I N AC U T E PA I N
that common opioid side effects may cause. Many symptoms,
such as nausea, constipation, respiratory suppression, and
For patients with severe, acute pain, morphine represents the delirium, may be avoided or minimized, and strategies are dis-
standard opioid against which all others are usually compared. cussed later in this chapter.
APPROXIM ATE IV
USUAL DOSING APPROXIM ATE OR AL EQUIVALENT TO
USUAL PO DOSE PAR ENTER AL INTERVAL EQUIVALENT TO 30 MG 10MG IV MOR PHINE
DRUG (MG) DOSE (MG) (HRS) OR AL MOR PHINE (MG) (MG) COMMENTS
Morphine 30 36 34
Sustained release 90120 812 60
Fentanyl transdermal (transdermal:25 ug/h) 72 0.2 Immediate release available but primarily
used for anesthesia
Levorphanol 4 2 68 48 2
Tramadol 50 34 300 Is a mu receptor agonist, however is not
an opioid.
F I X E D V E R S US AS -N EE DE D decubitus ulcer, it is reasonable to provide short-acting pre-
D O SE S C HE DU LES medication in anticipation of this event. When a fixed-dose
pain regimen is ordered, it is common practice to write an
When acute pain has been diagnosed, physicians must accompanying order for PRN medication to provide break-
consider whether analgesics should be prescribed on an through pain coverage. Generally, the appropriate PRN dose
as-needed or fixed-dose schedule. Severe, continuous pain is should be related to the total daily morphine equivalent of
better treated on a fixed schedule. A routine schedule not the standing dose medication. Frequent reassessments of the
only increases the likelihood of effective analgesia, but also amount of PRN medication being accessed may be useful in
will tend to minimize some of the common adverse effects guiding dose adjustments and optimizing pain management.
associated with shifting blood levels, including nausea and
respiratory depression (Lo Presti, Roscetti, Muriess, &
Mammucari, 2010). C HOIC E OF ROU T E OF
A schedule based on the half-life of the opioid pre- A DM I N I S T R AT ION
vents reemergence of pain before the next dose, but even
well-intentioned efforts to provide as-needed medication There are multiple routes available for opiate administration
based on half-life may provide insufficient analgesia, as drug that may be appropriate in providing acute pain management.
metabolism and duration of benefit may vary among indi- These vary in terms of onset, intensity, and duration of analge-
vidual patients. The dose required to treat reemergent pain sic effect; ease of dispensing; availability; and cost. Conversion
resulting from an as-needed or PRN (Latin:pro re nata liter- between forms is discussed later in this chapter.
ally, from the thing born; figuratively, as the need arises)
schedule often is larger than would be required to prevent it
OR A L
using a fixed schedule. Giving patients medications on a PRN
basis places them in a dependent position. The requirement Oral analgesic administration offers simplicity and econ-
that they must ask staff for each dose of pain medication can omy, avoids the discomforts and potential complications
be humiliating for the patient and can be negatively inter- of repeated injections, makes the patient less dependent on
preted by care providers as an excessive preoccupation with others for care, and may obviate the need for hospitaliza-
receiving medication. In patients who do have a propensity for tion in some cases. Dosage forms include tablets, capsules,
drug seeking, this type of regimen may reinforce this negative and liquids. Pure opiate and combination (opioid/NSAID
behavior. Patients who have cognitive impairments or fluctu- or paracetamol) forms are available. Oral medications are
ating levels of alertness may have difficulty being able to ask available in short-acting, immediate-release, and long-acting
for medication. release formulations. As discussed earlier in this chapter,
Another challenge to the PRN approach is in the man- short-acting opioid formulations with a quick onset of action
agement of nighttime pain. Lack of sleep creates a vicious are more likely to give immediate analgesia and are more eas-
cycle of increased pain, which causes more lack of sleep, and ily adjusted than longer acting medications. Opioids with
diminished sleep efficiency tends to lower the pain thresh- longer-half lives and extended release medications may have
old. Strategies to address this problem include administering a role in acute pain after stabilization has been achieved with
opioids before bedtime in patients whose sleep is being inter- short-acting medications, if the pain is likely to remain severe
rupted by pain or who awaken in the morning with excessive and continuous for several days or longer.
reemergent pain. Alternatively, the use of long-acting medica- Oral analgesics often are used in patients with dysphagia
tions may be associated with improved sleep, although these and/or feeding tubes. In these circumstances, the medications
formulations should be used with caution in older patients are crushed and mixed with food or liquid to allow for easier
and those with renal insufficiency. Conversely, if a patient is swallowing or feeding tube administration. Many long-acting
sleeping well and is not awakening with increased perception pain formulations (e.g., morphine sulfate controlled release,
of pain and its consequent anxiety, there is no need to sched- oxycodone controlled release), should not be crushed, as this
ule analgesic doses during the patients sleep time. results in a bolus dose of the medication. Morphine sulfate
An alternative opioid scheduling method is known as extended release capsules, as well as liquid formulations of
reverse PRN. This method involves offering the medication morphine and methadone, are available and may be used in
to the patient on a scheduled basis, allowing the patient to these circumstances.
accept, refuse, or delay the dose. This reverse PRN method
ensures that the medication is made available and offered, but
S U BL I NGUA L
also helps the patient maintain some autonomy and control
over titrating the dose. Sublingual administration may be a useful route when swal-
Although standing dose regimens may be more appropri- lowing is impaired. Sublingual opioids are directly absorbed
ate for persistent, acute pain, there are circumstances in which into the systemic circulation. The high opioid concentration
PRN regimens are preferred. Patients with hepatic or renal of commonly available formulations (e.g., morphine sulfate
impairment may not be optimal candidates for fixed dosing. concentrate), allows for immediate analgesia in patients with
There also are circumstances where pain is not continuous and limited or absent ability to swallow even small amounts of liq-
can be predicted. If a patient is undergoing debridement of a uid medication.
S U B C U TA N E OUS C ODE I N E
We know surprisingly little about the pharmacokinetics of Codeine is a pro-drug converted to its active metabolite, mor-
subcutaneous (SC) opioids. For morphine, the blood levels phine, by the CYP450 2D6. It is an opioid agonist that pro-
achieved with SC administration are probably comparable to duces analgesia, sedation, and antitussive effects. It is usually
IV administration. Due to local irritant effects, the dose of dispensed in an oral form (tablet or liquid) and is often com-
opiate that may be administered via the SC route tends to be pounded with other agents (e.g., acetaminophen, guaifenesin)
smaller than what is possible through the IV and intramuscu- depending on the desired effect. Its half-life generally ranges
lar routes. Other limitations to subcutaneous administration from 24 hours, and dosing may need to be adjusted in the
include more difficult administration and erratic absorption presence of renal impairment. As noted above, approximately
in patients with severe cachexia. 7% of the general population lacks the enzyme necessary to
T R EAT M E N T OF AC U T E PA I N
DE V EL OPM E N T OF TOLE R A NC E I N OPIOI D A DDIC T S
In addition to complicating opioid conversion, the develop- In situations involving acute pain treatment in the opioid
ment of tolerance has other implications in acute pain man- addict, it is often helpful to keep the management of the addic-
agement. Tolerance must be differentiated from loss of pain tion separate from the management of the pain. For example,
Meperidine 24 AC E TA M I N OPHE N
Methadone 47
Para-aminophenol (acetaminophen) is the most widely used
(longer with chronic use)
pharmaceutical analgesic and antipyretic agent in the United
Hydromorphone 46 States and the world. It has similar analgesic potency to the
NSAIDs. It is metabolized by the liver via CYP450 1A2 and
Pentazocine 34
2E1 substrates, but its analgesic mechanism of action is not
Codeine 47 entirely understood. It is commonly used alone for mild pain
relief, and in combination with various opiates for moderate
Propoxyphene 47
pain. It is limited by its toxic effect on the liver, and a maxi-
Oxycodone 35 mum dose of 4 grams/day is generally accepted. Its use is cau-
tioned in patients with chronic alcohol use and/or hepatic
Tramadol 46
impairment.
Although there are occasional analgesic reports of antipsy- Cannabinoids appear to have some analgesic effect. This effect
chotics being used as co-analgesics, the primary use of phe- is probably mediated by non-opioid receptors, which may
nothiazines in terminal cancer patients remains antiemetic or argue for an adjunctive role in pain management. Some inves-
anxiolytic in conjunction with morphine (Seidel etal., 2008). tigators have suggested that the cannabinergic neurotransmit-
ter system serves to modulate pain sensitivity. Whether other
cannabinoids such as dronabinol (an oral synthetic cannabi-
B E N Z ODI A Z E PI N ES noid) offer similar benefits with fewer ill effects is a matter
worthy of investigation. Dronabinol has the obvious advan-
Benzodiazepines do not appear to have a significant role tage of being legally available throughout the United States;
in the treatment of acute pain. They may modify the affec- it is used for nausea and as an appetite stimulant. There is
tive experience of pain and ameliorate some of the affective limited available evidence in the medical literature regarding
elements of nonpain symptoms such as nausea. Adjunctive whether it is effective as an analgesic (Kraft etal., 2008).
use benzodiazepines with opiates may increase respiratory
depressant effects. They may have some utility as muscle
relaxants, which can be beneficial in addressing some types ALT E R N AT I V E A N D C OM PLE M E N TA RY
of acute musculoskeletal pain such as neck pain (Malanga T R EAT M E N T S
etal., 2009).
A number of alternative treatments, such as Therapeutic
Touch, Reiki Healing, herbal remedies, dietary changes, or
T R A M A D OL nutritional supplements have all been used for the treatment
of pain, and, anecdotally, many individuals have attested to
Tramadol hydrochloride is a centrally acting analgesic. the relief provided by one or another approaches. However,
Tramadol is indicated for moderate to moderately severe the few studies that have rigorously investigated these treat-
pain, in a manner analogous to low-potency opioids. ments have largely been either negative or too flawed to be
Although marketed as a non-opioid analgesic it acts as a convincing.
weak mu-receptor agonist. It is also a weak norepinephrine An exception to this may be acupuncture. Most studies
and serotonin reuptake inhibitor and may act through this investigating acupuncture also suffer from methodological
mechanism as well. The most common side effect associated difficulties; however, there is some convincing evidence for
with tramadol is nausea, and while it is generally considered the efficacy of acupuncture in the treatment of dental pain,
to have fewer respiratory and gastrointestinal effects than tra- and preliminary data for lower back pain, headache, and
ditional opioids, there are multiple adverse effects including fibromyalgia (Sierpina & Frenkel, 2005).
lethargy, agitation, respiratory depression, and coma, which
are possible with overdose. Patients with a history of seizures
and those taking antidepressants, antipsychotics, or MAOIs USE OF PLAC E B O S
appear to be at relatively higher risk for seizures with trama-
dol. Tramadol levels are raised by drugs that inhibit the cyto- Placebo (Latin:I shall please) is a term that evokes emotion
chrome P-450 2D6 isoenzyme, such as paroxetine. Although in both healthcare givers and recipients. Aplacebo is an inert
initially described as less abusable than opioids, physical substance, given in any form, and without inherent pharma-
dependence and withdrawal syndromes have been described cologic property, which may have a desired effect on a given
(Duhmke, Cornblath,& Hollingshead, 2004). disorder by virtue of the environment in which it is taken, the
psychological state of the recipient, and the specific neuro-
physiological processes of the recipient. Unfortunately, there
M I X E D OPIOI D remains significant misunderstanding within the medical
AG O N I S T-A N TAG ON I S T DRUGS community regarding placebos and their purpose (Goldberg,
Leigh, & Quinlan, 1979). Up to 30%40% of patients are pla-
The mixed opioid agonist-antagonist drugs have moderate cebo responders, which may explain why occasionally clini-
to strong analgesic activity. The group consists of a number cians will administer placebo pills or injections when they are
of drugs, including pentazocine, buprenorphine, and nal- skeptical of a patients report of pain. Attempting to deceive
buphine. All of the members of this group cause respiratory a patient is unethical, and a positive response to placebo does
depression and can lead to physical dependence with pro- not prove that the pain was merely in the patients head. It
longed use, and to an opioid withdrawal syndrome (Heel, is more likely that the pain is a very real phenomenon, prob-
Brogden, Speight, & Avery, 1978); therefore, these drugs ably mediated by the release of endogenous substances such as
should be tapered gradually after chronic use. Overall, the endorphins.
mixed agonist-antagonist group is likely to be used as an When placebo use is encountered or contemplated, the
analgesic adjunct to anesthesia for relatively short-term pain physician should ask, What is happening in this treatment
problems. system? Typical answers include the following: inadequate
I N T RODUC T IO N can all activate the CTZ. The CTZ then sends signals to the
vomiting center(VC).
Nausea and vomiting are common complaints in the general The VC is anatomically more diffuse and includes the
population. In one study 3% of people had nausea once a week, nucleus of the tractus solitarius and the reticular formation
while 2% reported vomiting more than once a month (Talley, of the medulla. The VC is stimulated via multiple pathways
Zinsmeister, Schleck, & Melton, 1992). These symptoms are (described below) and, once activated, controls the physical
frequent causes of presentation to outpatient clinics (Britt & act of vomiting by coordinating parasympathetic and motor
Fahridin, 2007; Frese, Klauss, Herrmann, & Sandholzer, efferent activity (Krakauer, et al., 2005; Mannix, 2005;
2011)as well as highly prevalent in the inpatient population. Quigley, Hasler, & Parkman,2001).
In patients with advanced cancer, nausea and vomiting are The relationship of nausea to vomiting is unclear but is
estimated to affect between 40%70% of patients (Borison & hypothesized to be a quantitative one:nausea without vomit-
Wang, 1953). Nausea is a common side effect of many ing occurs when the VC is not sufficiently stimulated to trig-
medications. ger the vomiting reflex. Vomiting without preceding nausea is
Systematic and effective treatment of these often very less common and even less understood.
distressing symptoms requires knowledge of the physiologi-
cal mechanisms and potential treatments for nausea and
E M E TO G E N IC PAT H WAY S
vomiting. In some patients mental states significantly con-
tribute to or exacerbate the experience of these symptoms. The Vomiting Center (VC), the final common pathway in
While the relationship between ones emotional state and vomiting, is triggered via four pathways:
gastrointestinal (GI) function has been the subject of medi-
cal discussion for centuries, (Van Oudenhove, Vandenberghe, 1. The chemoreceptor trigger zone (CTZ), which is stimu-
Demyttenaere, & Tack, 2010), the details of these interac- lated by various endogenous and exogenous chemicals in
tions remain an unresolved question. We hope to elucidate the bloodstream.
known contributions of the central nervous system to nausea
and vomiting. 2. Afferent neural pathways from the GI tract. These
include the vagus nerve, the splanchnic nerves, sym-
pathetic ganglia, and the glossopharyngeal nerves.
PAT HOPH Y S IOL O G Y The vagus nerve is stimulated by mechanoreceptors
in the GI tract that sense stretch or distension and
The pathophysiology of nausea and vomiting involves both by chemoreceptors that sense mucosal irritation or
central nervous system (CNS) and peripheral mechanisms. damage, usually through the secretion of serotonin
The brainstem, specifically the medulla, is an important ana- by the GI mucosa. Conditions that cause stretch or
tomic area for nausea and vomiting with two separate areas distension include diabetic gastroparesis, slowed motil-
involved, the chemoreceptor trigger zone (CTZ) and the ity from opioids, bowel obstruction, and constipation.
vomiting center(VC). Conditions that cause mucosal irritation include infec-
The CTZ is located in the area postrema in the floor tions such as candidiasis or viral/bacterial gastroen-
of the fourth ventricle, a site with an ineffective or absent teritis, ulcers due to H.pylori infection or nonsteroidal
blood-brain barrier. The CTZ, despite its location in the antiinflammatory agents, alcoholic gastritis, and muco-
CNS, can sample blood for endogenous or exogenous toxins. sitis from chemotherapy. The vagus nerve sends signals
Electrolyte imbalances such as hypercalcemia and hyponatre- directly to theVC.
mia, liver or kidney failure with their associated endogenous 3. Afferent neural pathways from the viscera and
toxins, and exogenous toxins such as medications (including serosa of the thorax and abdomen. Signals originate
chemotherapy agents) and chemicals found in spoiled food in mechanoreceptors and chemoreceptors in all of
526
the viscera and serosa of the head and neck, thorax, Vestibular
abdomen, and pelvis. As in the GI tract, the mechano- system
CNS
receptors and chemoreceptors of the pharynx, heart, AChm
H1
liver, and kidneys, communicate primarily through
the vagus nerve. The vagus nerve (and to a lesser
extent the splanchnic and sympathetic nerves) send Emotional Vomiting IX & X Other
nausea-inducing signals to the VC when organ cap- centers Center Organs
AChm, H1, 5HT3, NK1? Mechanoreceptor
sules are stretched (e.g., hepatitis, liver metastases, or Chemoreceptors
4. Afferent neural pathways from CNS sites outside Pharmacologically relevant neuralpathways and
Figure26.1
the medulla, including the vestibular system, the neurotransmitters.
diencephalon, and the cerebral cortex. The vestibular
system is activated by motion in susceptible individuals
(i.e., motion sickness) and in conditions such as benign N EU ROT R A NS M I T T E R S A N D R E C E P TOR S
positional vertigo, labyrinthitis, and Menieres disease. I N VOLV E D I NN AUS E A A N D VOM I T I NG
Rarely, the vestibular system may be sensitized by opi-
oids, which can then cause nausea and vomiting through Figure 26.1 summarizes the neural pathways and neurotrans-
this pathway. Although the mechanism remains unclear, mitters thought to be important in nausea and vomiting.
one hypothesis is that nausea is mediated by the mu The most important receptor in the CTZ is the dopamine
receptors on the vestibular epithelium (Porreca & type 2 (D2) receptor; the primary receptors in the VC are
Ossipov, 2009). The vestibular system sends signals to muscarinic cholinergic (AChm) and histamine (H1) recep-
the VC and perhaps also to theCTZ. tors. Serotonin type 3 (5HT3) receptors are also present in
both sites and serotonin type 2 (5HT2) receptors in the VC.
Substance P is found in high concentrations in the CTZ and
Increased intracranial pressure and mass effect from trau-
VC and binds to neurokinin 1 (NK1) receptors; a role for
matic brain injury, hemorrhage, edema, or CNS infection
substance P in nausea and vomiting has been postulated.
can cause nausea and vomiting. Migraine headaches are often
H1 and AChm receptors mediate nausea in the vestibular
associated with nausea. The pathways involved are not fully
apparatus.
understood.
In the GI tract there are many receptors involved in
It has been postulated that the relationship between gas-
nausea and vomiting, including serotonin, acetylcholine,
trointestinal function and ones emotional/psychological state
histamine, and dopamine. 5HT3 receptors on vagal or
can be partially explained by the fact that CNS control of the
glossopharyngeal afferents are stimulated by release of
gut is primarily located in the limbic system (anatomically
serotonin from enterochromaffin cells in the GI tract.
comprised of the hypothalamus, amygdala, medial thalamus
Release of serotonin can occur with mucosal irritation from
and anterior cingulate cortex), the same area responsible for
drugs, radiotherapy, or bacterial endotoxins. Dopamine is
ones emotions (Jones, Dilley, Drossman, & Crowell, 2006).
also thought to be an important neurotransmitter in the
In addition, serotonin is an important neurotransmitter in
regulation of gastrointestinal function. While there are
both the GI tract and CNS system.
many subtypes of dopamine receptors throughout the GI
The cerebral cortex may provide inhibitory input to the VC,
tract, the mechanisms through which dopamine acts on
much as it provides inhibitory input to nociceptive neurons
the gut remain elusive. Outside the GI tract there are ace-
in the spinal cord and brainstem, although the mechanisms
tylcholine and histamine type 1 receptors on viscera and
are poorly understood. The rationale behind this thinking is
serosal surfaces (Mannix, 2005; Hernandez et al., 1987;
based on the limited data suggesting that nonpharmacological
Li, 2009; Krakauer etal., 2005; Mannix, 2005; Naylor &
interventions such as cognitive behavioral therapy and hypno-
Inall,1994).
sis decrease chemotherapy-related nausea and vomiting (Lotfi-
Jam, Carey, Jefford, Schofield, Charleson, & Aranda, 2008).
Nausea is often accompanied by strong emotional as well
as cognitive components (Muth, Stern, Thayer, Koch, 1996). E T IOL O G Y
The cerebral regions responsible for processing nausea in
humans are not well elucidated, but it has been hypothesized Table 26.1 is a comprehensive list of possible causes of nausea
that it is likely to include areas that are responsible for con- and vomiting. Acute causes usually are infectious, inflamma-
scious awareness of internal body states, including the insular tory or iatrogenic. Chronic nausea and vomiting have a wide
and dorsal anterior cingulate cortices (Napadow et al., 2013). differential diagnosis.
GASTROINTESTINAL
(AGA, 2001; Hall & Driscoll, 2005; Mannix, 2005; Murtagh, 2011; Scorza, Williams, Phillips, & Shaw, 2007; Talley,2007)
I N V E S T IG AT IONS
symptomatic relief. When possible, the underlying cause
Typical laboratory tests and imaging studies for patients pre- should be corrected. Cases requiring hospital admission
senting with nausea and vomiting are listed in Table26.2. include moderate to severe dehydration (especially in the
In more severe or prolonged episodes of vomiting, elevated elderly), possible bowel obstruction, increased intracranial
hemoglobin level and hematocrit may be seen secondary to pressure, acute myocardial infarction, and other gastrointes-
volume contraction, while hypochloremia is seen following tinal and neurological emergencies.
large losses of HCl with vomiting, often resulting in a hypo-
chloremic metabolic alkalosis.
NON PH A R M AC OL O G IC T R E AT M E N T S
Further testing will be guided by clinical suspicion and
may include serum drug levels (e.g., digoxin toxicity), gas- Simple measures such as avoiding noxious stimuli (e.g., strong
troscopy (proximal lesions), small bowel follow-through (for odors) and eating food frequently and in small amounts can
lesions up to the terminal ileum), abdominal ultrasounds (for be helpful. For more chronic cases, such as chemotherapy
liver, gallbladder or pancreatic disease), computed tomogra- related nausea and vomiting, a number of nonpharmaco-
phy (CT) with oral and IV contrast, and CT or MRI of the logical techniques can be considered. Relaxation techniques
brain (intracranial lesions). including biofeedback, self-hypnosis, progressive muscle
(AGA, 2001; Metz & Hebbard, 2007; Murtagh, 2011; relaxation, cognitive distraction, guided imagery, and system-
Scorza, etal.,2007) atic desensitization can be helpful particularly for patients
with anticipatory nausea and vomiting and for those with
prominent anxiety around chemotherapy. While many
M A N AG EME N T patients find these techniques effective, there have been
few controlled clinical trials. In an uncontrolled study of
Initially, management should be directed toward stabiliz- self-hypnosis for chemotherapy-related nausea and vomiting
ing the patient via methods including rehydration and cor- in 16 cancer patients, all had complete remission of anticipa-
rection of any electrolyte abnormalities. Empiric treatment tory symptoms and major decreases in post-chemotherapy
should also be instigated early in an attempt to provide some nausea and vomiting (Marchioro et al., 2000). However,
R ECEPTOR
ANTAGONIZED/ SITE PR IM ARY USUAL DOSAGES M AJOR SIDE-EFFECTS/
MEDICATION OFACTION INDICATIONS AND ROUTES NOTES
Dopamine Antagonists
536
to the respiratory complex. Central chemoreceptors are Brain Cortex
located in the medulla oblongata and primarily sense
Limbic system
carbon dioxide levels in the cerebrospinal fluid. Under
normal conditions, the respiratory drive is mainly
regulated by the partial pressure of carbon dioxide in Central chemoreceptors
the cerebrospinal fluid sensed at the central level. In Respiratory
certain circumstances during central nervous system Peripheral chemoreceptors Complex
depression (e.g., under the effect of anesthesia or when a (Brain Stem)
Vagal receptors
patient has hypercarbia), the central chemoreceptors are
inhibited and their ability to trigger normal ventilation Chest wall receptors
is decreased. Unlike central chemoreceptors, peripheral
chemoreceptors are not inhibited during central nervous
system depression. In these situations, the respiratory PULMONARY Respiratory
drive is maintained by the partial pressure of oxygen VENTILATION Muscles
sensed in the carotid and aortic bodies.
Figure27.1
A schematic diagram of the structures involved in the control
Vagal receptors:The upper airways have vagal receptors and regulation of breathing. Adapted from Duffin & Phillipson, 2010.
that are stimulated by cold air. There are stretch recep-
tors in the smooth muscle of the larger airways that are
activated by CO2 and inhaled furosamide (which can
explain the conscious awareness of the effort of breathing
help the sensation of dyspnea). In the parenchyma of the
that is described by some patients experiencing dyspnea
lungs, there are pulmonary irritant receptors that react
(Nishino, 2011; Schwartzstein & Adams, 2010).
to chemical irritants such as cigarette smoke, to inflam-
matory mediators, and to fluid and inflammation in the
lung parenchyma. Finally, there are C-fibre receptors Figure 27.1 describes the pathways involved in the regu-
that are in close proximity to either the pulmonary or lation of breathing. The respiratory complex triggers the
bronchial circulation. At this point, there is no defini- involuntary activation of different respiratory muscle groups
tive evidence that stimulation of these receptors causes involved in breathing. The brain cortex can voluntarily
dyspnea. activate the respiratory muscles. Changes in oxygenation,
acid-base balance, lung function, and muscle effort will be
Chest wall receptors:Mechanoreceptors in the joints, ten- communicated to the respiratory complex via a variety of
dons and muscles of the chest wall send afferent signals to receptors. Emotions, through limbic connections, influence
the respiratory complex. the perception and functioning of the respiratory complex
(De Peuter et al., 2004; Duffin & Phillipson, 2010; Evans,
Neural pathways from receptors to the brain:This wealth
Shea, & Saykin, 1999).
of information from the chemoreceptors in the medulla
and bloodstream, vagal receptors in the airways and lung
parenchyma, and mechanoreceptors in the chest wall
PAT HOPH Y S IOL O G Y OF DY S PN E A
provides continuous feedback to the respiratory complex
in the medulla, which sends signals to the thalamus and
Dyspnea is a complex symptom and its mechanisms are not
up to the cortex. Neuroimaging studies of dyspnea show
completely understood. Hypercarbia and hypoxia can induce
stimulation of specific areas of the brain cortex, includ-
dyspnea in normal subjects, but in individual patients the
ing the anterior right insula, the cerebellar vermis, the
sensation of breathlessness correlates poorly with the degree
amygdala, and the cingulated cortex. In response to these
of the abnormality (Burki & Lee, 2010). Dyspnea associated
sensory inputs, the medullary respiratory complex (or the
with blood gas abnormalities results from increased respira-
motor cortex when breathing is under conscious control)
tory motor activity mediated by chemoreceptor activation
sends efferent commands to the ventilatory muscles.
(American Thoracic Society, 1999), and it could also result
Corollary motor discharge:When a motor command from a direct dyspneogenic effect, independent of the venti-
is sent to the respiratory muscles, a copy of this com- latory motor output (Burki & Lee, 2010). This sensation is
mand, called corollary motor discharge, is relayed to the not due to the resulting increased respiratory muscle activity
sensory cortex (with an expected response from the as quadriplegic people experience dyspnea with hypercarbia.
respiratory muscles). The motor response of the respira- Studies of the hypoxic respiratory drive, in which pCO2 and
tory muscles will trigger a sensory input that will be ventilation are kept constant, show that PO2 has to drop
also relayed to the sensory cortex, which represents the below 6.7 kPa before subjects experience a sharp increase in
actual motor response. The corollary motor discharge dyspnea. The mechanism by which vagal afferents from the
(expected response) and the actual motor response airways and lungs and the mechanoreceptors from the chest
received by the sensory cortex will be compared allowing wall cause dyspnea is not known.
the sensory cortex to detect discrepancy between these The corollary motor discharge from the respiratory cen-
two sources of information. This mechanism could ter is thought to be key to the generation of the sensation of
Respiratory Airways Disease Asthma, Chronic obstructive pulmonary diseases, Upper airway
obstruction
Parenchymal lung disease Pneumonia, Interstitial lung disease, Adult respiratory distress
syndrome, Lung cancer
Pulmonary vascular disease Pulmonary embolism, primary pulmonary hypertension, chronic
pulmonary microemboli
Pleural Disease Pleural effusion, Pneumothorax
Neuromuscular and chest wall diseases Polymyositis, Myasthenia gravis, Guillain-Barre, kyphoscoliosis
Dyspnea can occur in other mental disorders with a high We would like to highlight again that as dyspnea is a
level of somatization, including somatization disorder, social symptom, it can only be perceived by the person experiencing
anxiety disorder, and stimulant abuse (W. Katon, Ries, & it. In fact, the correct assessment of dyspnea depends on self
Kleinman, 1984; Kroenke & Rosmalen, 2006). report. Therefore, it is important for clinicians to distinguish
dyspnea from the clinical signs that health care providers use
as evidence of respiratory dysfunction such as increased respi-
ratory rate, use of accessory breathing muscles and intercostal
P S YC H I AT R IC C OMOR B I DI T I E S I N
retraction (Parshall etal., 2012).
PAT I E N T S W I T H C A R DIOPU L MON A RY
Dyspnea scales have been developed to standardize the
DI S E A S E
magnitude or impact of the symptom. A large number and
variety of tools have been developed to assess dyspnea but
Patients with asthma have a higher prevalence of panic dis-
each tool measures specific domains. Recent reviews have
order and panic attacks than the general population (Hasler
recognized three different types of measures (Parshall etal.,
et al., 2005). According to one literature review, patients
2012): scales that assess the sensory-perceptual experience
with asthma have a frequency of panic attacks ranging
of the patient by measuring what breathing feels like to the
between 6.5% and 24% (W. J.Katon, Richardson, Lozano, &
patient (e.g.; modified Borg scale; Borg, 1982); scales that
McCauley, 2004). Patients with COPD have a higher preva-
assess the affective stress by measuring associated distress and
lence of generalized anxiety disorder (10%15.8%) and panic
the impact/burden of the symptom, focusing on the func-
disorder (32%37%) compared to the general population
tional ability of the patient (e.g., Medical Research Council
(3.6%5.1% and 3.4% respectively) (Periyakoil, Skultety, &
MRC scale; Fletcher, Elmes, Fairbairn, & Wood, 1959).
Sheikh, 2005). Depression is also common in patients with
In patients with dyspnea, the history, past medical history,
COPD (Chavannes etal., 2005). In patients with CHF dys-
and physical examination are the most important compo-
pnea is associated with fatigue, perception of poor health, and
nents of the diagnostic evaluation.
depression. Dyspnea and depression are associated in patients
The history should be directed at identifying the quality of
with asthma, cancer, and in mechanically ventilated patients
dyspnea, associated symptoms, triggers or alleviating factors,
(Ramasamy etal., 2006).
and comorbidities.
A thorough past medical and social history will provide
us with essential information about risk factors for dyspnea
ASSESSM ENT and for particular etiologies. The presence or absence of spe-
cific symptoms will orient us to a possible cause. For instance,
The goal of the clinical assessment is to characterize the mag- dyspnea associated with cough, sputum, hemoptysis, or
nitude and impact of the symptom and identify possible etiol- wheezing, may suggest a respiratory cause, although conges-
ogies. Two major groups of patients must be recognized:those tive heart failure can also present with cough and wheezing.
with no prior history of dyspnea, for whom we need to iden- The presence of stridor will point to central airway obstruc-
tify the cause of the symptom; and those with a known car- tion. The combination of dyspnea on exertion, orthopnea, and
diovascular, respiratory, or muscular disease with worsening lower extremity edema suggests heart failure. Dyspnea associ-
dyspnea, for whom we need to distinguish if the cause of the ated with generalized muscle weakness raises the possibility
symptom is a new problem or worsening of the underlying of neuromuscular disease. If the physical examination is nor-
disease (Parshall etal., 2012). mal and additional workup is negative, one could consider a
Ascites Paracentesis
S Y M P TOM AT IC T R E AT M E N T Congestive Heart Failure Diuretics, digoxin, betablockers,
ACE inhibitors
The treatment of dyspnea should focus on the underlying
Anemia Transfusions of packed RBC
cause and its complications. Interventions to treat the etiol-
ogy will reduce the intensity of the dyspnea and increase the Adapted from Del Fabbro, Dalal, & Bruera, 2006.
patients comfort. Table 27.3 describes common reversible eti-
ologies that cause dyspnea in terminal patients and their main
treatments. Interventions should be focused on treating the breathlessness itself when the underlying disease cannot be
effectively treated. Unfortunately, there are no completely sat-
Table27.2 INITIAL STUDIES TO EVALUATE DYSPNEA isfactory treatments for the various forms of dyspnea (Lanken
TESTS R ATIONALE
etal., 2008). Treatment should focus on both the physical and
psychological components of dyspnea. In this section we will
Lab Tests describe the available nonpharmacologic and pharmacologic
interventions for the symptomatic treatment of dyspnea.
Arterial and mixed venous blood Assess oxygenation and
gases acid-base status
CBC Detect anemia and infection NON PH A R M AC OLO GIC I N T E RV E N T IONS
Electrolytes and renal function Estimate anion gap and assess
kidney function Nonpharmacologic interventions tend to be inexpensive and
Sputum analysis and culture Identify infectious etiology
underutilized. A recent review published in the Cochrane
database analyzed the effectiveness of these interventions
Pleural fluid analysis and Identify cause of pleural effusion
cultures and infection (Bausewein, Booth, Gysels, & Higginson, 2008). In brief, the
available and effective interventions include the following:
Pulmonary Function Tests Fans:Hand-held fans that deliver cool air to the face have
been shown to decrease dyspnea both in patients with COPD
Spirometry and lung volumes Differentiate obstructive from and in normal volunteers (American Thoracic Society, 1999).
restrictive lung disease
This intervention is effective for any severity of dyspnea at
CO Diffusion Assess alveolar diffusion
any stage of disease (Booth, Moffat, Burkin, Galbraith, &
Cardiopulmonary exercise Differentiate pulmonary, Bausewein, 2011). The mechanism of action may be related to
testing cardiovascular and
musculoskeletal causes of stimulation of trigeminal receptors in the face.
dyspnea. Positioning: Leaning forward while standing or sitting
improves the efficiency of accessory muscles. This position
Imaging Techniques improves diaphragmatic function, especially in hyperin-
Chest X-ray Assess multiple etiologies
flated lungs as seen in emphysema and chronic severe asthma
(American Thoracic Society, 1999; Booth et al., 2011). It is
Chest CT scan/ PE CT scan Assess multiple etiologies and/
or detect PE useful mainly for patients with dyspnea at rest. Other benefi-
cial positions include lying on ones side in a semi-recumbent
Cardiac Evaluation position or leaning forward into a stack of pillows (Booth
etal., 2011).
EKG Detect arrhythmias or ischemia
Energy conservation interventions:Slowing ones gait can
Echocardiogram Assess heart structure and reduce physical effort and decrease the sense of breathlessness
function
at any stage of illness. It is important to encourage patients to
Morphine 510 mg po q4 hours prn dyspnea Long-acting morphine (e.g., MS 12 mg IV q4 hours prn dyspnea
Contin) 15 mg po q12 hours
*Only start long-acting if the patient is taking more than the equivalent dose of short-acting in a 24-hour period.
the anti-dypsnea effects of opioids. Most often, the need for of dyspnea. The challenge is to combine the tools of medicine
increasing doses would signify a worsening of the underlying and psychiatry to affect the emotional dimension.
disease process. All patients on opioids develop physiologic
dependence on opioids such that they will experience with-
drawal symptoms if the medications are stopped suddenly. C L I N IC A L PE A R L S
Anxiolytics: In a systematic review of interventions for
alleviating cancer-related dyspnea, only one study was identi- The perception of dyspnea refers to the unique manner in
fied that assessed the effect of benzodiazepines. In this study, which a particular individual experiences breathlessness
the addition of a benzodiazepine to an opioid eased the sense and it consists of three distinct dimensions:a sensory
of breathlessness compared to the opioid alone, without addi- dimension, i.e., the intensity of the symptom; an affective
tional adverse effects (Ben-Aharon et al., 2008). However, dimension, i.e., how unpleasant the symptom is; and a
there is no evidence to support the routine use of benzodi- functional dimension, i.e., the impact or burden of the
azepines in the management of dyspnea (Del Fabbro et al., symptom.
2006). Still, they may have a role in patients with significant Dyspnea in patients with stable asthma is explained by
anxiety related to their dyspnea. The clinician should monitor both the degree of airway obstruction and patients emo-
side effects closely and start the medications in sequence, not tional status (Martinez-Moragon, Perpina, Belloch, de
in parallel. One can also consider low-dose neuroleptics (e.g., Diego, & Martinez-Frances, 2003).
quetiapine or olanzapine) or an SSRI for the chronic anxi-
ety component related to the dyspnea. Given the high inci- In severe dyspnea, the insular cortex and anterior cingu-
dence of confusion or delirium in elderly patients or patients lated gyrus, both part of the limbic system, are activated
with chronic illness receiving benzodiazepines, as well as the in functional imaging studies. This evidence correlates
potent sedation caused by the combination of opioids and well with what we know clinically, that the experience of
benzodiazepines, many palliative care clinicians choose to use dyspnea is often accompanied by anxiety and fear.
neuroleptics for anxiety related to dyspnea. Individuals experiencing dyspnea who are able to shift
their attention to external stimuli have decreased sense of
breathlessness (Thornby, Haas, & Axen, 1995). Likewise,
S U M M A RY patients with COPD who listen to music while on a
rehabilitation program improve their performance com-
Dyspnea is a common symptom in patients with cancer, car- pared to patients who do not listen to music (Bauldoff,
diopulmonary disease and neuromuscular conditions that Hoffman, Zullo, & Sciurba, 2002).
affect respiratory muscles. Anxiety often accompanies the
dyspnea. While gaps in our knowledge remain, dyspnea is Negative emotions have been shown to be associated with
thought to represent a mismatch between the central respi- decreased accuracy in dyspnea perception (De Peuter
ratory motor command and incoming afferent information etal., 2004).
from sensory receptors. The perception of dyspnea is highly
Both types of dyspnea, air hunger and increased work
influenced by emotions. The history and physical examina-
of breathing are associated with increased respiratory
tion and the judicious use of laboratory and functional tests
drive. Athird description of dyspnea is chest tightness.
will help identify the possible etiologies and underlying
This phrase is often used by asthmatics and is thought to
mechanisms of dyspnea. Treatment should be focused first
be associated with bronchoconstriction
and whenever possible on the underlying cause of the dyspnea
and on the symptom itself when disease-modifying interven- Hand-held fans that deliver cool air to the face have been
tions are ineffective or have become burdensome. Opioids and shown to decrease dyspnea both in patients with COPD
other interventions, pharmacologic and non-pharmacologic, and in normal volunteers (American Thoracic Society,
can be implemented effectively for the symptomatic treatment 1999). This intervention is effective for any severity of
5 45
In counseling a patient to begin an alternative compounds believed to be essential for therapeutic activity
treatmentor even to continue one the patient has and/or to be unique to the species. High-pressure liquid chro-
already startedthe psychiatrist assumes clinical and matography (HLPC) can be employed to measure the pres-
legal responsibility. The clinician should share with ence and concentration of marker compounds, and for most
the patient what is known about the risks and benefits herbs this is sufficient. However, for certain rare and more
of the agent(s) involved and how they might interact expensive herbs, adulteration may still occur by spiking the
with the patients diseases and other treatments, and product with marker chemicals. Usually the reporting of one
why the patient might do better with the alternative or two marker compounds is adequate, but the testing of more
treatment than a conventional prescription psycho- marker compounds or comparison of the complete HPLC
tropic. This discussion should be documented in the profiles would be preferable for more complex herbs. The ulti-
record. Finally, the patients treatment choice and mate test of an extract is proven efficacy in a good quality con-
response to treatment should be documented in the trolled trial, published in a peer-reviewed journal.
medical record. Most supplements are stable enough that their qual-
ity is not significantly affected by differences in process-
ing. In this chapter, complex products whose quality is
more affected by differences in cultivation and extraction
INTRODUCTION proceduresfor example, Ginkgo biloba, Hypericum perfo-
ratum (St. Johns wort) and Rhodiola rosea (Arctic root)
Medical patients suffer from the psychological effects of their will be identified. The relative amounts of active compounds
medical conditions, the direct and indirect stressors of their ill- in herbs are affected by the soil, climate, time of harvest,
nesses, and the medications and procedures used to treat these and age of the plant at the time of harvest. The composi-
conditions. Therapeutic nutrients and herbs have an emerging tion of plant extracts depends upon the method of drying
role in ameliorating neuropsychiatric and physical symptoms and extraction. Some compounds are soluble in water, oth-
in medical patients. Synthetic psychotropic medications used to ers in alcohol. Procedures for extraction of certain herbs,
treat anxiety, insomnia, depression, and cognitive impairment such as R.rosea, use either water or alcohol or both. Volatile
can add to the burden of side effects in medical patients who may compounds can be lost if subjected to excessively high tem-
be more susceptible to adverse reactions and medication interac- perature during processing. Extracts are sold to companies
tions. Furthermore, prescription anxiolytics, sedative hypnotics, that encapsulate and market products under various brand
and analgesics have the potential for habituation, addiction, over- names. Companies may change the source of raw product
dose, and withdrawal symptoms. In general, herbs and nutrients as the cost and availability of plant extracts change. Product
have far fewer side effects and far less addiction potential. Rather labels rarely state the source of extracts. Ginkgo biloba is one
than taking an encyclopedic approach, this chapter focuses on exception. Many products containing Ginkgo biloba identify
clinically useful treatments, their mechanisms of action, and the their content as, for example, EGb 761 or Kira, which are
evidence for safety and efficacy. The safety of most herbs during both known to be reliable, potent extracts based on numer-
pregnancy and breastfeeding has not been adequately studied. ous scientific studies in which they were used. For other
Herbdrug interactions and the use of herbs to counteract medi- complex herbs, additional investigation is needed to iden-
cation side effects are covered in the last sections of this chapter. tify products containing high-quality extracts. For example,
Summaries of dose ranges, side effects, and drug interactions, are the Swedish Herbal Institute has a long history of produc-
provided in Tables 28.1, 28.2 and 28.3. ing high-quality products with demonstrated efficacy in
Many herbs and nutrients have been considered to be research studies. In determining the appropriate dosage, it
part of complementary and alternative medicine (CAM). is important to note not only the milligrams of the marker
Advances in neurophysiology, molecular biology, and genom- compounds but also the percentage of those marker com-
ics have created a deeper understanding of the mechanisms pounds. For example, 150 mg of an R.rosea product contain-
of action and the potential benefits of treatments that were ing 4% of marker compounds called rosavins is more potent
previously considered outside the purview of conventional than a brand containing 3% rosavins. The authors have pro-
medicine. Integrative medicine and integrative psychiatry are vided lists of high-quality products in previous publications
emerging fields that cultivate integrative approaches using (Brown, Gerbarg, & Muskin, 2009; Brown & Gerbarg,
herbs, nutrients, neurohormones, mindbody practices, and 2011). Proprietary preparations do not always reveal the
mainstream medical treatments. exact amount of each component. Companies may consider
secrecy to be a business necessity; however, prescribing a
product without knowing its exact contents is problematic
G ENERAL ISS U ES IN THE PU RS U IT for clinicians.
OF QUALITY Improved verification of the authenticity and quality of
herbal products is evolving with new technologies. Ideally, in
the future herbs may be identified by genomic analysis, the
S TA N DA R DI Z AT ION OFS U PPL E M E N T S
concentration of key constituents assessed at each stage of
Considerable progress has occurred in the standardization production, and supplement brands systematically tested for
of botanical extracts based on the concentration of marker purity and efficacy.
546 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
R E GU L ATORYI S S U E S ConsumerLab.com is one of the best nongovernmental
resources for up-to-date, detailed, practical information on
Each country has its own regulatory processes. Within the US
most of the supplements encountered in clinical practice.
Food and Drug Administration (FDA) the Center for Food
Companies pay a fee to ConsumerLab to analyze and report
Safety and Applied Nutrition monitors the safety of dietary
on the contents and quality of their products. Clinicians
supplements and the accuracy of labels and inserts. The US
and consumers pay a modest annual fee for access to reports
Federal Trade Commission requires and oversees truthful-
that cover thousands of brands. ConsumerLab purchases
ness in product advertising (www.ftc.gov).
products from stores, not directly from the manufacturer,
and sends them to independent laboratories for HPLC
RELIABLE SOURCES FORINFORMATION ABOUT assessment of marker compounds and other constituents
QUALITY AND SAFETY OFSUPPLEMENTS that play a role in therapeutic action. Products are tested
Information on the safety of specific supplements is avail- for lead and other contaminants as appropriate. Apassing
able at the FDA website: www.fda.gov/Food/Dietary score is given to products that meet US Pharmacopoeia
Supplements/Alerts. The Alerts and Advisories section of standards for tablet disintegration, fulfill FDA labeling
the National Center for Complementary and Alternative requirements, contain 100% of the label claims for content,
medicine (NCCAM) posts information about problem- do not exceed legal levels for lead contamination, and meet
atic supplements at www.nccam.nih.gov/news/alerts. The other product-specific quality indices.
National Institute of Health National Library of Medicine Herbal Contraindications and Drug Interactions by Francis
maintains the Dietary Supplement Labels Database contain- Brinker is an excellent resource providing precise explana-
ing information about the ingredients in over 2,000 brands of tions on the sources of information, limitations and contra-
supplements on their website, www.dietarysupplements.nlm. dictions in the literature, and the complexity of the available
nih.gov/dietary. evidence (Brinker, 2010). The publisher posts free updates at
In Germany, the German Commission E closely regulates www.eclecticherb.com/emp.
the quality of phytomedicines and publishes highly respected Herbs, Nutrients and Yoga in Mental Health Care by
monographs that are available at http://cms.herbalgram.org/ Richard P. Brown, Patricia Gerbarg, and Philip Muskin is
commissione/index.html. a practical clinicians guide that includes sources of quality
The American Herbal Pharmacopoeia (AHP) maintains products, recommended dosages, how to combine standard,
authentic botanical reference materials to insure the iden- complementary, and alternative treatments, and case illustra-
tity and quality of medicinal plants. These are used by aca- tions (Brown, Gerbarg, & Muskin,2009).
demic institutions, researchers, supplement manufacturers,
and those who evaluate products, such as ConsumerLab. The R E P ORT I NG S I DE E F F E C T S A N D A DV E R S E
AHP publishes scholarly qualitative and therapeutic mono- R E AC T ION S
graphs and books on herb safety (see http://www.herbal-ahp.
org/order_online.htm). As with prescription medications, adverse reactions to
The American Botanical Council (ABC) is an inde- phytomedicines and nutritional supplements are underre-
pendent, nonprofit research and education organization ported. Side effects can be reported to MedWatch by phone
that provides reliable information about herbs for consum- (1-888-463-6332) or through the FDA website at www.fda.
ers, healthcare practitioners, researchers, industry, and the gov/safety/MedWatch/How ToReport/ucm053074.htms.
media. The ABC publications are peer reviewed and include For reporting serious adverse reactions, healthcare providers
periodicals, books, monographs, safety reviews, continu- may call the MedWatch hotline at 1-800-FDA-1088.
ing education materials, and searchable online databases.
Herbalgram, the quarterly journal of the ABC, publishes L I A BI L I T YI S S U E S
extensive articles on the history of phytomedicines, modern
uses, and current issues that affect cultivation and quality. Individuals who request CAM treatments are entitled to
HerbClips reviews current research studies and books. The the same quality of diagnostic evaluation as those who seek
ABC website is accessible at http://abc.herbalgram.org/site/ conventional treatments. Malpractice experts note that
PageServer. the following categories of malpractice could be applied to
The Natural Medicines Comprehensive Database (NMCD) CAM:misdiagnosis, failure to treat, failure of informed con-
covers a great deal of information, even on obscure herbs, sent, fraud and misrepresentation, abandonment, vicarious
with yearly updates. The drawbacks are that it cites articles liability, and breach of privacy and confidentiality (Cohen &
that mention side effects even if based on weak or nonvali- Schouten, 2007). In general, the approach to liability
dated evidence. Most of the information is accurate, but some issuesand to all categories of liability in integrative mental
is not. Consequently, the long lists of potential side effects healthcare using nutrients and herbsare similar to those for
may include nonvalidated items, speculations based on infor- standard practices. The issue of failure to treat raises several
mation from in vitro or animal studies, or equivocal cases. potential scenarios worth noting:
The burden is on the reader to check the original citations to
determine the degree of validity and clinical relevance of the 1. The risk of liability is less if scientific evidence supports
information (Jellin,2010). the safety and efficacy of a CAM treatment. In cases in
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 547
which a patient does not tolerate or respond to conven- In their discussion of liability issues Brown, Gerbarg, and
tional treatments and whose condition could be treated Muskin include an example of a note for documentation of
effectively with a reasonably safe CAM therapy, one could the decision-making process that leads to the use of a CAM
argue that it would be negligent not to inform the patient treatment (Brown, Gerbarg, & Muskin,2009).
of the CAM treatment and offer the option to tryit.
2. If scientific evidence indicates that a particular CAM
AN X IETY DISORDERS AND INSOM NIA
treatment is ineffective or is likely to cause harm, then the
practitioner should try to dissuade the patient.
N U T R I E N T S FORA N X I E T Y DI S OR DE R S A N D
3. If the evidence for safety or efficacy of a CAM treat-
I N S OM N I A
ment is equivocal, then the patient should be informed
of all known potential risks as well as the quality of the Evaluating the nutritional status of medical patients is part
evidence both in favor and against the treatment. If the of standard practice. Nutritional deficiencies develop in asso-
patient chooses to try the treatment after this discussion ciation with poor diet, chronic illness, loss of appetite, aging,
(and the discussion has been documented in the chart), dementia, chemotherapy, malabsorption, gastrointestinal
then the practitioner should monitor the patient during problems, and substanceabuse.
the trial for benefits and side effects and should intervene
if any adverse reactionsoccur.
Gamma-aminobutyricAcid
4. If the patient has a condition that could be easily or
rapidly cured by standard treatment, and if the use of Gamma-aminobutyric acid (GABA), the major central
CAM delays effective treatment such that the patient nervous system inhibitory neurotransmitter, is involved in
suffers harm or illness progresses, this could be considered cardiovascular regulation, pituitary function, immunity,
malpractice, negligence, or substandardcare. fertilization, and renal function. Many foods contain small
amounts of GABA, and fermented food products may con-
The same principles that govern informed consent in con- tain high levels. Natural GABA produced by fermentation is
ventional treatments can be applied to CAM. Each state has widely used as a functional food supplement inJapan.
specific regulations governing the practice of CAM. The U.S. The effects on EEG of 100 mg of GABA produced by nat-
Federation of State Medical Boards (FSMB) has approved ural fermentation (pharma-GABA) were compared to 200
model guidelines for the use of CAM therapies in medical mg L-theanine and placebo in a double blind placebo con-
practice (Federation of State Medical Boards, 2007; see http:// trolled (DBPC) crossover study of 13 healthy adults. Alpha
www.fsmb.org/pdf/2002_grpol_complementary_alterna- waves are associated with relaxed, effortless alertness. Beta
tive_therapies.pdf). The FSMB recommends that the physician waves occur in highly stressful situations and during difficulty
conduct an appropriate medical history, physical examination, with mental concentration. GABA intake resulted in a sig-
and review of patient medical records before offering any rec- nificantly greater increase in alpha and decrease in beta com-
ommendation for treatment. The FSMB Guidelines notethat pared to both L-theanine and placebo control (Abdou etal.,
2006). The high alpha/beta ratio indicates a state of arousal
The evaluation shall include, but not be limited to, with relaxation or relaxed concentration. Low levels of sali-
conventional methods of diagnosis and may include vary immunoglobulin-A (IgA) found in highly anxious indi-
other methods of diagnosis as long as the methodology viduals drop further in stressful situations. In a double blind
utilized for diagnosis is based upon the same standards randomized placebo controlled (DBRCT) study, 8 adults
of safety and reliability as conventional methods, and with acrophobia (fear of heights) walked across a suspension
shall be documented in the patients medical record. bridge 300 meters long and 54 meters above the ground. In
The medical record shall also document: the placebo group, IgA levels (a marker of stress and immune
response) dropped substantially halfway across and at the end
what medical options have been discussed, offered of the bridge. In comparison, in subjects given 100 mg GABA
or tried, and if so, to what effect, or a statement (pharma-GABA), IgA levels dropped only slightly midway
as to whether or not certain options have been and rose above baseline by the end of the bridge (Abdou
refused by the patient or guardian; that proper etal.,2006).
referral has been offered for appropriate treatment; Pregabalin is a synthetic structural analogue of GABA
that the risks and benefits of the use of the recom- approved by the FDA for treatment of neuropathic pain and
mended treatment to the extent known have partial-onset seizures. It is being considered for approval as
been appropriately discussed with the patient or an adjunctive treatment for generalized anxiety disorder
guardian; (GAD). Several randomized controlled trials (RCTs) con-
firm that pregabalin is comparable to lorazepam (Ativan),
that the physician has determined the extent to alprazolam (Xanax), and venlafaxine (Effexor) for moderate
which the treatment could interfere with any to severe GAD. Pregabalin is generally safe and well toler-
other recommended or ongoing treatment. ated. Side effects include dizziness, somnolence, cognitive
548 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
interference, incoordination, headache, and some poten- abusers with presumed poor dietary habits, 13 were given 3
tial for dependence. The onset of anxiolytic effects requires gm of omega-3 polyunsaturated fatty acids (n-3 PUFAS; in
1 week of daily treatment (Bandelow, Wedekind, & Leon, this case, eicosapentaenoic acid, EPA + docosahexaenoic acid,
2007). In clinical practice, the authors (PLG and RPB) DHA) versus 11 given placebo. Compared to the placebo
use pregabalin only when first-line treatments have failed. group, those given n-3 PUFAS had significant progressive
Starting doses of 50 mg three times daily are titrated upward decline in anxiety scores over 6 months (Buydens-Branchey &
as tolerated. Branchey, 2006). One DBRPC crossover trial of EPA alone
in patients with obsessive compulsive disorder on serotonin
reuptake inhibitors (SSRIs) found no effect on anxiety (Fux,
L-lysine and L-arginine Benjamin, & Nemets, 2004). It is possible that a combina-
Lysine is an essential limiting amino acid in wheat-based tion of EPA + DHA might have been more effective than
diets. In a 3-month DBRCT in poor Syrian families whose EPA alone. The testing of n-3 FA levels is not done routinely,
diet is based on wheat, lysine fortification of wheat resulted in but it is available. In light of the general health benefits and
improvements in anxiety and stress response (Smriga, Ghosh, minimal side effects, n-3 FAs are worth trying in patients
Mouneimne, Pellett, & Scrimshaw, 2004). L-lysine combined with anxiety disorders, particularly if nutrition has been
with L-arginine may affect neurotransmitters involved in compromised.
stress and anxiety. Acting as a partial serotonin receptor 4
(5-HT4) antagonist, L-lysine was found to reduce serum cor-
tisol and braingut responses to stress. A study of men with HERBAL TREAT M ENTS FOR AN X IETY
high trait anxiety based on the Stait-Trait Anxiety Inventory DISORDERS
found that L-lysine/L-arginine improved the ability to han-
dle induced stress more than placebo (Jezova, Makatsori, Traditional research has focused on isolating single active
Smriga, Morinaga, & Duncko, 2005). A double blind ran- components from plantsfor example, aspirin (salicylic
domized placebo controlled (DBRPC) study found that after acid) from white willow (Salix alba) or digitoxin from fox-
one week of L-lysine (2.64 g/day) plus L-arginine (2.64 g/day), glove (Digitalis purpurea). However, many plant extracts
healthy Japanese men had lower basal salivary cortisol levels contain tens or hundreds of bioactive compounds that often
and reduction in state anxiety (Smriga et al., 2007). Lysine have synergistic and polyvalent effects (Sarris, Panossian,
supplementation may reduce anxiety in people with lysine- Schweitzer, Stough, & Scholey, 2011). Synergy implies that
deficient diets. The combination of L-lysine and L-arginine the sum of multiple compounds exerting one main biological
may be useful in treating anxiety. effect is greater than the effect of any one alone. Polyvalence
indicates that multiple biological actions contribute to an
Magnesium inCombination Products overall effect. This occurs when numerous constituents have
varying physiological effects or when one constituent exerts
Although research has not shown magnesium monotherapy multiple effects. Furthermore, one compound may influence
to be anxiolytic, a few studies of multivitamins contain- the absorption, distribution, metabolism, or excretion of
ing magnesium show some positive effects. A multivita- other components.
min with calcium, magnesium, and zinc reduced anxiety The mechanisms of action of phytomedicines include
in healthy young men in a 28-day DBRPC study (Carroll, binding to neurotransmitters and receptors, effects on syn-
Ring, Suter, & Willemsen, 2000). Another 1-month study thesis of neurotransmitters or the enzymes that metabolize
of 200 mg magnesium plus 50 mg vitamin B 6 reduced pre- them, stimulation or inhibition of CNS activities, modula-
menstrual anxiety in a DBR crossover study (De Souza, tion of neuroendocrine systems, neuroprotection (for exam-
Walker, Robinson, & Bolland, 2000). Without further ple, against free radicals, oxidative stress, toxins, or hypoxia),
study, however, anxiolytic effects in healthy normal sub- enhancement of energy production and cellular repair, and
jects should not be extrapolated to those with anxiety dis- support for neurogenesis. Sarris and colleagues (2011) use the
orders. In clinical practice, the authors (PLG and RPB) find term herbomics to mean the use of proteomic, genomic, and
600800 mg of magnesium to be beneficial for some anx- other omic technologies in herbal research. For example,
ious patients. in an animal model, after 8 weeks of daily doses St. Johns
wort extract (Hypericum perforatum) showed regulation of
66 genes compared with imipramine regulation of 74 genes.
Omega-3 FattyAcids
St. Johns wort (SJW) and imipramine had 6 transcripts in
Although few studies have used omega-3 fatty acids (n-3 FAs) common that were related to synaptic and energy metabolism
for anxiety disorders, evidence suggests that they may be ben- (Wong etal.,2004).
eficial, particularly in patients with low levels. Omega-3 FAs A systematic review of clinical studies found strong evi-
were approximately 30% lower in the red cell membranes of dence for herbal supplements containing passionflower
untreated patients with social anxiety disorder and showed (Passiflora incarnata) or kava (Piper methysticum) and insuffi-
a significant inverse correlation with social anxiety ratings cient evidence for SJW in the treatment of anxiety (Lakhan &
(Green et al., 2006). In a 3-month DBRPC study of substance Vieira, 2010). Asubsequent review of psychopharmacological
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 549
and clinical studies (Sarris et al., 2011) used the following Kieser, & Hoerr, 2007). European studies of ginkgo have
defined levels of evidence: tended to show more favorable results than American stud-
ies. This may be due to the use of better quality standard-
Ameta-analysis or replicated RCTs with positive ized ginkgo extracts in Europe. American researchers are
results; becoming more aware of the importance of testing the best
quality products in research studies. Whether the positive
Bone unreplicated RCT or studies with mixed but effects on anxiety seen with EGb761 would be the same with
mainly positive results;or other ginkgo preparations remains to be proven. Ginkgo will
Cone or more clinical trials with poor methodology or be discussed in greater detail in the section titled Herbs for
mixed evidence from clinical trials. Treatment of Cognitive Dysfunction.
The level of clinical evidence for effects on anxiety was rated Piper methysticum(Kava)
Afor kava; and B for chamomile (Matricaria recutita), pas-
sionflower, and Arctic root or roseroot (Rhodiola rosea). Kava (extracted from Piper methysticum), a traditional social
Preclinical in vitro and animal studies indicate that anxio- ceremonial drink in Pacific Islands, contains alpha-pyrones
lytic phytomedicines commonly affect the GABA system (kavalactones) which have been shown to block sodium and
by reducing CNS stimulation and quieting the overactivity calcium channels, reduce excitatory neurotransmitter release,
of the amygdala that occurs in posttraumatic stress disorder enhance ligand binding to GABA type A receptors, reversibly
(PTSD) and other anxiety disorders. Anxiolytic herbs that inhibit monoamine oxidase B, inhibit cyclogenase, and reduce
inhibit two enzymes known to metabolize GABA were tested reuptake of dopamine and noradrenaline. Kava has shown
in rat brain homogenates. Extracts of lemon balm (Melissa modest benefits in eight short-term RCTs of mild anxiety. In
officinalis) showed the strongest inhibition of GABA trans- a 6-week double-blind, randomized, placebo-controlled trial
aminase; extracts of chamomile (Matricicaria recutita) and in patients with generalized anxiety disorder (n = 75), Sarris
hops (Humulus lupulus) significantly inhibited glutamate and colleagues (2013a, 2013b) studied the effects of neu-
acid decarboxylase (Awad etal.,2007). rotransmitter polymorphisms on response to Kava. Subjects
given 120/140 mg kavalactones per day had significant reduc-
tions in anxiety compared to placebo. GABA transporter
Matricaria recutita (Chamomile) polymorphisms rs2601126 and rs2697153 were associated
Chamomile grows in Europe, Asia, North America, and with HAMA reduction in response to kava.
Australia. The aromatic flowers are used to make tea. Active Since 1998, reports of hepatotoxicity, including liver fail-
constituents include terpine bisabolol, farnesene, chamazu- ure requiring transplantation, led the FDA to issue a Letter to
lene, flavonoids (including apigenin, quescetin, patuletin, Health Care Professionals and a consumer advisory warning
and luteolin) and coumarin. Traditional uses are for stomach of potential liver injury (Kraft etal., 2001; US Food and Drug
ache and irritable bowel syndrome, and as a gentle sleep aid, Administration, 2002). Ships records left by Captain Cook
mild laxative, antiinflammatory, and bactericidal. An 8-week from the 1800s describe kava intoxication in natives and sea-
RCT of moderately anxious GAD patients given 2201100 men (Singh & Blumenthal, 1996). Among Maori in Australia,
mg/day of standardized chamomile extract found significant long-term kava users have developed facial swelling, scaly
improvement on Hamilton Anxiety scores versus placebo rash, increased patellar reflexes, dyspnea, low albumin levels,
(Amsterdam etal., 2009). Apigenin, a component of chamo- increased GGTPase, decreased white blood cell and platelet
mile with high affinity for benzodiazepine GABA receptors, counts, hematuria, and tall P waves on ECGs consistent with
modulates monoamine neurotransmission and neuroendo- pulmonary hypertension (Mathews etal., 1988). Side effects
crine activity but exerts minimal sedative or muscle-relaxant include gastrointestinal symptoms, allergic reactions, head-
effects. Chamomile can trigger allergic reactions in people ache, and light sensitivity. Less common side effects are rest-
who have ragweed allergy. In one case a 70-year-old patient lessness, drowsiness, lack of energy, and tremor. Investigations
on warfarin experienced increased internal bleeding when she of adverse reactions implicate the use of incorrect plant parts
drank chamomile tea (Segal & Pilote,2006). or species, acetonic or ethanolic extraction, and poor storage
resulting in hepatotoxic mold (Teschke, Qiu, & Lebot, 2011).
Recent short-term studies using high quality standardized
Ginkgo biloba (Ginkgo)
Kava report minimal side effects. Taking kava with alcohol,
An extract of ginkgo (EGb 761, Willmar Schwabe sedatives, or muscle relaxants can induce coma (Almeida &
Pharmaceutical Co., Germany), distributed in the United Grimsley, 1996). Extracts of kava and kava lactones inhibit
States by Natures Way as Ginkgold, reduced anxiety in two P450 enzymes (see HerbDrug Interactions) involved in the
studies. A DBRPC study of 170 adults (aged 1870 years) metabolism of many pharmaceuticals (Mathews, Etheridge, &
with GAD or adjustment disorder with anxious mood were Black, 2002; Gurley et al., 2005). Considering the risks of
given 480 mg/day EGb761, 240 mg/day EGb761, or placebo intoxication, abuse, dependency, medication interactions,
for 4 weeks. Hamilton Anxiety Rating scores decreased sig- and, rarely, severe adverse reactions, the authors do not rec-
nificantly (p=.0003) and (p=.003) in the higher and lower ommend prescribing kava until more compelling data on
doses respectively compared to placebo (Woelk, Arnoldt, safety and efficacy become available and until a consistently
550 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
high quality of manufacturing and reliable batch testing are evaluated as good or very good by 96.7% of the patients.
established. No herb-related adverse events occurred.
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 551
whose damaging effects on emotion regulatory systems have shown mixed results. One DBRPC theanine study in 16
been studied in PTSD (Cao, Du, & Wang, 2006). Studies healthy volunteers showed some evidence of a mild relaxing
have shown that R. rosea increases the capacity of muscle and effect under resting conditions, but not during experimen-
nerve cells to maintain production of the high energy mol- tally induced anxiety (Lu et al., 2004). Another DBRPC
ecules adenosine triphosphate (ATP) and creatine phosphate study of 12 healthy subjects given a mental arithmetic task
(CP), needed to sustain cellular activities and repair mecha- as a stressor found that those given L-theanine had reduced
nisms (Kurkin & Zapesochnaya, 1986b). In a pilot study heart rate and attenuation of SNS activation (Kimura, Ozeki,
(Bystritsky, Kerwin, & Feusner, 2008) 10 patients from the Juneja, & Ohira, 2007). In clinical practice, the authors (RPB
UCLA Anxiety Disorders Program between the ages of 34 and PLG) find that theanine can be helpful in mild to moder-
and 55 with DSM-IV diagnosis of GAD, given a total daily ate anxiety, particularly in patients who are highly sensitive to
dose of 340 mg R. rosea (Rhodax) for 10 weeks, showed sig- side effects of other agents. It has minimal and usually no side
nificant decreases in mean Hamilton Anxiety Rating Scale effects when given in a starting dose of 200 mg 13 times a day
scores at endpoint (t = 3.27, p = 0.01). Adverse events were up to a maximum of 6 times a day. In brain damaged patients,
generally mild or moderate, the most common being dizzi- large doses may cause paradoxical overactivation. Green tea
ness and dry mouth. These preliminary findings warrant fur- and theanine have numerous health benefits, including anti-
ther exploration. While the authors sometimes find moderate oxidant and antiproliferative activity. Decaffeinated green tea
doses of R. rosea beneficial in anxiety disorders, its stimulative and capsules work well for anxious or agitated patients.
effects may initially increase agitation in sensitive individu-
als. Nevertheless, in clinical practices the authors note that
Valeriana officinalis (Valerian)
over time it can increase stress resiliency and reduce symp-
toms of PTSD. Panossian and colleagues (Panossian, 2013; Studies in mice show that valerenic acid and vulerenos, two
Panossian, Hamm, Wikman, & Effert, 2014) continue to of the active constituents of valerian (Valeriana officina-
explore the molecular and genomic bases for these actions: lis) extract, bind to GABAA receptors (Benke et al., 2009).
See Figure 28.1, Hypothetical Neuroendocrine Mechanism of Reviews of studies using Valerian for sleep show inconsistent
Stress Protection by Adaptogens and Figure 28.2, Hypothetical or weak results (Bent, Padula, Moore, Patterson, & Mehling,
Molecular Mechanisms by which Adaptogens Activate Stress 2006; Fernandez-San-Martin et al., 2010; Krystal & Ressler,
Response G-protein Coupled Receptors (GPCR) Pathways. 2001), possibly due to differences in product quality, meth-
R. rosea will be discussed in greater detail under Herbs for ods of extraction, doses, and patient populations. Valerians
Treatment of Cognitive Dysfunction. anxiolytic activity has been attributed to GABAA receptor
effects. Also the effect of valerian improves over time and
maximal benefit may take 2 weeks. One advantage of valerian
Hypericum perforatum (St. JohnsWort)
over other sedative/hypnotics is that there have been no cases
Extracts from the flowers and leaves of St. Johns wort of habituation or abuse and only one case of possible with-
(Hypericum perforatum) are best known for their antide- drawal symptoms. Valerian should be avoided in pregnancy.
pressant effects. Case reports and some open-label studies of Valerian is more effective when combined with other herbs,
patients with generalized anxiety disorder suggesting response but isolated cases of adverse reactions in combination with
to SJW have appeared in the literature, but controlled stud- benzodiazepines have been reported.
ies have not been supportive (Kobak, Taylor, Warner, etal.,
2005; Kobak, Taylor, Bystritsky, et al., 2005). In clinical
practice with anxious patients, the authors prefer to use SJW NEU ROHOR MONES FOR AN X IETY AND
brand Kira rather than Perika (Natures Way) because it is less INSOM NIA
stimulating and therefore less likely to exacerbate anxiety and
agitation. However, Perika may be more helpful in activating
7-K E TO DH E A (3 -AC E T Y L-7-
patients who have a sluggish depression (e.g., apathy or psycho-
OXO -DE H Y DROE PI-A N DRO S T E RON E)
motor retardation). Side effects and dosage will be discussed
FORP T S D
in the section on Herbs for Treatment of Mood Disorders.
To date there is no specific pharmacological treatment for dis-
sociative disorder in PTSD. In a small case series five women
Camellia sinensis (Green Tea, Theanine)
with severe chronic PTSD due to extreme childhood abuse,
Green tea, made from leaves of Camillia sinensis, has been who were treated with 5075 mg/day of a metabolite of
used for centuries for its calming and medicinal effects. Three dehydroepiandrosterone (DHEA) known as 7-keto DHEA),
to four cups of green tea contain 60160 mg of theanine experienced rapid, substantial improvement in dissocia-
(5-N-ethylglutamine or -glutamylethylamide), an amino tive symptoms, emotional numbing, avoidance, irritability,
acid found in green tea that may reduce anxiety under con- energy, mood, memory, concentration, cognitive function,
ditions of stress. In animal studies, theanine perfusion into libido, anxiety, and insomnia (Sageman & Brown, 2006).
the brain increased dopamine release and possibly inhibited The patients had not responded previously to many years
excitatory neurotransmission (Yamada, Terashima, Okubo, of psychotherapy and pharmacotherapy. No adverse side
Juneja, & Yokogoshi, 2005). Small studies in humans have effects were reported. Previous studies have linked DHEA
552 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
cortisol-lowering effects in PTSD with improvements in melatonin given for 1 week improved sleep maintenance,
memory, cognition, and mood (Rasmusson et al., 2004). while 2 mg fast-release melatonin improved sleep initiation
Unlike DHEA, 7-keto DHEA is not converted to testoster- with no adverse effects (Haimov etal., 1995). Areview of 14
one or estrogen. Consequently, 7-keto DHEA is less likely RCTs found that melatonin reduced sleep onset latency in
to cause acne, baldness, hirsutism, prostatic changes, or people with delayed sleep phase syndrome (DSPS) more effec-
increased estrogenicity. Chronic treatment-resistant PTSD in tively than in those with a diagnosis of insomnia (Buscemi
patients with serum DHEA and DHEAS levels in the lower et al., 2005). The distinction between DSPS and insomnia
50% of normal may benefit from 7-keto DHEA. Side effects accounted for much of the heterogeneity in previous studies.
are minimal. Agitation may occur in some patients and there Melatonin has a low incidence of adverse events (headaches,
is an increased risk of mania in bipolar patients. drowsiness, dizziness, and nausea) with no difference between
melatonin and placebo in any study. Furthermore, melatonin
has strong antioxidant protective effects in the dopamine
M E L ATON I N FORI N S OM N I A
system.
Melatonin (N-acetyl-5-methoxytryptamine), a hormone
secreted by the pineal gland, affects sleep circadian rhythms.
Generally safe and easy to use, melatonin does not disturb
MOOD DISORDERS
sleep architecture nor lead to habituation. DBRPC tri-
als show that melatonin improves sleep, reduces sleep onset
latency (Kayumov, Brown, Jindal, Buttoo, & Shapiro, 2001), N U T R I E N T S FORMO OD DI S OR DE R S
and restores sleep efficiency (Zhdanova etal., 2001). It is also
effective in treating insomnia in dementia and Parkinsons
B Vitamins, Folic Acid, L-methylfolate
(Dowling et al., 2005), sundowning (Cohen-Mansfield, The most important vitamins for mental health, the B vita-
Garfinkel, & Lipson, 2000), and rapid eye movement behav- mins (including folic acid) are essential for the functioning
ior disorder (RBD) (Pandi-Perumal, Zisapel, Srinivasan, & of nerve cells and are the most likely to be depleted due to
Cardinali, 2005). RBD, a chronic progressive parasomnia, poor nutrition, malabsorption, rapid utilization, aging,
occurs in neurodegenerative disorders and in Parkinsons chronic illness, diabetes, cancer, smoking, alcohol use, envi-
patients treated with dopamine agonists and levodopa. In ronmental stress, or the use of medications such as mood
RBD the motor paralysis that normally occurs during rapid stabilizers, L-dopa, statins, oral antidiabetic drugs, and
eye movement (REM) sleep is lost, such that patients may chemotherapy.
act out dreams, thrashing and kicking, hurting themselves or Dietary folate and folic acid (supplemental form) must be
their partners. Stimulants, tricyclic antidepressants (TCAs), converted into L-methylfolate for use in numerous metabolic
and SSRIs can trigger RBD (Schenck, Bundlie, Ettinger, & pathways, including the synthesis of neurotransmitters. The
Mahowald, 1986), although this is more likely in patients final step in this conversion depends upon methyltetrahy-
with neurodegenerative diseases. Clonazepam or carbam- droxyfolate reductase (MTHFR), which is also required for
azepine, the standard treatments for RBD, can exacerbate production of methionine from homocysteine (see Figure
cognitive dysfunction or cause ataxia (increasing the risk of 28.1 Methylation Cycle, Folate Cycle). Polymorphisms of
falls). Side effects rarely occur with melatonin, even at 912 the MTHFR gene affect the capacity of MTHFR to convert
mg h.s., the doses necessary to treat RBD (Kunz & Bes, homocysteine to methionine, or methylene-tetrahydrofolate
1997; Paparrigopoulos, 2005). In a DBRPC study of elderly to L-methylfolate (see Box 28.1). For an in-depth discus-
melatonin-deficient insomniacs, 2 mg sustained-release sion of the relationship between folate, other B vitamins,
dietary
supplement
food source
Folic acid DHF dietary
supplement
Methionine
THF
MAT
SAMe CH3 DNA
Folate Methylation
Proteins
Methylene Cycle B Cycle
12 MS Phospholipids
THF
MTHFR SAH Neurotransmitters
SAHH
5-MTHF
Homocysteine
CBS B6
dietary
supplement Cystathionine
Figure28.1 Methylation Cycle, Folate Cycle, SAMe, and B Vitamins. Key:Relationship between folate, vitamin B12 and methylation. Abbreviations:DHF, dihydrofolate; THF, tetrahy-
drofolate, 5-MTHF, 5-methyltetrahydrofolate, SAMe, S-adenosylmethionine, SAH, S-adenosylhomocysteine, MTHFR, methyltetrahydrofolate reductase; MS, methionine synthase; MAT, methionine adenosyl-
transferase; SAHH, S-adenosylhomocysteine hydrolase. Reproduced with permission of Dr.Teodoro Bottiglieri, adapted from Psychiatric Clinics of North America, 2013, 36(1):3.
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 553
homocysteine, and depression, see the scholarly discus- less than 15 mM/L (Lange etal., 2004). Poor gastric absorp-
sions by Papakostos and Bottiglieri (Papakostas et al., 2005; tion of B12 may contribute to B12 deficiency, nonresponse
Bottiglieri, 2013). A mutation on the MTHFR gene at the to supplementation, and mixed results in clinical studies.
677 base positiondue to a substitution of a cytosine base Therefore, the use of sublingual B12 tablets may be more
(C) by a thymine (T), a CT polymorphismresults in a less effective.
active form of the enzyme. The normal genotype C/C has
100% MTHFR activity. However, MTHRF activity declines
VitaminD3
to 71% with C/T and 34% with T/T genotypes. The conse-
quences of a C/T or T/T polymorphism are increased homo- Vitamin D3 (cholecalciferol) is critical for normal brain
cysteine and reduced folate concentrations. About 40%50% development. Evidence from preclinical studies suggests that
of the population has C/T mutation, while 10%12% has vitamin D can affect neurotransmitters, calcium homeosta-
T/T genotype. In addition, S-adenosylmethionine (SAMe) sis, hypothalamic-pituitary-adrenal (HPA) axis function,
production may decline. Consequently, the reduction in inflammatory markers, and nerve growth factor. Population
SAMe and the metabolism of folate, along with the increase studies indicate an association between low vitamin D lev-
in homocysteine, may contribute to depression, poor response els and depression, Alzheimers disease (AD), Parkinsons
to antidepressants, and progression of other illnesses such as disease, and cognitive decline. Vitamin D deficiency occurs
cardiovascular disease. Supplementation with L-methylfolate at serum levels below 20 ng/ml 25-hydroxyvitamin D
may be more effective than folic acid in patients with poly- [25(OH)D]; insufficiency occurs below 30 ng/ml; and opti-
morphisms, because it bypasses the final MTHFR conversion mal levels are between 3080 ng/ml. Although small clini-
step. L-methylfolate is well absorbed and readily crosses the cal trials showed improvement in symptoms of depression
bloodbrain barrier. For example, in a DBRPC study of 123 with vitamin D, large population studies have yielded mixed
patients with major depression or schizophrenia, 33% had results. Across-sectional study of 12,594 adults in a primary
low or borderline folate levels. Among the low-folate patients care clinic revealed that individuals with a prior history of
on standard psychotropic medication, the addition of 15 mg/ depression showed a significant correlation between high
day methylfolate resulted in significantly greater improve- vitamin D levels and reduced risk of depression, whereas those
ments compared to placebo (Procter, 1991). Studies suggest with no prior history of depression did not (Hoang et al.,
that L-methylfolate 15 mg/day is useful in the treatment of 2011). Reduction of light exposure during winter months
SSRI-resistant depression. Two DBR parallel sequential tri- results in a decrease in production of vitamin D.The relation-
als in adults with major depression (total n = 223) found 2 ship between sun exposure, vitamin D levels, and seasonal
weeks of 15 mg/day L-methylfolate augmentation of SSRI to affective disorder has been explored in several small random-
be safe, well tolerated, and significantly better in improving ized studies with mixed results (Bell etal.,1992).
response rates and reducing scores on Hamilton Depression In a study of 104 adolescents presenting for treatment for
Scale compared with SSRI augmentation with placebo or 7.5 serious acute symptoms of mental illness, 34% had vitamin
mg/day L-methylfolate (Papakostas et al., 2012). Testing of D deficiency and 38% insufficiency. Vitamin D deficiency
MTHFR polymorphisms is becoming more widely used to was strongly associated with psychotic features (Gracious,
identify patients who would be more likely to benefit. Deplin, Finucane, Freidman-Campbell, Messing, & Parkhurst,2012).
a prescription form of L-methylfolate is available. However, Administration of vitamin D to all depressed patients
most insurance companies do not cover the costs. Consumers is not justifiable based on current evidence. However, it is
can obtain the supplement online from established commer- appropriate to check 25(OH)D levels in those at risk for defi-
cial brands less expensively. ciency due to prior history of depression, age above 65years,
In depressed patients and in the elderly, low levels of B12 adolescents with severe mental illness, lack of regular outdoor
(cyanocobalamin) and folate have been associated with dis- activity, and residence in northern latitudes with reduced sun
orders of mood, memory, and cognition (Bottiglieri, 1996; exposure. Documented vitamin D deficiency can be treated
Crellin, Bottiglieri, & Reynolds, 1993). Proton pump inhibi- acutely with high-dose vitamin D3 (cholecalciferol) until
tors interfere with B12 absorption. If there is reason to think serum levels reach normal, followed by a maintenance dose of
that a patient may have impaired B12 absorption, for example, 2000 to 6,000 IU/day.
due to loss of intrinsic factor with aging or the use of a pro-
ton pump inhibitor (e.g., cimetidine, ranitidine, omeprazole,
S-adenosyl-L-methionine, Adometionine,SAMe
esomeprazole, famotidine), then sublingual B12 should be
administered. Testing for serum methylmalonic acid provides SAMe (S-adenosyl-L-methionine or S-adenosylmethionine),
a more accurate indicator of intracellular B12 than serum B12 a first-line mainstream antidepressant and antiarthritic in
levels. many European countries, is still viewed as an alternative treat-
Studies of B vitamins and folic acid as solo treatments for ment in the United States. The FDA approved its use as an
depression show mixed results. Methylfolate and B vitamins over-the-counter nutraceutical in 1998. The US Department
are generally quite safe and low in side effects. Allergic reac- of Health and Human Services Agency for Healthcare
tions may occur. B Vitamins and folic acid stimulate endo- Research and Quality published an evidence report (Agency for
thelial proliferation and may accelerate occlusion of cardiac Healthcare Research and Quality, 2007)concluding that SAMe
stents, but only in men whose baseline homocysteine level is was equivalent to standard pharmacotherapy for treatment of
554 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
Box 28.1NEUROPROTECTIVE EFFECTS OFSAME, through the condensation of methionine and ATP, a reac-
FOLATE, AND VITAMINB12 tion catalyzed by methionine methyltransferase (MAT) (see
Figure 28.3). SAMe donates methyl groups for production of
AD is associated with decreased plasma folate and increased DNA, proteins, phospholipids, neurotransmitters (serotonin,
plasma homocysteine . Substantial evidence associates increased norepinephrine, and dopamine), and other cellular compo-
serum homocysteine with AD (Coppede, 2010) and low brain nents. These methylation reactions are catalyzed by meth-
SAMe levels with AD. Folate deficiency leads to a decline in SAMe yltransferase enzymes and require vitamin B12 and folate as
with decreased DNA methylation and increased DNA breakage cofactors. SAMe also contributes sulfate groups for synthesis
during aging and AD (See Figure28.3). The reduction in folate of the major endogenous antioxidant, glutathione (Bottiglieri,
and SAMe potentiates AD risk factorsincreased neurotoxicity 2002, 2013). B12 1000 mcg/day, folic acid 400800 mcg/day,
from elevated homocysteine, presenilin-1 (PS-1) over-expression, and B6 50100 mg/day can be effective for augmentation of
reduced use of glutathione, and increased beta-amyloid deposi- SAMe and other antidepressants.
tion. The C677T polymorphism of MTHFR uses folate to regen- SAMe was shown to be safe and effective for the treatment
erate methionine from homocysteine. Condensation of ATP and of major depression in 16 open trials, 13 DBRPC studies, and
methionine produce SAMe. Therefore, insufficiency of tetrahy- 19 DBRCTs in comparison to standard antidepressants. See
drofolate leads to accumulation of homocysteine and decreased reviews of SAMe metabolism research (Brown, Gerbarg, &
production of SAMe as methionine becomes less available. Bottiglieri, 2000; Bottiglieri, 2013)and clinical applications
In human neuronal cells folate and B12 deprivation were asso- (Brown, Gerbarg, & Muskin,2009).
ciated with reduced production of SAMe and methylation of the A 12-week double-blind, randomized, placebo controlled
promoter of the preselin-1 (PSEN1) gene, resulting in increased trial of S-adenosylmethionine (SAMe) versus escitalopram
production of preselin-1 and amyloid precursor protein. This epi- in 189 outpatients with major depressive disorder (MDD)
genetic modification in the PSEN1 gene would result in increased was reported as a failed trial by Mischoulon and colleagues
beta-amyloid (A) peptide production. Furthermore, addition of (2014). No significant differences were found in response
SAMe to human neuroblastoma cell cultures led to downregula- rates: 36% for SAMe, 34% for escitalopram, and 30% for
tion of PSEN1 expression and a decrease in A peptide produc- placebo. Remission rates suggested that both SAMe and esci-
tion (Coppede, 2010). The MTHFR C677T polymorphism is talopram had more robust effects compared to placebo:28%
an apolipoprotein E4-dependent risk factor for AD: as SAMe for SAMe, 28% for escitalopram, and 17% for placebo.
decreases, S-adenosylhomocysteine increases, further inhibiting Placebo response rates 30% are correlated with lower risk
methylation (Bottiglieri,2013). ratio of response to antidepressants versus placebo (Iovieno
Cognitive impairment and increased aggression were found in and Papakostas, 2012). Studies with placebo response rates
mice lacking murine ApoE and mice expressing human E4 when 30%, as seen in this study, reported worse performance
fed a diet deficient in folic acid and vitamin E with iron-induced of drug versus placebo (Rutherford and Roose, 2013).
oxidative stress. Supplementation with SAMe attenuated these Furthermore, the sample size was only 2/3 of the number for
adverse effects. Furthermore, supplementation with SAMe which the study was powered.
improved cognitive performance in mice 9 to 12months of age Bias was introduced in the discussion of the study results.
that were lacking murine ApoE and expressing human E2, E3, Mischoulon and colleagues wrote that the sample was large
or E4 alleles. SAMe also indirectly contributed to acetylcholine enough to provide a conclusive statement about the efficacy
synthesis (Chan, Tchantchou, Rogers, & Shea,2009). of SAMe as a monotherapy for MDD and that SAMe may
SAMe reduced impairments in primates and facilitated recov- be better suited as an augmentation therapy than as a mono-
ery from vascular lesions in motor and dorsolateral prefrontal cor- therapy. They made no such statement about escitalopram,
tex. In rats SAMe substantially decreased free radical production, though it performed no better than SAMe. A critique of this
increased glutathione, glutathione peroxidase, and transferase, study noted, The manner in which researchers discuss study
and improved cholinergic function and learning. SAMe signifi- results impacts clinical practice and can be particularly dam-
cantly improved survival when given within 24 hours of ischemia aging in the case of less well known or less conventional treat-
or hemorrhagic stroke (Monaco et al., 1996). In patients with ments and suggested that the causes for the failure of both
traumatic brain injury (TBI), 1month of SAMe decreased mean treatments to produce higher response rates than placebo are
postconcussion symptom scores by 77% compared to 49% in a more likely be found in problems with the patient selection
placebo group. Symptoms of headache, vertigo, depressed mood, process and the heterogeneity within patient groups with
cognitive slowing, slow thought, speech, and decreased concen- respect to genomic and metabolic biomarkers. At the very
tration improved (Bacci Ballerini, Lopez Anguera, Alcaraz, & least, until the true causes of invalidity are identified, such
Hernandez Reyes,1983). studies should not be used to create unwarranted doubt about
the efficacy of highly beneficial treatments such as SAMe.
(Gerbarg, Muskin, Bottiglieri, & Brown, 2014).
depression and osteoarthritis. SAMe was also found to be more As a natural metabolite, SAMe is very low in side effects
effective than placebo in reducing bilirubin and pruritis in intra- compared with synthetic antidepressants and it has a more
hepatic cholestasis and cholestasis of pregnancy. rapid onset of action. There are credible reports of adverse
An essential molecule in hundreds of biochemical reac- interactions with other medications. In fact, SAMe pro-
tions within the cells of all organisms, SAMe is produced tects the liver and bone marrow from toxic effects of other
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 555
medications (Brown, Gerbarg, & Muskin, 2009). The most effects of the prescription antidepressant and reduces the
common side effect of SAMe is nausea. This can usually be cost ofSAMe.
relieved by eating a light snack before taking SAMe, using gin-
ger capsules or tea, or by reducing the SAMe dose. Loose bow- SAMe toAugment Antidepressants
els, flatulence, and abdominal pain can occur. Occasionally There are few pharmacological agents for treatment resis-
patients complain of headache. In rare cases patients with tant depression and overall outcomes are poor. Results from
palpitations have complained of an increase in irregular the US National Institute of Mental Health's (NIMH)
heartbeats when given SAMe, although it is generally well tol- STAR*D (Sequenced Treatment Alternatives to Relieve
erated by individuals with cardiovascular disease. However, if Depression) programme indicate that after the failure of two
it exacerbates symptoms it should be discontinued. The most treatment trials, the chances of remission decrease signifi-
serious potential side effect is the potential to induce mania in cantly (Shelton, Osuntokun, Heinloth, & Corya,2010).
bipolar I patients. The neuronal effects of SAMe overlap those of TCAs
As an activating antidepressant, SAMe helps energize with additional dopamine stimulating effects, but SAMe has
patients whose depression is characterized by low energy, fewer side effects. Three controlled studies have shown that
tiredness, low motivation, and hypersomnia. It absorbs best SAMe enhances the action of TCAs (Brown, Gerbarg, &
when taken at least 2030 minutes before breakfast and Bottiglieri, 2000). One DBRPC trail (n = 350) demon-
lunch on an empty stomach or 2 hours after a meal. If taken strated that SAMe accelerated the response to imipramine
late in the day, it may interfere with sleep. For patients whose (Berlanga, Ortega-Soto, Ontiveros, & Senties, 1992). SAMe
depression includes anxiety and agitation, it may be necessary has been shown to enhance the effectiveness of prescription
to use an anxiolytic during the first few weeks to counteract antidepressants and hasten onset of action. In an open trial
the stimulative effects of SAMe and to avoid exacerbating at Massachusetts General Hospital, 30 depressed nonre-
anxiety (as also occurs with stimulating antidepressants such sponders to either SSRIs or venlafaxine were administered
as SSRIs). However, within 23 weeks, as the antidepressant SAMe (8001600 mg/day). SAMe augmentation showed
action is established, it is usually possible to taper off of anx- a response rate of 50% and a remission rate of 43% (Alpert
iolytics. SAMe does not cause sexual side effects, sedation, etal.,2004).
weight gain, or cognitive interference. In patients who have Further controlled trials for treatment resistant depres-
medication sensitivities, significant anxiety, gastrointestinal sion are warranted. A meta-analysis of European-licensed
problems, or serious medical conditions, one can start with a therapies in patients with MDD and inadequate response
test dose of 200 mg SAMe 20 minutes before breakfast for a to antidepressant monotherapy identified 7 RCTs that met
few days. If this is well tolerated, it can be increased to 400 mg criteria for analysis. This meta-analysis concluded that the
20 minutes before breakfast for 37 days. The rate of increase likelihood of response was significantly greater with SAMe
in SAMe doses depends on clinical assessment of the patient. augmentation versus placebo or lithium (Turner, Kantaria, &
For elderly, frail, or unstable patients, more time may be Young,2014).
needed before each increase. If the patient reports side effects, The addition of SAMe caused no adverse reactions in
then more time may be allowed before the next increase. In 500 patients on benzodiazepines, 60 on monoamine oxidase
general, the dose for mild depression is 400600 mg/day; inhibitors (MAOIs), 45 on anticonvulsants, and 18 alcohol-
moderate depression 6001200 mg/day; severe depression ics on antidepressants or anticonvulsants. Moreover, SAMe
12001600 mg/day; and very severe, treatment-resistant reversed or prevented liver toxicity, reducing the elevated lev-
depression 16002400 mg/day. els of gamma-glutamyl-transpeptidase (GGT) in all patients
taking MAOIs, anticonvulsants, or antidepressants (Torta et
Clinical Applications and Practical Considerations al., 1988). SAMe is the only antidepressant that has been stud-
SAMe has unique benefits in treating depression in ied in combination with MAO inhibitors with good results
patients with arthritis, fibromyalgia, liver disease, or HIV/ and no adverse reactions. In addition to its antidepressant
AIDS. It should also be seriously considered for patients who effects, SAMe has numerous long-term health benefits in a
take medications that may impair liver function, for example, wide range of serious medical conditions.
statins and/or prescription antidepressants. SAMe has no
adverse hepatic effects and it protects against liver damage SAMe forTreatment ofDepression, Arthritis, and
from prescription medications (Torta etal.,1988). Fibromyalgia
Cost is a major drawback for SAMe because it is not yet Depression and arthritis are often comorbid and are exac-
covered by medical insurance in many countries. Prices vary erbated by chronic progressive pain, disrupted sleep, aging,
from $20 to $60 for a package of 20 of the 400mg tablets. debilitation, and side effects from antiinflammatory and pain
Patients can comparison shop (for quality brands) or get medications. Twelve studies in more than 20,000 adults have
pharmaceutical grade SAMe online (Brown, Gerbarg, & shown that SAMe provides analgesic and antiinflammatory
Muskin, 2009). Unfortunately, at higher doses many people effects equal to nonsteroidal antiinflammatories in osteo-
cannot afford the expense of SAMe. However, since SAMe arthritis, but causes fewer side effects. Six studies reported
combines well with all other antidepressants, it is possible that SAMe improved both depression and pain in patients
to combine a smaller dose of SAMe with a reduced dose of with fibromyalgia at doses equivalent to 800 mg/day with
a prescription antidepressant. This approach reduces side no side effects (Grassetto & Varatto, 1994; Ianiello et al.,
556 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
1994; Tavoni, Vitali, Bombardieri, & Pasero, 1987; Tavoni, B6 levels, and/or the absence of supplemental support for the
Jeracitano, & Cirigliano,1998). SAMe treatment. In cases of significant hepatic fibrosis, it is
necessary to augment SAMe with polyenolphosphatidylcho-
SAMe forTreatment ofDepression and Liver line, L-methtylfolate, B12, B6, and sometimes herbal formu-
Disease las containing bupleurum. Without the necessary cofactors
Patients with liver diseases often have comorbid depres- and maintenance of SAMe supplies, the treatment is not as
sion that may be primary, secondary to the hepatic dysfunc- effective.
tion, or due to medications (e.g., interferon). Moreover,
psychotropic medications (particularly SSRIs) can cause
elevations of liver function tests (LFTs) or exacerbate preex- SAMe forTreatment ofDepression and Parkinsons
isting liver dysfunction. Alcohol abuse depletes the liver of Disease
SAMe and causes oxidative stress that contributes to tissue Carbidopa is a common treatment for Parkinsons dis-
damage. Numerous studies have demonstrated that SAMe ease, a degenerative disorder characterized by difficulty
improves liver function and reverses biochemical markers initiating movements, dyskinesias, stiffness, tremor, rigid-
(abnormal LFTs) in patients with cirrhosis or hepatitis due ity, mask-like facies (loss of facial expression), and unsteady
to alcohol, drugs, toxins, infections, or gallstones, including gait. It often leads to social withdrawal and the loss of all
during pregnancy (Frezza, Centini, Cammareri, Le Grazie, spontaneous activity and communication. L-dopa treatment
& Di Padova, 1990; Friedel, Goa, & Benfield, 1989; Lieber, further reduces the already depleted brain stores of SAMe
1999; Mato etal., 1999; Milkiewicz etal., 1999). In a 2-year in patients with Parkinsons, exacerbating the depression
DBRPC study of alcohol-induced liver cirrhosis (Childs which is highly resistant to treatment with standard anti-
Class Aand B cases) SAMe 1200 mg/day increased survival depressants. In a double blind crossover study of 21 patients
and delayed liver transplants (Mato etal., 1999). Many cases with Parkinsons disease, depression improved significantly
of undiagnosed hepatitis are discovered when LFTs rise in 8 of the patients given SAMe 1200 mg/day (Carrieri,
in patients taking SSRIs for depression. Discontinuation Indaco, & Gentile, 1990). Depression also improved in 11
of the prescription antidepressant and initiation of SAMe out of 13 subjects in an open series of Parkinsons patients
usually restores LFTs to normal range. Treatment of mildly given SAMe 16004000 mg/day (Di Rocco, Rogers,
elevated LFTs usually requires SAMe 800 mg in the morn- Brown, Werner, & Bottiglieri, 2000). At these doses, neu-
ing (except in bipolar patients). In bipolar patients Ease-2 rological symptoms such as dyskinesia and poor balance
or Ease-Plus (CraneHerb)Chinese herbal preparations also improved in some cases. A Phase II 12-week DBRPC
containing bupleurummay be used. Hepatoprotection study compared SAMe 12002400 mg versus escitalopram
by Bupleurum kaoi includes antiinflammatory and antifi- (Lexapro) 1020 mg in the treatment of depression associ-
brotic effects, enhanced glutathione production, and liver ated with Parkinsons disease. Both SAMe and escitalo-
cell regeneration (Yen, Weng, Liu, Chai, & Lin, 2005). LFT pram significantly reduced depression (HAMD) scores with
increases greater than three times normal respond better to greater improvements on escitalopram. However, SAMe
SAMe 12001600 mg/day enhanced with polyenylphos- significantly improved motor symptoms compared to no
phatidylcholine. SAMe is depleted during the conversion of change on escitalopram (Varanese, Birnbaum, Rossi, &
phosphatidyl ethanolamine to phosphatidylcholine. Taking Di Rocco,2011).
polyenylphosphatidylcholine replenishes phosphatidyl-
choline supplies, preventing depletion of SAMe. As SAMe SAMe forTreatment ofDepression and HIV/AIDS
reserves increase, more glutathione is produced to counter- Depression occurs in about 30%50% of HIV+ patients
act oxidative damage to the liver (Aleynik & Lieber, 2003; and is associated with low immune response, disease pro-
Lieber, 2001, 2005). In patients with serious underlying gression, and diminished quality of life. SAMe deficiency
liver disease with documented fibrosis, adding B vitamins has been found in HIV-infected patients. An open 8-week
(including B6) and alpha-lipoic acid can enhance response. If study of 20 patients with HIV and major depression, given
LFT elevations persist, betaine (trimethylglycine) can aug- SAMe 400 mg twice a day with folic acid (800 mcg/day)
ment the response to SAMe by elevating glutathione (anti- and B12 (1000 mcg/day), showed significant improvement in
oxidant), protecting the liver from chemical damage, and depression by week four (Shippy, Mendez, Jones, Cergnul, &
improving liver function (Barak, Beckenhauer, & Tuma, Karpiak,2004).
1996; Kharbanda etal.,2005).
In a 24-week DBRPC trial, 37 outpatients with alco- Perinatal Depression
holic liver disease were administered either SAMe 400 mg Clinical studies show the safety and efficacy of SAMe for
three times daily or placebo. No significant differences were improving liver function in the treatment of cholestasis due to
found in LFTs or fibrosis in liver biopsies for the entire group. gallstones of pregnancy (Frezza etal., 1990; Friedel, Goa, &
However, in the cases with less severe fibrosis, SAMe was Benfield, 1989; Lieber, 1999; Mato etal., 1999; Milkiewicz
more beneficial than placebo (Medici et al., 2011), but vita- etal., 1999). No adverse effects on infant development have
min B6 levels were subnormal. The negative results could be been identified. The normal level of SAMe in the spinal fluid
attributed to the severity of fibrosis, short duration of treat- of infants is 3 to 7 times higher than that of adults (Surtees &
ment compared with other studies, presence of subnormal Hyland, 1990). Studies of children with inborn errors of
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 557
metabolism affecting methyl transfer pathways found that (enzymes, receptors, ion channels) may impair neurotrans-
SAMe deficiency in the cerebrospinal fluid of children was mission. Increased eicosanoids and proinflammatory cyto-
associated with demyelination and that treatment with kines may also be contributory. Omega-3 FA deficiency has
SAMe was associated with remyelination (Surtees, Leonard, been associated with increased depression and risk of sui-
& Austin, 1991); therefore, it is unlikely that the administra- cide (McNamara et al., 2007; Sublette, Hibbeln, Galfalvy,
tion of therapeutic doses of SAMe to mothers experiencing Oquendo, & Mann, 2006), and n-3FA supplementation has
perinatal depression would be harmful during pregnancy or been found to reduce depression and suicidality (Hallahan,
breastfeeding (Brown, Gerbarg, & Muskin, 2009). Longer Hibbeln, Davis, & Garland, 2007). For a clinical review of
follow-up studies including neuropsychological testing of n-3FAs see Mischoulon and Freeman (2013). However, a
children would provide further assurance of safety during meta-analysis of 13 RCTs, detecting heterogeneity and pub-
pregnancy. lication bias, concluded that although the balance of omega-3
to omega-6 fatty acids may be involved in the pathogenesis
SAMe forTreatment ofDepression inChildren of depression, there was little evidence of significant benefit
There are no published controlled studies on the safety from n-3FAs in the treatment of major depressive disorder
and efficacy of SAMe in children. However, SAMe has been (Bloch & Hannestad,2012).
used successfully to treat depression in children and adoles-
cents in clinical practice. Three cases were reported including Perinatal Depression
two sisters, aged 8 and 11, and one boy, aged 16. Both parents Omega 3-FAs are crucial for brain development in utero
of the girls had strong family histories of depression and cred- and after birth, particularly arachidonic acid (AA) and DHA.
ited SAMe with providing full relief of their own depressions. The recommended intake of DHA during pregnancy is
They did not want to expose their children to side effects 200300 mg/day. During the first 6months of life, a ratio of
from prescription medications. The girls had developed severe 4:10 n-6FA:n-3FAs is advised (Rombaldi Bernardi, de Souza
major depression including crying, withdrawal, sadness, and Escobar, Ferreira, & Pelufo Silveira, 2012). Omega3 FAs are
preoccupation with themes of death. The 11-year-old was generally considered to be safe during pregnancy and breast-
started on 200 mg/day SAMe. When her dose was increased feeding, although an upper dose limit has not been established.
to 600 mg/day, her depression rapidly and completely remit- Many prenatal vitamins and infant formulas contain n-3 FAs.
ted with no side effects. Her 8-year-old sisters depression also In their review of n-FAs, Mischoulon and Freedman (2013)
remitted on 200 mg SAMe twice a day (Schaller, Thomas, & found that DBRCTs in pregnant and postpartum women
Bazzan,2004). yielded mixed results. They concluded that n-3FAs could help
to alleviate perinatal depression in a ratio of 2:1 EPA:DHA
Quality and Potency ofSAMeBrands as an alternative or adjunctive to standard treatment. Lin and
SAMe rapidly oxidizes when exposed to air. It is stabilized colleagues (2012) observed that 5 meta-analyses concluded
in the form of a salt. Tablets are enterically coated to resist that n-3 FAs had antidepressant effects in patients with major
degradation by gastric enzymes. The quality of the SAMe and depressive disorder based on DSM criteria, but that evidence
the quality of the tablet are critical for maintaining potency did not support mood improvement in symptomatic individu-
over time. If the manufacturing is flawed, tablets lose most als with unconfirmed diagnoses. They critiqued a meta-analysis
of their potency while sitting on shelves. Unfortunately, some that included studies that reported no benefits from n-FAs, in
companies are producing low-grade SAMe and selling it at which the subjects were not evaluated for major depressive dis-
bargain prices. Not only do these products lack efficacy, they order with rigorous measures such as theHAMD.
can also cause more side effects. Patients should be advised to
purchase only products of proven quality and those in which Omega-3 Fatty Acids and Bipolar Disorder
each tablet is protected within its own foil blister pack. SAMe Depressive symptoms in bipolar disorder respond better to
should not be refrigerated because tablets can be damaged adjunctive treatment with a combination of EPA and DHA
by condensation of water within the blister packs. Also, tab- using total daily doses ranging from 19 gm (Frangou, Lewis, &
lets should not be cut because the enteric coating would be McCrone, 2006; Osher, Bersudsky, & Belmaker, 2005;
disrupted. Stoll et al., 1999). Although there have been some reports
of n-3FAs triggering manic symptoms, this did not occur in
Omega-3-Fatty Acids forDepression and the studies by Frangou, Osher, or Stoll. Anecdotally, some
Bipolar Disorder cases show marked improvement in both manic and depres-
sive symptoms enabling reduction of prescription medication
Omega-3fatty acids (n-3FAs), particularly eicosapentaenoic doses. In a meta-analysis of n-3FAs for bipolar disorder, Sarris
acid (EPA) and docosahexaenoic acid (DHA) help maintain and colleagues found a significant effect on bipolar depres-
cell membrane fluidity. EPA and DHA also reduce produc- sion and a nonspecific effect for mania (Sarris, Mischoulon, &
tion of inflammatory eicosanoids and the release of proin- Schweitzer, 2012).
flammatory cytokines. Data suggest that the substitution of
omega-6FAs for n-3FAs in cell membranes is associated with Geriatric Depression
unipolar and bipolar depression (Hirashima et al., 2004). Depression in the elderly is often overlooked, and deple-
The loss of membrane fluidity affecting membrane proteins tion of n-3FAs has been associated with depression. An 8-week
558 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
DBRPC parallel group study of 46 elderly (6595 years) levels and reduced markers of oxidative stress. Increased
depressed women in a nursing home found that 2.5g/day oxidative stress and disturbed glutathione metabolism have
of n-3FA (EPA:DHA of 2:1) significantly improved scores been associated with bipolar disorder and depression. In
on the Geriatric Depression Scale and lowered the ratio of a 6-month DBRPC study of 75 patients with bipolar dis-
AA to EPA in whole blood and red cell membranes (Rizzo order, the addition of NAC 2g/day to the usual treatment
etal.,2012). regimen resulted in significant improvements on measures
of depression, mania, quality of life, and social and occu-
Side Effects and Dosages pational functioning compared to placebo. Response took
The most common side effects of n-3FAs are gastrointes- 812 weeks with no significant side effects (Berk, Copolov,
tinal:nausea, heartburn, stomach pain, belching, bloating, or Dean, etal., 2008b).
diarrhea. These are more likely to occur at doses above 6 g/day. Psychotropic medications, particularly antipsychotics, can
The FDA has approved prescription forms of fish oil, Omacor damage fibers in the striatum leading to tremors, stiffness,
and Lovaza, for treatment of hypertriglyceridemia (Medical or abnormal movements. In animal studies NAC protected
Letter, 2006). Each 900mg capsule contains 465 mg EPA and rat striatum from oxidative stress and lipid peroxidation due
375 mg DHA. Nonprescription high-quality refined fish oil to an antipsychotic medication, haloperidol (Haldol). This
in concentrated liquid form has a light, non-fishy taste and raises the possibility that NAC could protect patients from
is less likely to cause gastrointestinal side effects. Because some of the adverse effects of treatment with antipsychotic
n-3FAs reduce platelet aggregation, patients on anticoagu- medications. NAC has also been used to treat acetaminophen
lants should be monitored more closely when taking n-3FAs. overdose and to reduce the risk of respiratory infections and
It is best to refrigerate fish oil products to prevent them from flu. Because NAC is safe, well tolerated, and has additional
turning rancid. health benefits, it is a useful complementary treatment. Apos-
itive response usually takes 812 weeks using daily doses of
5-Hydroxy-L-Tryptophan (5-HTP) 24003600 mg/day.
The rationale for using the amino acid, 5-hydroxy-
L-tryptophan (5-HTP) for depression is based on its role H E R B S FORT R E AT M E N T OFMO OD DI S OR DE R S
as the precursor for synthesis of serotonin. 5-HTP replaced Hypericum perforatum (St. JohnsWort)
L-tryptophan, which was taken off the market in 1989 after a
contaminated product from a single manufacturer was linked Meta-analyses of RCTs of St. Johns wort for mild to moder-
to eosinophilia malignant syndrome. Since then, studies ate depression show significant benefits compared to placebo,
of 5-HTP have found no evidence of toxicity (Das, Bagchi, effects comparable to imipramine and SSRIs, and far fewer
Bagchi, & Preuss, 2004). The efficacy of 5-HTP in depres- side effects than synthetic antidepressants but slower onset of
sion has been reviewed (Das et al., 2004; Turner, Loftis, & action (36 weeks imipramine vs. 612 weeks SJW) (Linde
Blackwell, 2006). Out of 27 studies 11 were DBRPC. Of the etal., 1996; Rahimi, Nikfar, & Abdollahi, 2009; Sarris etal.,
11 DBRPC studies, 7 reported that 5-HTP performed bet- 2011, 2013). See section titled HerbDrug Interactions.
ter than placebo, but only 5 of those showed statistical sig- Rigorous research has shown more consistent results in
nificance. Several studies have shown that the addition of studies using adequate doses of better quality standardized
5-HTP to prescription antidepressants such as nialamide, pharmaceutical grade SJW extracts, such as Kira (LI 160)
chlomipramine, and nomifensine significantly improved anti- 600 mg three times daily (Vorbach, Arnoldt, & Hubner,
depressant response. The average dosage of 5-HTP in adults is 1997) or Remotiv (ZE 117) 500 mg/day (Schrader, 2000)
200300 mg/day given in divided doses. Overall, studies sug- for mild to moderate depression and Ws5570 900-1800 mg/
gest that 5-HTP may have limited benefit for depression with day for moderate to severe depression (Szegedi, Kohnen,
some support for its use as an augmentation. Common side Dienel, & Kieser, 2005). Treating severe depression with
effects include nausea, vomiting, and diarrhea. Less frequent SJW requires higher doses (1800 mg/day) for longer periods
side effects include headache and insomnia. Although rodent of time (612 weeks). At higher doses SJW has side effects
studies have shown that doses above 100 mg/kg/day induce that are milder but similar to SSRIs, including nausea,
serotonin syndrome, no cases of serotonin syndrome have heartburn, loose stools, sexual dysfunction, bruxism (teeth
been reported in humans using 5-HTP alone or in combina- clenching), and restless leg syndrome. SJW can augment
tion with SSRIs. Studies combining 5-HTP with MAOIs response to antidepressants such as tricyclics, buproprion,
report no adverse effects. The use of a peripheral decarbox- venlafaxine, and SAMe, but it should not be combined with
ylase inhibitor such as carbidopa may increase the level of MAOIs. Combining SJW with other serotonergic anti-
5-HTP in serum 14-fold (Gijsman etal.,2002). depressants may increase the risk of serotonin syndrome.
SJW can induce mania in bipolar patients. A review of data
from 35 DBRCTs found that dropout and adverse effects
N-Acetylcysteine forBipolar Disorder rates in patients receiving SJW extracts were similar to pla-
N-acetylcysteine (NAC) is a precursor for synthesis of the cebo. However, medically ill patients probably have higher
antioxidant glutathione. In animal studies oral adminis- rates of adverse reactions than patients selected for depres-
tration of NAC over time increased peripheral glutathione sion studies, which usually exclude serious medical illness
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 559
and patients on medication. Phototoxic rash occurs in less respond well to R.rosea. For a discussion of mechanisms of
than 1% of people taking SJW 900 mg/day or more. SJW action, see the section titled Herbs for Treatment of Cognitive
should be discontinued 2 or 3 weeks prior to surgery because Dysfunction.
it can affect heart rate and blood pressure during anesthe-
sia. SJW has been found to interfere with absorption and Rhodiola rosea forDepression inMenopause
metabolism of numerous medications in humans. See the Although it has not been formally studied in menopausal
section on HerbDrug Interactions for discussion of clini- women for depression, fatigue, and memory decline, the
cally significant effects that are probably due to induction authors (PLG and RPB) find that R. rosea restores energy,
of cytochrome P450 3A4 and 1A2 enzymes as well as intes- mental clarity, and sense of joyfulness. For further discus-
tinal wall P-glycoprotein (Knuppel & Linde, 2004; Russo, sion, see subsections on Herbal Treatments for Cognitive
Scicchitano, Whalley, Mazzitello, Ciriaco, Esposito, et al., Dysfunction and Herbs for Female Sexual Function.
2014). Nevertheless, in some settings SJW is particularly
beneficial, for example, in mild depression with wintertime Rhodiola rosea Side Effects andDosage
seasonal affective disorder (Cott & Fugh-Berman, 1998; R. rosea has an energizing or mildly stimulating effect
Hansgen, Vesper, & Ploch, 1994; Wheatley, 1999) and but is usually emotionally calming. Unlike prescription
in somatoform disorder (Volz, Murck, Kasper, & Moller, stimulants (e.g., amphetamines) this adaptogen does not
2002). The authors (PLG and RPB) usually do not recom- cause addiction, habituation, or withdrawal symptoms.
mend SJW as a first-line solo treatment for depression unless Individuals who are sensitive to stimulants such as caffeine
the patient has a history of good response to low dose SSRI may initially feel more anxious, agitated, jittery, or wired.
(e.g., 5mg/day fluoxetine) but complains of intolerable side Patients should reduce their intake of caffeine when using
effects such as weight gain or sexual dysfunction. Because this herb, because the stimulative effects can be additive.
there is such variability in the quality of SJW products, For those who are sensitive it is possible to give a fraction
selecting brands that are standardized (0.3%0.5% hyper- of the usual dose and then increase gradually as tolerated.
forin) and that have proven efficacy based on their use in Starting doses of 100150 mg in the morning on the first
clinical trials is advised. 2 days for mild to moderate depression can be increased
by one capsule every 37 days to a maximum of 600 mg/
Rhodiola rosea (Roseroot, Arctic Root, GoldenRoot) day. As an adjunctive treatment for depression, R.rosea is
usually effective in doses of 200400 mg/day. As a solo
Although Rhodiola rosea has mainly been used for fatigue, treatment, higher doses up to 750 mg/day are sometimes
cognitive disorders, memory, and performance under stress needed. Above 900 mg/day, mild effects on blood coagula-
(see below), it can alleviate depression, increase transport of tion may occur with increased bruising. R.rosea should be
tryptophan and 5-HT (serotonin) into the brain, and sup- given with caution and with close monitoring to patients
port cellular energy transport. In the first study of R.rosea as taking anticoagulants. Physicians should question patients
a treatment for for depression, 128 patients with mixed types who use sports drinks, which can contain 1000 mg or
of depression were given 150 mg three times daily of R.rosea more of R. rosea often in combination with caffeine. This
or placebo. Two-thirds of those on R.rosea improved signifi- may increase the risk of adverse effects such as tachycardia,
cantly (Brichenko & Skorokhodova, 1987). Although this particularly in athletes who may consume more than one
study did not fulfill modern methodological standards, it sug- bottle of such drinks to enhance sports performance. There
gested positive effects. More recently, a standardized extract is no evidence that increasing the dose of R. rosea above
(SHR-5 from Swedish Herbal Institute) of R.rosea rhizomes 900 mg/day provides greater benefits, and it may entail
was used in a DBRPC study of 89 adults between 18 and increased risks. R.rosea should be taken in the early part of
70years of age who met DSM-IV criteria for mild to moderate the day to avoid interference with sleep. Some people report
depression (HAMD scores 1231). Subjects were randomly vivid dreams (not nightmares) during the first 2 weeks.
assigned to three groups. Group Areceived moderate doses of Occasionally, the herb may cause mild nausea. This can usu-
SHR-5 (340 mg/day); Group B received SHR-5 680 mg/day; ally be managed by taking two ginger capsules 20 minutes
and Group C received placebo. At the end of six weeks, mean before ingesting R.rosea or by drinking ginger tea. For dis-
HAMD scores dropped significantly in Groups Aand B but cussion of potential hormonal and anticarcinogenic effects,
not in Group C.No serious side effects were reported in any see the section on Adaptogens and Herbs with Adaptogenic
group (Darbinyan etal.,2007). Properties for Menopause and HerbDrug Interactions.
The authors routinely use R. rosea as augmentation in
treating depression because it increases mental and physical Quality and Potency ofRhodiolarosea
energy, which are often low. It also improves mood and stress R. rosea is one of the complex herbs whose quality
tolerance. Prescription antidepressants may alleviate negative can be affected by the factors described in the section on
mood states but often fall short of producing positive mood. Standardization of Supplements. Among the dozens of
Many patients anecdotally report that addition of R. rosea medicinal compounds in R.rosea root extracts, salidrosides
engenders a sense of well-being with increased motivation to and rosavins have been identified as active components and
get out of bed and do things. In the authors clinical expe- used as marker compounds, although no one has yet iden-
rience, patients with asthenia (mental and physical fatigue) tified which combinations of the numerous antioxidants
560 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
and other bioactive constituents are responsible for its State-Traint Anxiety inventory. Greater benefits were found
many effects. Also, it may be subject to the addition of in patients with atypical depression (Lopresti et al., 2014).
marker compounds to products that have been adulterated In a double-blind study, 11 adults with MDD were ran-
with less expensive herbs. The marker compounds alone do domized to receive stanhdard antidepressants or standard
not account for all of the medicinal effects; therefore, it is antidepressants augmented with curcuminoids-piperine
important to use only those brands that have been proven to compbination 1000/10 mg/day). Reductions in BDI-II and
be clinically effective or that have been tested for at least 6 MADS were significantly greater in the group given curcumi-
marker compounds. noids versus control (p < 0.001) (Panahi et al., 2014).
Curumen is very low in side effects, may be better absorbed
in combination with piperine, and could serve as a useful
Eleutherococcus senticosus or Acanthopanax senticosus
add-on to standard antidepressants.
(Siberian Ginseng)
Extracts from the fruit and seeds of Eleutherococcus sen-
ticosus were studied in the USSR for mental disorders. CO G NITI V E F U NCTION
In their reviews, Panossian and Wikman found that the
methodologies in most of the Soviet studies between 1950 Disorders of cognition and memory develop from processes
and 1980 do not meet current standards. Nevertheless, the in which the damage to neurons compromises function and
improvements reported in depression, bipolar disorder, exceeds the capacity for repair. Nutrients and herbs that are
schizophrenia, addictions, and alcoholic hallucinosis would neuroprotective and that support brain functions, energy pro-
be intriguing pathways for future research (Panossian & duction, cellular repair, and neuroplasticity will be reviewed.
Wikman, 2009; Panossian, 2013). In a more recent study, Neural fatigue or neurasthenia refers to a condition in which
E. senticosus 750 mg three times daily augmentation of lith- the patient experiences excess mental fatigue after a shorter
ium resulted in response and remission rates that were com- than normal period of cognitive activity (resulting in reduced
parable to augmentation of lithium with fluoxetine 20 mg/ work capacity), increased perception of effort, and reduced
day in a 6-week DBRCT of 79 Chinese adolescents with endurance for sustained mental activity. It is more likely to
bipolar disorder. Furthermore, side effects and switching to occur under stress and/or following brain injury of any kind.
mania were far less with E. senticosus than with fluoxetine Adaptogens have been shown to be particularly beneficial in
(Weng, 2007). patients with symptoms of neurasthenia or neural fatigue,
which include a subjective sense of mental fatigue, reduced
efficiency for mental tasks, and decreased work productivity
Crocus sativus (Saffron)
(usually occurring with mental exertion), often with head-
Concentrated extracts of the stamen and petals of saffron ache or malaise. The term synaptic fatigue attributes mental
were tested in two RCTs and found to significantly improve fatigue to depletion of presynaptic neurotransmitters, but
depression compared to placebo (Akhondzadeh et al., 2005; more recently central fatigue has been linked to activation of
Moshiri et al., 2006). In three additional RCTs, the effects of microglia and/or increased cytokines and chemokines in the
C. sativus on HAMD scores were equivalent to the effects of brain, implicating dysfunction in the ascending arousal sys-
imipramine and fluoxetine (Akhondzadeh Basti, et al., 2007; tem; pathways connecting basal ganglia, thalamus, limbic sys-
Moshiri, Noorbala, et al., 2007; Noorbala, Akhondzadeh, tem, and higher cortical centers; sleep executive control areas;
Tahmacebi-Pour, & Jamshidi, 2005). The occurrence of side reward areas; and the suprachiasmatic nucleus. (Harrington,
effects including anxiety, tachycardia, nausea, dyspepsia, and 2012).
appetite changes was not statistically significant compared
to placebo. All of the studies thus far have been conducted
PAT HOPH Y S IOL O G IC A L TA RG E T S
by one group of researchers. Trials at other centers would
FORI N T E G R AT I V E T R E AT M E N T S
help validate these encouraging findings. Evidence from one
RCT suggested that saffron can reduce carbohydrate crav- Nutrients and phytomedicines target mediators of the stress
ing and help with weight loss (Gout, Bourges, & Paineau- response, energy metabolism, neuroprotection, cellular repair,
Dubreuil, 2010). For a clinical review see Modabbernia and neuroplasticity, and the neuroendocrine system.
Akhondzadeh (2013). The membrane hypothesis of aging proposes that oxidative
damage to cellular membranes leads to loss of permeability,
increased intracellular density, accumulation of cross-linked
Curcuma longa (Curcumin fromTumeric) proteins and lipofuscin (waste products), breaks in DNA,
Curcuminoids from the spice, turmeric, piperine, the alkaloid slowing of RNA synthesis, and decreased protein turnover
that gives black pepper its taste, is used to enhance the absorp- and repair. Free radical damage to mitochondria compro-
tion of nutrients. mises the ability of the cell to maintain sufficient energy pro-
A randomized double-blind placebo-controlled 8-week duction to sustain normal functions and to fuel cellular repair
trial of curcumin 500 mg twice daily showed that curcumin systems. Substances that have antioxidant properties or that
was more effective than placebo in improving scores on the increase production of antioxidants are candidates for preven-
Inventory of Depressive Symptomatology ad the Spielberger tion and treatment of age-associated cognitive and memory
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 561
Table28.1ANXIETY DISORDERS AND INSOMNIA INTHE MEDICAL PATIENT
CONDITIONS/
SYMPTOMS DOSE R ANGES SIDE EFFECTS* DRUG INTER ACTIONS COMMENTS
NUTRIENTS
Omega-3-fatty acids Anxiety 24 gm/d Belching, loose stools EPA:DHA ratio 2:1
HERBS
Butterbur Petasites Migraines, allergic 100 mg 24 times/d Minimal Poor quality brands may Use in combination with
hybridus rhinitis interact with CYP3A4 lemon balm, passion
substrates flower, valerian.
Chamomile Matricaria Minimal sedative 2001000 mg/d Ragweed familyallergic reactions Avoid during pregnancy
recutita Generalized
Anxiety Disorder
Ginkgo Ginkgo biloba Anxiety depression 240280 mg/d Minimal:headache Anticoagulants** Discontinue 2 weeks prior
dementia to surgery
Kava Piper methysticum Anxiety, insomnia 100 mg standardized extract Gastrointestinal distress, allergic rash, effects of levodopa Avoid during pregnancy
(70 mg kavalactones) t.i.d. photosensitivity, headache, Occasional: Toxicity may occur
energy, drowsiness, tremor, restlessness, at doses > 240 mg
dystonia, hepatitis, liver failure. kavalactones/d
Lemon balm Melissa Anxiety, insomnia (400600 mg/d depending No serious side effects Mild anxiolytic
officianalis on preparation)
St. Johns wort Hypericum Depression mildmod 300600 mg t.i.d. Nausea, heartburn, loose bowels, Induces CYP 3A4, and Discontinue 2 weeks prior
perforatum jitteriness, insomnia, fatigue, bruxism, P-glycoprotein: digoxin, to surgery.
phototoxic rash, mania in bipolar. warfarin, indivir, cyclosporine, Avoid during pregnancy.
theophylline, birth control Evidence for use in
pills, anesthetics, and others. depression is weak.
Theanine Mild anxiety 200 mg 13x/d Minimal Anticoagulants Monitor if given with
Greentea anticoagulants
Camellia sinensis
Valerian Sleep 450900 mg h.s. Occasional gastrointestinal distress, Avoid during pregnancy.
Valeriana officianalis headaches, minimal hangover on high Contraindication:hepatic
doses > 600 mg. disease
NEUROHORMONES
7-keto DHEA PTSD dissociative 25200 mg/d Bipolar patients may become agitated, Contraindication:
symptoms irritable, anxious. Estrogen sensitive or
prostate cancer patients.
Melatonin Sleep 112 mg h.s. Occasional agitation, abdominal cramps, Contraindication:
fatigue, dizziness, headache, vivid pregnancy
dreams.
*In addition to the listed side effects, rare side effects can occur. Most supplements have not been tested for safety during pregnancy and breastfeeding. Patients taking anticoagulants and those with high blood pressure,
diabetes, hepatic disease, or any chronic or serious medical condition may be at increased risk for side effects and therefore require closer monitoring. Herbal side effects are more frequent with lower quality products which may
contain contaminants or adulturants.
**No cases of bleeding have been reported with products containing pharmaceutical grade Ginkgo biloba, such as EGb761.
Key:PTSD, Posttraumatic stress disorder; EPA, eicosapentanoic acid; DHA, dicosahexaenoic acid; hs, bedtime; b.i.d., twice a day; t.i.d., three times a day; gm, grams; mg, milligrams; mcg, microgram; , decreases
decline as well as cerebrovascular and neurodegenerative dis- a risk factor for cognitive decline and AD (Eyles, Burne, &
eases (Aliev, Palacios, & Obrenovich,2011). McGrath, 2012; Annweiler et al., 2012). Stronger evi-
Mitochondrial energy enhancers support production of mol- dence supports the combined use of B vitamins, folic acid,
ecules such as ATP, necessary for energy transport withincells. S-adenosylmethionine, and n-3FAs in disorders of cognition,
The calcium hypothesis of neuronal aging has been modified including age-related cognitive decline, dementia, AD, stroke,
in tandem with increasing information about the role of sub- and traumatic brain injury.
tle age-related changes in Ca2+ in mitochondrial dysfunction
(Toescu & Verkhratsky, 2007). According to the membrane
B Vitamins, Folic Acid, S-adenosylmethionine(SAMe)
hypothesis (Long & Pekala, 1996; Zs-Nagy, 1997), reactive
oxygen species damage cell membranes and organelles through Methylation (donation of methyl groups) pathways, depen-
lipid peroxidation that contributes to neurodegenerative disor- dent on B vitamins and folate cofactors, are essential for syn-
ders such as Alzheimers (AD) and Parkinsons disease(PD). thesis of proteins, neurotransmitters, antioxidants, and other
Endothelial damage due to arteriosclerosis and free radi- cellular components used to maintain function, membrane
cals leads to hypoperfusion in cerebrovascular diseases such integrity, and repair of DNA and RNA (Bottiglieri, 1996,
as multi-infarct dementia and ischemic stroke. Cerebral vaso- 2013; Hassing, Wahlin, Winblad, & Backman, 1999). SAMe,
dilators and antioxidants can be used to prevent or amelio- the bodys most active donator of methyl groups, participates
rate perfusion-related problems. Membrane fluidity, which in more than 200 different biochemical reactions in humans,
is essential for neurotransmission, enables receptors to fold including three central metabolic pathways: transmethyl-
and unfold for optimal opening and closing of membrane ion ation (donation of methyl groups, CH3); transsulfuration
channels. Oxidative damage and loss of membrane n-3FAs (donation of sulfur); and transaminopropylation (donation of
contribute to increased membrane rigidity. Evidence suggests aminopropyl moieties; see Figure 28.3). Foods supply part of
that sustained inflammation may also be a factor in neurode- the bodys need for SAMe, the remainder being generated by
generative disorders such as AD andPD. de novo synthesis from methionine and ATPprimarily in
The cholinergic hypothesis attributes a significant role in the liver, which produces 3 gms/day. SAMe levels are easily
the pathophysiology of AD to loss of cholinergic neurons increased by oral supplementation.
resulting in synaptic changes in cerebral cortex, hippocam-
pus, and other brain areas involved in cognitive functions
Vitamin and Nutrient Formulas
(Arciniegas,2001).
Neuroplasticity, involving changes in synaptic connec- Three studies using a vitamin/nutrient formula (NF) contain-
tivity and neurogenesis depends on brain-derived neuro- ing folic acid 400 mcg, B12 6 mcg, vitamin E alpha-tocopherol
trophic factor (BDNF). BDNF and its receptor, tropomyosin 30 IU, S-adenosylmethionine 400 mg, N-acetylcysteine
receptorrelated kinase B, modulate numerous neuropro- 600 mg, and acetyl-L-carnitine 500 mg found positive
tective functions. Long-term potentiation, a form of neuro- effects on cognitive function. A DBRPC study of 115
plasticity, is based on increased interneuronal connectivity. community-dwelling adults aged 2273 years without
N-methyl-D-aspartate (NMDA) excitatory amino acid recep- dementia found that after 2 weeks, the test scores of subjects
tors modulated by BDNF are involved in rapid connectivity taking NF improved significantly on the California Verbal
changes such as long-term potentiation. Learning Test II (CLVT) and the Trail-making Test com-
Mediators of stress response include neuropeptide Y, nitric pared with those on placebo. This was followed by a 3-month
oxide, membrane bound G-protein receptors, heat shock open-label extension during which those taking NF showed
proteins, and others, and will be discussed in the section on additional improvement. During a 3-month discontinuation
Mediators of the Stress Response. of NF, test measures reverted to baseline. Resumption of NF
restored improvements (Chan etal., 2010). A12-month open
label study of the same NF given to 14 community-dwelling
V I TA M I N S A N D N U T R I E N T S FORC O G N I T I V E
adults with early-stage AD rated mild to moderate on the
F U NC T ION
Dementia Rating Scale (DRS) found that within 6months,
Vitamins and trace elements are essential for energy produc- total performance on DRS improved significantly by about
tion, brain development, cognitive function, neuroprotection, 30% (p < .02) with improvements maintained at 12months
and recovery from damage (Bourre, 2006; Brown, Gerbarg, & (Chan, Paskavitz, Remington, Rasmussen, & Shea, 2008).
Muskin, 2009; Brown & Gerbarg, 2011). Limited evidence Another DBRPC study of NF in 12 institutionalized patients
suggests that a combination of Vitamins C and E may reduce with moderate to late-stage AD showed that those given the
the incidence of AD (Zandi etal., 2004). Synthetic vitamin NF had clinically significant delay in decline on DRS and
E (d-alpha tocopherol) is no longer recommended for preven- on the Clock Drawing Test (CLOX 1 and 2) over a period
tion of cognitive decline because a prospective study of 35,533 of 9 months compared to those given placebo (Remington,
healthy men followed for 7 to 12years found that the absolute Chan, Paskavitz, & Shea, 2009). These small studies are
increase in risk of prostate cancer per 1000 person-years was promising but should be interpreted with some caution pend-
1.6 for synthetic vitamin E (400 IU/d of all rac--tocopheryl ing validation by large studies done by other research groups.
acetate), 0.8 for selenium, and 0.4 for a combination of the Given recent controversy regarding increased risk of prostate
two (Klein etal., 2011). Suboptimal vitamin D levels may be cancer in men taking vitamin E, the vitamin/nutrient formula
564 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
may need to be modified. The composition of vitamin/nutri- Omega-3 Fatty Acids (n-3FAs)
ent/herbal formulas (VNHF) could include constituents that
target as many as possible of the relevant pathophysiological Polyunsaturated fatty acids (PUFAs), including the n-3FAs,
mechanisms described above to optimize synergistic effects. DHA, EPA, and AA are necessary to maintain cell membrane
function and the production of molecules involved in inflam-
matory modulation (Bourre, 2005). It is preferable to take a
B Vitamins and Antioxidants 1000mg/day blend of EPA and DHA in a 2:1 ratio. For mech-
anisms of action, dosages, and side effects, see the section on
Combining B vitamins with antioxidants may be more effec-
Omega-3 Fatty Acids for Depression and Bipolar Disorder.
tive than either alone. However, there may be differences in
Low levels of n-3FAs have been found in patients with
the absorption and activity of natural vitamins compared
dementia and AD. In an 8-year prospective study of 1,200
to synthetic. For example, natural folate is absorbed less
elderly subjects, those with low serum DHA had a 67% greater
than synthetic. The authors prefer to use a product called
chance of developing AD than those with high DHA (Kyle &
Bio-Strath containing natural vitamins produced by yeast
Arterburn, 1998). A5-year prospective study of 210 healthy
cultivated with vitamin enriched nutrients. In a 3-month
men aged 7089years found that those who ate fish equiva-
DBRPC trial, Bio-Strath (B vitamin + antioxidants) at double
lent to EPA/DHA 400 mg/day had slower cognitive decline
the usual adult dose was given to 75 patients aged 5585years
than those who did not (van Gelder, Tijhuis, Kalmijn, &
with mild dementia. The placebo group deteriorated while the
Kromhout, 2007). Another study of 2251 older adults found
Bio-Strath group showed improvement in short-term memory
less decline in verbal ability in those with higher serum levels
with physical and emotional benefits at 3 months (Pelka &
of EPA/DHA, especially in those with high blood pressure
Leuchtgens, 1995). For geriatric patients with neurodegenera-
and high lipid levels (Beydoun, Kaufman, Satia, Rosamond, &
tive disorders and cognitive decline, studies suggest a dose of
Folsom,2007).
2 tablets three times a day or 1 tablespoon twice a day of the
DHA supplementation improved neurological symptoms
liquid preparation. In healthy adults, 3 tablets twice a day or 1
in Alzheimers patients (Nidecker, 1997). In a DBRPC study
teaspoon three times daily is usually sufficient. Alternatively,
of 174 very mildly impaired Alzheimers disease patients,
patients can be treated with folic acid 400800 mcg/day, B12
600 mg EPA slowed cognitive decline over a 6-month period
500 mcg/day (preferably sublingual), and B6 in the range of
(Freund-Levi et al., 2006). More studies are needed to con-
25 mg/day. Considering the importance of B vitamins for
firm the neuroprotective effects of antioxidants and n-3FAs in
cognitive function and the low incidence of side effects, the
patients with neurodegenerative conditions. Patients unwill-
authors use them in the treatment of patients with brain
ing to eat fish regularly can be encouraged to take fish oil or
injury, dementia, and many other conditions affecting brain
flax oil capsules. In general, fish oils are preferable because
function. Sublingual B12 is better absorbed than oral capsues,
only a fraction of the linolenic acid in flax oil gets converted
particularly in patients with impaired gastrointestinal absorp-
into DHA. Credible evidence suggests that PUFAs enhance
tion. Serum methylmalonic acid is a more accurate measure of
cognitive development and protect against neurodegenera-
intracellular B12 than serumB12.
tion. While increasing dietary unsaturated nonhydrogenated
In some studies folic acid, B12, and B6 have been found to
fats may lower the risk of AD, large amounts of saturated
lower homocysteine levels. A review of the literature found
trans fats increase the risk of AD (Morris etal.,2003).
the evidence on the homocysteine-lowering effect of folic
acid and B vitamin therapy in coronary artery restenosis to
be contradictory (van Hattum, Doevendans, & Moll, 2007). Phosphatidylserine
In a 7-month DBRPC study of 205 patients following bal- Phosphatidylserine (Pdt Ser) is a naturally occurring phos-
loon angioplasty, among those treated with folic acid and B pholipid thought to contribute to nerve cell membrane flu-
vitamins the rate of restenosis in subjects without stents was idity. DBRPC studies of bovine-derived Ptd Ser (containing
10.3% versus placebo 41.9% (p <0.001); in subjects with stents high amounts of DHA) showing modest memory improve-
it was 20.6% versus 29.9% (p=0.32) respectively (Schnyder ments in age-associated memory decline have been reported
et al., 2001). A 6-month DBRPC study of coronary stent with bovine Ptd Ser. However, the risk of acquiring prions, an
replacement in 636 patients found that reduction in restenosis infectious agent composed of misfolded protein from animals
was associated with the lowering of homocysteine by folic acid with Mad Cow disease, has not been assessed. At this time we
and B vitamins, the greatest reductions occurring in women advise limiting the use of Ptd Ser to products derived from
and men with baseline homocysteine levels above 15M/L. fish, soy beans, or cows raised in New Zealand and Australia
However, an 8% increase in the rate of restenosis was found where surveillance for prion-related diseases is carefully regu-
only in men (not in women) with baseline homocysteine lev- lated. Ptd Ser may be safer when derived from cow blood as
els less than 15M/L, who were given folic acid with B12 and opposed to neural tissues or organs where prions accumu-
B6 supplementation (Lange etal., 2004). No study reported late. Although studies of soy-derived Ptd Ser are limited, it
a significant difference in cardiovascular events in patients appears to be of some benefit. Ptd Ser is often combined
treated with folic acid versus placebo. There does not appear with other nutrients such as ginkgo (McDaniel, Maier, &
to be any increased risk of vascular occlusion in individuals Einstein, 2003). In clinical practice, soy-derived Ptd Ser
who take folic acid and B vitamins and who do not have car- may be a useful complementary treatment for age-associated
diac stents.
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 565
Table28.2 MOOD DISORDERS INTHE MEDICAL PATIENT
NUTRIENTS
* In addition to the listed side effects, rare side effects can occur. Most supplements have not been tested for safety during pregnancy and breastfeeding. Patients taking anticoagulants and those with high blood pressure, diabetes,
hepatic disease, or any chronic or serious medical condition may be at increased risk for side effects and therefore require closer monitoring. Herbal side effects are more frequent with lower quality products which may contain
contaminants or adulturants.
** Folate + B12+ B6 reduce the rate of cardiac stent restenosis in women and in men with baseline homocysteine level >15mM/L.
Table Key:b.i.d., twice a day; t.i.d., three times a day; gm, grams; mg, milligrams; mcg, microgram; IU. International Units;, increases; , decreases; <, less than; >, morethan
memory decline but not for more severe memory disorders. or in augmentation of cholinesterase inhibitors in mild AD
Amarine source of PtS with omega-3 long chain polyunsatu- (Bianchetti, Rozzini, & Trabucchi, 2003). In patients with
rated fatty acids attached to its backbone, PS-DHA, was used TBI and cerebrovascular disease, the authors find that ALC
in a 15-week DBRPC study of 157 nondemented elderly per- 1500 mg twice daily often improves energy and cognitive func-
sons with memory complaints. Those who received PS-DHA tion within 2 weeks. ALC is low-risk and has few side effects.
(300 mg PS/day) showed significant improvements in imme- Rarely, it may trigger mania in bipolar patients.
diate verbal recall. Those with higher baseline cognitive status
had additional improvements in delayed verbal recall, learn- Alpha-LipoicAcid
ing abilities, and time to copy figures (Vakhapova, Richter, Alpha-lipoic acid (ALA), a metabolic antioxidant, has
Cohen, Herzog, & Korczyn,2011). been used as a prescription drug in Europe for treatment of
cardiac autonomic problems related to diabetic neuropathy
as well as other consequences of diabetes. Neuroprotective
Mitochondrial Energy Production and Antioxidant effects have been described in cerebral ischemia/reperfusion
Protection animal models, excitotoxic amino acid brain injury, mito-
Substances that support mitochondrial ATP-producing elec- chondrial dysfunction, diabetic neuropathy, inborn errors of
tron transport help maintain adequate energy supplies for cel- metabolism, and other causes of acute or chronic damage to
lular function, production of antioxidants, cellular repair, and nerve tissue including excess levels of iron, copper, or other
neurogenesis. metals (Packer & Colman, 1999). ALA and CoQ-10 may
be helpful in poststroke recovery and ischemic heart disease.
Acetyl-L-Carnitine and Propionyl-L-Carnitine ALA generates large amounts of glutathione in animal brain
Derivatives of carnitine, an essential nutrient, improve models (similar to SAMe). For patients who cannot afford
mitochondrial function and reduce oxidative damage. SAMe, ALA in combination with vinpocetine (cerebral vaso-
Acetyl-l-carnitine (ALC) facilitates acetyl coenzyme dilator) can be helpful when ischemia is a major factor and in
Auptake into mitochondria during fatty acid oxidation and other brain injuries. The authors find an ALA dose of 300 mg
increases energy production via the oxidative phosphorylation three times daily to be useful inTBI.
chain (Pettegrew, Levine, & McClure, 2000; Abdul Muneer,
Alikunju, Szlachetka, & Haorah, 2011). Malaguarrera (2012) Coenzyme Q-10 (Idebenone)
reviewed preclinical and clinical studies of ALC, PLC, and Coenzyme Q10 (CoQ10, idebenone) enhances
other carnitines. Positive effects of ALC were reported in ATP-producing mitochondrial electron transport
diabetic, antiretroviral, and chemotherapy-induced neu- (Gillis, Benefield, & McTavish, 1994; Matsumoto et al.,
ropathies, insulin resistance, hypertension, Peyronies dis- 1998). CoQ10 variants which enhance both cellular energy
ease, coronary artery disease, hepatic encephalopathy, sperm production and antioxidant defense are of interest for preven-
motility, and fibromyalgia. In animal models, ALC was tion and treatment of neurodegenerative, cerebrovascular,
neuroprotective and enhanced recovery from stroke (Lolic, and cardiovascular diseases. In clinical practice the authors
Fiskum, & Rosenthal, 1997). In a study of oxidative toxicity find that sluggish, psychomotor-retarded patients respond
using 4-hydroxy-2-nonenal, ALC plus alpha-lipoic acid (see well to idebenone, which improves alertness. For individu-
below) protected rat cortical neurons from protein oxida- als who become overstimulated by prescription cholinester-
tion, lipid peroxidation, antioxidant depletion, and apoptosis ase inhibitors (e.g., donepezil, Aricept), idebenone serves as
(Abdul & Butterfield, 2007). ALC protected neurons from a less stimulating alternative. Combined with other supple-
ethanol-induced oxidative injury in animal brain tissue slices ments, it is particularly useful in cerebrovascular disease
(Rump etal., 2010). In an in vitro study of human brain endo- (e.g., multi-infarct dementia) and disorders of mitochondrial
thelial cells, ALC stabilized superoxide dismutase (antioxidant function (e.g., Friedreichs Ataxia) (Brown & Gerbarg, 2011).
preventing mitochondrial membrane damage) and protected Ubiquinol, a reduced form of CoQ10, is an effective antioxi-
the bloodbrain barrier, brain vascular tone, and vasodilation dant protecting membranes from peroxidation. Muscle biop-
(Haorah, Floreani, Knipe, & Persidsky, 2011). ALC may be sies from patients with myopathies (e.g., myofiber atrophy and
more effective in delaying age-related deterioration of mito- muscular dystrophy) showed significant positive correlations
chondria when combined with alpha-lipoic acid, CoQ10, and between CoQ10 and ubiquinone concentrations versus the
essential fatty acids (Di Donato etal., 1986; Lolic, Fiskum, & percentage of myofibrils containing mitochondrial aggregates
Rosenthal, 1997). Alcar showed modest slowing of the devel- (Miles etal., 2005). The authors find ubiquinol to be benefi-
opment of AD in subjects 60years of age or younger (Brooks, cial in treating statin-induced myopathy.
Yesavage, Carta, & Bravi, 1998). In a DBPC study of 12
elderly subjects with cerebral vascular disease, alcar improved Creatine
reaction time, memory, and cognitive performance (Arrigo, Creatine enhances cellular energy production in brain
Casale, Buonocore, & Ciano, 1990). Alcar 1500 mg adminis- injury, muscular dystrophy, and other mitochondrial cytopa-
tered intravenuosly increased regional cerebral blood flow in thies (Brown & Gerbarg, 2011). Phosphorylated creatine pro-
8 out of 10 men with cerebral ischemia (Rosadini, Marenco, vides a phosphate group in the conversion of ADP to ATP.
Nobili, Novellone, & Rodriguez, 1990). Although stud- In an open-label RCT pilot study, 39 children with TBI were
ies of ALC in AD are weak, it may have a role in prevention
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 567
Table28.3COGNITIVE DISORDERS INTHE MEDICAL PATIENT
NUTRIENTS
Acetyl-l-carnitine TBI, AD, CVA, CVD, 500 mg b.i.d. startingdose Mild gastric upset, heartburn. None May slow progressionofAD
ALCAR Alzheimers, fatigue, energy, Up to maximum dose 1,500 mg Take with food.
alertness b.i.d.
(Apoaequorin TBI, memory 1040 mg/day Headache, drowsiness, allergic Unknown One RCT (n = 218)
Synthetic jelly fish protein) reactions
Centrophenoxine TBI, Alzheimers 250 mg b.i.d startingdose Minimal, gastric upset, When combined with other
(Meclophenoxate) Memory, alertness, focus Up to maximum dose 1,000 heartburn cholinergic agents:headache,
mg b.i.d. muscle tension, insomnia,
irritability, agitation, facial tics
CoenzymeQ10 CVD, TBI, Alzheimers, 270900 mg/d None Less stimulating alternative
Ubiquinol Neurodegenerative disease to cholinesterase inhibitors
Creatine TBI, memory, cognition, focus 0.4 gm/kg/d Minimal One study positive effects in
5000 mg q.i.d for 5days, then children
5000 mg b.i.d.
L-Deprenyl CVD, TBI, Alzheimers, 2.55 mg/d Minimal None <10 mg/d has no significant
Parkinsonss, cognitive, MAOI effect
memory, preventive
Omega-3-fatty acids Alzheimers, 2,0003,000 mg/d Belching, loose stools, nausea, Anticoagulants:monitor EFA:DHA ratio 2:1
neurodegeneration abdominal pain
Phosphatidyl serine AAMI Loading dose 300 mg/d for Minimal None
1month,
Then 100 mg/d
Picamilon TBI, CVA, CVD, ischemia, 50 mg b.i.d. up to 100 mg t.i.d. High dose:postural In CVD improves alertness,
Parkinsons, toxic brain hypotension confusion, anxiety,
lesions depression
Pyrrolodones Poststroke aphasia, dyslexia aniracetam 750 mg b.i.d. Minimal. Rarely:anxiety, Safe in children
Racetams Med-related cognitive insomnia, agitation, irritability,
aniracetam, piracetam, impairment headache
pramiracetam
S-adenosyl-L-methionine Alzheimers, Parkinsons 4004,000 mg/d in Nausea, loose bowels, activation, Combines well and augments all
(SAMe) TBI divideddoses anxiety, headache, occasional classes of antidepressants tested.
Depression 4001,600mg/d palpitations Give with L-dopa to reverse
Arthritis, liver diseases 1,2001,600 mg/d depletion of SAMe
HERBS
Eleuthero, Acanthopanax Fatigue, alertness 750 mg t.i.d. Uncommon:diarrhea, dizziness, Interferes with some digoxin tests, Combine with R.rosea and
Eleutherococcus senticosus insomnia, headache, hypertension, but does not lower digoxin levels other adaptogens
irregular or rapid heart beat
Ginkgo biloba Neuropsychiatric symptoms 60120 mg b.i.d. Minimal, headache, Monitor with anticoagulants and Combine with
in AAMI, MCI, CVD, VAD, gastrointestinal upset, nausea, antiplatelet drugs** acetylcholinesterase
Alzheimers. platelet aggregation. Rare Anesthetics inhibitors for better effect in
Attention, memory. agitation, allergic reactions. dememtia.
Peripheral vascular disease, Reported cases of bleeding not Discontinue 2 weeks prior to
claudication. confirmed by recent reviews** surgery.
Vascular related vertigo and
tinnitus.
Ginseng Dementia, cognitive 300800 mg/d Activation, gastrointestinal, Anticoagulants, steroids, MAOIs For CVA, TBI:better
Panax ginseng function, alertness, focus, anxiety, insomnia, tachycardia, combined with adaptogens.
neurasthenia platelet aggregation, diarrhea. Caution:Bipolar,
Hormonal:vaginal bleeding, swollen hypertension.
breasts. Excess doses:headache, Contraindication:hormone
vomiting, nervousness. sensitive cancers.
Doses > 3 gm/d may have toxic
effects: blood pressure, agitation,
confusion
Maca Neural fatigue, memory, Approximately 750 mgt.i.d. Occasional:overactivation, Human studies are needed.
Lepidium myenii hearing, energy (dose depends on preparation) jitteriness, insomnia, headache Contraindication:hormone
sensitive cancers.
(continued)
Table28.3(CONTINUED)
Rhodiola TBI, post CNS infection 50900 mg/d Occasional:Agitation, insomnia, Doses >750 mg/d may platelet Caution in Bipolar:may
ArcticRoot (e.g., Neuro-Lyme), post anxiety, headache aggregation. benefit depression but may
Rhodiola rosea stroke, dementia for cognitive Rare:palpitations, chest pain Additive effects with other exacerbate mania
recovery and memory stimulants (eg. caffeine)
Schizandra Concentration, energy, 110200 mg/d Heartburn, acid indigestion, Emotional calming
Schizandra chinensis agitation stomach pain, allergic rashes
St. Johns wort Hypericum Depression mildmoderate 300600 mg t.i.d. Nausea, heartburn, loose bowels, Induces CYP 3A4, and Discontinue 2 weeks prior to
perforatum jitteriness, insomnia, fatigue, P-glycoprotein: digoxin, surgery.
bruxism, phototoxic rash, mania warfarin, indivir, cyclosporine, Avoid during pregnancy.
in bipolar. birth control pills, anesthetics,
theophyline, and others.
Vinpocetine CVA, CVD, ischemia 10 mg t.i.d. Mild indigestion, nausea, Monitor closely with agents that
Snowdrop dizziness, anxiety, facial flushing, platelet aggregation
Vinca minor insomnia, headache, drowsiness
and dry mouth
NEUROHORMONES
Dehydro- Cognitive, memory 25100 mg/d Mild insomnia, irritability. Steroids Pharmaceutical grade isbest.
epiandrosterone Bipolar patients may become Benefits patients with low or
DHEA agitated, irritable, or anxious. low normal baseline DHEA
levels.
Contraindications:Estrogen
sensitive or prostate cancer
Melatonin Sleep, sundowning 112 mg h.s. Occasional agitation, abdominal Avoid during pregnancy
cramps, fatigue, dizziness,
headache, vivid dreams.
* In addition to the listed side effects, rare side effects can occur. Most supplements have not been tested for safety during pregnancy or breastfeeding. Patients taking anticoagulants and those with high blood pressure, diabetes, hepatic
disease, or any chronic or serious medical condition may be at increased risk for side effects and therefore require closer monitoring. Herbal side effects are more frequent with lower quality products which may contain contaminants or
adulturants.
** Folate + B12+ B6 may increase the rate of cardiac stent restenosis in in men only with baseline homocysteine level <15mM/L.
***Recent trials with pharmaceutical grade Ginkgo biloba, EGb761 do not confirm earlier reports of bleeding (Diamond,2013).
Table Key:AAMI, Age Associated Memory Impairment; CVD, cerebrovascular disease; CVA, cerebrovascular accident; MCI, minimal cognitive impairment; TBI, traumatic brain injury; VAD, vascular dementia; h.s., bedtime; b.i.d.,
twice a day; t.i.d., three times a day; g, grams; mg, milligrams; mcg, microgram; , decreases; , increases; <, less than; >, morethan.
randomized to standard treatment alone versus standard treat- studies (including three DBRPC trials) of TBI found evidence
ment plus creatine for 6months. The duration of posttraumatic of acute and long-term benefits (Arenth, Russell, Ricker, H.,
amnesia, intubation, and ICU stay were reduced in children & Zafonte, 2011). Davalos and colleagues (2012) conducted a
treated with 0.4 g/kg/day creatine. Those given creatine showed 6-week multicenter DBRPC of CDP-choline 2000 mg/day in
significant improvement in headaches, dizziness, and fatigue patients (n = 2,298) with moderate to severe acute ischemic
compared with the standard treatment only group (Sakellaris stroke. Unlike previous studies, patients given CDP-choline
etal., 2008). The authors note that creatine can ameliorate neu- did not have better outcomes than the placebo group. A sub-
ral fatigue, dizziness, and headaches in TBI patients. group analysis revealed better outcomes with CDP-choline in
patients above 70 years old, those with moderate stroke sever-
ity, and those who were not being given a fibrinolytic (Davalos
Cholinergic Enhancing Treatments
et al., 2012). A review of choline in mental and behavioral
Cholinergic deficits underlie the main symptoms of AD. disorders by Akhondzadeh and colleagues pointed out that
Treatments that enhance cholinergic transmissionby pro- the multicenter study by Davelos used a dose of 2000 mg/day
tecting cholinergic neurons, increasing availability of choline CDP-choline, which could have been subtherapeutic in com-
(precursor of acetyl choline), or reducing breakdown of acetyl parison to findings from previous studies that doses greater
choline (ACh)improve cognitive function and delay dete- than 2000 mg/day had greater efficacy (Akhondzadeh,
rioration in some studies of cerebrovascular accidents, AD, Gerbarg, & Brown, 2013). Moreover, the duration (6 weeks)
and other dementias and brain disorders (Akhondzadeh, was short considering that benefits are generally seen 912
Gerbarg, & Brown, 2013). Plant-derived alkaloid extracts that weeks after the initiation of treatment. A comprehensive
act as acetyl cholinesterase inhibitors (AChEI) are discussed review of drug surveillance studies in over 4,000 acute isch-
in Herbal Treatments for Cognitive Dysfunction. emic stroke patients concluded that CDP-choline was asso-
ciated with better outcomes than standard treatment alone
Citicholine (CDP-choline,Cch) (Cho & Kim, 2009; Leon-Jimenez et al., 2010). CDP-choline
Cytidine 5-diphosphocholine (CDP-choline), a phospho- is safe with virtually no side effects.
lipid cholinergic precursor used to treat stroke, dementia, and
brain injury (Alvarez etal., 1999)is well absorbed, crosses the
bloodbrain barrier, and breaks down into choline and cyti- Cerebral Vasodilators
dine (a ribonucleoside). Acetyl coenzyme Aand choline form Picamilon
the neurotransmitter acetyl choline. Choline is incorporated Picamilon, a cerebral vasodilator, is composed of GABA
into cell membrane phospholipids, improves mitochondrial and Vitamin B3 (niacin). Vasodilation through reduction
metabolism, increases ATP levels and synthesis of phospho- of smooth muscle tone in the walls of cerebral blood vessels
lipids, reduces glutamate release, and raises levels of norepi- increases cerebral blood flow (Mirzoian, Ganshina, Kosoi,
nephrine, dopamine, and 5HT. In animal models it alleviates Aleksandrin, & Aleksandrin, 1989). Picamilon has both a
cerebral hypoxia and protects against ischemia, edema, and mild tranquilizing action that can reduce aggressive behavior
neuronal death in the cerebral cortex, forebrain, and hippo- and a mild stimulative action that can improve alertness and
campus (Baskaya, Dogan, Rao, & Dempsey, 2000; Hurtado cognitive function. Picamilon readily crosses the bloodbrain
et al., 2005; Rao, Hatcher, & Dempsey, 1999). In rat brain barrier (Dorofeev & Kholodov 1991) and has low toxicity
injury and aging models, CDP-choline improved memory in animal experiments (median lethal oral dose >10 g/kg of
and cognitive performance and potentiated neuroplasticity body weight). Large open clinical trials in 16 medical cen-
(Dixon, Ma, & Marion,1997). ters in Russia, using picamilon 20-50 mg 2 to 3 times a day
A 6-week study of 214 patients with acute middle cerebral in treatments ranging from 2 weeks to 3months, showed the
artery ischemic stroke found that those given CDP-choline best results in patients with organic brain syndromes due to
within the first 24 hours showed significantly less enlarge- head trauma, cerebral atherosclerosis, and toxic brain lesions
ment in lesion volume on repeat MRI 12 weeks after the (Kruglikova, 1997). Controlled trials are warranted. In clini-
stroke (Mitka, 2002). Meta-analysis of controlled trials of cal practice the authors find picamilon to be beneficial in
CDP-choline by the Cochrane Stroke Review Group con- patients with cerebral vascular impairment, particularly with
cluded that there is some evidence that CDP-choline has posi- decreased alertness, confusion, anxiety, and depression as the
tive effects on memory and behavior in the short to medium following case illustrates.
term in cerebral disorders in the elderly (Fioravanti &
Yanagi, 2005). It may be necessary to start CDP-choline CASE STUDY:80YEAR-OLD WOMAN WITHCERE-
within 24 hours of stroke onset for benefits to occur (Parnetti, BRAL INSUFFICIENCY RESPONDS TOCEREBRAL
Mignini, Tomassoni, Traini, & Amenta, 2007). In a review VASODILATOR
of 4 trials with a total of 1,472 patients, oral CDP-choline
improved recovery when started within 24 hours of the onset An active 80-year-old, Joyce managed her home, balanced the
of stroke symptoms. Maintenance on CDP-choline in first- checkbook, and drove herself to the grocery store, church, and
stroke patients for 6 months prevented cognitive decline volunteer activities. Her mild bipolar disorder was well con-
and improved temporal orientation, attention, and executive trolled with quetiapine 50 mg h.s. until she required surgery for
functions (Alvarez-Sabin & Roman, 2011). A review of eight hernia repair. After awakening from anesthesia, Joyce was in a
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 571
confusional state that persisted for 4 weeks after leaving the hos- with neuroprotective properties including protection
pital. Her family took shifts caring for her, as she tended to sit against hydrogen peroxide free radicals, B-amyloid protein
for hours doing nothing unless prompted. Usually outspoken, formation, glutamate, and ischemia (Zhao et al., 2011). It
her responses dwindled to a few barely audible words. Based on protects mitochondria, reduces oxidative stress, and upregu-
an fMRI showing reduced perfusion and the possibility that lates nerve growth factor. Huperzine-A is rapidly absorbed,
surgical anesthesia had further compromised cerebral circula- readily penetrates the bloodbrain barrier, and has a rela-
tion, she was treated with a cerebral vasodilator, picamilon 100 tively long duration of AChE inhibitory action. In ani-
mg twice daily. Two days into treatment she began to improve. mal and primate studies it improves learning and memory
At follow-up three 3 weeks later Joyce was talkative, oriented, (Tang, 1996). Three DBRCTs with more than 450 people
and reengaged in her previous activities. Nine months later, the and one open trial done in China showed significant ben-
patients family brought her for re-evaluation of recurrent symp- efits in AD. Four trials in vascular dementia and AD, using
toms of confusion, reduced activity and paucity of speech. Joyce huperzine-A in combination with other medicines, nicer-
had stopped taking picamilon four weeks earlier when her sup- goline (a nootropic antiinflammatory that upregulates neu-
ply ran out. Once she resumed taking the cerebral vasodilator, rotrophic factors in glial cells), and estrogen compounds or
all of these symptoms remitted within two weeks. mental training, showed favorable outcomes. In a DBRPC
study of 78 patients with mild to moderate vascular demen-
tia (VaD), those given Huperzine A0.1 mg twice daily sig-
Apoaequorin (Aequorea Victoria)
nificantly improved in scores on the Mini Mental Status
Apoaequorin is a calcium binding protein first isolated
Exam (MMSE), clinical dementia rating, and activities of
from jellyfish (Aequorea victoria). Potassium calcium chan-
daily living after 12 weeks (p < .01) No significant adverse
nels in smooth muscle and endothelial cells are involved in
events occurred (Xu etal., 2011). A16-week DBRPC study
regulation of vascular tone. Vascular dysfunction during isch-
of 210 individuals with mild-to-moderate AD reported
emia reperfusion is associated with modulations of potassium
cognitive enhancement only at doses above 0.4 mg/day at
and calcium. A company that marketings apoaequorin con-
week 16 (Rafii et al., 2011). Other trials showed positive
ducted a 90-day DBRPC study in 218 adults aged 40 to 91
outcomes in vascular dementia, TBI, age-associate memory
years with self-reported memory issues. Compared to placebo,
decline, and schizophrenia (Akhondzadeh & Abbasi, 2006;
subjects given apoaequorin showed significant improvements
Wang, Yan, & Tang, 2006). Huperzine-A is well tolerated
on tests of recall performance, executive functioning, mem-
with few side effects and minimal peripheral cholinergic
ory, delayed recall, and verbal learning. The study reported no
effects.
adverse events and good tolerability (Underwood, Sivesind,
Gabourie, & Lerner, 2011). Peer-reviewed studies by research
groups are needed to evaluate apoaequorin as a potential treat- Galanthus nivalis (Snowdrop) Galantamine
ment for cognitive and memory decline. However, in light of
An alkaloid extract of snowdrop (Galanthus nivalis) was
the low risks, clinicians could offer patients the option of a
used in folk medicines of Russia and Eastern Europe to pre-
3-month to 6-month trial in doses of 10, 20, or 40 mg/day.
serve memory as people aged. Galantamine, FDA-approved
for treatment of AD, is an allosteric modulator of nico-
H E R BA L T R E AT M E N T S FORC O G N I T I V E tinic receptors and a weak inhibitor of acetylcholinesterase
DY S F U NC T ION (Raskind, Peskind, Wessel, & Yuan, 2000). In an openlabel
Medicinal plants contain bioactive substances in the roots, study, 280 AD patients included in the Swedish Alzheimer
leaves, flowers, and fruit. Unlike most synthetic drugs with Treatment Study were given galantamine starting with 8
one target of action, the presence of numerous medicinal mg/day and gradually increasing to 16 mg/day at 4 weeks
compounds within one herb results in multiple effects. While and then 24 mg/day as tolerated. After 3 years, subjects
the active constituents have been identified in some herbs, in had mean increases of 2.6 points on the MMSE and 5.6
others they have not. Moreover, the synergistic effects of con- points in Alzheimers Disease Assessment Scale-Cognitive
stituents can be more powerful than any one alone. See the (ADAS-cog) (Wallin, Wattmo, & Minthon 2011). Many
excellent review by Howes and Perry on the mechanisms of patients do not tolerate the gastrointestinal disturbances
action and the use of phytochemicals in prevention and treat- caused by prescription galantamine or donepezil. In the
ment of dementia (Howes & Perry, 2011). In vitro and animal authors (RPB) clinical experience, the herbal extract of
studies are shedding light on physiological and genetic aspects Galanthus nivalis combined with R.rosea can be as effective
of herbal medicines. For example, the cognitive enhanc- as galantamine and more tolerable.
ing effects observed with galantamine and huperzine may
be due to potentiation of cholinergic and NMDA activity Vinpocetine from Vinca minor (the Lesser Periwinkle)
(Narahashi, Moriguchi, Zhao, Marszalec, & Yeh,2004).
Vinpocetine (ethyl apovincaminate), is a semisynthetic ethyl ester
of an alkaloid extract from leaves of the lesser periwinkle (Vinca
Huperzia serrata (Huperzine-A) minor). As a cerebrovascular vasodilator, it has been used for treat-
Huperzine-A, an alkaloid derived from Chinese club moss ment of cerebrovascular disorders. Studies show neuroprotec-
(Huperzia serrata) is a strong, selective, reversible AChEI tant and anticonvulsant activity through inhibition of calcium/
572 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
calmodulindependent cyclic guanosine monophosphate-phos- stress response. Furthermore, they propose that adaptogens
phodiesterase, enhancing intracellular cyclic guanosine mono- modulate gene expression of key mediators of stress-induced
phosphate levels in vascular smooth muscle, reducing resistance transduction pathways (Panossian et al., 2013). A full discus-
of cerebral blood vessels, and increasing blood flow without sig- sion of these hypotheses and their evidence base is beyond the
nificantly affecting blood pressure or peripheral vascular resis- scope of this chapter. Here we briefly outline the hypotheses
tance (Patyar, Prakash, Modi, & Medhi, 2011). Vinpocetine and refer to the works of Panossian and colleagues for the
inhibits the molecular cascade caused by the rise of intracellu- details.
lar calcium and selectively inhibits voltage-sensitive sodiaum
channels, reducing excess extracellular calcium associated with
M E DI ATOR S OFT H E S T R E S S R E S P ON S E
ischemia/reperfusion, edema, and glutamate toxicity (Brown &
Gerbarg, 2011; Patyar et al., 2011). It scavenges hydroxyl radicals, Molecular Chaperones, Heat Shock Proteins
inhibits IKB kinase complex, inhibits platelet aggregation, and
Heat shock proteins (HSP70) protect cellular proteins from
increases erythrocyte deformability, reducing blood viscosity
free radicals and enable the repair of damaged proteins, the
and further enhancing blood flow. Stimulation of locus ceruleus
disposal of defective proteins, and the inhibition of cell death.
neurons may enhance alertness, concentration and information
ADAPT- 232 (a fixed combination of R. rosea, E. senticosus,
processing. In a DBRPC study of 43 stroke patients, transcranial
and S. chinensis) and salidroside (an active constituent of R.
Doppler and near infrared spectroscopy showed that vinpocetine
rosea) were found to increase serum levels of HSP70 in mice
improved cerebral perfusion in the peristroke area (Bnczk
under stress and the expression and release of HSP70 from
et al., 2002). PET scans of 13 stroke patients showed improved
human neuroglial cells in vitro (See Figure 29.2).
peristroke cerebral glucose kinetics and blood flow (Szilagyi et
al., 2005). In a 1-year study of 61 children with hypoxic ischemic
encephalopathy due to intracranial birth trauma, vinpocetine NeuropeptideY
reduced seizures, intracranial hypertension, and psychomotor
sequelae (Dutov et al., 1991). Mild side effects include indiges- During stress response, neuropeptide Y (NPY) is released
tion, nausea, dizziness, anxiety, facial flushing, insomnia, head- from sympathetic nerves. Peripherally, it potentiates the
ache, drowsiness, and dry mouth. Patients taking other blood stress response. Centrally NPY inhibits SNS activity and
thinners concurrently should be closely monitored. The average has an anxiolytic effect. NPY can promote ATP formation,
dose is 10 mg three times a day. The authors find vinpocetine to inhibit NO synthesis (relieving the suppression of ATP
be most helpful in cases with evidence of blood flow abnormali- formation by NO), reduce elevated protein kinases, affect
ties on brain imaging studies. modulators of immune response that control DNA tran-
scription, and modulate the release of neuropeptides from
the hypothalamus (See Figure 28.2). ADAPT-232 and sali-
Adaptogens:Rhodiola rosea, Schizandra chinensis, droside have been shown to increase expression and release
Eleutherococcus senticosus, Panax ginseng, Lepidium of NPY from human glioblastoma cells in culture. Panossian
peruvianumChacon and colleagues hypothesize that, analogous to the strength-
An adaptogen is a plant that increases resistance against ening effects of regular physical exercise, adaptogens act as
multiple stressors (biological, chemical, or physical), normal- mild stressors that increase stress tolerance and adaptation
izes physiological parameters, and does not disturb normal by stimulating the release of stress mediators HSP70 and
body functions more than necessary to improve resistance NPY (Panossian et al., 2012; Panossian, 2014).
(Brekhman & Dardymov, 1969). Adaptogens contain bio-
active compounds that function as metabolic regulators. In
MODU L AT ION OFG E N E E X PR E S S ION
reviewing the effects of adaptogens on the central nervous sys-
tem, Panossian and Wagner (2005) suggest that extracts from Genomic studies show that in combination, R. rosea, E. sen-
adaptogenic herbs have synergistic effects on stress response. ticosus, and S. chinensis upregulate and downregulate a total
R.rosea qualified as an adaptogen because it protected every of 2,188 genes in human neuroglial cells T98G. One active
organism tested, from snails to humans, against physical and constituent, salidroside, alters expression of more than 700
mental stress including fatigue, heat, cold, toxins, chemother- genes. Among the genes affected by these adaptogens are
apy cytotoxicity, heavy metals, ischemia, hypoxia, and radia- those that encode cell membrane bound G-protein coupled
tion (Panossian & Wagner, 2005; Brown, 2002; Brown & receptors, including 5-HT3 receptors involved in the release
Gerbarg,2004). of neurotransmitters and neurohormones (Panossian et al.,
Panossian, Wikman, Wagner, and colleagues have been 2013). Adaptogens also target SERPIN1, the gene encoding
testing hypotheses regarding the mechanisms by which neuroserpin, which is involved in growth of axons, develop-
adaptogens exert numerous effects, including improving ment of synapses, and synaptic plasticity (Panossian, 2013).
stress resilience, energy, mood, cognitive function, attention, Further studies in human neuroglial cells found that extract
memory, physical performance, and others (Panossian, 2013; of Rhodiola upregulated 336 genes and down-regulated 295.
Panossian & Wikman, 2009; Panossian, Wikman, Kaur, & Downstream effects of these genes are associated with car-
Asea, 2012). They propose that adaptogens support homeo- diovascular (72 genes), metabolic (63 genes), gastrointestinal
stasis and regulation of the HPA axis via mediators of the (163 genes), neurological (95 genes), endocrine (60 genes),
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 573
System level
Cellular level
Stress
Hypothalamus
SAPK/JNK NO ATP
X
CRH GR
Glia cell
Hsp70 NPY
Pituitary
Adrenaline Cortisol
Hypothetical Mechanisms of Stress Protection by Adaptogens: Rhodiola SHR-5 extract, salidroside, and ADAPT-232. Reproduced
Figure 28.2
with permission of Dr.Alexander Panossian (Panossian,2013). Key: Stress induces hypothalamic release of corticotropin releasing hormone (CRH) followed by pituitary release of
adrenocorticotropic releasing hormone (ACTH) , which simulates release of adrenal hormones and Neuropeptide Y (NPY) to mobilize energy resources and cope with the stress. Feedback regulation of overreaction is
initiated by cortisol release from adrenal cortex. Cortisol binds to glucocorticoid receptors (GR) in the brain, stopping further release of brain neurohormones and reducing the stress induced increase of cortisol down
to baseline (pre-stress) levels. Although brief and mild stress (eustress or challenge) is essential to life, severe stress (distress or overload) is associated with extensive generation of oxygen free radicals, including nitric
oxide (NO), which inhibit adenosine triphosphate (ATP) formation. Stress-activated protein kinases (SAPK/JNK/MAPK) inhibit GR, blocking this feedback downregulation such that serum cortisol remains high
in fatigue, depression, and other stress-related conditions. Adaptogens normalize stress-induced elevated levels of cortisol and other extracellular and intracellular mediators of stress response, including elevated NO,
SAPK (via upregulation of NPY expression), heat shock factor (HSF-1) and heat shock proteins (Hsp70), which inhibit SAPK. Consequently, NO generation is reduced and ATP production is no longer suppressed.
Intracellularly Hsp70 enhances antiapoptotic mechanisms and protects proteins against mitochondria generated oxygen-containing radicals, including NO and superoxide anion. Hsp70 acts as an endogenous danger
signal and has a vital role in immune stimulation. NPY is crucial in the HPA axis function and energy balance maintenance. Both NPY and Hsp70 are involved in enhancement of cellular adaptation to stress, survival,
longevity and cognitive function. Hsp70 inhibits foxhead O transcription factor (FOXO), playing an important role in adaptation to stress and longevity. These pathways contribute to adaptogenic effects, such as
antifatigue, improved attention and enhanced cognitive function. cognitivecognitive function .
behavioral (50 genes), and psychological disorders (62 genes) contain many antioxidant compounds and mitochondrial
(Panossian, et al., 2014). enhancers found to maintain higher levels of ATP and
creatine phosphate (CP) in brain, muscle, liver, and blood
(Furmanowa, Skopinska-Rozewska, Rogala, & Malgorzata,
Rhodiola, Golden Root, Arctic Root, or Roseroot
1998; Kurkin & Zapesochnaya, 1986a). In animal stud-
(Rhodiolarosea)
ies R. rosea was shown to increase brain norepinephrine,
Although many of the 19 species in the Rhodiola genus are DA, and 5-HT and stimulate nicotinic cholinergic sys-
used as traditional medicines in Europe and Asia, Rhodiola tems (Petkov et al., 1986; Stancheva & Mosharrof, 1987).
rosea has been the most intensely studied. Starting in the R. rosea increases bloodbrain barrier permeability to DA
1950s under the Ministry of Defense of the former Soviet and 5-HT precursors, consistent with activation of the
Union, 30 years of unpublished systematic research was kept cerebral cortex and limbic systems. Extracts also reversed
in classified documents while the strategic use of R. rosea the blockage of acetylcholine in pathways ascending from
and other adaptogenic herbs to enhance physical, cogni- limbic system to cortex that are involved in memory. Two
tive, and psychological functions was explored in military flavonoid glycosides (gossypetin-7-O-l-rhamnopyranoside
personnel, cosmonauts, Olympic athletes, scientists, and and rhodio-flavonoside) from the alcohol extract of R. rosea
students (Baranov, 1994; Brown, Gerbarg, & Ramazanov, (5 g/L) were found to cause 58 15% and 38 4% AChE inhi-
2002; Brown & Gerbarg, 2004; Brown, Gerbarg, & bition respectively and may account in part for cognitive and
Muskin, 2009; Stancheva, Mosharrof, & Petkov, 1986; memory-enhancing properties (Hill-House, Ming, French, &
Panossian, 2013). A formula called ADAPT, containing Towers, 2004).
Rhodiola rosea, Eleutherococcus senticosus, and Schizandra In healthy individuals, R.rosea enhances intellectual work
chinensis was developed and tested the most extensively. capacity, abstract thinking, accuracy on tedious tasks, and
Most of these studies were written as government reports, reaction time (Shevtsov etal., 2003; Spasov, Mandrikov, &
not for publication. However, current research is confirm- Mironova, 2000). For example, a DBRPC study of 60
ing many of the findings. Since the 1960s the Russian first-year college students under stress found that those given
Pharmacopoeia has described the approved medicinal uses low-dose R.rosea (100 mg/day) had significant improvement
of root extracts of R. rosea. Soviet researchers observed ther- in mental fatigue, psychomotor function, overall well-being,
apeutic effects in posttraumatic and vascular brain lesions, physical work capacity, and heart rate (Spasov, Wikman,
especially in early post-injury stages. Rhodiola species Mandrikov, Mironova, & Neumoin, 2000). The ADAPT
574 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
formula, now labeled ADAPT-232 (Swedish Herbal function and memory may take 112 weeks. Some individuals
Institute) was recently tested in a DBRPC single-dose experience a decline in effectiveness after 3 to 12months. In
effect study in 40 healthy but psychologically stressed, tired such cases a dose increase or a 2-week holiday off of the herb
women aged 2068years. Compared to the placebo group, may restore efficacy. Alternatively, using a well-tested, quality
within 2 hours of consuming 270 mg ADAPT-232 sub- brand may increase and sustain the benefits longer. This adap-
jects gained significant improvements in attention, speed, togen can be used intermittently, prior to and during times of
and accuracy during stressful cognitive tasks (Aslanyan increased stress, or continuously for chronic conditions. For
et al., 2010). R. rosea has no reported adverse interactions example, R.rosea could be started 2 or 3 weeks before exami-
with drugs. However, caffeine and other stimulants can nations to reduce stress and improve academic performance.
have additive effects. In older Soviet studies, R. rosea was
reported to exacerbate a condition in patients described as
volatile or euphoric (Saratikov & Krasnov, 1987). These Schizandra chinensis (Schizandra or Schisandra)
were probably patients with bipolar disorder and there may Schizandra chinensis is a Chinese medicinal herb (Bei Wu
be some risk of inducing mania in bipolar patients, as can Wei Zi or Chosen-Gomishi) used to improve concentration,
occur with antidepressants and stimulants. However, in the energy, and physical endurance. Bioactive components (lig-
authors (PLG and RPB) experience, R. rosea can be quite nans), including schizandrin and gomisan A, are polypheno-
helpful for depression and for patients on mood stabilizers lic. Extracts of the schizandra fruit showed significant AChE
whose mood swings are primarily the depressed type with inhibition (Hung etal., 2007)as well as antidepressant, anti-
occasional mild hypomanic symptoms. inflammatory, and hepatoprotective effects. The emotional
In patients with brain injury, R.rosea has a mild cogni- calming effect of S.chinensis counterbalances the stimulating
tive stimulant effect while it is also emotionally calming. effect of R.rosea in patients who tend to become anxious. The
Doses and precautions are the same as described in the sec- pharmacology and clinical research on schizandra has been
tion titled Herbs for Treatment of Mood Disorders. Highly reviewed (Panossian & Wikman,2008).
anxious patients may not tolerate higher doses, because the
activating effects sometimes exacerbate anxiety. R. rosea is
best absorbed when ingested 20 minutes before breakfast Eleutherococcus senticosus or Acanthopanax senticosus
and/or lunch when the stomach is empty, starting with 150 (Siberian Ginseng or Eleuthero)
mg/day and increasing by 150 mg every 37days. If tolerated,
Eleutherococcus senticosus is often called Acanthopanax senti-
the entire dose can be given in the morning to increase com-
cosus, Oriental ginseng, or Siberian ginseng, though it is not
pliance. In some cases the single morning dose has a better
in the ginseng family. Athorny shrub that grows in Siberia
effect. Elderly, medically ill, or anxious patients should start
and northern China, it has a long history of use in Russia,
by taking one-fourth to one-half of a capsule (3775 mg) per
China, Korea, and Japan as an adaptogen to enhance nonspe-
day dissolved in tea or juice and increased slowly. Response
cific resistance to stress and fatigue. Animal studies of bioac-
takes 112weeks.
tive compounds from E. senticosus, including eleutherosides
Since R. rosea is known to have a mild effect on plate-
and isoflaxidin, demonstrated reduced fatigue and improved
let aggregation at high doses, patients should be advised
recovery of natural killer cell activity and corticosterone lev-
to watch for signs of increased bruising, especially at doses
els following stress induced by swimming in mice. E. senti-
above 750 mg/day. Patients on coumadin or other medica-
cosus, used as an antiinflammatory in rheumatic diseases in
tions that affect platelet aggregation or clotting factors should
oriental medicine, was found to downregulate inflammatory
have their International Normalized Ratio (INR) checked
inducible nitric oxide synthase (iNOS) expression (Jung etal.,
(following each increase in R. rosea dose) and their couma-
2007). Extracts have been used by athletes to enhance physical
din doses adjusted accordingly (see section on HerbDrug
strength and endurance. While human studies of E.senticosus
Interactions).
monotherapy are limited, it has been shown to contribute to the
The authors find R.rosea to be effective in a variety of con-
anti-fatigue and mental stimulatory effects of adaptogen com-
ditions:disorders of memory, cognition, and fatigue; enhance-
bination formulas, particularly ADAPT-232 (Panossian &
ment of physical endurance, cognitive performance, memory,
Wagner, 2005). Adverse events have been reported with intra-
and energy in healthy individuals and in those with a wide
venous administration but not with oral ingestions (Weng
range of disorders including age-related cognitive decline,
etal.,2007).
poststroke, TBI, and cognitive impairment due to medical ill-
ness (e.g., cancer, HIV, or other chronic conditions); reduction
of medication side effects; and recovery from central nervous Panax ginseng (Korean or Asian Ginseng) and Panax
system infections such as neuro-Lyme disease. Augmentation quinquefolius (American Ginseng)
of R. rosea with Eleutherococcus senticosus, Schizandra chi-
nensis, Panax ginseng, Ginkgo biloba, Withania somnifera Ginsengs contain numerous bioactive compounds. Panax
(ashwaganda), and/or piracetam can further increase the ben- ginseng increases nitric oxide production in endothelial cells,
eficial effects on memory and cognition. Patients often report which is essential for blood flow and oxygen delivery. Panax
improved energy, mental clarity, and memory. Energy usually ginseng (400 mg/day) significantly improved abstract think-
improves within the first week. Improvements in cognitive ing and reaction time compared to placebo in a DBRPC
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 575
8-week study of healthy volunteers (age >40years). However, OT H E R H E R B S W I T HN EU ROPROT E C T I V E A N D
there was no effect on memory or concentration (Sorensen & C O G N I T I V E BE N E F I T S
Sonne, 1996). Panax ginseng 100 mg also significantly
Ginkgo biloba (Ginkgo) fromLeaves of
improved reaction time, accuracy, calmness, and working
the MaidenhairTree
memory in a DBRPC crossover study of 32 healthy adults
aged 1840 years (Reay, Scholey, & Kennedy, 2010). In a Leaf extracts of Ginkgo biloba contain flavones associated
12-week RCT of 97 Alzheimer disease patients, improve- with antioxidant effects and terpene lactones responsible
ments were reported in cognitive function and MMSE (Lee, for antiplatelet activating factor. The EEG profile associ-
Chu, et al., 2008). However, literature reviews find meth- ated with ginkgo is indicative of cognitive activation with
odological limitations in ginseng studies, a lack of convinc- increased alpha and low-beta frequencies as well as decreased
ing evidence, and a need for better quality studies (Geng slow theta and delta, a pattern typical of cognitive activators
etal.,2010). (such as donepezil) and stimulants. A review of 22 controlled
A DBRPC trial in 32 healthy young adults found sig- ginkgo studies in cerebrovascular disease, memory impair-
nificant acute improvements in working memory in subjects ment, cognitive impairment, AD, multi-infarct dementia,
given a single dose of 100, 200, and 400 mg American gin- subarachnoid hemorrhage, aging, hypoxia, and vestibular dis-
seng, P. quinquefolius (Cereboost, standardized to 10.65% order, and in healthy volunteers, found evidence for clinically
ginsenosides) compared to those given placebo (Scholey et meaningful (though subtle) improvements (Diamond et al.,
al., 2010). Of note, American ginseng (preparation HT100) 2000; Diamond & Bailey, 2013). In a DBRPC 52-week study
significantly improved verbal memory and reduced extrapy- of 236 Alzheimers patients, G. biloba (EGB 761) 120 mg/
ramidal symptoms in a 4-week DBRPC study of 64 schizo- day improved cognitive performance in patients with mild to
phrenic patients (Chen & Hui, 2012). American ginseng moderate cognitive impairment and slowed deterioration in
is less activating than Panax ginseng. The concentration patients with severe impairment. A DBRPC 22-week trial of
of active ginsenosides in P. ginseng preparations can vary 400 patients with mild to moderate dementia given 240 mg/day
considerably. EGB 761 documented that the ginkgo group had better cogni-
In clinical practice, ginseng augments the activating tive outcome compared to placebo (Napryeyenko, Borzenko,
effects of other agents, improving alertness, mental focus, & Gindem-Np Study Group, 2007). Although 120 mg twice
energy, and cognitive function. One of the authors (RPB) daily of ginkgo (EGb761) failed to prevent dementia in the
attains better results by combining P.ginseng, American gin- DBRPC Ginkgo Evaluation of Memory study of over 3,000
seng, and E. senticosus when treating cognitive dysfunction subjects followed for an average of 6.1 years (DeKosky et al.,
due to stroke, trauma, or vascular disease. 2008), issues of compliance and diagnostic heterogeneity limit
conclusions. Other DBRPC studies indicate that gingko may
be particularly beneficial for neuropsychiatric and behav-
Lepidium myenii Walpers, Lepidium peruvianum ioral symptoms in dementia, especially when combined with
Chacon(Maca) 10 mg/day donepezil (Bachinskaya, Hoerr, & Ihl, 2011; Ihl,
Maca is a Peruvian adaptogenic herb that grows at high alti- 2012; Ihl et al., 2012). A comprehensive review of EGb761 by
tudes in the Andes. The Peruvian species has been referred to Diamond and Bailey (2013) noted that the largest proportion
as Lepidium myenii, but the Peruvian government and univer- of cognitive effects in RCTs are in fluid intelligence, selective
sities chose to recognize its official name as Lepidium peruvia- attention, short-term and long-term verbal and visual mem-
num Chacon. Its many active components include alkaloids, ory, and executive functions. They also reviewed RCTs show-
polyunsaturated acids, and their amides, and plant sterols. ing EGB761 to be beneficial for multiple sclerosis and anxiety
Maca is used as a nutritional supplement to improve alertness, disorders (Diamond & Bailey, 2013). EGb761 is standardized
mental focus, and physical resilience. Although it is mainly to contain 24% ginkgo-flavone glycosides and 6% terpenoids
used to enhance sexual function and fertility, the roots have with numerous other active constituents, which may account
other medicinal properties. L.peruvianum is considered to be for its effects on cerebrovascular tone, neurotransmitter and
a nonhormonal phytomedicine that has the properties of an receptor activity, glucose metabolism, and electrical activity.
adaptogen. The key active constituents have not been identi- The authors clinical experience suggests that ginkgo is
fied. Among the 13 phenotypes of L.peruvianum, each has its best used to augment centrophenoxine and racetams (see
own color and variation in the balance of active constituents. below) in patients with TBI because its effects alone are mild.
A review of maca studies discussed the following findings Side effects are rare with occasional nausea, headache, or rash.
(Gonzales,2012). Cases of bleeding in patients with poor quality ginkgo, and
The black variety of maca shows positive effects on learn- usually with concurrent antiplatelet or anticoagulant medi-
ing and memory in animal models. Black maca reduced cations, have been reported. High quality pharmaceutical
human brain malondialdehyde levels (marker of oxidative grade ginkgo such as EGb761 has not been shown to affect
stress) and decreased acetylcholinesterase levels in ovariecto- bleeding time and does not potentiate anticoagulant drugs
mized mice. Toxic effects have not been reported if the herb is (Weinmann, Roll, Schwarzbach, Vauth, & Willich, 2010).
boiled before consumption. It is neither teratogenic nor carci- Nevertheless, the current recommendations in the medical
nogenic. The authors (PLG and RPB) find maca to be a useful literature are that ginkgo not be given with warfarin and that
adjunctive treatment for neural fatigue. it be discontinued 2 weeks prior to surgery.
576 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
Labiatae Family:Melissa officinalis (Lemon Balm), prescribed in Europe, but are not well known in the United
Salvia officianalis (Sage) and Salvia lavandulaefolia States. Froestl and colleagues recently proposed a nootropic
(SpanishSage) classification system with 19 categories based on mecha-
nisms of actionfor example, interactions with receptors,
Modabbernia and Akhondzadeh (2013) recently reviewed the enzymes, ion channels, nerve growth factors, reuptake trans-
use of Labiatae phytomedicines in mental health. Preliminary porters, antioxidants, metal chelators, and monoclonal anti-
small RCTs suggest that lemon balm and sage may enhance bodies interacting with amyloid-B and tau (Froestl, Muhs, &
cognition and reduce agitation in patients with dementia Pfeifer, 2012). They have reviewed the interactions of noo-
(Akhondzadeh & Abbasi, 2006; Akhondzadeh etal., 2003). tropics with enzymes, receptors, (Froestl, Muhs, & Pfeifer,
In 4-week DBRPC trial in 71 severely demented patients, 2013) and other targets (Froestl, Pfeifer, & Muhs, 2012).
M. officianalis aromatherapy decreased agitation and with- Evidence suggests that nootropics improve antioxidant sta-
drawal and improved activities of daily living. A DBRPC tus, membrane fluidity, mitochondrial function, neurotrans-
trial in 18 healthy volunteers found that a 300 mg/day dose mitter levels, mRNA protein synthesis, cerebral blood
improved math processing speed while maintaining accuracy. flow, neuroplasticity, and long-term potentiation (Brown,
Furthermore, at 600 mg/day lemon balm reduced effects of Gerbarg, & Muskin, 2009).
stress and improved calmness (Kennedy, Little, & Scholey,
2004). Side effects are insignificant. The authors find that
800 mg lemon balm helps reduce agitation in patients with Pyrrolidinones (Racetams):Piracetam, Aniracetam,
dementia. Pramiracetam
A DBRPC crossover study in 24 healthy undergradu-
The modest neuroprotective effects of piracetam can be
ates (ages 1837) found that those given 50 l Spanish sage
potentiated by CDP-choline, idebenone, vinpocetine, cen-
had significant improvements in speed of memory, alertness,
trophenoxine, and deprenyl. Oxiracetam, aniracetam, and
calmness, and contentedness compared to those on placebo.
pramiracetam produce somewhat stronger effects than pirace-
Spanish sage (S. lavandulaefolia) was used instead of sage
tam (Brown, Gerbarg, & Muskin, 2009). Large DBPC stud-
(S. officianalis) because it contains the same bioactive com-
ies indicate that racetams improve symptoms in dyslexia and
pounds as S. officianalis but has a lower concentration of
augment the benefits of speech therapy in poststroke aphasia
thujone, a terpenoid ketone that can be toxic in high doses
(De Deyn, Reuck, Deberdt, Vlietinck, & Orgogozo, 1997).
(Tildesley et al., 2005). Side effects and drug interactions of
One PET scan study demonstrated improved task-related
sage and Spanish sage are minimal. In the authors experi-
blood flow in left hemisphere speech areas (Kessler, Thiel,
ence with dementia, 50 drops of 1.5% tincture of Spanish
Karbe, & Heiss, 2000). In postconcussion syndrome, pirace-
sage improves memory and alertness while ameliorating agi-
tam may reduce symptoms (especially vertigo and headache)
tation. The cognitive effects of these herbs warrant further
and accelerate recovery with EEG normalization. In patients
study.
with dyslexia and aphasia, ginkgo improved attention and
perception and augmented piracetam in cognitive retraining
Croccus sativus (Saffron) (Deberdt, 1994; Enderby, Broeckx, Hospers, Schildermans, &
Deberdt,1994).
Preclinical and clinical evidence on the benefits of saffron In a DBRPC study of cognitive impairment and isch-
have been reviewed (Modabbernia & Akhondzadeh, 2013). emic stroke following coronary artery bypass surgery, 98
It may exert AChEI effects, antagonize glutamatergic patients were randomized to either placebo or piracetam IV
activity at NMDA receptors, and inhibit aggregation and (150 mg/kg/day; 300 mg/kg on the day of surgery) starting
deposition of amyloid . In a 16-week DBRPC trial of 46 1day before surgery to 6days after surgery and then 12 mg/
patients with probable mild to moderate AD, those treated day orally for up to 6 weeks. Patients given piracetam showed
with saffron 15 mg twice daily (extracted from stigmas of significant improvement in cognitive function compared to
saffron) improved significantly on tests of cognitive func- placebo (Szalma etal.,2006).
tion and had markedly reduced agitation compared to pla- Racetams are very low in side effects. The authors (PLG
cebo (Akhondzadeh, Sabet, et al., 2010). A DBRPC Phase and RPB) use aniracetam 750 mg twice daily to improve cog-
II 22-week trial (n = 54) found saffron 15 mg b.i.d. to be nitive function in adults and children with learning disabili-
as effective as donepezil 10 mg/day in community dwell- ties, dyslexia, stuttering, anticonvulsant-induced cognitive
ing adults over the age of 55 years with mild-to-moderate impairment, bipolar disorder, unipolar depressives on antide-
Alzheimers disease (Akhondzadeh, Shafiee Sabet, et al., pressants, and chronic fatigue syndrome. For the treatment
2010). of children, pramiracetam is less activating and more calming
than aniracetam.
NO OT ROPIC S C E N T ROPH E NOX I N E
(M E C L OF E NOX AT E , LUC I DR I L), L-DE PR E N Y L L-Deprenyl (Eldepryl, Selegiline, Emsam,Jumex)
(S E L E G I L I N E), P Y R ROL I DI NON E S (R AC E TA M S)
Although L-deprenyl is a prescription MAOI antidepres-
Nootropics are manufactured cognitive enhancing and neu- sant in the United States, most physicians are not aware
roprotective agents that have been extensively studied and of its neuroprotective effects. In low doses (<10 mg/day) it
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 577
does not act as an MAO-A inhibitor and does not require a showed no impact on cognition or well-being (van Niekerk,
low tyramine diet. Preclinical evidence suggests that selegi- Huppert, & Herbert, 2001). Patients whose DHEA is low
line enhances mesencephalic drive regulation and resiliency for age, menopausal women who have had ovariectomies
under stress; increases release of BDNF, catecholamines, and adrenalectomies (Gurnell & Chatterjee, 2001), and
and 5HT, (most markedly in the hippocampus; see Knoll debilitated geriatric patients are more likely to respond
2000, 2003); improves dopamine function and cognitive to DHEA with improvements in energy, memory, mood,
function; and exerts neuroprotective effects (particularly and weight maintenance. Side effects, including insom-
in catecholaminergic and cholinergic neurons) including nia and irritability, are usually mild. Slight increases in
protection against glutamate excitotoxicity (Ebadi et al., estrogen, potential interactions with steroids, and effects
2006). In ultra-low doses (2.55.0 mg/d) L-deprenyl may on prostate are concerns. Serial prostate-specific antigen
be modestly beneficial in treatment of TBI, AAMD, neu- testing is advisable. Patients with a history of prostate
rodegenerative or vascular cognitive impairment, AD, or cancer or other hormone-sensitive cancers should not be
a family history of dementia. As an enhancer regulator, given DHEA. Pharmaceutical grade DHEA is preferable
L-deprenyl was associated with increased activity levels in in doses sufficient to restore physiologic levels, usually
enhancer-sensitive neurons that are associated with delay in 2550 mg/day.
age-related neurodegenerative changes, and it significantly
increased longevity in 6 different animal species (Denes,
Melatonin
Szilagyi, Gal, Bori, & Nagy, 2006). Further study on neu-
roprotection is needed. Melatonin, a methoxyindole neurohormone secreted pri-
marily by the pineal gland, diffuses readily through mem-
branes and enters cell organelles. Best known for its role in
Centrophenoxine (Meclofenoxate, Lucidril) sleep and circadian rhythms, melatonin is also a robust neu-
Dimethyl-aminoethanol (DMAE) is the precursor to roprotectant that avidly scavenges reactive oxygen species
phosphatidyl-DMAE, an avid scavenger of OH-radicals including reactive hydroxyl radicals, carbonate radicals,
in cell membranes. Centrophenoxine (CPH) is an ester of and reactive nitrogen species (Srinivasan, Pandi-Perumal,
DMAE and p-chlorophenoxyacetic acid, a synthetic form Cardinali, Poeggeler, & Hardeland, 2006). In addition,
of a plant growth hormone (Nandy, 1978). CPH elevates melatonin prevents excitation-dependent generation of
levels of brain acetyl choline (ACh) and has antioxidant free radicals, reduces lipid peroxidation, upregulates anti-
properties. CPH delivers DMAE rapidly to the brain oxidant enzymes, and potentiates other antioxidants.
where it is incorporated into nerve cell membranes as phos- Melatonin levels decline with aging and in neurodegenera-
phatidyl-DMAE thereby providing antioxidant protective tive conditions. Beneficial effects of melatonin in AD and
effects (Zs-Nagy, Dajko, Uray, & Zs-Nagy, 1994). In ani- PD may involve antioxidant protection of mitochondrial
mal models of ischemia and in aged rats, CPH reduced membranes and DNA, enhanced glutathione production
cognitive deficits (Liao, Wang, & Tang, 2004). CPH and regeneration, improved electron transport capacity,
increased activity of catalase, superoxide dismutase, gluta- and antiamyloid- and antifibrillogenic effects. In elderly
thione reductase, and glutathione, as well as diminishing patients, early AD, and mild cognitive impairment (MCI),
lipid peroxidation (Bhalla & Nehru, 2005). Significantly small studies found that melatonin improved sleep, mood,
increased psychomotor and behavioral performance was memory, and sundowning, and possibly slowed progres-
observed in patients treated with centrophenoxine com- sion of cognitive decline. In a DBPC study of 20 patients
pared to placebo in an 8-week DBRPC trial in patients with AD, those given melatonin 3 mg at bedtime showed
with moderate dementia (Pek, Fulop, & Zs-Nagy, 1989). significantly greater improvements on ADAS cognitive
In a 3-month DBRPC study 62 geriatric patients with and noncognitive behavioral scores compared to the pla-
mild to moderate AD, a preparation of CPH, vitamins, cebo group, but no significant differences were found on
and nutrients (Antagonic Stress) was associated with sig- MMSE (Asayama et al., 2003). A review of melatonin
nificant improvements in memory, cognitive function, studies in patients with MCI included 5 DBRPC trials
and behavior compared to nicergoline (Schneider et al., and 1 open-label retrospective study, and all concurred
1994). Nootropics may be more effective when combined in finding that evening treatment with melatonin signifi-
with vitamins, minerals, and other nootropics (Fischer, cantly improved sleep quality and cognitive performance
Schmidt, & Wustmann, 1984). (Cardinali, Furio, & Brusco, 2010). Studies with additional
measures also showed better mood. Larger studies are
needed to evaluate long-term benefits of melatonin on dis-
HOR MON E S FORC O G N I T I V E DY S F U NC T ION ease progression in AD. In elderly patients, including those
Dehydroepiandrosterone(DHEA) with AD and PD, melatonin in doses of 39 mg at bedtime
can help to improve sleep, mood, memory, and sundown-
Clinical studies of memory and cognitive enhancement ing. It probably slows progression of cognitive decline in
with DHEA, produced primarily in the adrenal glands MCI and, possibly, early AD. Melatonin may have a role in
and secondarily in the ovaries and testes, show mixed long-term prevention of neurodegeneration, particularly if
results. In a 3-month study of normal older men, DHEA begun by age45.
578 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
M ENOPAUSE , ANDROPAUSE , AND antioxidant activity (Overk etal., 2005). Hops, traditionally
SE X UAL F U NCTION used to brew beer, binds to estrogen receptors in vitro but
does not stimulate uterine growth in ovariectomized rats
(Beckham, 1995; Fackleman, 1998). In vitro studies indicate
PH Y TOE S T RO G E N S A N D OT H E R H E R B S
that one constituent, 8-prenylnaringenin, has high estrogenic
FORF E M A L E M E NOPAUS E
activity and binding to estrogen receptors Aand B (Milligan
Recent reviews pertaining to the safety and efficacy of etal., 2000). Hops may have mild additive effects with other
phytoestrogens for menopausal symptoms, bone loss, and sedative agents.
breast cancer highlight difficulties interpreting research Epidemiologic data and animal studies suggest that the
studies and the complexities of clinical decision making health benefits of soy (lowering cholesterol and cancer pre-
(Bedell, Nachtigall, & Naftolin, 2012; Lagari & Levis, vention) are best obtained from whole soy (i.e., whole food)
2012; Leclercq & Jacquot, 2012). Interest in alternatives to rather than from isolated isoflavones. Areview of 22 RCTs by
hormone replacement therapy (HRT) has been growing, the American Heart Association Nutrition Committee con-
particularly in light of long-term studies showing increased cluded that isolated soy protein with isoflavones, compared
risk of breast and uterine cancer among women taking with milk or other proteins, decreased LDL cholesterol con-
HRT. Evidence of risk versus benefit is insufficient to jus- centrations on average approximately 3%a small change rel-
tify the use of HRT to prevent osteoporosis, cardiovascular ative to the large amount of soy protein (averaging 50 g/day)
disease, or dementia. Although dietary supplements and tested. There were no significant effects on HDL cholesterol,
herbs are widely used for relief of menopausal symptoms, triglycerides, lipoprotein, or blood pressure. Furthermore, in
more research is needed to confirm their benefits and safety. 19 studies of soy isoflavones, the average effect on LDL choles-
terol and other lipid risk factors wasnil.
Isoflavones exert estrogenic and anti-estrogenic effects,
Phytoestrogens both stimulating and inhibiting growth in breast cancer
Phytoestrogens are plant-derived selective estrogen receptor cells in vitro. The net effect has been no change in the risks
modulators (SERMs) with structural similarities to estradiol. of breast, endometrial, or other cancers. A meta-analysis of
They bind to estrogen receptors and may act as estrogen ago- soy studies identified a small reduction in breast cancer risk
nists or antagonists depending on the specific tissue, the pres- associated with the use of whole soy but not high-dose isofla-
ence of other SERMs, and their ability to recruit coactivator or vone supplements (Trock, Hilakivi-Clarke, & Clarke, 2006).
corepressor complexes (Bedell, Nachtigall, & Naftolin, 2012). Aprospective study of 15,555 women aged 5069 concluded
Current research on SERMs aims to reduce menopausal that high intake of isoflavones had no significant relation-
symptoms and the risk of bone fractures and cardiovascular ship to breast cancer risk (Keinan-Boker, van Der Schouw,
disease without increasing the risk of breast, uterine, or ovar- Grobbee, & Peeters,2004).
ian cancer (Blizzard, 2008). An ideal SERM would exert ago- The efficacy and safety of soy isoflavones for preventing
nistic effects on estrogen receptors in bone, the cardiovascular or treating cancer of the breast, endometrium, and prostate
system, and the central nervous system, but have anti-estro- are not established. No evidence from clinical trials points to
genic or no effects on healthy breast and endometrial tissues increased risk of cancer. The use of isoflavone supplements in
(Hendrix & McNeeley, 2001). Tamoxifen, the first SERM food or pills is not recommended. Earlier research indicating
used to reduce breast cancer risk, increased risks of endome- that soy protein has important favorable effects compared to
trial cancer and blood clots (Cuzick et al., 2013). Other syn- other proteins has not been confirmed. The benefits of many
thetic SERMs (e.g., ralozafen and bazedoxifene) have shown soy products may be attributed partly to the high content of
mixed results and side effects such as headache, arthralgias, polyunsaturated fats, fiber, vitamins, and minerals, and low
hot flashes, and back pain (Gatti, Rossini, Sblendorio, & Lello, content of saturated fat (Sacks etal.,2006).
2013; Kawate & Takayanagi, 2011). Research is needed on the Animal studies suggest that red clover isoflavones decrease
potential role of plant-derived SERMs in treating menopausal bone loss induced by ovariectomy, probably by reducing the
symptoms and reducing risks of osteoporosis, cardiovascular rate of bone turnover via inhibition of bone resorption
disease, and breast cancer. (Occhiuto et al., 2007). Most clinical studies show lack of
Plants containing phystoestrogensfor example, soy effectiveness of isoflavones derived from soy or red clover
(Glycine max), red clover (Trifolium pratense), and hops in preventing menopause-related bone loss. However, three
(Humulus lupulus)have been widely used and studied. Soy meta-analyses of RCTs in menopausal women found evidence
constituents include phytoestrogen isoflavones, diadzein, and that ingesting soy isoflavones for 6months significantly but
genistein, as well as the precursor to mammalian lignans. moderately improved bone marrow density in the lumbar
Although the mechanisms of action are not entirely known, spine but not in total hip, femoral neck, and trochanter. The
soy isoflavones show selective weak binding to estrogen recep- supplements were associated with significant reductions in
tors, preferentially estrogen receptor B. Mildly estrogenic urine deoxypyridinoline (a bone resorption marker) but not
isoflavones in red clover, similar to those in soy, also bind to serum alkaline phosphatase or osteocalcin (Taku, Melby,
human estrogen receptors (Booth etal., 2006). Extracts from Nishi, Omori, & Kurzer, 2011). Further studies are needed
red clover and hops upregulate progesterone receptor mRNA, to assess the magnitude of these effects and potential inter-
interact with transcription factors (NF-KappaB), and possess actions between isoflavones and anti-osteoporosis drugs. In a
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 579
DBRPC study of women aged 4560years within 5years of 5. Gastrointestinal microflora:Soybean isoflavones are
menopause, with baseline bone marrow density T score >- hydrolyzed to aglycone, diadzein, and genistein by intesti-
2.0, daily intake of 200 mg isoflavone tablets for 2years did nal enzymes and further metabolized to other compounds
not prevent bone loss or menopausal symptoms (Levis etal., such as equol. The estrogen-agonist potency of equol is
2011). However, interpretation of this study should be cau- much higher than diadzein. Women who lack the intes-
tious because it included women who were up to 5years post- tinal microflora needed to convert daidzein to equol are
menopausal. Isoflavones in soy foods and red clover may have called nonproducers. Equol production can be affected
a modest positive effect on plasma lipid concentrations, bone by diet, antibiotics, and illness. Consequently, women who
mass density, and cognitive function. are nonproducers of equol would have less response to the
The evidence for the therapeutic value of phytoestrogens ingestion of isoflavones (Bedell, Nachtigall, & Naftolin,
in perimenopause is mixed with more positive results in recent 2012). The differentiation of womens capacities for equol
studies. Stronger evidence supports the use of isoflavones production may be relevant for interpretation of study
for management of vasomotor symptoms (Molla, Hidalgo- results and for adjusting either isoflavone dosages and/or
Mora, & Soteras, 2011). For example, In a 12-week DBRPC correcting factors that may influence microflora.
study of 84 postmenopausal women, those given 30 mg/day
synthetic genistein experienced a 51% decrease in the num- Based on more recent research, Bedell and colleagues are more
ber and duration of hot flushes versus a 27% decrease in the optimistic about phytoestrogens, particularly isoflavones, lig-
placebo group (p = 0.026). There were no differences between nans, and coumestoms for treatment of vasomotor symptoms,
groups in follicle stimulating hormone (FSH), 17--estradiol, vaginal atrophy, insomnia, and osteoporosis. They concluded
endometrial thickness, or adverse events (Evans, Elliott, that phytoestrogens reduce the intensity of hot flushes and
Sharma, Berman, & Guthrie, 2011). Assessment of risks and that some combinations reduce the frequency. Their review
benefits of phytoestrogens in women with breast cancer and indicates that phystoestrogens can reduce vaginal atrophy,
breast cancer survivors remains controversial. Recent stud- improve sleep, cognition, and possibly bone health, primarily
ies have not found an increase in the risk of breast cancer or in the spine (Bedell, Nachtigall, & Naftolin, 2012). Leclercq
endometrial hyperplasia. However, trials specifically designed and colleagues note that phytoestrogens can induce epigen-
to detect cancer are needed. Lignans do not seem to increase etic change in genes involved in estrogen receptor regula-
risk of blood clots. Most studies suggest minimal health tion, for example, DNA methylation and histone acetylation/
risks with phytoestrogens (Bedell, Nachtigall, & Naftolin, methylation. Their investigations in breast cancer cell lines
2012). Including whole soy in the diet of postmenopausal incubated with genistein and daidzen documented effects
women may be beneficial, but the optimal dose range remains on DNA hypermethylation and the restoration of the expres-
unknown. Women could be informed that although there is sion of BRCA1 and BRCA2 oncosupressor gene expression.
some evidence of efficacy, it is not conclusive. While there is They support a quest for specific estrogen receptor ligands to
no evidence of harm, long-term safety studies in humans have treat endocrine-disrupting diseases, including breast cancer
not beendone. (Leclercq & Jacquot,2012).
Recent assessments of previous reviews of hundreds of Data from large RCTs suggest that SSRIs and SNRIs are
phytoestrogen studies find inconsistencies that could be promising treatments for perimenopausal vasomotor and
attributed to several important factors. mood symptoms. However, SSRIs (e.g., fluoxetine, parox-
etine) inhibit CYP2D6 and can interfere with the clinical
1. Patient selection:The inclusion of women who are more benefit of anticancer drugs such as tamoxifen. While estrogen
than 1year postmenopause, whose menopausal symptoms receptor modulators (e.g., raloxifene and bazedoxifene) may
would wane naturally over time, reduces the likelihood of reduce vulvovaginal atrophy, vasomotor symptoms, and the
positive results. risk of osteoporosis, they impart an increased risk of venous
2. Targets of measurements:Although it is easier to measure thrombosis, stroke, or blood clots in the legs, lungs, or eyes.
changes in frequency of hot flushes rather than severity, Other side effects of raloxifene are vasodilation (hot flushes),
the latter is a better indicator of efficacy. affecting about 10%25% of users, and leg cramps, affecting
about 7% (Wooltorton, 2006). The long-term safety (beyond
3. Increased consumption of phytoestrogens and exposure 3years) of SERMs regarding cancer and cardiovascular risks
to endocrine disruptors:Longer term studies may be has not yet been established (Levine, 2011). Women who
affected by the increasing consumption of phystoestro- object to raloxifene and bazedoxifene, find them intolerable,
gens such as soy in commercial products and the exposure or cannot afford the costs may consider herbal or nutritional
to estrogenic substances in products such as cosmetics, therapy after being fully informed of the risks and limitations
food containers, and meat from animals given hormones of the evidence of safety and efficacy.
(Guerrero-Bosagna & Skinner,2012).
4. Polymorphisms:Genetic polymorphisms of enzymes Black Cohosh (Cimicifuga racemosa or Actaea
involved in metabolism of phytoestrogens play a role in racemosa)
the individual and ethnic differences that occur in diges- Black cohosh has been used for over 60 years in Europe
tion, absorption, and dose requirements for efficacy. for its ability to decrease hot flushes by reducing the level of
580 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
luteinizing hormone (LH). Studies show no binding to estro- Dong Quai (Angelica sinensis)
gen receptors in vitro, no clinical estrogenic effect, no car- Dong quai has been used in traditional Chinese medicine
cinogenicity, and no more side effects than placebo at usual in tonics for thousands of years. Now it is added to many com-
dosages. In fact, black cohosh augmented the antiproliferative bination products. Evidence of estrogenicity includes strong
activity of tamoxifen in vitro (Fackleman, 1998; Foster, 1999; binding to estrogen receptors in vitro, stimulation of uterine
Lieberman, 1998). Although stimulation of some uterine growth in ovariectomized rats, and induction of progester-
growth in ovariectomized rats had been reported, in a multi- one secretion (Belford-Courtney, 1993). The water-soluble
national study of 400 postmenopausal women given 40 mg/ extract regulates uterine contractions, while the essential oil
day black cohosh (Cimicifuga racemosa BNO 1055) for 52 relaxes uterine muscles. One DBRPC trial of dong quai as a
weeks, there were no cases of endometrial hyperplasia. The monotherapy found no benefits for menopause (Hirata etal.,
number and intensity of hot flushes was markedly reduced 1997). The use of dong quai for perimenopausal symptoms,
and the herb was well tolerated (Raus, Brucker, Gorkow, & especially in women with breast cancer may entail some risks
Wuttke, 2006). Several controlled studies, including one due to estrogen agonist effects. Considering the lack of evi-
DBRPC study, showed efficacy equivalent to estrogen replace- dence for effectiveness and the well-documented risks, the use
ment therapy (Foster, 1999; Lieberman,1998). of dong quai is not recommended.
Studies of black cohosh have yielded inconsistent
results. For example, a DBRPC 12-week study assigned Vitex (Vitex agnus castus)
62 postmenopausal women to Cimicifuga racemosa extract Vitex from chaste tree berry, often used to relieve symp-
(CR BNO 1055), the equivalent of 40 mg/day of the toms in premenstrual syndrome, modulates prolactin secre-
raw herb; conjugated estrogens (0.6 mg/day); or placebo. tion and binds to dopamine receptors. Vitex slightly binds to
Women in the groups receiving conjugated estrogens or estrogen receptors in vitro and modestly stimulates uterine
black cohosh extract had better sleep quality and fewer growth in ovariectomized rats. Although vitex has not been
menopausal symptoms than those taking placebo. Both studied in menopause, anecdotal reports suggest beneficial
CR BNO 1055 and conjugated estrogens increased vaginal effects for hot flushes, fluid retention, and weight gain. It
superficial cells; CR BNO 1055 had no effect on endome- has been used to treat hyperprolactinemia (Wuttke, Jarry,
trial thickness, which was significantly increased by con- Christoffel, Spengler, & Seidlova-Wuttke, 2003). One of
jugated estrogens (Wuttke, Seidlova-Wuttke, & Gorkow, the authors (RPB) finds vitex to effectively counteract eleva-
2003). In contrast, a one-year DBRPC study of 351 women tions in prolactin levels induced by antipsychotic medications
(ages 4555years) found no difference between frequency without interfering with antipsychotic effects. Vitex has been
or intensity of vasomotor symptoms in those given a dif- shown to be safe in studies lasting up to 18months. Infrequent
ferent herbal preparation of 160 mg/day black cohosh side effects include gastrointestinal upset, headache, diarrhea,
(Pure World, Inc. Cimicifuga racemosa; 2.5% triterpine nausea, itching, urticaria, rash, acne, insomnia, weight gain,
glycosides; 70% ethanol extract) versus placebo (Newton and irregular menstrual bleeding. It may be unsafe during
et al., 2006). This study was limited to women in late pregnancy.
menopausal transition or postmenopause. Although this
study concluded that black cohosh is unlikely to have an
important role in the treatment of vasomotor symptoms, A DA P TO G E NS A N D H E R B S
the findings may not be generalizable because in late W I T HA DA P TO G E N IC PROPE RT I E S
menopause hot flushes usually subside within a year, the FORM E NOPAUS E
length of thestudy. Rhodiola, Arctic Root, Golden Root, Roseroot
Differences in the outcomes of DBRPCs may be due to (RhodiolaRosea)
differences in herbal preparations, patient selection criteria,
length of study, and symptom measurements. Levels of bio- Rhodiola rosea has been used for centuries in Russia, Asia,
active compounds can be significantly affected by extrac- Eastern Europe, and Scandinavia to enhance fertility and sex-
tion procedures. A major problem in assessing this research ual function in people living at high altitudes, where it grows
is that studies using proprietary components may not reveal naturally in cold climates. The authors (PLG) found evidence
the process that makes their product special. This leaves for the use of R.rosea in an epic poem dating back to Bronze
open the question of whether the difference in outcomes of Age Greece (Brown & Gerbarg,2004).
studies using BNO 1055 versus other brands could be due to In an open study of 40 women with primary and sec-
significant differences in the quality and efficacy of the prod- ondary amenorrhea given R. rosea extract 100 mg twice
ucts or to other factors. Nonetheless, given the excellent safety daily, normal menstrual cycles were restored and uterine
profile of black cohosh, it could be recommended for relief length increased to normal size in 25 women. Of these, 11
of menopausal symptoms in women who do not want or do became pregnant (Gerasimova, 1970). Dr. Patricia Eagon at
not respond well to conventional treatments such as SSRIs, the University of Pittsburgh discovered that R. rosea showed
SNRIs, or synthetic SERMs. Compared to synthetic SERMs, strong estrogen receptor binding in vitro, but it did not
black cohosh reduces menopausal symptoms without stimu- activate estrogen receptors, elevate circulating estradiol lev-
lating uterine estrogen receptors, has fewer side effects, and els, nor increase uterine size in ovariectomized rats (Eagon
provides additional health benefits. et al., 2003). These findings indicate that R. rosea could
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 581
also be considered to contain selective estrogen receptor on mood, menopausal symptoms, attention, or memory
modulator(s). Of note, Eagon also found that when ovari- (Hartley, Elsabagh, & File,2004).
ectomized rats given estrogen implants (which elevate cir-
culating estradiol to levels above normal) were fed R. rosea, Lepidium peruvianum Chacon, formerly
the excess estradiol levels decreased toward normal. This Lepidium meyenii(Maca)
is an example of the normalizing effect of adaptogens. The
discrepancy between the lack of estrogenicity in the Eagon In the Andean region of Peru, people living in the mountains
study versus Gerasimovas observations is most likely due traditionally use maca to enhance fertility in humans and in
to differences in the method of preparation and/or route of livestock, particularly at high altitudes (see section on Herbs
administration. Gerasimova administered the herb intraperi- for Female Sexual Function). Asystematic review found four
toneally. Dr. Eagon fed the animals a proprietary Rhodiola RCTs showing positive benefits for menopausal symptoms.
rosea product, Rosavin (Ameriden International) that is used Due to the small sample size and mixed quality of methodolo-
in humans. Digestion and metabolism of the orally ingested gies, no firm conclusions were drawn (Lee, Shin, Yang, Lim, &
herb alters the properties of constituents. Other differences Ernst, 2011). Estrogenic effects are a contraindication for
were in the source of the herb (wild-grown versus cultivated) use in women with fibroids, breast cancer, or endometriosis.
and extraction procedures. Evidence suggests that R. rosea Effects on long-term cancer risk are unknown.
may exert anticarcinogenic as well as hepatoprotective effects
(see section on Adaptogens in Cancer Treatment). Hypericum perforatum (St. JohnsWort)
In clinical practice, the authors (PLG and RPB) find
that R.rosea can reduce vaginal dryness and improve libido St. Johns wort 900 mg/day given to 111 menopausal women
in many cases. It is be particularly beneficial in menopausal in a 12-week open series significantly improved self-esteem,
women for symptoms of fatigue, forgetfulness, cognitive dys- self-image, irritability, anxiety, and depression. Improvements
function, and depressedmood. not reaching statistical significance were observed in psycho-
Many women who delay childbirth encounter problems somatic symptoms (insomnia, headache, and palpitations),
with infertility. The onset of menopause can range from the vasomotor symptoms (sweating, flushing, and dizziness), and
mid 30s to the late 50s and is generally not predictable.It may sexual desire (Grube, Walper, & Wheatley, 1999). In clinical
be possible for women who delay childbearing past the age practice, the authors find SJW to be mildly helpful in meno-
of 35 to use R.rosea, maca, and vitex to prolong fertility and pause, but the risk of drug interactions and phototoxicity may
possibly delay the onset of menopause. Given a choice, some outweigh the benefits.
women would opt to start R.rosea by age 35 to possibly main-
tain fertility if they find it necessary to delay childbearing.
Studies show that R.rosea enhances cognitive function
Linum usitatissimum (Flaxseed) and Triticum aestivum
(see section on Adaptogens for Cognitive Dysfunction).
or vulgaris (Wheatgerm)
Although no specific studies have been done on perimeno- Flaxseed and wheat germ have been used to relieve hot flushes
pausal women, the authors (PLG and RPB) have found in and night sweats. A DBRPC trial comparing flaxseed to
more than 100 cases that it is particularly helpful in improv- wheat germ in menopausal women found them equally help-
ing memory, mental clarity, cognitive speed, energy, and ful in relieving hot flushes, but neither improved bone mineral
mood in women before, during, and after menopause. These density or lipid profile (Dodin etal., 2005). Flaxseed is rich in
clinical observations should be extended through research lignans which have weak estrogenic and weak anti-estrogenic
on the mechanisms of action and clinical applications of effects. Lignans and their metabolites increase serum estro-
R. rosea in treating perimenopausal decline in memory gens by stimulating synthesis of sex hormone binding globu-
and cognitive functions, as well as other hormone-related lin (SHBG), which reduces clearance of circulating estrogens.
conditions. Lignans also bind to estrogen receptors, act as SERMs, and the-
oretically could impede tumor genesis (Bedell, Nachtigall, &
Ginkgo biloba and Panax ginseng (Ginkgo and Naftolin,2012).
Asian Ginseng)
Trials of G. biloba for fatigue and cognitive decline in HOR MON A L T R E AT M E N T S FORF E M A L E
menopause have had mixed results. In a 6-week DBRPC M E NOPAUS E
study of G. biloba in postmenopausal women, those in Dehydroepiandrosterone (DHEA),
Stage +1 (mean age 55) performed better than those in dehydroepiandrosterone sulfate (DHEAS) and
Stage +2 (mean age 61)at baseline on tests of memory and 7-ketoDHEA
cognitive function. After 6 weeks, in the ginkgo group
the only clear benefit was greater mental flexibility among The authors have found that patients whose DHEA and/
Stage +2 women (Elsabagh, Hartley, & File, 2005). In a or DHEAS levels are low normal or below normal for age
12-week DBRPC study, 57 postmenopausal women (aged (particularly menopausal women) often respond to treat-
5166 years) were given G. biloba 120 mg plus P. ginseng ment with DHEA 2575 mg/day with enhanced mood,
200 mg or placebo. No significant effects were found cognitive function, memory, energy, and sexual function
582 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
(see discussion of DHEA in the sections Hormones In addition to dietary improvements, exercise, sleep
for Treatment of Cognitive Dysfunction, Menopause, hygiene, and stress reduction, the following integrative treat-
Andropause, and Sexual Function). Astarting daily morning ments can be considered for specific target symptoms. Each
dose of DHEA 25 mg and a maintenance dose of 50 mg each treatment can be added to the others sequentially for stronger
morning are generally sufficient for menopausal symptoms. synergistic effects.
Side effects are usually minimal and include activation, anxi-
ety, agitation, and occasionally seborrhea. DHEA, DHEAS, 1. Hot flushes:black cohosh.
and total and free testosterone levels should be checked before
treatment. If testosterone is low, DHEA may modestly increase 2. Vaginal dryness, dyspareunia:intravaginal DHEA as an
levels enough to alleviate cognitive and sexual dysfunction but alternative to estrogen cream, DHEA, R.rosea.
not enough to correct androgen deficiency states. However, 3. Hot flushes with cognitive/memory impairment and low
treatment with testosterone resulting in higher testosterone energy:black cohosh plus R.rosea.
levels may increase long-term risk of breast cancer. Therefore,
in comparison to treatment with testosterone DHEA may pro- 4. Primarily complaints of cognition/memory
vide a more modest but safer elevation of testosterone into the decline:R.rosea and/or DHEA or 7-keto DHEA (in
low normal range, enhancing DHEAS and sexual function. women with low DHEA or DHEAS).
Because there are no clear data on DHEA and long-term risk 5. Low energy, fatigue:R.rosea.
of breast cancer, DHEA is relatively contraindicated in women
with a personal or family history of breast cancer. In such cases 6. Sexual dysfunction:
7-keto DHEA would be preferable, as it does not convert to a. low libido:maca, R.rosea, P.ginseng, marapuama,
testosterone, estrogen, or progesterone. DHEA, 7-ketoDHEA
Intravaginal DHEA is a promising treatment for sex- b. problems of arousal, sensation or orgasm:R.rosea,
ual function (Tan, Bradshaw, & Carr, 2012). In a 12-week maca, P.ginseng, L-arginine, DHEA, 7-ketoDHEA
DBRPC Phase II trial, 216 postmenopausal women were 7. Mood changes or depression:DHEA, 7-keto DHEA,
randomized to four groups. Each group was instructed to R.rosea.
insert at bedtime a different concentration of DHEA:0 mg,
3.25 mg, 6.5 mg, or 13 mg. Sexual function showed signifi- 8. Pervasive complaints (hot flushes, cognitive, memory, low
cant time-dependent and dose-dependent improvements in energy, sexual dysfunction) in women with low DHEA or
desire, arousal/sensation, arousal/lubrication, orgasm, and DHEAS (lower quartile or subnormal), a trial of DHEA
dryness during intercourse. The doses of DHEA were low or 7-keto DHEA with cognitive enhancers is often helpful.
enough that serum steroids stayed within normal postmeno-
pausal range. Unlike estrogens, which only affect superficial F E M A L E S E X UA L E N H A NC E M E N T
epithelial cells, the DHEA transforms into androgens and/or
estrogens locally and appears to affect cells in all three layers Sexual function in women can be affected by psychological
of the vagina (epithelium, lamina propria, and muscularis) or physical stressors, age-related hormonal changes, relation-
(Labrie et al., 2009). Long-term trials are needed to verify ship issues, medical illnesses, or medications. In many cul-
safety. tures potions from plants and animal parts have been used
for centuries as aphrodisiacs. Scientific evidence for improve-
ment in sexual function using herbs and nutrients is limited.
INTE G RATI V E A PPROACH Nevertheless, products promising sexual enhancement are
FOR M ENOPAUSE-RELATED DISORDERS sold widely. Possible mechanisms of action include vasodila-
tion, improved circulation, antiinflammatory, antioxidant,
Evaluating patients who might benefit from integrative treat- hormonal, stimulant, and mood enhancement (Rowland &
ments begins with obtaining the personal and family history Tai, 2003). This discussion is limited to sexual enhancers for
regarding menstruation, menopause, cancer, and cancer risk which there is some research evidence, frequent consumer use,
factors to identify contraindications for hormonal, phytoes- and/or positive clinical experience. Herbs and nutrients can
trogen, or other herbal treatments. Target symptoms of con- be helpful adjuncts to standard treatments including psycho-
cern to the patient may include hot flushes, vaginal dryness, therapy, pharmacotherapy, couples counseling, sex therapy,
dyspareunia, sexual dysfunction, insomnia, cognitive impair- and life style changes to improve physical fitness and to reduce
ment, memory decline, fatigue, low energy, or mood changes. stress, fatigue, and substanceabuse.
If the history reveals insomnia, daytime fatigue, snoring, gaps
in breathing, leg movements at night, or uncomfortable leg Herbs forFemale Sexual Function
sensations relieved by walking, a sleep evaluation (often fol-
lowed by polysomnography) is indicated to rule out sleep
apnea and restless leg syndrome. Appropriate laboratory test- Panax ginseng (Asian or Korean Ginseng)
ing of hormone levels includes FSH, LH, estrogens, proges-
terone, DHEA, DHEAS, free testosterone, total testosterone, In a DBRPC trial, 32 postmenopausal women aged 4060
thyroid functions, and possibly prolactin. years who had no menses for 1 year were given 1 g Korean
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 583
red ginseng three times daily or placebo. Twenty-eight out of Crocus sativus (Saffron)
32 reported improved sexual arousal with ginseng compared The ability of saffron to reverse SSRI-induced sexual dys-
to placebo. Two cases of vaginal bleeding were reported (Oh function was evaluated in a DBRPC study of 38 women (ages
et al., 2010). Infrequent side effects include insomnia, amen- 1845years) with major depressive disorder who had responded
orrhea, pruritus, headache, and vertigo. Human studies sug- to fluoxetine 40 mg/day with at least 50% improvement in
gest that ginseng does not affect platelet aggregation. Because depression. All of the women continued fluoxetine 40 mg/day.
ginseng may have hypoglycemic effects, insulin-dependent Those who were also given saffron 15 mg twice daily had signif-
patients may require dose reductions when taking ginseng icantly greater improvements in sexual arousal on the Female
(Natural Medicines Database, 2010, pp. 780781). Sexual Function Inventory, lubrication, and reduction in pain
with intercourse. The reduction in pain may be attributed to
antinocioceptive effects of saffron (Kashani etal.,2012).
Lepidium peruvianum Chacon, Lepidium myenii(Maca)
Maca is a Peruvian adaptogen used to improve energy,
sexual function, fertility at high altitudes, stress tolerance, Nutrients and Combination Formulas forFemale Sexual
nutritional status, and menopausal symptoms; it contains Function
sterols, glucosinolates, and alkaloid components. Increased
FSH, estrogen, and testosterone levels were noted in female L-Arginine (2-amino-5-guanidinopentanoicacid)
rats given doses far in excess of those used clinically (Quiros L-arginine is the precursor to nitric oxide (NO), which is
& Cardenas, 1997; Chacon, 1997). These effects have not involved in vasodilation of genitalia during sexual arousal.
been found to occur in humans using clinical doses. An Arginine in combination products has been used to enhance
aqueous extract of yellow maca increased litter size in sexual dysfunction in women. A multi-herb supplement,
female mice and increased uterine weight in ovariectomized ArginMax comes in two gender-specific forms. Arginmax for
rodents, evidence of estrogenic effects (Ruiz-Luna et al., Women contains L-arginine, P.ginseng, G.biloba, damiana leaf
2005). These findings cannot be extrapolated to humans (Turnera diffusa), multiple B-vitamins, folic acid, vitamins A,
without further clinical trials. Excess doses may cause over- C, and E, calcium, iron, and zinc. Damiana is considered safe in
activation or breast tenderness. Maca should not be used medicinal doses, but excess amounts may have adverse effects.
in patients with fibroids, estrogen receptorrelated cancer In a 4-week DBRPC study of 77 women, 73.5% of the
risk, family history of breast cancer, or endometriosis. No subjects taking ArginMax reported improvements in their
behavioral toxicity has been reported in human or animal sex lives, including improved desire, vaginal lubrication, fre-
studies. However, the authors find that maca may precipi- quency of intercourse and orgasm, and clitoral sensation, ver-
tate agitation or mania in bipolar patients. Therefore, it sus 37.2% of those on placebo. ArginMax had no significant
should be used cautiously and in lower doses in cases of side effects (Ito, Trant, & Polan, 2001). In a 4-week DBRPC
bipolar disorder. In clinical practice, the authors (RPB and trial, ArginMax for Women was studied in108 women (aged
PLG) find that monotherapy with a good quality brand of 2273years) who had reported lack of sexual desire. Among
maca at doses between 3000 and 6000 mg/day can help the premenopausal subjects, those taking ArginMax reported
many men and women improve libido, arousal, sensation, significant improvements in sexual desire, frequency of inter-
and orgasm. The effects may be mild, moderate, or strong. course, and satisfaction with sex life compared with the
Maca can be useful in treating sexual dysfunction due to placebo group. Perimenopausal women reported improve-
medical illness or medications (SSRI, SNRI, or antipsy- ments in frequency of intercourse, less vaginal dryness, and
chotics). In a DBRCT in subjects (intent-to-treat n = 16) greater satisfaction with their sexual relationships compared
with SSRI-induced sexual dysfunction, 3.0 g/day of maca with the placebo group. Postmenopausal women showed an
significantly improved libido (p < 0.05) on the Arizona increased level of sexual desire (51%) compared with placebo
Sexual Scale and the Massachusetts General Hospital (8%). Anecdotally, the authors find ArginMax to be benefi-
Function Questionnaire (Dording et al., 2008). The ben- cial for sexual dysfunction secondary to medical illness or
efits can be augmented with R.rosea, P.ginseng, and occa- medications. This study highlights two important issues.
sionally Epimidium sagitatum (see below). First, the effects of herbal treatments can vary with hormonal
status. Second, combinations of synergistic herbs and other
Ptychopetalium olacoides or Uncinatum guyanna nutrients can be more effective than monotherapies.
(Muira puama or Marapuama) In vitro studies of ArginMax have not shown estrogenic
Marapuama, from the rain forests of Brazil, is used as an activity (Ito, Polan, Whipple, & Trant, 2006). Infrequent
aphrodisiac, nerve tonic, and antiarthritic (Mowrey, 1996). side effects included abdominal pain, bloating, gout, allergic
An open trial in 202 healthy women complaining of low sex response, or exacerbation of airway inflammation in asthma
drive found that after 1 month of taking marapuama com- (Jellin et al., 2010). There have been no long-term toxicity
bined with G. biloba 65% reported improvements in libido, studies. The balance of L-arginine and lysine affects replica-
intercourse, sexual satisfaction, intensity of orgasm, and other tion of herpes virus. In practice, the authors (RPB and PLG)
measures (Waynberg & Brewer, 2000). Mechanisms of action, have seen outbreaks of oral-buccal herpes in patients who take
side effects, and drug interactions have not been studied. L-arginine or ArginMax. This can be prevented or treated by
Controlled studies with objective measures are needed. the addition of lysine tablets and/or lipbalm.
584 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
Hormones forFemale Sexual Function While standard treatments for sexual performance (e.g.,
phosphodiesterase-5 inhibitors) can be helpful in many cases,
Dehydroepiandrosterone (DHEA) forSexual conventional treatments for loss of libido are more limited.
Arousal Herbs and nutrients for treatment of sexual dysfunction will
A double-blind randomized crossover study of 16 post- be discussed first, followed by treatments for benign prostatic
menopausal sexually active women showed that a single oral hypertrophy.
dose of 300 mg DHEA taken 60 minutes before viewing
an erotic video increased subjective ratings of physical (p <
0.036) and mental (p < 0.016) arousal compared to placebo Erectile Dysfunction
(Hackbert & Heiman, 2002). The possible risks of intermit-
Erectile dysfunction (ED) is the most frequent among male
tent use of relatively high-dose DHEA for sexual enhance-
sexual function disorders. Although 60%70% of men
ment compared with the risks of testosterone or other
respond to phosphodiesterase-5 inhibitors such as sildenafil
treatments has not been studied.
with improved erectile function, many cannot tolerate side
effects such as headache, gastrointestinal upset, and nasal
Integrative Approach toSexual Dysfunction inWomen congestion. Rare side effects include anterior ischemic optic
neuropathy and deafness. Serious risks with this class of drugs
1. History and physical examination. involve interactions with nitrates, pulmonary hypertension,
2. Rule out medical conditions that could affect sexual func- rarely anterior ischemic optic neuropathy, and deafness, espe-
tion. Also, evaluate for iatrogenic factors such as medica- cially with long-acting phosphodiesterase-5 inhibitors such as
tions that may impair libido, arousal, and/or orgasm, tadalafil (Cialis).
such as birth control pills or other hormonal products,
antidepressants (particularly SSRIs, venlafaxine), antipsy- Herbs forMale Sexual Function
chotics, blood pressure medications, and over-the-counter
preparations. Panax ginseng (Asian or Korean ginseng)
Panax ginseng is a sexual stimulant often found in herbal
3. Evaluate psychological, emotional, and relationship fac- preparations. It has been shown to increase nitric oxide syn-
tors contributing to sexual dysfunction. thesis, sperm count, testicular weight, testosterone level, and
4. Obtain the following laboratory studies:DHEA, DHEAS, mating counts in animal studies (Kang, Kim, Schini, & Kim,
free testosterone, total testosterone, and prolactin. DHEA 1995). P. ginseng 300 mg/day improved sexual performance
or DHEAS levels in the lower quartile may be worth more than placebo in a 3-month controlled study of 60 men
treating in patients with sexual dysfunction or depression. (Choi, Seong, & Rha, 1995). In an 8-week DBRPC study 143
Increased levels of prolactinnot uncommon in patients men with ED were given 1000 mg twice daily P. ginseng).
taking antipsychotics or SSRIsare often missed. Among the 86 completers, the ginseng extract significantly
improved libido, erectile function, and orgasmic function
5. If stress or lack of sleep are significant causative factors, compared to placebo. Insignificant changes in testosterone
then advise life style changes and mind-body practices levels were found in the ginseng group. Levels of FSH, LH,
such as yoga breathing, yoga postures, meditation, and prolactin, and estradiol did not change significantly (Kim et
exercise. al., 2009). There have been anecdotal reports of hypersexual
6. For lack of libido in women, try maca, R.rosea, Herbal-vX behavior induced by ginseng. Further studies are needed.
(Muira puama + ginkgo), orDHEA.
Ginkgo biloba (Ginkgo)
7. For problems with arousal or orgasm, suggest ArginMax, Ginkgo increases blood flow to the brain and genitalia.
maca, R.rosea, DHEA or 7-keto-DHEA. These treat- In an open 6-month nonblinded study of 50 men with ED
ments can be layered for combined effects. with antidepressant-induced sexual dysfunction, ginkgo
(EGb761) was reported to improve erectile function (Sohn
M A L E S E X UA L F U NC T ION A N D A N DROPAUS E
& Sikora, 1991). These studies suffered from poor methodol-
ogy. Furthermore, studies of treatments for sexual dysfunc-
Physical or psychological stress, anxiety, depression, fatigue, tion tend to have high rates of placebo response. An 8-week
poor nutrition, substance abuse, low hormone levels, envi- DBRPC study (n=37) of antidepressant-induced sexual dys-
ronmental toxins, alcohol abuse, medical conditions (e.g., function found no difference between G.biloba and placebo
benign prostatic hypertrophy, hypertension, and vascular (Kang, Lee, Kim, & Cho, 2002). Limited evidence supports
disease), and medications such as nonthiazide diuretics, ben- benefits of ginkgo monotherapy for mild symptoms of impo-
zodiazepines, antidepressants (particularly SSRIs and venla- tence in middle-aged men, but not for problems with libido or
faxine) can adversely affect sexual function in men. Although orgasm, when givenalone.
low libido, disorders of arousal, premature ejaculation, and
inability to climax can occur at any age, these problems tend Maca (Lepidium myenii)
to worsen after age 45 during andropause when changes in Peruvians living at high altitudes where maca (Lepidium
hormone levels and prostatic enlargement are occurring. myenii) grows have used it for centuries to enhance sexual
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 585
function and fertility. In reviewing maca research, Gonzales teratogenicity, effects on fertility, or other adverse effects
noted that, in rodent studies, black maca increased testoster- in dogs given 150 mg/kg. Among 2,000 patients, a 1.5%
one levels and spermatogenesis, prevented high-altitude sper- incidence of minor side effects was reported including gas-
matogenic disruption, and improved sexual performance in trointestinal disturbance, dizziness, nausea, and headache
normal rats and in those with erectile dysfunction (Gonzales, (Rohdewald, 2002). Evidence suggests that pycnogenol may
2012). One small study (n = 9) of normal men found that impart long-term health benefits, including antioxidant, anti-
4 months of taking maca resulted in increased seminal vol- inflammatory, antihypertensive, and cognitive enhancement.
ume, sperm count, and sperm motility. Serum hormone lev-
els were not changed by maca. Larger studies are needed to
Combination Formulas forMale Sexual Function
confirm long-term safety and efficacy (Gonzales etal., 2001).
In a 12-week DBRPC trial of two different maca doses (1500 Arginine and ArginMax forMen
mg or 3000 mg/day), among the 57 men taking maca 40% ArginMax for Men contains L-arginine, P. ginseng,
reported significant improvements in self-perception of ginkgo, and 13 vitamins and minerals. L-Arginine is a precur-
sexual desire at week 8 and 42.2% at week 12 compared to sor to nitric oxide (NO). The NO signaling pathway affects
0.0% in the placebo group. Nine men who were treated with specific sexual dysfunctions. In a small DBRPC study of
maca in this study were selected for additional testing, which 50 men with ED, L-arginine monotherapy resulted in 9/29
showed no increases in serum testosterone, LH, FSH, prolac- responders versus 2/17 on placebo. All nine responders had
tin, or estradiol, and no change in ratings for depression (or reduced NO excretion or production at baseline (Chen etal.,
anxiety. Aweakness in this study was that the assessment of 1999). A 2-week DBRPC crossover study of 45 men with
sexual desire was based on one question only with a scale of ED compared a combination of L-arginine glutamate 6 gm/
05 (Gonzales etal., 2002). It would be worthwhile to rep- day plus yohimbine 6 mg/day; yohimbine 6 mg/day alone;
licate these findings using additional validated assessments and placebo taken 12 hours prior to sexual intercourse. At
of desire. No major side effects have been reported in human the end of each treatment period, erectile function domain
or animal studies. Excess doses may cause overactivation. scores for L-arginine plus yohimbine, yohimbine alone,
Prostate cancer may be a contraindication to the use ofmaca. and placebo were 17.2+/-7.17, 15.4+/-6.49 and 14.1+/-
6.56, respectively. The difference between L-arginine plus
Ptychopetalium olacoides or Ptychopetalium unicatum yohimbine versus placebo reached statistical significance
(Muira Puama or Marpuama) and Ptychopetali (p = 0.006). Stratification according to baseline scores above
lignum (Muira Puama Wood) 14 indicated that patients with mild to moderate ED had bet-
Extracts from the bark and roots of small trees in ter erectile function domain responses to both treatments
the Amazon rainforest, Ptychopetalium olacoides or compared to placebo (Lebret, Herve, Gorny, Worcel, &
Ptychopetalium unicatum, are used to make an aphrodisiac Botto,2002).
called muira puama. Prelox is a proprietary blend containing 720 mg total of
In an open study of 262 men complaining of lack of sexual L-arginine HCl, aspartic acid, pycnogenol, and 50 mg of
desire and impotence who were treated with muira puama Epimedium sagittatum extract standardized to 60.0% (30
1500 mg/day for 2 weeks, 62% reported enhanced libido and mg) icariin. E. sagittatum is used in traditional Chinese medi-
51% reported better erections (Waynberg, 1990). Controlled cine to prolong male sexual response. A DBRPC study of 50
studies with objective measures are needed to confirm these men with mild to moderate ED found that those given Prelox
findings. The authors (RPB and PLG) observe that some more than doubled the mean number of intercourse events
patients report significant improvement in sexual desire and significantly increased testosterone levels. Systolic and
and satisfaction with muira puama, whereas most have no diastolic blood pressure both declined. No adverse effects were
response. Side effects tend to bemild. observed. The onset of action required 19 days (Stanislova,
Nikolova, & Rohdewald, 2008). In a 6-month DBRPC study
Pinus maritime (French Maritime Pine Bark, of 124 men ages 3050 years with moderate ED and normal
Pycnogenol) baseline testosterone levels, Prelox significantly improved ED
A standardized extract of Pinus maritime called pycno- and testosterone levels compared to placebo (Ledda, Belcaro,
genol inhibits cyclo-oxygenase and reduces prostaglandin Cesarone, Dugall, & Schonlau, 2010). For a discussion of side
production and inflammation. When combined with the effects see Nutrients and Combination Formulas for Female
substrate L-arginine, pycnogenol increases production of Sexual Function. In most studies and in clinical practice,
NO by nitric oxide synthase, relaxing the cavernous smooth L-arginine is effective when combined with other herbs.
muscle that is necessary for penile erection. A3-month open
study of men with ED compared L-arginine (1.7 g/day) with Yohimbine (Pausinystalia yohimbe or Corynanthe
L-arginine (1.7 g/day) plus pycnogenol (40 mg twice daily for johimbe)
2months, then 40 mg three times daily for the third month). Yohimbine, extracted from the bark of a tropical African
Of the men given the combination, 92.5% reported normal tree (P. yohimbe), contains an alkaloid chemically similar
erections (Stanislavov & Nikolova, 2003). The lack of placebo to reserpine. Yohimbine inhibits adrenergic receptors that
control or objective documentation of erectile function limits innervate the genitals. A meta-analysis of seven well-done
the import of this study. Pycnogenol showed no mutagenicity, DBPC studies surmised that 1543 mg/day yohimbine
586 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
alleviated ED more effectively than placebo in 40% of men Modenini, & Biagiotti, 2004). Evidence suggests that carni-
with sexual dysfunction (Ernst & Pittler, 1998). Higher tines can enhance the response to sildenafil.
quality prescription yohimbine is preferable in 5.4 mg pills,
with a usual dose of 1842 mg/day. Over-the-counter prod-
ucts account for 98% of reported side effects and these often Prostatic Enlargement and Sexual Dysfunction
contain only negligible amounts of yohimbine (Betz, White, Pygeum (Pygeum africanum), Saw Palmetto (Serenoa
& der Marderosian, 1995). Some patients, for example the repens), and Stinging Nettle Root (Urtica dioica)
elderly, are unable to tolerate yohimbine side effects such Prostatic enlargement is a common factor in sexual dys-
as anxiety, nausea, dizziness, chills, sweating, headache, function in middle and late life. Free testosterone declines,
insomnia, and, at higher doses, increased blood pressure. and the prostate is stimulated by increasing levels of estradiol,
Yohimbine can exacerbate symptoms in patients with anxi- prolactin, SHBG, and dihydrotestosterone. Reducing the size
ety, panic, obsessive compulsive disorder, or posttraumatic of an enlarged prostate sometimes improves sexual function.
stress disorder. Treatments for benign prostatic hypertrophy (BPH) include
Epimidium sagittatum (Horny Goat Weed) finasteride, alpha-adrenergic blockers (terazosin, doxazosin,
Epimidium sagittatum contains the phystoestro- or tamsulosin), and surgery. Surgical procedures are expen-
gens icariin, genistein, and daidzein. Icariin inhibits sive and may exacerbate sexual dysfunction. Alpha adrenergic
phosphodiesterase-5 and enhances cGMP in cells of cavern- blockers can cause tiredness, dizziness, depression, headache,
ous smooth muscle. It is used in traditional Chinese medicine abnormal ejaculation, and rhinitis (Medical Letter, 1997).
to prolong male sexual response. In vitro and animal studies Reduction of BPH has been reported for three herbs: saw
of icariin and of herbal products containing E. sagittatum palmetto (Serenoa repens), pygeum (Pygeum africanum), and
show no serious adverse effects and stronger phosphodiester- stinging nettle root (Urtica dioica). Recent studies and sys-
ase inhibition than sildenafil (Ning et al., 2006). However, tematic reviews of saw palmetto find no evidence to support
human safety and efficacy trials are needed. The authors use its use for sexual dysfunction related to BPH (Barry et al.,
E.sagittatum occasionally to augment otherherbs. 2011; Tacklind, Macdonald, Rutks, Stanke, & Wilt,2012).
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 587
options. Phytomedicines can either interfere with or enhance significant HDIs in humans. The gastrointestinal digestion,
the benefits of synthetic drugs such as psychotropics, antico- absorption, and metabolism of herbal constituents alter their
agulants, or chemotherapy agents. Among the herbs discussed properties and, therefore, their effects in living organisms as
in this chapter, only a few pose clinically significant risks of opposed to tissue cultures. Potential risks can be minimized
HDIs. Assessing the likelihood of HDIs and methods to by systematic monitoring for efficacy, side effects, and serum
minimize or obviate risks will be highlighted before address- levels of medications that have a low therapeutic index (a small
ing specific herbs. Understanding these issues will enable cli- margin of safety between therapeutic and toxic effects or
nicians to take advantage of the therapeutic contribution of between therapeutic and subtherapeutic benefits) and mean-
phytomedicines while avoiding adverse effects. ingful serum levels. Herbs that have demonstrated, verified,
serious HDIs in humans should not be used in combination
with those specific medications. For extensive reviews show-
PH A R M AC OK I N E T IC A N D
ing the level of the evidence on HDIs, including whether the
PH A R M AC ODY N A M IC I N T E R AC T IONS
study is based on in vitro, in vivo, animal, or human trials, see
The two main aspects of pharmacokinetic interactions that Kennedy and Seely (2010). In his highly recommended book,
can affect medication serum levels are the induction or Herbal Contraindications and Drug Interactions, Francis
inhibition of cytochrome P450 (CYP) isozymes and p-gly- Brinker not only provides extensive details on HDIs and
coproteins. Pharmacodynamic interactions include risks of the evidence sources but also differentiates herbal effects on
increased CNS side effects (e.g., serotonin syndrome), hepato- each of three phases of metabolism:Phase I, CYP450 system
toxicity, or bleeding. Additive effects such as excess sedation of isozymes; Phase II, conjugating enzymes; and phase III,
or activation can occur in the absence of pharmacokinetic or transporter proteins (Brinker,2010).
pharmacodynamic interactions. In a systematic review of 21 Phytomedicines can potentially enhance the effective-
whole herb extracts (not isolated constituents) with human- ness of chemotherapy agents and reduce chemotoxic effects.
level evidence regarding HDIs, Kennedy and Seely (2010) Studies of human tumors in animals with metabolizing
acknowledge the limitations of the information about poten- enzyme systems similar to humans would clarify when to
tial HDIs. When isolated, the concentration of a constituent use and when to avoid herbals in patients undergoing cancer
far exceeds that which occurs in the whole herb extract. This treatments. To date most cancer-related studies have been
review made several important points. done in cell cultures or in rodents whose enzyme systems dif-
fer too much from human systems to permit extrapolation of
1. Many herbdrug combinations that had preclinical evi- results. However, clinical studies are appearing that will take
dence of drug interaction in vitro and in animal studies into account the digestive and metabolic factors as well as
showed no evidence of interaction in humans. tissue-specific and tumor-specific effects. Overall, the avail-
able evidence indicates potential for highly significant ben-
2. For most of the herbs that had evidence of drug interac- efits of phytomedicinals in cancer treatment.
tion in preclinical studies, the actual effect on serum
levels of medications is quite small and of no clinical
significance. Actea racemosa (Black Cohosh)
3. Caution is most needed when combining herbs with Human studies of black cohosh demonstrate no impact
drugs that have a narrow therapeutic window such as on CYP3A4, CYP1A2, CYP2E1, or digoxin pharmaco-
warfarin or digoxin. kinetics. At doses above therapeutic level, there was weak,
insignificant inhibition of CYP2D6. In vitro studies of
4. The effects of whole herbs or whole herbal extracts are estrogen-responsive breast cancer cells showed that black
often different from those of single isolated constituents. cohosh enhanced the antiproliferative activity of tamoxifen
5. The impact of a botanical extract on the CYP450 metab- (Kennedy & Seely,2010).
olism of one drug does not necessarily generalize to other
drugs that are processed by the same isoenzyme because Curcuma longa or Curcuma domestica (Curcumin)
they may have different binding affinities. The affinity of
the botanical extract could be stronger for one drug but No adverse interactions with drugs have been reported. In vitro
weaker for another. and animal studies indicate that curcumin at high doses (over
15 gms/day) can inhibit platelet aggregation. Curcumin extract
6. The interaction of herbs with many anesthetics and anti- reduced or enhanced antitumor effects of chemotherapy agents
depressants requires further study. and reduced hepatotoxic and cardiotoxic effects in vitro and in
animal studies, depending on the type of cancer (Brinker,2010).
The impact of a botanical extract on CYP450 metabolism
from in vitro and in vivo animal studies is often not seen
in human studies and may merely indicate a need for addi- Angelica sinensis (DongQuai)
tional information. For example, not only phytomedicinals In vitro and animal studies found that water and ethanol
but also common fruits and vegetables consumed in our daily extracts of dong quai increased activity of CYP2D6 and
diet inhibit or induce CYP450 isozymes in vitro but have no
588 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
CYP3A subfamily. Dong quai is not recommended for CYP3A2 by higher than therapeutic doses occurred in an
patients taking chemotherapy medications such as tamoxi- animal study. Diamond and Bailey (2013) concluded that
fen, temsirolimus, and other drugs metabolized by these in therapeutic doses (80 to 720 mg/day in divided doses),
enzymes (Yap, Kuo, Lee, Chui, & Chan, 2010). Individual standardized high quality ginkgo extracts are generally safe
case reports showed that concurrent use of dong quai with but may entail synergistic effects when administered with
warfarin increased prothrombin time and INR (Brinker, anticoagulants such as warfarin or aspirin (Diamond &
2010). Theoretically, antiplatelet/anticoagulant effects of Bailey,2013).
dong quai could increase the risk of bleeding in patients
on anticoagulants. The clinical use of dong quai is not
recommended. Panax ginseng (Asian or Korean Ginseng)
Human studies had shown no impact of P. ginseng on
Camellia sinensis (GreenTea) probe substrates of CYP2D6, CYP3A4, CYP2E1 or
A supplement containing decaffeinated green tea had no CYP1A2. The herb also had no effect of serum levels of
effect on CYP3A4 or CYP2D6. Astudy using drug probes warfarin (Kennedy & Seely, 2010). However, in a more
found no impact on CYP2D6, 1A2, or 2C9. A20% increase recent study, 12 healthy adults were given an oral dose of
in buspirone area under the curve (AUC), indicating some midazolam 8 mg (a CYP3A substrate) and fexofenadine
inhibition of CYP3A4, was deemed not to be clinically sig- 120 mg (probe for P-gp function) before and after tak-
nificant (Kennedy & Seely,2010). ing P.ginseng 500 mg twice daily (Vitamar Laboratories,
5% ginsenocides from whole root powder) for 28 days.
Pharmacokinetic calculations comparing before and after
Eleuthero, Siberian Ginseng (Eleutherococcus senticosus, midazolam serum levels found reductions in AUC of 0.66
Acanthopanax) (0.550.78), half-life of 0.71 (0.530.90), and maximum
Preliminary evidence from in vitro and animal studies of E. concentration of 0.74 (0.560.93). No change occurred in
senticosus suggested possible inhibition of P450 enzymes 1A2, fexofenadine pharmacokinetics (Malati et al., 2012). As
2C9, 2D6, and 3A4. However, human studies of E. senticosus a CYP3A probe, the metabolism of midazolam can vary
show no impact on any of these isozymes and no evidence of significantly depending on CYP3A polymorphisms (Elens
effects on digoxin levels (Kennedy & Seely, 2010). Mild hypo- etal.,2013).
glycemic effects indicate a need to monitor serum blood sugar
of insulin dependent diabetics and adjust the dosage of anti- Panax quinquefolius (American Ginseng)
diabetic medications as needed.
American ginseng extract (1 g q8 hrs for 14 days) had no
effect on the pharmacokinetics of indinavir (800 mg q8 hrs
Zingiber officinale (Ginger) for 3 days) (Andrade et al., 2008). Two weeks of American
Although ginger has exhibited antiinflammatory and anti- ginseng extract 200 mg twice daily did not alter zidovudine
platelet activity, it did not alter clotting states or warfarin pharmacokinetics, but it did reduce oxidative stress mark-
pharmacokinetics at doses of 3.6 gms/day for one week or ers (Lee, Wise, et al., 2008). However, in a 4-week DBRPC
100 mg/kg for 4 days in human trials (Kennedy & Seely, study, 20 healthy subjects were given warfarin 5 mg/day for
2010). Rare cases of increased bleeding have been reported in 3 consecutive days during weeks 1 and 4. After the first week
patients on long-term phenprocoumon. they received either American ginseng 1.0 g/day or placebo
for 3 weeks. The peak INR, peak plasma warfarin level,
and warfarin AUC significantly decreased after 2 weeks of
Ginkgo biloba (Ginkgo) ginseng administration, indicating that American ginseng
In reviewing studies of ginkgo, Diamond and Bailey can reduce the anticoagulant effect of warfarin (Yuan et al.,
(2013) pointed out that flavones, ginkolides Aand B, and 2004).
bilobalide are thought to be involved in antioxidant, meta-
bolic, neurotransmitter, and regulatory actions. Ginkolides
Piper methysticum(Kava)
inhibit platelet anti-activating factor. Although ginkgo
has been shown to reduce blood viscosity and to thereby In vitro studies of the effects of kava extract and kava lac-
increase perfusion in elderly patients and in peripheral tones on human liver microsomes found significant inhibi-
artery disease, it has not shown significant effects on plate- tion of P450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4, and
let aggregation, fibrinogen, partial thromboplastin time, 4A9/11) (Mathews, Etheridge, & Black, 2002)and CYP2E1
or prothrombin time. Case reports of increased bleeding (Gurley et al., 2005) involved in the metabolism of many
include patients on warfarin, aspirin, nonsteroidal antiin- pharmaceuticals. Taking kava with alcohol, sedatives, or
flammatories, and other drugs. Attribution of bleeding to muscle relaxants can induce coma (Almeida & Grimsley,
ginkgo is unsubstantiated in most cases. Reviews of RCTs 1996). Hepatotoxic effects have been reported, particularly
and case reports did not find changes in objective measures when kava is consumed by individuals who regularly drink
of coagulation (Diamond & Bailey, 2013). Induction of alcohol.
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 589
Rhodiola, Arctic Root, Rose Root (Rhodiolarosea) g kg (1), qd 7d) significantly induced CYP2E1, inhib-
ited CYP2D2, and had no effect on CYP2C6, CYP3A1/2,
An in vitro study found that 95% ethanol extracts from CYP1A2 or (Wang, Hu, Sheng, & Li, 2011). In China
R. rosea plants grown in different areas of Norway showed Schisandra sphenanthera is commonly used with tacroli-
inhibition of CYP3A4 and P-glycoprotein (P-gp) in cell cul- mus, an immunosuppressant that reduces organ rejection in
tures (Hellum etal., 2010). There was no correlation between transplant patients. Compared to treatments with tacrolimus
the concentrations of the six marker constituents (which alone, liver transplant patients given both tacrolimus and
were presumed to be active) with these inhibitory effects. The schisandra showed markedly increased serum concentrations
component(s) responsible for in vitro inhibition of CYP3A4 of tacrolimus, improved liver function, and reduced incidence
and P-gp have not been identified. However, as with other of tacrolimus-associated side effects of diarrhea and agitation
herbs, CYP3A4 inhibitory activity in vitro did not trans- (Jiang, Wang, Xu, & Kong,2010).
late to CYP3A4 inhibitory activity in vivo or in humans. In
a rat study, R.rosea (SHR-5) was given with either warfarin
(CYP450 test substrate) or theophylline (CYP1A2 substrate). Hypericum perforatum (St. JohnsWort)
No significant effects on drug pharmacokinetics were found
St. Johns wort extracts induce cytochrome P450 iso-
and there were no significant changes in the anticoagulant
zymes including CYP3A4, 2C19, 2C9, and 1A2, as well
activity of warfarin (Panossian, Hovhannisyan, Abrahamyan,
as intestinal wall p-glycoprotein (P-gp) transporter. Case
Gabrielyan, & Wikman, 2009). The authors (RPB and PLG)
reports and human studies indicate SJW can interfere
have used R. rosea in patients taking many different medi-
with absorption, metabolism, and clinical effectiveness
cations without adverse effects (Brown, Gerbarg, Muskin
of numerous medications including digoxin, warfarin,
2009). One author (RPB) treated one patient on warfarin
phenprocoumon, HIV protease inhibitors, reverse tran-
with R. rosea 150 mg/day and another on warfarin with
scriptase inhibitors, indinavir, irinotecan, theophylline,
R.rosea 300 mg/day. There was no change in INR in either
cyclosporine, alprazolam, amitriptyline, clonazapine, dex-
case. Without information from in vivo and human studies,
tromethorphan, simvastatin, tacrolimus, and oral contra-
it cannot be assumed that R. rosea would interact adversely
ceptives (Knuppel & Linde, 2004; Van Strater & Bogers,
with medications. Nevertheless, the checking of serum lev-
2012). SJW constituents hypericin, hyperforin, and fla-
els (eg. digoxin) and INR (eg. warfarin) would minimize any
vones are used for standardization. The hypericin content
potentialrisks.
is associated with antidepressant effects and hyperforin is
associated with CYP3A4 induction. An excellent review
Serenoa repens (Saw Palmetto) of SJW by Sarris noted that studies using high-dose
hyperforin extracts >10 mg/day induced CYP3A4,
Two studies indicate that saw palmetto does not affect whereas those containing low-dose hyperforin <4 mg/day
CYP3A4, CYP1A2, CYP2D6, or CYP2E1 activity showed no significant effects on CYP3A4 (Sarris, 2013).
(Kennedy & Seely, 2010). A study of 10 adults given saw pal- However, low-dose hyperforin extracts are not clinically
metto for 2 weeks found no increase in coagulation time or effective. SJW should be discontinued 23 weeks prior to
platelet function. One case of intraoperative hemorrhage in surgery because it can affect heart rate and blood pressure
association with saw palmetto use was reported. In vitro stud- during anesthesia.
ies of saw palmetto extracts show inhibition of tamsulosin
binding to alpha1-adrenoceptors. Saw palmetto alpha1-adre-
noceptors antagonism was less than for prazosin in human Valeriana officianalis (Valerian)
trials (Brinker, 2010). Until more studies are completed,
Two studies evaluating valerian did not find any effects
discontinuation of saw palmetto 2 weeks prior to surgery is
on CYP1A2, CYP2E1, CYP2D6, or CYP3A4/5 activity
advised. Given the lack of clinical effect in the most recent
(Kennedy & Seely, 2010). However, in 12 healthy subjects
studies and reviews, it is hard to justify the use of saw pal-
the maximum concentration of alprazolam (CYP3A4 sub-
metto (Tacklind et al., 2012).
strate) at baseline was significantly increased after 14days of
taking 1000 mg nightly of valerian extract (1.1% valerenic
Schizandra chinensis and Schisandra sphenanthera acids), a dose that is greater than the usual clinical dose
(Schisandra) (Donovan etal., 2004). In a study of 12 adults taking 375
mg/day for 28 days of a valerian root extract that did not
In vitro studies show that schisandra inhibits CYP3A4 contain valerenic acids, there was no effect on metabolism
enzymes. However, schisandra induces the same enzymes in of the CYP3A4 substrate midazolam (Brinker, 2010). The
in vivo animal studies. Molecular changes that occur through absence of the active compound, valerenic acid, limits the
digestion of herbals can alter their effects on CYP450 clinical usefulness of this study. This illustrates the point
enzymes. In animal models schisandra reduced warfarin lev- that differences in the content of extracts and variations in
els, but this has not been demonstrated in human subjects. affinities among substrates of the same isozymes can yield
Until more is known, INR should be monitored in patients different effects. Based on animal studies, valerian could
taking anticoagulants who are given schisandra. In rat studies potentiate the action of sedative drugs, possibly by additive
multiple dosing of Schisandra chinensis alcoholic extract (1.5 effects.
590 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
Vitex agnes-castus (Vitex, ChasteTree) mg or more/day). If this combination is not effective
enough, maca (34 750 mg tablets b.i.d.) may be added.
In fluorogenic in vitro assays a vitex preparation did not ADAPT-232 (24 tablets/day) contains R.rosea, E.sentico-
affect CYP1A1 or CYP2C9, but it impacted CYP2C19 sus, and S.chinensis.
and CYP3A4 (Ho, Singh, Holloway, & Crankshaw, 2011).
No HDIs involving vitex in humans have been reported,
although caution is recommended when used with dopamine CACHEXIA INCANCER PATIENTS
agonists, hormone replacement therapy, and possibly birth ONCHEMOTHERAPY OR RADIATION THERAPY
control pills. Asystematic review of adverse events based on
Cancer cachexia is characterized by anorexia, weight loss,
data from clinical trials, postmarketing surveillance studies,
muscle wasting, weakness, fatigue, and changes in metabolism
surveys, spontaneous reporting, manufacturers, and herb-
of carbohydrates, lipids, and proteins. Oxidative stress and sys-
alist organizations reported no drug interactions (Daniele,
temic inflammation are considered to be contributory factors.
Thompson Coon, Pittler, & Ernst,2005).
Bio-Strath
S U M M A RY
Bio-Strath, a traditional Swiss herbal preparation derived
Many physicians are reluctant to recommend or condone the
from brewers yeast grown on a bed rich in medicinal
use of herbal medicines because they lack familiarity with the
alpine herbs, contains a high concentration of B Vitamins
benefits, the potential side effects, and the simple methods to
and antioxidants. A DBRPC stratified trial in 177 cancer
minimize risks. In contrast, most physicians become comfort-
patients undergoing radiation therapy found that those who
able prescribing medications that are known to have more
were administered Bio-Strath showed improved energy,
frequent and more severe drug interactions and side effects.
appetite, weight gain, and red blood cell counts compared
Although the number of phytomedicines may seem daunting
with placebo. Bio-Strath did not affect tumor growth or
at first, in reality only a handful of them would have a sig-
the antitumor effect of radiotherapy (Schwarzenbach &
nificant impact in most clinical practices. Knowledge of just a
Brunner,1996).
few of the most useful herbs, how to monitor for benefits and
side effects, and where to obtain reliable brands, would enable
the physician to responsibly integrate phytomedicines with L-Carnitine
standard treatments to optimize patient outcomes (Brown,
A review of L-carnitine found evidence that it can reduce
Gerbarg, & Muskin,2009).
chronic inflammation and oxidative stress in cancer patients.
Cancer patients are at risk for carnitine deficiency due to
reduced food intake, increased metabolic demands, and
COU NTERACTIN G M EDICATION SIDE
interference by chemotherapy drugs with carnitine absorp-
EFFECTS W ITH N U TRIENTS AND HERBS
tion, synthesis, and excretion. Studies of carnitine (4 g/day)
in cancer patients find improvement in fatigue, mood, sleep,
Intolerance of medication side effects is a major cause of non-
and appetite, with an increase in lean body mass (Silverio,
compliance. When dose reduction or switching medications
Laviano, Rossi Fanelli, & Seelaender, 2011). A review of
is ineffective, herbs, nutrients, and hormones can be used
L-carnitine reported evidence that it helps reduce the side
either to substitute for the offending medication or to coun-
effects of radiochemotherapy (Kahn, 2004). Animal studies
teract side effects of medications that cannot be discontinued.
demonstrate protection against radiation-induced germ cell
Although only a few natural medicines have been studied as
apoptosis and reduced damage to brain, retina, cochlea, and
antidotes to side effects, in clinical practice, the authors find
kidneys. L-carnitine has been used to prevent cardiotoxicity
the following treatments to be useful in preventing or revers-
from chemotherapy.
ing medication-induced side effects. Dosage guidelines are
included for some supplements. Where there is no specific
dose recommended, the practitioner should start by following Rhodiolarosea
the instructions on the product label and increase gradually A nonblinded 28-week RCT in 58 patients with advanced
while monitoring for symptom relief and side effects. nonsmall-cell lung cancer showed that those who were
given 10 intravenous 30-hour ATP infusions at 2- to 4-week
A S T H E N I A , FAT IGU E , S OM NOL E NC E intervals had statistically significant improvements in
weight, serum albumin, muscle strength, energy and fatigue
Many drugs cause fatigue or somnolence, particularly psy- (p <0.0001), and quality of life. Side effects included chest
chotropics, antihypertensives, antihistamines, opiates, beta heaviness (Agteresch, Dagnelie, van der Gaast, Stijnen, &
blockers, tamsulosin, and chemotherapy treatments. If it is Wilson, 2000). While this treatment was effective, it has lim-
not possible to change the medication, the following treat- ited practicality because of the need for intravenous infusion.
ments can be combined to increase daytime energy (mental However, since R.rosea can be easily given by mouth it would
and physical) without causing addiction:R.rosea (300750 be worthwhile to study this as a simpler way to increase ATP
mg/day), E.senticosus (500 mg b.i.d.), and P.ginseng (300 (Panossian, 2013), particularly because it has already been
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 591
found to improve muscle strength, energy, and fatigue in ani- of psychotic disorders, the severity of antipsychotic medica-
mal studies, normal subjects, and patients with other illnesses. tion side effects (e.g., weight gain, diabetes, cardiovascular
disease, sedation, fatigue, extrapyramidal symptoms, and
tardive dyskinesia) and the low side-effect risk with herbs
N AUS E A A N D VOM I T I NG
and nutrients, a lower threshold of evidence is reasonable in
Nausea and vomiting sometimes respond to ginger tea or gin- offering complementary treatments. Oxidative stress causing
ger capsules taken 40 minutes prior to medication. A small damage to neurotransmitter systems, particularly dopami-
container of candied ginger can be carried easily for sudden epi- nergic nerves in striatal tissues, has been implicated in the
sodes of nausea. Nausea can also be relieved using acupressure pathogenesis of the following psychotropic medication side
bands applied to acupressure points at the wrist. Amrit Kalash effects:
(two complex Ayurvedic herbal formulas) can be used for
severe nausea, fatigue, and other side effects of chemotherapy. 1. Extrapyramidal symptoms:dystonias (muscle spasms),
oculogyric crises (spasm of muscles controlling eye move-
H E PAT IC DY S F U NC T ION ments), pseudoparkinsonism (muscle rigidity, tremor,
bradykinesia, mask-like facies), akinesia (difficulty initiat-
Many medications can cause hepatitis as indicated by eleva- ing movement), akathisia (motor restlessness), restless
tions in liver enzymes. See the section titled Nutrients for legs, bruxism (jaw clenching), and blepherospasm (eyelid
Mood Disorders for a discussion of the hepatoprotection by spasms).
SAMe, polyenolphosphatidyl serine, and bupleurum.
2. Tardive dyskinesia (TD): involuntary movements of the
tongue, jaw, trunk, or extremities may be choreiform
C ONS T I PAT ION , H E MOR R HOI D S , A N D (rapid, jerky, discontinuous) or athetoid (slow, sinuous,
VA R IC O S EV E I N S continuous).
Constipation caused by medications often responds to triphala
24 capsules/day (an Ayurvedic herbal preparation) (Munshi Reduced levels of antioxidant defense enzymes in schizo-
et al., 2011) or magnesium 600800 mg/day (Guerrera, Volpe, & phrenic patients, oxidative damage, toxins, and inflam-
Mao, 2009). Patients who become constipated on medica- matory processes may contribute to the development of
tions (e.g., opioids) may engage in constipation-prolonged schizophrenia and medication side effects (Sivrioglu, Kirli,
forceful valsalva during defecation, which can exacerbate Sipahioglu, Gursoy, & Sarandol, 2007). The incidence and
hemorrhoids. Herbs that strengthen the walls of blood ves- severity of side effects could be ameliorated by substances
sels and help to heal and prevent hemorrhoids and varicose with known neuroprotective, cognitive enhancing, antioxi-
veins include Ruscus aculeatus (butchers broom; CircuCaps) dant, and antiinflammatory actions in patients taking anti-
and Aesculus hippocastanum (horse chestnut extract). These psychotic medications.
vasotonic herbs also reduce capillary filtration rate and edema
in chronic venous insufficiency (MacKay, 2001). In addition, GinkgoBiloba
butchers broom has antiinflammatory properties and inhib- Ginkgo increases circulating and membrane PUFAs (par-
its macromolecular permeability and elastase. Meta-analysis ticularly eicosapentanoic acid) and protects against oxidative
of 20 clinical trials of Cyclo 3 Fort (root extract of the Ruscus stress in vivo (Drieu etal., 2000). Reducing oxidative damage
aculeatus 150 mg, hesperidin methyl chalcone 150 mg, and to neurons by increasing PUFAs could help alleviate adverse
ascorbic acid 100 mg)including 20 placebo controlled, effects of antipsychotic medications. Ginkgo may protect
randomized double blind studies and 5 randomized studies against the neural damage associated with antipsychotics and
against a comparator drug found strong evidence of effi- extrapyramidal symptoms. For example, a 12-week DBRPC
cacy in the treatment of chronic venous insufficiency (Boyle, trial in patients with treatment-resistant schizophrenia com-
Diehm, & Robertson, 2003). Horse chestnut exhibits vaso- pared (n = 56) ginkgo 360 mg/day plus haloperidol 0.25 mg/
tonic, vascular protective, antiinflammatory, and free-radical kg/day with (n = 53) placebo plus haloperidol 0.25 mg/kg/
scavenging properties. In vitro studies demonstrated inhibi- day; 57% of the ginkgo group were rated as responders ver-
tion of the enzymes elastase and hyaluronidase. These herbs sus 38% of the placebo group. The ginkgo group showed a
are safe and generally well tolerated. Isolated adverse effects of lower incidence of extrapyramidal symptoms and greater
horse chestnut have been reported in one patient on anticoag- improvement in positive symptoms of schizophrenia such
ulant medication with angiomyolipoma and in one anorexic as delusions, hallucinations, disorganized speech, grossly
patient with renal insufficiency. disorganized or catatonic behavior, and in negative symp-
toms such flattening of affect, alogia (restriction in the flu-
ency and productivity of thought and speech), and avolition
N E RVOUSS Y S T E M (restriction in goal-directed behavior) (Zhang et al., 2001).
Similarly, in an 8-week DBRCT of schizophrenic patients
Extrapyramidal Symptoms those given olanzapine with gingko (EGb) augmentation (n
Controlled studies of herbs and nutrients in psychotic disor- = 15) had a significant reduction on the Positive Syndrome
ders are limited. However, considering the devastating effects Scale (PANSS) versus those given olanzapine alone (n = 14).
592 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
The group taking gingko had significantly greater reductions increase in lipid peroxidation and improved the glutathione/
in superoxide dismutase and catalase, indicating reduced reduced glutathione ratio. In animals not pretreated with halo-
oxidative stress (Atmaca, Tezcan, Kuloglu, Ustundag, & peridol, 50 mg/day and 500 mg/day NAC reduced oxidative
Kirtas,2005). stress markers, but 1500 mg/day increased levels of superoxide,
decreased lipid peroxidation, and increased consumption of
B Vitamins reduced glutathione (Harvey, Joubert, du Preez, & Berk, 2007).
Pyridoxine (vitamin B 6) may reduce side effects of anti- Doses up to 1800 mg twice daily are being used in human stud-
psychotic medications. In a 4-week DBPCR trial in 15 ies. Excessive doses of NAC may promote oxidative processes.
schizophrenic and schizo-affective patients with TD, B6 Caution is advised in the use of high-dose intravenous NAC.
400 mg/day markedly reduced TD symptoms (Lerner et The use of NAC in addiction, compulsive and grooming dis-
al., 2001). A 5-day DBRPC study of 20 schizophrenic and orders, schizophrenia, and bipolar disorder has been reviewed
schizo-affective patients with neuroleptic-induced akathi- (Dean, Giorlando, & Berk 2011).
sia found B6 600 mg b.i.d. improved the subjective sense In a 6-month DBRPC study of 140 patients with schizo-
of restlessness, distress and global ratings significantly more phrenia, NAC 1000 mg twice daily reduced symptoms of
than placebo (Lerner, Bergman, Statsenko, & Miodownik, akathisia and improved Clinical Global Impression (effect
2004). In another DBRPC trail, 60 schizophrenia and size = 0.40) compared to placebo (Berk, Copolov, Dean, et
schizoaffective inpatients with neuroleptic-induced akathi- al., 2008a). In appropriate doses, NAC may reduce prevent
sia were randomized to receive vitamin B6 1200 mg/day, or reduce medication-induced damage to striatal tissues
mianserin 15 mg/day (tricyclic noradrenergic and spe- and the ensuing side effects. NAC is available in 600 mg
cific serotonergic antidepressant), or placebo for 5 days. tablets in the United States. Two 600mg tablets twice a day
Compared with the placebo group, the vitamin B 6 -treated would have about the same effect as the doses used in clini-
and mianserin-treated patients had a significant improve- cal trials.
ment in subjective distress and Clinical Global Impression
subscales, but not in the objective subscale. A reduction Dehydroepiandrosterone(DHEA)
of at least 2 points on the Barnes Akathisia Rating Scale In a 12-week DBRPC study of chronic schizophrenic
global subscale was noted in the vitamin B6 group (13/23, patients (n = 40), DHEA (up to 150 mg/day) reduced nega-
56%) and in the mianserin groups (13/20, 65%) compared tive symptoms, extrapyramidal symptoms, akathisia, and
to only one patient in the placebo group (Miodownik et al., glucose levels better than placebo (Strous et al., 2007). The
2006). High doses of B6 with low doses of mianserin may reduction in negative symptoms and medication side effects
be a useful addition to current treatments of neuroleptic- may be attributable to potentiation of NMDA-receptor activ-
induced akathisia. ity, suppression of GABA inhibition, and enhancement of
frontal dopamine release.
Combination SupplementOmega-3 FA, Vitamin
E, and VitaminC Melatonin
In an open study, 17 schizophrenic patients being treated Melatonin (10 mg/day sustained release) alleviated symp-
with haloperidol were given a 1000 mg capsule of n-3 FAs toms of TD in 17 out of 22 patients with schizophrenia (mean
(180 mg EPA + 120 mg DHA) twice daily, vitamin E 400 IU duration of 25years) in a 6-week DBPC crossover study. Scores
twice daily and vitamin C 1000 mg/day for 4months. At the on the Abnormal Involuntary Movement Scale decreased
end of the study, scores were significantly lower compared to 3 points in seven patients on melatonin versus one patient on
baseline on the Brief Psychiatric Rating Scale, Scale for the placebo (Shamir etal.,2001).
Assessment of Negative Symptoms, Simpson Angus Scale,
and Barnes Akathisia Rating Scale. In addition, superoxide
dismutase levels were significantly lower at the end of study, Restless Leg Syndrome
but gluthatione peroxidase, malondialdehyde, vitamin E and
C levels were not (Sivrioglu etal.,2007). Restless leg syndrome is characterized by abnormal uncom-
fortable sensations and/or movements of the legs, usually
N-acetylcysteine worse at night or at rest and often relieved by walking around.
N-acetylcysteine scavenges for free radicals and increases Antipsychotics and antidepressants, particularly SSRIs,
intracellular glutathione, the primary neuroprotective antioxi- can cause restless leg syndrome with secondary loss of sleep.
dant in the brain. Studies of animals given haloperidol 1.5 mg/ A combination of lemon balm, passion flower, and valerian
kg/day for 21 days showed significant elevations in striatal super- can be helpful.
oxide (free radicals) and lipid peroxidation (free radical damage
to membranes) compared with animals not given haloperidol.
Cognition, Memory, and Word Finding
Next, both groups of animals were given N-acetylcysteine
(NAC) for 21 days in 3 different doses: 50 mg/day, 500 mg/ Patients often complain of cognitive impairment,
day, and 1500 mg/day. All three doses of NAC prevented the decreased memory, and/or word-finding problems related
haloperidol-induced increase in superoxide (free radical) levels. to medication. Many of the treatments described in the
The 1500 mg/day dose of NAC prevented haloperidol-induced section titled Cognitive Function can help to counteract
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 593
cognitive and memory dysfunction due to medication side H E M ATOL O G IC A L DI S OR DE R S , I M M U N E
effects, including the following: R.rosea 450750 mg/ DE F E N S E , CH E MOT H E R A P Y TOX IC I T Y
day; ADAPT-232 24 tablets/day; Aniracetam 750 mg
Erythrocytes
twice daily; and Huperzine-A 200400 mg twice daily.
Artichoke extract may be of benefit in cognitive impair- Medication-induced decreases in red blood cell count with
ment secondary to chronic use of benzodiazepines, based a hematocrit >32 can be reversed with R.rosea, E.senticosus,
on animal studies. and/or shark liver oil. Toxicity from contaminants and gastro-
In a DBRCT of schizophrenic inpatients (n = 42) with intestinal disturbances with low-quality shark liver oil prod-
elevated homocysteine (increased oxidative stress), those who ucts has been reported. Therefore, the authors recommend
were given a daily vitamin combination (folic acid 2 mg, B12 only high-quality shark oil products such as Immunofin 26
400 mcg, B6 25 mg) showed significantly greater reduction in capsules/day (Lane Labs) or shark liver oil (Life Extension
homocysteine levels and PANSS scores and improved cognitive Foundation) (Brown etal.,2009).
function compared to the placebo group (Levine etal.,2006).
Leukocytes
Insomnia
Medication-induced decreases in white cells with a total
Medication-induced insomnia can respond to Melatonin count >3500 and a neutrophil count >1500, can be reversed
39 mg hs. Melatonin reduces sleep onset latency; extended using shark liver oil (26 capsules/day Immunofin,) E.senti-
release melatonin maintains sleep. Chronic schizophrenic cosus 500 mg b.i.d., Astragalus, and/or lithium 600 mg/day or
patients have shown blunted nocturnal melatonin levels. more (Brown etal.,2009).
ADBRPC study in schizophrenic outpatients (n = 40) dem-
onstrated that in patients receiving haloperidol 10-15 mg/day,
Platelets
melatonin 3 mg hs improved sleep measures and quality of
life in comparison to placebo (Kumar, Andrade, Bhakta, & Medication-induced decreases in platelets, when the count is
Singh,2007). >80,000 and without bruising or bleeding, can sometimes be
treated with shark liver oil (Immunofin) 26 capsules/day.
The platelet count should be monitored to avoid supranormal
C A R DIOVA S C U L A RS Y S T E M levels (Brown etal.,2009).
PedalEdema If erythrocyte, leukocyte, or platelet counts drop below the
minimal levels mentioned above, then the offending medica-
Antipsychotics, mood stabilizers (such as valproate and lith- tion should be discontinued and the natural treatments contin-
ium carbonate), SSRIs, and other medications can cause pedal ued until cell counts return to normal. If cell counts continue to
edema (swelling of the feet and ankles due to leakage of fluid decline or fail to improve, a hematologist should be consulted.
from veins into tissues. (See section on constipation, hemor-
rhoids, and venous insufficiency.) By strengthening the veins,
butchers broom (Sanhelios CircuCaps 900 mg/d) and horse A DA P TO G E NS I NC A NC E R T R E AT M E N T
chestnut extract (Natures Way Standardized Extract 1 tablet R E DUC E CH E MOTOX IC E F F E C T S ONB ON E
b.i.d.) can reduce pedaledema. M A R ROW A N DL I V E R
Chemotherapy drugs often damage stem cells in the liver and
M US C U L O S K E L E TA LS Y S T E M bone marrow, resulting in increased susceptibility to infec-
tions and other medical problems. When blood cell counts
In a university department of cardiology clinic, more than fall too low, chemotherapy may be interrupted.
30% of patients taking statins reported myopathy, myalgia, Rhodiola rosea extracts demonstrated antitumor and
or myositis (Riphagen, van der Veer, Muskiet, & DeJongste, antimetastatic activity in studies of human cancers trans-
2012). Statin myotoxicity has been linked to impairment planted into mice (Lewis lung carcinoma, Ehrlichs sarcoma,
of mitochondrial functions, such as electron transport, and Pliss lymphosarcoma, NK/Ly tumor, and melanoma B16).
depletion of CoQ10. Preliminary studies of CoQ10 supple- Moreover, R. rosea protected liver and bone marrow cells
mentation to relieve statin-induced myalgia and muscle from chemotoxic effects of adriamycin and cyclophospha-
weakness have yielded inconsistent results. Patients on main- mide, while at the same time enhancing the effectiveness of
tenance statin treatment should have CoQ10 levels moni- the chemotherapy in destroying cancer cells and reducing
tored. If the levels are low, or if the patient develops symptoms metastases (Dementeva & Iaremenko, 1987; Razina, Zueva,
of muscle pain or weakness, then supplemental CoQ10 (pref- Amosova, & Krylova, 2000; Udintsev, Krylova, & Fomina,
erably ubiquinol, a reduced form of CoQ10) is indicated. The 1992; Udintsev & Schakhov, 1989, 1990,1991).
ongoing Co-Enzyme Q10 in Statin Myopathy study intends to In 12 patients with superficial bladder carcinoma, R.rosea
determine the effects of CoQ10 on pain intensity in patients improved urothelial tissue, leukocyte integrines, and T-cell
with statin-induced myalgia who are being treated for hyper- immunity with a trend toward reduction in frequency of
cholesterolemia (Parker etal.,2013). relapse (Bocharova et al., 1995). A 95% ethanol extract of
594 P s yc h i at r i c C a r e o f t h e M e d i c a l Pat i e n t
R. rosea stems exhibited cytotoxic activity against prostate clinical practice the authors find that patients who take Amrit
cancer cells (Ming etal.,2005). Kalash during a course of chemotherapy report improved
Studies in rodents with transplants of human cancers energy, digestion, and sense of well-being, as well as little or
(Lewis lung sarcoma, Pliss lymphosarcoma, Ehrlichs sar- no hairloss.
coma, NKY/LY tumor, and melanoma B16) given adriamy-
cin or cyclophosphamide found that the addition of R.rosea
did not interfere with the actions of the chemotherapy agents. R E S PI R ATORY I N F E C T ION S
In fact, the R.rosea increased the effectiveness of the chemo-
Certain medications (e.g., modafinil) increase the occur-
therapy drugs, reduced metastases, and protected the liver and
rence of upper respiratory infections. Herbs and vitamins
bone marrow stem cells from toxic effects of the chemother-
for stimulating immune defense include sambucol (concen-
apy. R.rosea is administered to cancer patients in the former
trated extract of elderberries) and astragalus, reishi, shii-
Soviet Union. RCTs are needed to confirm safety and efficacy.
take, and maitake mushrooms. Red mangrove (Rhizophora
Since fatigue is the most common complaint among cancer
mangle) bark extract from Fiji (Natures Nurse, Respigard)
patients and since R. rosea is so beneficial for fatigue, trials
is used to increase resistance to respiratory infection and to
would be helpful in cancer treatment and recovery.
accelerate recovery. Traditional Polynesian medicine uses
The inaccessibility of R. rosea cancer research (much of
red mangrove for its astringent, antiseptic, hemostatic,
which is published in foreign language journals) combined
antifungal, and anti-ulcerogenic properties (de Armas,
with reluctance to use herbal preparations in cancer patients
Sarracent, Marrero, Fernandez, & Branford-White, 2005;
and lack of funding to study adaptogens has prevented oncol-
Marrero etal., 2006). Based on in vitro and in vivo stud-
ogists from discovering the potential benefits of R.rosea and
ies, Andrographis paniculata (king of bitters), an Asian
other adaptogenicherbs.
phytomedicinal, manifests anticancer, antiinflamma-
tory, and immunomodulatory action, and possibly reduc-
Adaptogen Combination Treatments tion of autoimmune responses (Denzler , Waters, Jacobs,
In a study of 28 women with stage IIIIV ovarian cancer Rochon, & Langland, 2010; Iruretagoyena et al., 2005;
treated with cisplatin and cyclophosphamide, subjects who Yang etal.,2010).
took AdMax 270 mg/day (combination of extracts from
roots of Leuzea carthamoides, R. rosea, E. senticosus, and
fruits of S.chinensis) for 4 weeks following chemotherapy S U M M ARY
showed increases in T cell subclasses (CD3, CD4, CD5,
and CD8), IgG and IgM compared with those who did not Phytomedicines, nutrients, and neurohormones have the
(Kormosh, Laktionov, & Antoshechkina,2006). potential to relieve psychological and physical symptoms in
medical patients. The growing reliance on synthetic medi-
Ashwagandha (Withania somnifera) cations has brought unintended consequences: side effects,
Ashwagandha is an adaptogenic herb known in Indian serious adverse reactions, drug interactions, high costs of
medicine for its antistress, antiinflammatory, antioxidant, development passed on to consumers, substance abuse, and
analgesic, antidepressant, and immunomodulatory effects. An withdrawal symptoms. In addition, the manufacturing of
in vitro and in vivo study of selective tumor inhibition by an synthetic drugs creates environmental pollutants, and the
ashwagandha leaf extract found that one of the constituents, disposal of nonbiodegradable medications contributes to
withanone, activated p53, a gene responsible for tumor cell toxic water pollution. In comparison, herbs and nutrients
apoptosis. The herbal extract selectively killed various human have far fewer side effects, less addiction potential, and
tumor cells but not normal human cells (Widodo etal., 2007). lowercosts.
However, because ashwaganda has estrogenic properties, fur- Biodiversity in medicinal plants and their innumer-
ther studies are needed regarding long-term safety inwomen. able related species is an untapped resource for the future
development of medical treatments. Once the bioactive
AmritKalash constituents are identified in a plant part, it is possible to
Amrit Kalash, a proprietary Ayurvedic formula contain- alter the relative concentrations of therapeutic compounds
ing many herbs including ashwagandha, enhanced immune by cross-breeding and by changing the composition of nutri-
function and protected against free radical damage and toxic ents in the soil and water. Such methods mimic some of the
effects of chemotherapy in animal and cell culture studies. forces of natural evolution and, therefore, are less likely to
Amrit Nectar tablets (MA-7, containing 38 herbs) showed produce harmful new compounds with unexpected effects
antioxidant activity and protected against toxicity from adria- as compared to artificial synthetic processes or genetic inser-
mycin and cisplatin (Dwivedi, Natarajan, & Matthees, 2005). tions. Genomic analysis is expanding our understanding of
It is reported to improve energy, well being, sleep, appetite, speciation and the subtle genetic differences that may deter-
vomiting, diarrhea, and tolerance of cancer treatment without mine therapeutic effectiveness. Furthermore, phytomedi-
interfering with chemotherapy agents. Additional RCTs are cines are a natural, renewable resource that can help farming
needed to confirm safety and efficacy for cancer patients. In communities flourish.
2 8 . T h e r a p e u t i c Nu t r i e n t s , H e r b s , a n d H o r m o n e s 595
CLINICAL PEARLS DI S C L O S U R E S TAT E M E N T S
Considerable progress has been made in the standardiza- Dr.Richard P.Brown holds a patent for the use of 3-acetyl-7-
tion of botanical extracts based on the concentration of oxo-dehydroepi-androsterone (7-Keto DHEA) in the treat-
marker compounds believed to be essential for therapeu- ments of PTSD and dissociative disorders. He has no other
tic activity and/or to be unique to the species. conflicts of interest.
The ultimate test of an extract is proven efficacy in a Dr. Patricia L. Gerbarg is married to Dr. Richard
good quality controlled trial published in a peer-reviewed P. Brown who holds a pantent on the use of 3-acetyl-7-
journal. oxo-dehydroepi-androsterone (7-Keto DHEA) in the treat-
ments of PTSD and dissociative disorders. She has no other
Safety of most herbs during pregnancy and breastfeeding conflicts of interest.
has not been adequately studied.
Certain complex products are more affected by dif-
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PA RT I V
I N T RODUC T IO N AC U T E , I N T E G R AT E D, A N D
C OM PL IC AT E D G R I E F
Grief is a universal mammalian experience. Generally, grief
is considered to be self-limited, adaptive, and outside the gen- Grief can be further subcategorized as acute grief, the initial
eral domain of psychiatric concerns. However, there are times painful response, and integrated grief, the ongoing, attenu-
when grieving persons can and should be referred for mental ated adaptation to the death of a loved one. Complicated grief,
health care, such as when the death of a loved one also triggers sometimes called prolonged, traumatic, or unresolved grief,
a major depressive disorder, a prolonged stress or trauma reac- refers to acute grief that remains intense and persistent with-
tion, or when healing does not occur spontaneouslya con- out transitioning into integrated grief.
dition called complicated grief. In those circumstances grief
can be associated with important general medical and mental
health consequences (Ajdacic-Gross etal., 2008; M.K. Shear AC U T E G R I E F
etal., 2011; Stroebe, Stroebe, & Abakoumkin, 2005; Zisook &
Grief is conceptualized as a universal, natural, adaptive,
Shear, 2009). This chapter will cover the clinical features of
and instinctual reaction to the loss of a loved one. The acute
normal grief, the complex relationship between grief and
manifestations of grief can span the full gamut of inten-
depression (where does one end and the other begin?), the clin-
sity from barely noticeable discomfort and dysfunction to
ical features of complicated grief (CG), and evidence-based
among the most painful, distressing, and debilitating expe-
interventions for bereavement-related depression and CG.
riences of a persons life. In acute grief there may be disbe-
lief and difficulty comprehending the finality of the loss.
T E R M I NOL O G Y
Acute grief is a preoccupying experience in which feelings
Since terms used to describe emotions and behaviors following of yearning and longing for the deceased are accompanied
the death of a loved one are imprecise and used idiosyncrati- by pangs of intense emotions, often experienced as unfamil-
cally by clinicians and experts alike, it is useful to review con- iar and difficult to control. The bereaved person is consumed
temporary definitions of key terms. Grief may be defined as the with thoughts and memories of the deceased and relatively
constellation of feelings, cognitions, behaviors, and changes uninterested in other people and usual life occupations.
in function associated with loss of any kind. This definition However, even when the predominant features are pain and
applies to the medically ill population, as many medically ill loss, pleasant and positive emotions also occur. The bereaved
individuals are grieving numerous losses including their loss of person may experience enjoyment in recalling happy times
health, function, and independence; and to individuals under- and sharing amusing anecdotes, warmth in recalling close-
going any number of other losses, such as divorce, financial ness, pride in honoring the deceased, relief from the bur-
security, employment, and home. Alternatively, bereavement, den, and joy in being alive (Bonanno, Moskowitz, Papa, &
the state of having lost a loved one or someone close specifi- Folkman, 2005). Typically, intense emotions come in waves,
cally through death, is sometimes used to connote grief after the so-called pangs of grief, which gradually become less fre-
the death of a loved one (Stroebe, Hansson, Stroebe, & Schut, quent and intense. While there is no accepted time frame
2001). For the purposes of the rest of this chapter, grief and for grief to last, the current consensus is that the most pain-
bereavement will be used interchangeably. Another term that ful features at least begin to abate by about 6 months. By
sometimes is used to refer to grief reactions is mourning. We then, wounds begin to heal, and the bereaved person finds
define mourning as the social, cultural, and behavioral rituals his or her way back to a fulfilling life. The reality and mean-
of grief, while Shear etal. define mourning as the psychosocial ing of the death are assimilated, and the bereaved are able to
process by which one transitions from acute to integrated grief engage once again in pleasurable and satisfying relationships
(M. K.Shear etal., 2011). and activities (Zisook & Shear, 2009).
611
I N T E G R AT E D G R I E F 2004; Morina, Rudari, Bleichhardt, & Prigerson, 2010;
H.Prigerson etal., 2002; Schaal, Elbert, & Neuner, 2009).
Normally, acute grief instinctively transitions to integrated
Box 29.1 provides a brief screening questionnaire for CG.
grief within several months. As the permanence of the loss
The clinical symptoms of CG include persistent difficulty
is comprehended, acute grief resolves, and memories of the
accepting the death, preoccupation with thoughts and images
deceased are integrated into the ongoing psychological life
of the deceased, recurrent pangs of intense grief, avoidance of
of the bereaved. Engagement in constructive daily occupa-
reminders of the loss, anger, guilt, and difficulty adjusting to
tions is reestablished, and the person is able to fully resume
life without the deceased (H. G.Prigerson etal., 1995; M.K.
old roles and functions as well as develop new ones that may
Shear, 2010). Excessive proximity-seeking is common, and in
be necessary for ongoing life. Thoughts and memories of the
its most extreme form can manifest as wishes to die or suicidal
deceased remain accessible but are no longer preoccupying.
behavior with the belief that life has no purpose or meaning
After such integration there is diminished intensity of sadness
without the deceased. Additionally, individuals with CG
and retreat of preoccupying thoughts. Integrated grief may be
often experience ruminating thoughts about the circum-
life-long and often continues to evolve over time (M.K.Shear,
stances around the death (M. K.Shear etal., 2011). Without
2010). Notably, symptoms of acute grief can recur transiently,
treatment, CG tends to persist indefinitely.
oftentimes during anniversaries, holidays, stresses, special
Although CG often is comorbid with major depressive
occasions, and other losses.
disorder (MDD)either as a risk and/or as a consequence
it is important to differentiate between the two conditions, as
treatments and prognosis vary (M. K.Shear etal., 2011). Akey
C OM PL IC AT E D G R I E F
difference is that the core features of CGlonging, pining,
Complicated grief is a recognizable syndrome of prolonged, preoccupation, and avoidanceare not characteristic features
intense grief that occurs when acute grief does not transition of MDD. The core features of MDD (persistent and pervasive
to integrated grief by 6months (Zisook, Simon etal., 2010). sadness, anhedonia, and low self esteem) are not characteristic
Time moves on, but healing does not. It is not always clear features of CG. Table 29.1 summarizes phenomenological and
why the natural healing process of grief is impeded in any clinical distinctions between CG and MDD. CG also shares
given individual, but several risk factors have been identified. many features with posttraumatic stress disorder (PTSD) and
For example, CG has been found more often after suicide often co-occurs with PTSD, but they can be differentiated by
or when the deceased is a soul-mate (Jordan, 2008; M.K. several key distinguishing features (M. K.Shear etal., 2011).
Shear et al., 2011). Past and current major depressive disor- The predominant trauma in CG is loss-related, while the
der also is associated with increased risk for CG. Sometimes, major trauma in PTSD is threat-related. The characteristic
the resolution of grief is impeded by maladaptive attitudes affects of CG (longing and yearning) are not the same as the
and behaviors such as intense blame of self or others, fear of predominant affect of PTSD (fear).
being overwhelmed by the intensity of grief, persistent avoid- CG is associated with functional impairment in multiple
ance of reminders of the deceased, the prospect of life without modalities, including daily activities (Monk, Houck, & Shear,
the deceased, or a disinclination to engage in activities that 2006), socializing (Boelen & Prigerson, 2007; Melhem,
were shared with the deceased (Boelen, van den Bout, & van Moritz, Walker, Shear, & Brent, 2007), work (Lannen, Wolfe,
den Hout, 2006; K.Shear etal., 2007). On occasion, practical Prigerson, Onelov, & Kreicbergs, 2008; H.G. Prigerson etal.,
and/or interpersonal problems may complicate the adjustment 1997), and relationships (Monk, Houck, & Shear, 2006).
process and delay the healing of grief. Persistent avoidance of Additionally, individuals with CG have increased rates of
reminders of the loss is another major impediment to adjust-
ment. When resolution of acute grief is blocked, the resulting Box 29.1 BRIEF GRIEF QUESTIONNAIR E:
complicated grief can persist for years, decades, or even a life- ASCR EENING TOOL FOR COMPLICATED GRIEF
time, with prolonged suffering and failure to find avenues for
constructive activities in a world without the deceased. Rate as:0=Not at all, 1=Somewhat, 2=A lot
Approximately 10% of bereaved individuals may experi- Screen positive:Scores 4
ence CG (Middleton, Raphael, Burnett, & Martinek, 1998;
H.G. Prigerson etal., 2009). Arecent large population-based 1. How much trouble are you having accepting the death?
study of older adults in the Netherlands indicates a CG preva- 2. How much does grief interfere with your life?
lence of 4.8% of the general older adult population, 7% of the
general 7585-year-old population, and 25.4% of the older 3. Are you having troublesome or preoccupying images or
grieving population (Newson, Boelen, Hek, Hofman, & thoughts of ?
Tiemeier, 2011). CG is observed across various ethnic groups 4. Are there things you used to do when was alive that
in the United States (Cruz etal., 2007; Goldsmith, Morrison, you dont feel comfortable doing anymore, that you avoid?
Vanderwerker, & Prigerson, 2008) and cultures through-
out the world (Bonanno, Papa, Lalande, Zhang, & Noll, 5. How much are you feeling cut off or distant from other
2005; Ghaffari-Nejad, Ahmadi-Mousavi, Gandomkar, & people since died?
Reihani-Kermani, 2007; Kersting et al., 2007; Langner & (Shear etal., Psychiatric Service, 2006).
Maercker, 2005; Momartin, Silove, Manicavasagar, & Steel,
Suicidal Ideation If present, focused on joining the deceased loved one Frequent, focused on not being worthy of living
Preoccupying Thoughts Of the deceased; guilt and self blame focused Of low self esteem and related to a sense of guilt
on the deceased orshame
Avoidance Avoidance of activities, situations and people General withdrawal from activities and people
because of the death
psychiatric comorbidity (Newson, Boelen, Hek, Hofman, & is a pathological condition, certain individuals find that their
Tiemeier, 2011; Simon et al., 2007), worsening symptoms desire to explore and make sense of their grief motivates them
of other psychiatric illnesses (M. K. Shear et al., 2011), to initiate a productive exploratory or supportive therapy.
and insomnia (Hardison, Neimeyer, & Lichstein, 2005). Uncomplicated acute and integrated grief generally do
Importantly, CG is associated with increased suicidal ideation not require formal interventionsbut CG does. Without
and behavior across various age groups (Latham & Prigerson, treatment, CG symptoms follow an unrelenting course. The
2004; Mitchell, Kim, Prigerson, & Mortimer, 2005; H. G. effectiveness and role of pharmacologic management of CG
Prigerson etal., 1999; Szanto, Prigerson, Houck, Ehrenpreis, & is not yet established. An open pilot study (Pasternak etal.,
Reynolds, 1997; Szanto etal., 2006). 1991) and a randomized controlled trial (Reynolds et al.,
In addition, CG negatively affects individuals physical 1999)of bereavement-related major depression in patients
health outcomes (Lichtenthal, Cruess, & Prigerson, 2004; many of whom also had symptoms of CGdemonstrated
M. Stroebe et al., 2007). CG is associated with increased little response in grief symptoms to nortriptyline. Another
tobacco and alcohol use (Zisook, Shuchter, & Lyons, 1987). In small, open trial of sustained-release bupropion for recently
their study of bereaved widows and widowers, H.G. Prigerson bereaved individuals with bereavement-related depression was
et al. (1997) found that CG predicted numerous negative associated with an improvement in both grief and depres-
health changes. Individuals with CG had increased rates of sive symptoms (Zisook, Shuchter, Pedrelli, Sable, & Deaciuc,
cancer, cardiac disease, and hypertension. Moreover, widows 2001), but CG was not targeted in this study. However, a
and widowers with CG had significantly higher rates of the flu, small case series of participants with CG suggested that
headaches, and cardiac issues around the anniversary of the escitalopram may be an effective treatment for CG (Simon,
death of their spouse than did bereaved spouses without CG. Thompson, Pollack, & Shear, 2007), and another study indi-
Gender differences exist in these health outcomes. Widowers cated that the response of individuals with CG to two forms of
with CG tend to have worse health outcomes than do widows psychotherapy improved with concurrent escitalopram treat-
(Chen etal., 1999). Despite their increased risk for develop- ment (Simon etal., 2008). In light of these findings suggest-
ing health problems, individuals with CG underutilize health ing a potential role for pharmacological interventions for CG,
services (H. Prigerson et al., 2001). Overall, untreated CG a large multisite randomized controlled trial exploring the
results in suffering, impairment, and poor health outcomes. efficacy of citalopram for the treatment of CG is currently in
progress (http://clinicaltrials.gov/ct2/show/NCT01179568).
A recent meta-analysis of studies assessing psychothera-
T R E AT M E N T OF C OM PL IC AT E D G R I E F
peutic strategies for the prevention and treatment of CG was
Considering that grief is a normal, adaptive response to loss, not able to confirm the effectiveness of preventive interven-
noncomplicated grief that is not comorbid with depression tions, but it did show that certain psychotherapy interventions
does not warrant any intervention in most circumstances. are effective. Moreover, benefits increase over time (Wittouck,
When support, reassurance, and information generally pro- Van Autreve, De Jaegere, Portzky, & van Heeringen, 2011).
vided by family, friends, and sometimes clergy, is not available Studies substantiate the use of cognitive behavioral ther-
or sufficient, bereavement support groups may help fill the gap apy (Boelen & Prigerson, 2007; Wagner, Knaevelsrud, &
(Lieberman & Videkasherman, 1986; Marmar, Horowitz, Maercker, 2006), time-limited interpretive group therapy
Weiss, Wilner, & Kaltreider, 1988). Support groups can be (Piper, McCallum, Joyce, Rosie, & Ogrodniczuk, 2001; Piper,
particularly helpful after traumatic losses such as the death of Ogrodniczuk, Joyce, Weideman, & Rosie, 2007; Saindon
a child, a death after suicide, or deaths from other unnatu- etal., 2014), and complicated grief therapy (K. Shear, Frank,
ral causes. While we do not mean to imply that acute grief Houck, & Reynolds, 2005).
Table29.2 QUALITATIVE PHENOMENOLOGICAL DIFFER ENCES BET W EEN GR IEF AND DEPR ESSION
Mood/Sadness Comes in waves and mixed with happy emotions, especially Pervasive
when recounting pleasant memories of the deceased loved one
Suicidal Ideation Connected with longing for reunion with the deceased Connected with feelings of not deserving
loved one to live
Guilt Focused on letting the deceased loved one down Focused on self loathing and worthlessness
Functional Impairment Intermittent, typically lasts days to weeks Pervasive, often lasts weeks to months
620
events could be receiving the diagnosis, fear of the surgery PE R I T R AU M AT IC R E AC T ION S
and chemotherapy, or detecting a lump (Mehnert & Koch,
2007). This is important as it suggests that clinicians should When confronted with a traumatic event, individuals often
be aware that giving a diagnosis of cancer may results in develop immediate reactions of distress. Reactions experi-
PTSD, which may in turn result in poorer psychological and enced during and immediately after trauma are called peri-
physical outcome. Further, death may also be considered an traumatic and recent developments have identified certain
A1 qualifying event. trauma-specific peritraumatic reactions (distress defined in a
specific way) and dissociation as robust predictors of the devel-
opment of chronic and debilitating PTSD (Brewin, Andrews, &
E PI DE M IOL O G Y
Valentine, 2000; Ozer, Best, Lipsey, & Weiss, 2003). While
Estimates of the lifetime prevalence of exposure to a trau- peritraumatic dissociation has been studied for a significant
matic event range from 39% to 74% for the United States and period of time, peritraumatic distress has only become the
Canada (Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; focus of attention lately.
Norris, 1992; Resnick, Kilpatrick, Dansky, Saunders, & Peritraumatic distress was proposed as a measure of the
Best, 1993); some other developed countries (e.g., intensity of DSM-IV PTSD criterion A2 (Brunet et al.,
Netherlands and New Zealand) fall within that range but 2001)the feeling of fear, helplessness and horror experi-
some studies suggest a lower rate for others (Hepp et al., enced by an individual during or immediately after exposure
2006; Perkonigg, Kessler, Storz, & Wittchen, 2000; Vaiva to a traumatizing event. Furthermore, this dimension also
etal., 2008). Variances might be accounted for by confound- includes such phenomena as feeling ashamed of ones emo-
ers such as age, gender, or type of events (Breslau, 2001). tional reactions or having difficulty controlling ones bowel
Additionally, discrepancies might result from differences in and bladder. The Peritraumatic Distress Inventory (PDI)
measurement methods and the way traumatic events have was introduced in 2001 as a measure of peritraumatic distress
been defined (Solomon & Davidson, 1997). criterion A2 (Brunet et al., 2001) and evaluates feelings of
Although research on the prevalence of medical illness- helplessness, sadness, guilt, shame, frustration, fright, horror,
related traumatic events is scarce, some studies reported passing out, worry for others, loss of bowel and bladder con-
that a substantial amount of life threatening illness patients trol, physical reactions, and thoughts of dying. The self-report
met DSM-IV PTSD criterion A, as is typical in 41%54% PDI includes 13 Likert-type items scored from 04 (not at
of breast cancer patients (Mehnert & Koch, 2007; Palmer, all true to extremely true) with a total score ranging from
Kagee, Coyne, & DeMichele, 2004). 0 to 52 (Table 30.1). To date, no cut-off has been reported
Please check the boxes corresponding to the best to what you felt during and immediately after the event. If the phrase doesnt apply to how
you experienced the event, check the box not true at all.
NOT
AT ALL EXTR EMELY
HOW MUCH IS EACH OF THE FOLLOW ING STATEMENTS TRUE OF YOU? TRUE TRUE
11. Ihad physical reactions like sweating, shaking, and pounding heart 0 1 2 3 4
Traumatic Event Men (n=2812) Women (n=3065) Men (n=2812) Women (n=3065)
Physical attack 11.1% (1.0) 6.9% (0.9) 1.8% (0.9) 21.3% (7.3)
Threat with weapon 19% (1.3) 6.8% (0.6) 1.9% (0.8) 32.6% (7.8)
Natural disaster with fire 18.9% (1.4) 15.2% (1.2) 3.7% (1.8) 5.4% (3.8)
Physical abuse 3.2% (0.4) 4.8% (0.6) 22.3% (5.2) 48.5% (9.5)
Other qualifying trauma 2.2% (0.5) 2.7% (0.4) 12.7% (4.8) 33.4% (8.0)
Any trauma 60.7% (1.9) 51.2% (1.9) 8.1% (1.0) 20.4% (1.5)
* The probability that a particular trauma type, once selected as the basis for the assessment of PTSD, will be associated with PTSD.
On how many days did you experience any of the above symptoms of distress? (Please mark one):
No days
One day
Two days
Three days
Four days
Five or more days
life-threatening situations are diverse. Contrary to some ear- The diagnosis is further defined in criteria BE as neces-
lier concepts of nosology, the life-threatening situation that sitating the presence of symptoms in the four clusters of
is the basis of PTSD does not need to be outside the range of intrusion, avoidance, alterations in mood and cognition,
normal human experience. and alterations in arousal and reactivity. In particular, the
METHOD OF TIME
INSTRUMENT ABBR EVI ATION ADMINISTR ATION # ITEMS ADVANTAGES LIMITATIONS COMMENTS R EQUIR EMENT
Structured Clinical SCIDI Interviewerrated 21 Comprehensive assessment tool; Dichotomous rating; Can use only the PTSD module; 210 minutes for
Interview for the DSMIV Flexibility in administration focus on worst event Anxiety disorders, mood PTSD module,
experienced; lengthy; disorders, and substance 20 minsseveral
recommended for only use disorders modules hours for the entire
trained clinicians recommended instrument
Clinician Administered CAPS Interviewerrated 30 Separate ratings for frequency Needs training; Shorten by only assessing 30 mins1 hour
PTSD Scale and intensity; Flexibility in Timeconsuming 17 core symptoms; Child
administration Adolescent Version
CAPSCA
PTSD Symptom Scale PSSI Interviewerrated 17 Can be administered by trained Measures symptoms over past Recommended for use with 20 mins
Interview paraprofessionals 2 weeks rather than 1month sexual assault survivors; Child
Adolescent Version CPSS
Structured Interview for SIPTSD Interviewerrated 27 Can be administered by trained Also assesses survival and 1030 mins
PTSD paraprofessionals behavioral guilt
Anxiety Disorders Interview ADISPTSD Interviewerrated Yields both dichotomous and Mixed results in reliability Module of ADISIV
SchedulePTSD continuous information and validity studies;
recommended for only
trained interviewers
Short PostTraumatic Stress SPRINT Interviewerrated 8 Used for screening Not diagnostic Sensitive to change 3 min
Disorder Rating Interview
PTSDInterview PTSDI Interviewerrated / Yields both dichotomous and Patients are given a copy of
Selfreport continuous information the scale to read along with
interviewer
Impact of Event IESR Selfreport 22 Short; Widely used, enabling Does not closely match Widely used 10 mins
ScaleRevised comparisons DSMIV criteria
Mississippi Scale for MPTSD Selfreport 35 Well validated for combat Correspond to DSMIII Recommended for use with 1015 mins
CombatRelated PTSD related PTSD criteria combatrelated PTSD
Keane PTSD Scale of the MMPI2, PK Selfreport 46 Dichotomous rating Recommended for use with 15 mins
MMPI2 veterans
Posttraumatic Stress PDS Selfreport 49 Yields both dichotomous and 1015 mins
Diagnostic Scale continuous information
PTSD Checklist PCL Selfreport 17 Closely match DSMIV criteria Does not provide diagnosis Civilian Version (PCLC), 510 mins
Military Version (PCLM) and
Specific Version (PCLS)
Los Angeles Symptom LASC Selfreport 43 Yields both dichotomous and Also assesses general 15 mins
Checklist continuous information psychological distress
Distressing Events DEQ Selfreport 35 Yields both dichotomous and Does not assess criterion A1 Also assesses guilt, anger, and 57 mins
Questionnaire continuous information grief
DI F F E R E N T I A L DI AG NO S E S PTSD symptoms with specific PTSD treatment was associ-
ated with a reduction in substance use. In contrast, reduction
The time elapsed since the trauma is the main point to con-
in substance use did not necessarily reduce PTSD symptoms
sider when determining the difference between PTSD and
in this study (Hien etal., 2010).
ASD, although ASD also comprises dissociative symptom
PTSD is also comorbid with physical conditions. Arecent
that are not included in the syndrome of PTSD except as a
study reported that even after adjusting for sociodemograph-
specifier. Generally, ASD occurs within the first month after
ics and comorbid psychiatric disorders, PTSD was signifi-
trauma exposure, while PTSD is diagnosed beyond that.
cantly associated with an increased likelihood of suffering
Patients with anxiety disorders (panic disorder, general
from a physical disorder in the past year, including neuro-
anxiety disorder, social anxiety disorder, etc) also may experi-
logical, vascular, gastrointestinal, metabolic, as well as auto-
ence a certain level of hyperarousal and avoidant behaviors;
immune, bone, and joint conditions (Sareen, Cox, Clara, &
however, both the trauma exposure and the reexperiencing
Asmundson, 2005). Thus, chronic PTSD and chronic medical
of symptoms are missing from their clinical presentation.
conditions can influence one another adversely. Medical con-
Depressive disorders may be triggered by a stressful experi-
ditions that are painful or life-threatening can increase arousal
ence and can also include concentration difficulties, insom-
and thereby aggravate PTSD symptoms. At the same time
nia, social withdrawal or detachment, and anhedonia, but
patients with PTSD may have problems with medical treat-
they do not include trauma reexperiencing or trauma-related
ment adherence, may have unhealthy behavior, and may show
avoidance. Finally, an adjustment disorder can also occur after
adverse physiologic effects of their chronic stress (Shemesh
exposure to a stressor. However, in that condition either the
etal., 2001). There is evidence that PTSD is accompanied by
stressor is not extreme or life threatening (e.g., divorce or job
dysregulation in the hypothalamic-pituitary-adrenal axis,
loss) and/or the reaction to it is not severe enough to meet
associated with low cortisol levels frequently found in PTSD
criteria for PTSD. Furthermore, according to criterion C for
patients (Meewisse, Reitsma, de Vries, Gersons, & Olff, 2007).
adjustment disorder, meeting the criteria for any other mental
Further, recent data also suggest that patients with PTSD may
disorder preempts a diagnosis of adjustment disorder.
exhibit immune modifications including increased circulat-
ing inflammatory markers, reactivity to antigen skin tests, and
C OMOR BI DI T I E S lower natural killer cell activity or total T lymphocyte counts
(Pace & Heim, 2011).
PTSD commonly co-occurs with other psychiatric disorders,
such as other anxiety disorders, affective disorders (depres-
sion, dysthymia, bipolar disorder), and substance use dis- ASSESSM ENT
orders (Kessler et al., 1995). Typically, PTSD precedes the
A range of both lengthy interviewer-based and brief self-rated
development of the comorbid condition (Kessler etal., 1995;
instruments have been developed to assess or screen for PTSD
Perkonigg et al., 2000), although PTSD can occur before,
(Pratt, Brief, & Keane, 2006). Although exhaustive description
after, or concurrently with any other mental disorder. As
of all available instruments is beyond the score of the present
noted, preexisting psychiatric conditions serve as risk factors
chapter, Table 30.3 reports those most commonly used in clin-
for PTSD in the face of trauma exposure. Regarding comor-
ical practice, along with their usefulness and the time needed
bidity of PTSD and other conditions, it may be important to
to administer them. Of note, the gold standard to assess PTSD
address PTSD first in order to adequately treat the comor-
is not the SCID, but the clinician-administered PTSD scale
bid problem. Arecent study of women treated for comorbid
(Blake etal., 1995), which usually takes up to one hour to be
PTSD and substance dependence showed that a reduction in
administered. Anumber of the self-report scales, such as the
Box 30.2 PRIMARY CAR E PTSD SCR EEN Impact of Event ScaleRevised and the Posttraumatic Stress
Diagnostic Scale have been used as screening instruments in
In your life, have you ever had any experience that was so frighten- medical settings with consistently strong results (Davydow,
ing, horrible, or upsetting that, in the past month, you... etal., 2008). Recently, a 4-item screening instrument has been
developed for use in primary care (Box 30.2). Endorsing three
1. Have had nightmares about it or thought about it when you items (yes/no) yields a sensitivity of 0.77 with a specificity of
did not want to? 0.85 for detecting PTSD (Prins etal., 2004).
YESNO
2. Tried hard not to think about it or went out of your way to
avoid situations that reminded you of it?
T R E AT M E N T S A N D PR E V E N T IO N
YESNO
PR I NC I PL E S OF AC U T E S T R E S S DI S OR DE R
3. Were constantly on guard, watchful, or easily startled?
T R E AT M E N T A N D P O S T T R AU M AT IC S T R E S S
YESNO
DI S OR DE R PR E V E N T ION
4. Felt numb or detached from others, activities, or your
surroundings?
It is worth highlighting that many individuals will experience
YESNO
a range of psychological and somatic stress response symp-
toms in the wake of trauma such as hyperarousal, anxiety,
Brief Psychotherapy
Cognitive Behavioral Therapy (CBT) Bryant, 1998a Brief (5 sessions) CBT within 2 weeks > Supportive
counseling in preventing PTSD
Memory Structured Intervention (MSI) Gidron, 2007 No differences between MSI and supportive listening
Pharmacotherapy
Vaiva, 2003 PTSD rate and symptoms lower in the propanolol group
Morphine Bryant etal. (2008c) Patients with PTSD received significantly less morphine
than those who did not develop PTSD
Holbrook etal. (2010) Wounded, morphine shortly after the injury reduced
development of PTSD
From 2010 VA/DOD Clinical Practice Guidelines for Management of PostTraumatic Stress.
and emotional distress. These may not show enough sever- assistance following a traumatic event and those who dis-
ity or impairment to meet ASD criteria; when they do not, play the syndrome of ASD should always be offered care, it
they usually do not require professional intervention and the is not advisable to require or urge all individuals exposed
symptoms generally resolve spontaneously. Requiring acutely to a trauma to talk about the trauma in detail, to partici-
traumatized individuals to debrief in a group setting, pate in groups, or to receive services from a mental health
termed critical incident debriefing, may actually increase rates professional. It is enough to ensure that trauma survivors
of PTSD and related distress through interference with indi- have access to information about the usual course and reac-
viduals spontaneous coping mechanisms (Adler etal., 2008; tions to trauma, to focus on basic medical and safety needs
Rose et al., 2002; van Emmerik, Kamphuis, Hulsbosch, & and to facilitate access to social supports (Zohar, Sonnino,
Emmelkamp, 2002). While those who seek professional Juven-Wetzler, & Cohen, 2009).
Exposurebased therapies
Selfmontoring of anxiety
Cognitivebased therapies
Cognitive restructuring
Relaxation techniques
Selfmontoring of anxiety
First-line pharmacological treatment of PTSD focuses as adjunctive agents in limited cases, those with PTSD are at
on SSRIs, with some support for comparable efficacy of sero- heightened risk for substance abuse and dependence. In addi-
tonin norepinephrine reuptake inhibitors such as venlafaxine tion, benzodiazepines may interfere with CBT efficacy, poten-
(J. Davidson et al., 2006). Although recent research sug- tially even more so when used on an as needed basis. Some data
gests that SSRIs might not be as effective as previously support the use of alternative agents for insomnia and night-
thought (Orsillo etal., 2002; van Emmerik etal., 2002)and mares in patients with PTSD. These include the alpha blocker
that chronic combat-related PTSD may be somewhat less prazosin and newer sleep agents such as eszopiclone (Pollack
responsive, there is strong empirical evidence suggesting etal., 2011; Taylor etal., 2008). Again, an excellent review of
that SSRIs should be the preferred first-line medication for evidence for pharmacotherapy approaches beyond the scope
PTSD based on results from a number of well-conducted of this chapter is available in the recent VA/DoD Clinical
random controlled trials. To date, two agents have been Practice Guidelines for the Management of Post-traumatic Stress
approved by the Food and Drug Administration for the (Department of Veterans Affairs & Department of Defense,
treatment of PTSD: sertraline and paroxetine. SSRIs are 2010).
well tolerated and may also be useful to treat comorbid
depression; however, because of a possible initial increase
in anxiety symptoms, they should be initiated more slowly F U T U R E A N D C ON T ROV E R S I E S
than in depression. Other medications that have been
studied as monotherapy in the treatment of PTSD include The fifth revision of the DSM includes a number of changes
other antidepressants, anticonvulsants, antipsychotics, in the formulation of the diagnostic criteria for acute and
and antihypertensive drugs. While evidence supporting chronic reactions to trauma. ASD and PTSD no longer
their use as first-line treatments is limited by the lack of belong to the anxiety disorder spectrum, but to a new class
large randomized controlled trials, several antidepressants of trauma and stressor-related disorders. The requirement for
including mirtazapine, nefazodone, amitriptyline, imipra- a subjective negative response to the stressor (DSMIVTR
mine and phenelzine might be considered as second-line criterion A2, intense fear, helplessness, horror) has been
choices for monotherapy (Department of Veterans Affairs suppressed in both ASD and PTSD. Finally, in the DSMV,
& Department of Defense, 2010). ASD symptoms are no longer organized in four symptom
Although atypical antipsychotics such as risperidone and clusters but are now grouped into one single criterion. PTSD
olanzapine have not been shown to be effective in monother- symptoms are now reclassified into four clusters (reexpe-
apy on PTSD symptoms, some evidence suggests that their riencing, avoidance, alterations in cognition and mood,
use as adjunctive may be beneficial on associated symptoms of hyperarousal) instead of three. Future studies will deter-
psychosis (Department of Veterans Affairs & Department of mine whether these changes in symptoms criteria will result
Defense, 2010). No large randomized studies support the effi- in changes in prevalence rates, and yield significant clinical
cacy of benzodiazepines for PTSD. While they may be useful implications.
I N T RODUC T IO N Caffeine
Caffeine is one of the most widely used psychotropic drugs
The anxiety that accompanies medical illness contributes
in the United States and one which causes anxiety; it is
greatly to each patients functional impairment (Marcus
found in many beverages and drug combinations (Abelson &
et al., 1997). Recognition and reduction of excessive anxi-
Fishburne, 1976). The approximate amount of caffeine in a
ety facilitates the ability to cope. This chapter presents
cup of coffee is 150 mg; tea generally has about 50100 mg
an approach to the evaluation and treatment of anxiety in
per cup; cola drinks have about 4050 mg/12 oz.; and a small
medical patients that includes both biological and psycho-
chocolate bar has about 1525 mg. Caffeine-containing med-
logical dimensions and requires full medical and psychi-
ications (as it is usually combined with aspirin or acetamino-
atric consideration. First, we review medication-induced
phen) have about 32 mg of caffeine per tablet. Consumption
or substance-induced symptoms and notable underlying
of these medications is associated with an increase in sleep
medical bases for anxiety. Once these possibilities have been
difficulties (Brown etal., 1995). Although sensitivity varies,
considered, a clinician draws on the patients personal and
symptoms of caffeinism may occur at doses of only 200 mg
psychiatric history to determine whether anxiety is part of
(Victor, Lubetsky, & Greden, 1981). Patients with generalized
an underlying psychiatric disorder, such as panic disorder,
anxiety disorder are abnormally sensitive to caffeine for both
mood disorder, or personality disorder. Simultaneously,
subjective and physiologic arousal measures (Bruce et al.,
the clinician assesses the anxiety as a reactive psychological
1992). Caffeine increases norepinephrine levels in the plasma
adjustment response.
and urine (Robertson etal., 1978), inhibits phosphodiester-
ase breakdown of cyclic adenosine monophosphate in the
M E DIC A L DI S OR DE R S T H AT PR E S E N T central nervous system (CNS), and sensitizes central catechol-
ASA NX I ET Y amine receptors, particularly for dopamine (Waldeck, 1975).
Caffeine can precipitate an actual panic attack in patients
Medical disorders can produce anxiety directly or indirectly. with panic disorder (Charney, Heninger, & Jatlow, 1985). In
Some medical disorders have specific effects on neurotrans- chronic users, caffeine abstinence should also be considered as
mitter systems that stimulate anxiety, such as hyperthyroid- a possible source of intermittent anxiety (White etal., 1980).
ism (Hall, 1983; MacCrimmon et al., 1979); others have After ceasing consumption, people who have consumed even
specific effects on neuroanatomic sites associated directly low or moderate amounts of caffeine (mean amounts of 235
with the production of anxiety, for example, tumors of the mg/day, which is equivalent to 2.5 cups of coffee) may have
temporal lobe (Dietch, 1984). Other medical disorders pro- withdrawal syndromes such as moderate to severe headache,
duce anxiety through autonomic arousal, which the patient fatigue, or psychic distress (Silverman etal., 1992). Since caf-
interprets as a psychological state. Medical disorders that can feine is like other psychoactive drugs with the development of
present with anxiety as a prominent symptom are listed in dependence and withdrawal syndrome (Strain et al., 1994),
Box 31.1. patients should be advised to taper off caffeine gradually
rather than stop abruptly.
Energy drinks have moderate to relatively high levels and
TOX IC A N D W I T H DR AWA L E F F E C T S OFDRUG S
concentrations of caffeine (2.535.7 mg per oz) compared to
The toxic and withdrawal effects of drugs are a common cause other caffeinated beverages such as a 12oz. cola or 6oz. cup of
of anxiety in medical patients See Box 31.2. If there is any coffee (see Box 31.3). Energy shots are low volume (12oz.)
doubt about what drugs the patient has been taking, a toxi- and have an even higher concentration of caffeine than other
cology screen should be ordered. Such screening is especially energy drinks. Also, hot beverages like coffee are usually
useful when the patient is suspected of surreptitious drug use. drunk more slowly than cold energy drinks, so in the latter
Review of the patients medication list should also pay atten- case larger quantities of caffeine can be consumed in short
tion to what drugs have been stopped. order. Energy drinks have also been linked to drinking high
635
Box 31.1 MEDICAL CONDITIONS ASSOCIATED Box 31.2 DRUGS THAT CAUSE ANXIETY
WITHANXIETY SYMPTOMS
Stimulants
Cardiovascular Conditions
Amphetamines
Angina pectoris Aminophylline
Arrhythmias Caffeine
Congestive heart failure Cocaine
Hypovolemia Methylphenidate
Myocardial infarction Theophylline
Valvular disease
Sympathomimetics
Endocrine Conditions
Ephedrine
Carcinoid syndrome Epinephrine
Hyperadrenalism Phentermine
Hypercalcemia Phenylpropanolamine
Hyperthyroidism Pseudoephedrine
Hypocalcemia
Hypothyroidism Drug Withdrawal
Pheochromocytoma Benzodiazepines
Narcotics
Metabolic Conditions
Barbiturates
Hyperkalemia Sedatives
Hyperthermia Alcohol
Hypoglycemia
Hyponatremia Anticholinergics
Hypoxia Trihexyphenidyl
Porphyria Benztropine
Diphenhydramine
Neurologic Conditions
Oxybutynin
Akathisia Propantheline
Encephalopathy Meperidine
Masslesion Tricyclics
Postconcussion syndrome Pilocarpine (including ocular)
Seizure disorder
Vertigo Dopaminergics
Amantadine
Peptic Ulcer Disease
Bromocriptine
Respiratory Conditions L-dopa
Carbidopa-leuodopa
Asthma
Metoclopramide
Chronic obstructive pulmonary disease
Neuroleptics
Pneumothorax
Pergolide
Pulmonaryedema
Pulmonary embolism Miscellaneous
Immunologic Conditions Baclofen
Cycloserine
Anaphylaxis
Hallucinogens
Systemic lupus erythematosus
Indomethacin
Anabolic steroids
Captopril
Disopyramide
volumes of alcohol per drinking session, with more injudi-
Dronabinol
cious consequences (Arria & OBrien, 2011). The American
Estrogens
Academy of Pediatrics recommends that adolescents should
Fluoroquinolone antibiotics
not have more than 100 mg of caffeine each day, and adults
Metrizamide
should limit caffeine to 500 mg per day. Older patients may be
*Average values; individual brands may vary. Neuroleptics and Other Dopamine Blockers
Source:Center for Military Psychiatry and Neuroscience at the Walter Reed
Army Institute of Research 2012 (more info on www. jama.com)
From Torpy & Livingston,2013)
Akathisia, an extrapyramidal side effect of typical neuro-
leptics, mimics anxiety. Patients may be aware of inability
Demoxepam (1495)
Desmethyldiazepam 73(30100)
Oxazepam 7(515)
Oxazepam 7(515)
Oxazepam 7(515)
Oxazepam 7(515)
N-desalkylflurazepam 74(36120)
Drugs marked with (*)are prodrugs; all CNS effects are due to their active metabolites.
doses of diazepam (Busto et al., 1986; Pevnick, Jasinski, & prevalence and severity of withdrawal reactions, because their
Haertzen, 1978; Winokur etal., 1980). There are also reports plasma concentrations decline more rapidly following discon-
of seizures occurring in association with the discontinuation tinuation. Withdrawal symptoms can be minimized by slow
of moderate doses of lorazepam (de la Fuenta etal., 1980)and tapering rather than abruptly discontinuing thedrug.
triazolam (Tien & Gujavarty, 1985). One advantage of During withdrawal, autonomic symptoms can be relieved
long-acting benzodiazepines such as clonazepam is that they by a beta-adrenergic blocker (Abernethy, Greenblatt, & Shader,
tend to self-taper if discontinued. Although abrupt discontin- 1981)and possibly by carbamazepine as well (Malcolm etal.,
uation of long-acting benzodiazepines is usually not danger- 1989; Ries etal., 1989). It should be kept in mind that with-
ous, it can lead to a persistent state of heightened anxiety. The drawal symptoms from alprazolam and triazolam may not be
short-acting benzodiazepines are associated with a greater fully covered by other benzodiazepines (Schneider, Syapin, &
I N T RODUC T IO N The hallmark of AN is low body weight for sex and age.
To meet criteria for AN, individuals must either express
Eating disorders (EDs) are common, especially among young an intense fear of becoming fat or exhibit behaviors that
women. EDs are serious illnesses associated with significant interfere with weight restoration; and exhibit a lack of rec-
medical and psychiatric morbidity. Particularly when chronic ognition of the possible health consequences of low weight.
and severe, EDs have relatively high mortality rates when DSM-5 no longer requires cessation of menstruation for
compared with other psychiatric disorders. Because of the 3 months (American Psychiatric Association, 2013). Low
ego-syntonic nature of many EDs, patients often first present body weight is considered a body mass index (BMI) < 18.5
in the medical sector due to the unwanted and unintended for adults, or a BMI < 5th percentile for sex and age using
physical consequences. Frequently patients are embarrassed growth charts for children and adolescents (American
about the underlying behaviors causing their physical prob- Psychiatric Association, 2013).
lems and are therefore reluctant to report disordered eating. In contrast to those with AN, individuals with BN are
For these reasons, it is crucial that clinicians be knowledge- normal weight, overweight, or obese. BN is characterized by a
able about EDs and know when to suspect that one is pres- pattern of binge eating followed by compensatory behaviors to
ent. Early identification and treatment can help prevent the make up for calories consumed, occurring at least once weekly
associated morbidity and mortality. for at least 3 months. Compensatory behavior may comprise
purging (i.e., self-induced vomiting, laxative or diuretic mis-
use) or non-purging (i.e., fasting, excessive exercise) symptoms.
DI AG NO S I S Similar to AN, the self-image of individuals with BN is domi-
nated by their weight and shape. DSM-5 differentiates sub-
In 2013, the Diagnostic and Statistical Manual of Mental types of AN (restricting and binge-eating/purging type), such
Disorders fourth edition text revision (DSM-IV-TR) was that an individual who meets criteria for both disorders would
updated to the fifth edition (DSM-5). The Eating Disorders be diagnosed as AN binge-eating/purging type (American
Work Group made several revisions to enhance the clini- Psychiatric Association, 2013).
cal utility of ED diagnoses in DSM-5. The primary DSM-5 BED is characterized by frequent episodes of binge eat-
changes included combining feeding disorders and EDs ing, but does not feature the compensatory behaviors that
into a single chapter; broadening and clarifying the criteria characterize BN. To meet diagnostic criteria, binge episodes
for anorexia nervosa (AN) and bulimia nervosa (BN); add- must be associated with at least 3 of 5 key physical and psycho-
ing binge eating disorder (BED) as a formal diagnosis; and logical characteristics (e.g., eating rapidly or when not hungy;
re-classifying feeding disorder of infancy or early child- feeling disgusted or guilty after bingeing). To distinguish
hood as avoidant/restrictive food intake disorder (ARFID). binge eating from simple overeating, binges are defined as
Moreover, DSM-5 separated the single DSM-IV residual cat- consuming a large amount of food in a short period of time
egory of eating disorder not otherwise specified (EDNOS) while concurrently feeling out of control (i.e., unable to stop
into two separate residual categories of other specified feed- eating) (American Psychiatric Publishing, 2013).
ing or eating disorder (OSFED) and unspecified feeding OSFED, previously referred as EDNOS, comprises five
or eating disorder (UFED). OSFED comprises a list of five non-exhaustive example presentations:atypical anorexia ner-
example presentations, whereas UFED is reserved for cases vosa (anorexic features without low weight), subthreshold BN
in which a clinically significant ED is present but the clini- (bingeing and purging less than once per week or for fewer
cian does not have sufficient information to characterize than 3 months), subthreshold BED (binge eating less than
the presentation (e.g., in an emergency room setting) (see once per week or for fewer than 3months), purging disorder
below). In this chapter, we will focus mainly on AN, BN (regular purging in the absence of binge eating), and night
and BED because their phenomenology and treatment is eating syndrome (characterized by nocturnal eating episodes
currently better understood, and clinicians treating adults are after awakening from sleep, or consuming a large propor-
most likely to encounter patients with these diagnoses. See tion of daily calories after the evening meal). Although many
Table 32.1 for descriptions of each ED diagnosis. DSM-5 changes aimed to reduce the large number of patients
656
Table32 .1 EATING DISOR DERS
Anorexia Nervosa Low body weight for sex and age accompanied by an intense fear of becoming fat and/
or persistent behaviors that interfere with gaining weight; and lack of recognition of the
possible health consequences of low weight. Subtypes are based on whether low weight is
maintained by pure restriction or by bingeing and/or purging.
Bulimia Nervosa Binge eating followed by compensatory behaviors to make up for calories consumed,
occurring at least once weekly for at least 3months. Self-image is dominated by weight
and shape. Individuals with BN can be normal weight, overweight, or obese.
Binge Eating Disorder Frequent episodes of binge eating that are not followed by compensatory behaviors.
During binges individuals feel out of control. Afterward, they may feel embarrassed,
disgusted with themselves, depressed, and/or guilty. Patients can be normal weight,
overweight, or obese.
Other Specified Feeding or Eating Disorder This group comprises eating disturbances that cause clinical impairment but do not
meet diagnostic criteria for AN, BN, BED, or ARFID. Specific examples include partial
syndromes of either AN or BN, as well as other forms of ED such as repeatedly purging in
the absence of binge eating, or night eating syndrome.
falling into this residual category, available data suggest that At times a patient is relieved when a clinician ascertains a
a substantial minority of cases will still receive an OSFED or covert ED. In turn, the patient may become forthcoming with
UFED diagnosis (Thomas etal., under review). information and motivated to accept treatment. This is satis-
fying for both patient and clinician. However, when a patient
continues to deny there is an eating problem and refuses
E PI DE M IOL O G Y recommended treatments, the clinician may feel frustrated,
exhausted, and unsure how to proceedespecially when
Although epidemiological data on EDs are limited, findings behaviors have potentially dangerous medical consequences.
from the National Comorbidity Survey Replication (NCS-R) Although difficult for all involved, this is a crucial time to
provide estimates (Hudson, Hiripi, Pope, & Kessler, 2007). strengthen the patientclinician alliance and motivate the
Lifetime prevalence estimates for women and men are 0.9% patient toward ED treatment.
and 0.3% for AN, 1.5% and 0.5% for BN, and 3.5% and 2.0%
for BED, respectively (Hudson et al., 2007). These are likely
underestimates, given that individuals with disordered eating C OMOR B I DI T Y
may be reluctant to report behaviors and also because the
NCS-R did not include operational definitions, OSFED EDs are typically comorbid with other psychiatric disorders.
examples or new DSM-5 presentations such as ARFID. Traits common to AN and BN include perfectionism and dys-
Also according to NCS-R data, only a minority of indi- phoric mood. Other traits presage the specific ED symptoms
viduals with EDs seek mental health treatment. In this repre- that an individual may ultimately adopt. For example, obses-
sentative study, only 50%63% of those with lifetime EDs had sive compulsive traits contribute to restrictive eating patterns,
ever sought treatment for emotional problems, and less than whereas borderline personality traits promote impulsive eat-
50% had ever sought treatment specifically for EDs. For those ing patterns such as binge eating and self-induced vomiting
patients with 12-month histories of ED, only 15.6% of those (Sansone & Sansone, 2010). Similarly, high constraint, con-
with BN and 28.5% of those with BED reported seeking treat- stricted affect, and asceticism are often associated with AN,
ment for emotional problems in the preceding 12months. whereas high impulsivity and sensation-seeking are associated
The most common site of treatment in the NCS-R study with BN (Kaye, 2008). Impulse control disorders have been
was the medical sector (e.g., primary care). In medical settings associated with both normal-weight and obese presentations
patients rarely present with a chief complaint of disordered of BED (Keel, Holm-Denoma, & Crosby, 2011).
eating (e.g., restricting food, purging, using laxatives); rather, The majority of individuals with EDs in the NCS-R also
most present with nonspecific physical or emotional com- had a lifetime history of another psychiatric disorder. Anxiety,
plaints. For example, patients with AN may report lighthead- mood, and substance use disorders are highly comorbid with
edness or constipation; patients with BN may present with EDs. Rates of lifetime anxiety disorders among patients with
acid reflux or other gastrointestinal problems; and patients EDs range from 54%83% (Kaye, 2007). Patients with AN
with BED may present with obesity or depression. In our who binge and purge have higher rates of substance use dis-
clinical experience, it is sometimes only after months of frus- orders than patients with restricting-type AN (Root et al.,
trating and seemingly treatment-resistant physical symptoms 2010). Higher comorbidity is typically associated with worse
that suspicion of an ED develops. overall ED outcome.
Table32 .3 PERTINENT FINDINGS ON R EVIEW OF SYSTEMS IN PATIENTS WITH EATING DISOR DERS
General High, low, or dramatic change in weight Restricting, bingeing and/or purging
Lethargy Restricting/starvation
Gyn Irregular menses or amenorrhea Low body fat and/or low weight, stress
the weigh-in to falsely increase weight. Checking urine specific Medical Assessment in Anorexia Nervosa
gravity can help rule out water loading.
For many patients, being weighed is highly distressing. It Physical signs common to patients with AN are related to food
is therefore a difficult procedure for clinicians who are work- restriction, malnutrition, and bingeing/purging if those behav-
ing diligently to decrease patients distress, not increase it. iors are present. On physical exam, cachexia, parotid and sub-
Instead of forgoing the weighing procedure entirely or engag- mandibular gland swelling (if purging type), brittle and thinning
ing in lengthy struggles with patients, we suggest taking an head hair, lanugo, acrocyanosis, and breast atrophy are typical.
empathic but firm approach with patients. The following Assessment of the cardiovascular system on physical exam typi-
statement may be used:I realize getting weighed may be dif- cally reveals sinus bradycardia. There may be signs associated with
ficult for you. In order for me to provide you with good and mitral valve prolapse, which occurs related to reduced left ven-
safe care, Iwill have to weigh you at each visit. It is likely to tricular mass (Cooke & Chambers, 1995). Echocardiograms of
be more difficult in the beginning and get easier with time. patients with AN often demonstrate atrophic myocardium and
Lets go ahead and get it out of the way for todays visit. The low cardiac output (Casiero, 2006). In very underweight patients
majority of patients, however reluctant, typically agree to be (e.g. BMI less than or equal to 13.5kg/mg2), pericardial effusion
weighed. may be present. It is most often asymptomatic but in rare cases
Although the physical signs common to EDs are nonspecific, may require pericardiocentesis to prevent tamponade (Docx
patterns or combinations of physical signs can help identify etal., 2010; Polli etal., 2006). Electrocardiogram may demon-
an ED and support diagnosis. Table 32.4 outlines some of the strate prolongation of the QTc and PR intervals, first-degree
physical signs common to EDs. heart block, and ST-T wave abnormalities. Most cardiac abnor-
Attention to vital signs is important for all ED patients, malities improve with careful nutritional rehabilitation.
but particularly for those who are significantly underweight Evaluation of the gastrointestinal system in patients with AN
or with severe bingeing, purging, or hyper-exercise. Sinus bra- may reveal diminished bowel sounds consistent with inactivity
dycardia, low blood pressure, orthostatic hypotension, and and slowed metabolism. Although rare, there have been several
hypothermia are ominous signs of starvation and typically reports of patients with AN having massive gastric dilatation fol-
indications for inpatient hospitalization on a medical unit to lowing binges (Barada et al., 2006; Mathevon, Rougier, Ducher,
begin weight restoration and nutrition repletion. In a study of Pic, Garcier, & Schmidt, 2004), as well as gastric rupture and
medical findings in community-dwelling patients with AN, death (Sinicina, Pankratz, Bttner, & Mall, 2005). Patients with
41.3% had bradycardia, 16.1% hypotension, and 22.4% had common complaints of early fullness, nausea, and bloating are
hypothermia (Miller et al., 2005). In normal-weight patients often referred to gastroenterology to rule out organic pathology.
with BN, changes in heart rate and blood pressure, particu- Gastric and bowel studies, in the absence of organic pathology, are
larly hypotension and tachycardia, may indicate presence of often positive for delayed emptying (Zipfel et al., 2006, Hultson &
rapid fluid shifts and dehydration from bingeing and purging Wald, 1990; Benini et al., 2004) and increased whole bowel and
as well as more concerning behaviors such as ipecac use, which colonic transit time (Waldholtz & Andersen, 1990). Studies
is known to cause cardiomyopathy (Rashid, 2006; Schneider demonstrate that nutritional rehabilitation improves gastroin-
et al., 1996). testinal dysfunction (Rigaud et al., 1988).
EVIDENCE OF EFFICACY
DI AGNOSIS TR EATMENT SUMM ARY IN AT LEAST 2 RCTS
Anorexia Nervosa Family Based Treatment Parents restore patients weight by taking Yes
charge of refeeding their child, exploring
how the illness affects family dynamics,
and working to support patients ability
to make proper food choices.
Bulimia Nervosa Cognitive Behavior Patients learn how thoughts and behaviors Yes
Therapy maintain BN. Patients normalize their eating
while concurrently challenging and reducing
thoughts and behaviors that maintain BN.
Patients also identify and reduce triggers for
binge eating such as dietary restriction, poor
body image, and mood intolerance.
EVIDENCE OF EFFICACY
DI AGNOSIS TR EATMENT SUMM ARY IN AT LEAST 2 RCTS
Binge Eating Disorder Cognitive Behavioral Therapy Normalizes eating behaviors and decreases Yes
maladaptive thoughts about weight and
shape. Emphasizes healthy dietary restraint
with patients who are overweight.
and slower rate of weight loss following discharge (Kaplan vital organ function, and have achieved steady weight gain. This
etal., 2009). More specifically, lower rates of weight loss over is a critical transition period, and, without ongoing intensive
the first 28days postdischarge predicted better weight mainte- treatment, patients tend to relapse rapidly.
nance at 6 and 12months (Kaplan etal., 2009). Additionally, Patients with AN are generally hospitalized on inpatient
many of the medical complications improve or entirely reverse psychiatry units for any of the following combinations of cri-
with weight restoration. teria: underweight or rapidly changing weight but not yet
For the most acute patients, inpatient medical and/or psy- significantly medically compromised, moderate to severe ED
chiatric hospitalization is necessary. Psychiatric units vary behaviors (e.g., bingeing and purging multiple times per day,
considerably in their capacity to manage medically ill patients; severe restriction), moderate to severe comorbid psychiatric ill-
inpatient medical admission is indicated if BMI is very low ness (e.g., major depression), self-injurious behavior and/or sui-
or if any of the following are present: significant bradycardia cidality (intensifying or active thoughts, developing intentions
(<40bpm), hypothermia, significant or symptomatic orthostatic or plans to act on thoughts). In our experience, insurance com-
hypotension, hypokalemia or electrolyte disarray, signs of organ panies will generally approve inpatient treatment when patients
failure, or any acute medical complications (e.g., hematemesis). meet any of the above criteria. For patients who are on the bor-
Given the risks associated with refeeding syndromea derline of these criteria, lower levels of care such as residential
potentially life-threatening syndrome involving large fluid or intensive outpatient programs may be covered. If physicians
and electrolyte shifts associated with introducing nutrition to come up against resistance from insurance companies, it is help-
the severely malnourishedrefeeding severely underweight ful to emphasize that patients are failing the current level of
patients (i.e., BMI < 16.0 kg/m2, Mehler et al., 2010) is done treatment and, therefore, no less intensive option exists.
in a medically monitored setting. Refeeding syndrome is associ- Given high rates of relapse following inpatient treatment
ated with hypophosphatemia, hypomagnesemia, hypokalemia, for refeeding, a range of treatment options between the inpa-
congestive heart failure, edema, delirium, coma, and even death tient and outpatient setting have developed in recent years
(Gunarathne, McKay, Pillans, McKinlay, & Crockett, 2010). It including residential (Delinsky etal., 2010), day hospital, and
can be prevented by gradually introducing nutrition and closely intensive outpatient treatments.
monitoring electrolytes, volume status, and vital organ func-
tion. In general, nutrition starts very slowly to make sure organ
Psychological Treatments for Anorexia Nervosa
systems demonstrate capacity to withstand the stress of reintro-
ducing nutrition. During acute starvation, AN patients typically Family-Based Treatment
have a suppressed resting metabolic rate even when accounting The psychosocial treatment modality for AN with
for their low weight. Therefore, during refeeding patients meta- the greatest empirical support is a three-phase manual-
bolic rates increase substantially and they often require a very ized family-based treatment (FBT) designed for the outpa-
high daily caloric intake to gain weight, for example, as much tient care of adolescent patients (Lock, le Grange, Agras, &
as 100 kcal/kg per day. Consulting dieticians with experience Dare, 2001). In phase one, the patients parents are encour-
refeeding severely malnourished patients is essential for safe and aged to correct the patients malnutrition by planning and
effective treatment. Patients can be transitioned to other levels implementing a nutritious, calorie-dense meal plan. The
of care once they reach reasonable medical stability. Medical therapist supports the parents in their efforts by absolv-
stability is somewhat vague, but in general it is when patients ing them of blame for the etiology of the illness and help-
are no longer at risk of refeeding syndrome, demonstrate stable ing them encourage their child to eat adequately during an
S U M M A RY
I N VOLU N TA RY T R E AT M E N T
Involuntary hospitalization usually occurs when there are In summary, EDs are common psychiatric illnesses that are
emergent psychiatric or medical problems. Psychiatrically this associated with substantial medical and psychiatric morbid-
is when patients are suicidal, homicidal, actively engaging in ity. As most patients with ED first present in the medical
severe self-harm behavior, or suffering severe comorbid illness setting, medical clinicians are uniquely poised to make the
such as depression, mania, or psychosis. For example, a patient first diagnosis of a previously covert ED. Patients with EDs
with BN who gains 20 pounds, develops suicidal thoughts, often require multidisciplinary teams composed of a medi-
and buys a bottle of acetaminophen with the intention to cal clinician, therapist, and sometimes a dietitian and/or
overdose would be hospitalized involuntarily on a psychiatric psychiatrist. With treatment, most patients achieve signifi-
unit. cant improvement and many fully remit. Although treat-
Medically, patients may be hospitalized and treated against ment can be challenging for both patients and clinicians, it
their will when two conditions are met: (1) when emergent can be rewarding as well. Increasingly there are empirically
medical conditions related to the ED arise, and (2) when supported psychosocial and pharmacologic treatments for
patients fail to demonstrate adequate decision-making capac- EDs. Although nutritional stabilization and psychosocial
ity. In these situations clinicians must make a determination therapies remain mainstays of treatment, some pharmaco-
of whether the patient maintains decision-making capacity to logical interventions, particularly fluoxetine in BN, have
refuse treatment, similar to any other situation in medicine demonstrated efficacy. The main supported treatments
when patients refuse treatment. An example would be a young currently are FBT for AN; CBT and fluoxetine for BN;
woman with AN with a BMI of 14.0kg/m2, heart rate of 40 and CBT (including a guided self-help format) for BED.
beats per minute, low potassium, and complete food and water Research into promising novel therapies is needed and is
refusal. She refuses to be hospitalized for refeeding despite ongoing.
E N D O C R I N E DI S OR DE R S Diabetes Mellitus
Type 2 diabetes is a major public health concern with high
Hypothyroidism morbidity, mortality, and health-care costs. Increased preva-
lence of sleep problems including difficulty initiating sleep,
Patients with hypothyroidism may present with excessive difficulty maintaining sleep, excessive daytime drowsiness,
sleepiness and fatigue. Polysomnography changes in sleep and sleep-disordered breathing have been reported in patients
in hypothyroid patients include decreased slow wave sleep with type 2 diabetes mellitus.
(SWS), which tends to normalize after thyroid replacement. A growing number of epidemiologic studies, originating
Ahigher incidence of obstructive sleep apnea (OSA) has been from various geographic regions and involving diverse study
noted in patients with untreated hypothyroidism. Factors populations, have suggested the existence of an independent
such as obesity, myopathy, and upper airway edema may link between markers of severity of OSA and an increased
contribute to increased incidence of OSA in patients with risk of type 2 diabetes. Numerous studies have examined the
hypothyroidism. effects of continuous positive airway pressure (CPAP) treat-
ment on glucose metabolism both in diabetic and nondia-
Acromegaly betic populations. There is accumulating evidence suggesting
that metabolic abnormalities can be partially corrected by
Acromegaly is characterized by hypersecretion of growth hor- CPAP treatment, which supports the concept of a causal link
mone, usually secondary to pituitary adenoma. Approximately between OSA and altered glucose control.
60%80% of the patients with acromegaly complain of sleep The pathophysiological mechanisms leading to altera-
apnea which is primarily obstructive in nature, although, tions in glucose metabolism in OSA patients are likely to be
678
multiple. High sympathetic nervous system activity, intermit- PU L MON A RY DI S OR DE R S
tent hypoxia, sleep fragmentation and sleep loss, dysregulation
More than 50% of the patients with COPD experience dif-
of the hypothalamic-pituitary axis, endothelial dysfunction,
ficulty initiating and maintaining sleep. Sleep is interrupted
and alterations in cytokine and adipokine release have all
in COPD patients due to production of secretions, coughing,
been proposed as potential mechanisms for abnormal glucose
and dyspnea related to airway constriction. Patients com-
metabolism in OSA patients.
plain of multiple awakenings during night, daytime fatigue
and somnolence. COPD is associated with nocturnal hypox-
Obesity emia, especially during REM sleep, due to loss of muscle tone
of the accessory muscles of respiration during REM sleep.
Obesity is a serious medical disorder resulting in increased Coexistence of obstructive sleep apnea (OSA) and COPD
risk of morbidity and mortality due to both acute and chronic is termed overlap syndrome, and its prevalence has been esti-
medical conditions. Sleep disorders including sleep-disordered mated at 29% according to one study. Patients with overlap
breathing (SDB), excessive daytime somnolence, night eating syndrome are at greater risk of prolonged oxygen desatura-
syndrome, and sleep-related eating disorders have been noted tions at night as compared to those with OSA alone, and it
in obese patients. appears to be associated with increased morbidity and mortal-
Increased incidence of SDB, including OSA and obesity ity in these patients. Treatment of OSA with CPAP therapy
hypoventilation syndrome, has been noted in obese patients. has been associated with improved outcomes and decreased
For every 10 kg increment in weight, the risk for OSA mortality in patients with overlap syndrome.
increases by more than twofold, while an increase in the body Patients with restrictive lung disorders and chest wall
mass index (BMI) by one standard deviation is associated abnormalities (kyphoscoliosis) are at risk of sleep related
with a fourfold increase in the prevalence of OSA. The pos- hypoventilation/hypoxemia. Polysomnography findings
sible etiological factors may include gender (OSA more com- include frequent arousals, increased wakefulness after sleep
mon in obese males), anatomical and neuromuscular factors, onset, and nocturnal hypoxemia. Other consequences of noc-
and hormonal and genetic factors. turnal hypoxemia include pulmonary hypertension, cor pul-
Obesity hypoventilation syndrome is defined as a monale, and neurocognitive dysfunction. These patients likely
combination of obesity, chronic daytime hypercapnia require BPAP for treatment of sleep-related hypoventilation/
(PaCO2 > 45mm Hg), and a SDB in the absence of other hypoxemia.
known causes of hypercapnia. The prevalence of OHS in
sleep apnea syndrome is 8%10% when BMI is between
3034 kg/m2 and 18%25% when BMI is >40 kg/m2.
C A R DIOVA S C U L A R DI S OR DE R S
Conversely, not all patients with OHS have sleep apnea
syndrome. In approximately 90% of patients with OHS Consistent data suggest strong associations between
the SDB consists of OSA. The remaining 10% of patients sleep-disordered breathing and hypertension, coronary artery
with OHS have an apneahypopnea index less than 5.The disease, congestive heart failure, and cardiac arrhythmias.
pathophysiology of OHS results from complex interactions, Potential mechanisms of increased of cardiovascular events
among which are increased work of breathing related to in patients with OSA include increased sympathetic activity
obesity, abnormal load responsiveness, and repeated airway during sleep, inflammation due to increased proinflammatory
occlusion during sleep. cytokines in OSA, hypercoagulability, endothelial dysfunc-
The most important therapy for OSA in obese patients tion, oxidative stress, and insulin resistance.
is weight loss. Weight loss changes pharyngeal anatomy and OSA has been implicated as a cause of nocturnal ST
decreases airway collapsibility by increasing the pharyngeal depression and angina pectoris. Higher incidence of fatal and
closing pressure. A longitudinal study with a 4-year poly- non-fatal cardiovascular events has been reported in patients
somnogram follow-up showed that a 3% change in AHI with severe OSA. Nocturnal arrhythmias may contribute to
was noted with each percent change in weight. In one con- higher night time prevalence of sudden death in patients with
trolled study, 23 obese patients were assigned to receive either OSA. Early recognition and treatment of sleep-disordered
dietary counseling or no intervention. Those who experi- breathing with positive airway pressure therapy in patients
enced weight loss of 10kg or more had significant reduction with cardiovascular disorders has been associated with
in apnea index (AI), improvement in daytime sleepiness, and improved morbidity and mortality.
oxyhemoglobin saturation. The most impressive results of Patients with congestive heart failure (CHF) may develop
AHI improvement are derived from those morbidly obese both OSA and central sleep apnea (CSA). CHF patients CSA
patients who underwent bariatric surgery. One of the stud- may develop Cheyne Stokes respiration (CSR) with periodic
ies noted a 72% reduction in the mean AHI of 47 morbidly crescendo-decrescendo breathing accompanied with apneas
obese patients after 1year of undergoing Roux-en-Y gastric predominantly during NREM stages 1 and 2. The risk fac-
surgery. However, at 7-year follow-up, 47% had regained tors for CSA-CSR pattern include old age, male gender,
considerable weight and were diagnosed with severe OSA. PaCO2 <38 mm Hg, atrial fibrillation, and left ventricular
Alternative treatment options for OSA and OHS in obese ejection fraction <40%. CHF patients with CSA-CSR pat-
patients include CPAP and bilevel positive airway pressure tern have a greater mortality risk as compared to those with-
(BPAP) devices. out CSR pattern. Therapy for CSA-CSR pattern begins with
ACETYLCHOLINESTERASE
INHIBITORS
ALCOHOL
Acute 1 1 1 6 1
Withdrawal 1 1 1 1 1 111
ANALGESICS
Opioids
Acute 6 1 6 1 1
Withdrawal 1 1
ANORECTICS 1
ANTIBIOTIC
Quinolones 1
ANTICHOLINERGICS 1 1 6 6
ANTICONVULSANTS
Carbamazepine 1 1
Phenytoin
Valproate 1 1
ANTIDEPRESSANTS
Bupropion 1 Nightmares
and PLMs
MAOI
Acute 1
Withdrawal 1
Mirtazepine 1 1 1
SSRI 6 6 6 1 6 6
Trazodone 1 1 1
(continued)
Table33.2(CONTINUED)
Tricyclics
Acute 1 6 1
Withdrawal 1 1 1 1 1
Venlafaxine 1 1
ANTIHISTAMINES
H1 agonists 11 1
H1 antagonists
ANTIHYPERTENSIVES
2 agonist 1 1 1 1 1 1 Nightmares
1 antagonist 1 1
B-blocker
Lipophilic 1 Nightmares
Ca channel agonist 1
5HT2 agonist 1
Methyldopa 1 Nightmares
ANTINEOPLASTIC 1 1 Nightmares
Flutamide 1 1 Nightmares
Procarbazine 1 Nightmares
Interferons 1
ANTIPARKINSONIAN
L-dopa
Acute 1 1 Nightmares
Chronic 1
Amantadine 1
Selegiline
ANTIPSYCHOTICS
Acute 1 1 1
Withdrawal 1 1 1
ANXIOLYTICS 1
Buspirone
BARBITURATES AND 1 1
BENZODIAZEPINES
Acute 1 1 1 1
Withdrawal 1 1 1
CAFFEINE 1 1 1 Nightmares
CORTICOSTEROIDS 1 1 1 1 1
LITHIUM
NICOTINE
Acute 1 1
Withdrawal 1 1 1 1
STIMULANTS 1
TETRAHYDROCANNABINOL 1 1
Yohimbine
(1)=that the drug is known to produce an increase in the sleep parameter or phenomenon; ()=that the drug is known to produce a decrease in the sleep parameter or phenomenon; (6)=that the drug is known to produce
variable effect on the sleep parameter or phenomenon; (blank)=indicates that there are no reliable data on the effect of this drug on sleep parameters; (11) or (111)=degree of the effect; (NO)=zero effect; TST=total sleep
time; #A=number of arousals; SL=sleep latency; %II=percentage stage II sleep; %SWS=percent slow wave sleep; %REM=percent rapid eye movement sleep; REML=REM sleep latency.
produce REM sleep rebound and often nightmares, though metals), there is more information becoming available about
withdrawal from other antidepressants can, less commonly, potential adverse effects of herbal preparations taken as sleep
cause sleep disturbance. aids, daytime stimulants, or for other purposes. Table 33.3
Excessive daytime sleepiness is associated with drugs indicates toxicity described from the use of herbal substances
that cause sleep loss or sleep disruption as well as withdrawal for sedative or stimulant purposes as abstracted from a review
from chronic CNS stimulants and direct effects of opioids, of the use of herbal medications among consultation popula-
antihistamines, certain beta blockers, and many dopamine tions (Crone & Wise, 1998).
antagonists including antiemetics. Hypnotics such as flu-
razepam, with long half-lives or active metabolites that have
long half-lives, commonly produce daytime hangovers and HO S PI TA L E N V I RON M E N TA L FAC TOR S
sedation.
Neuroleptics, commonly used in medical patients for Hospitalization is in itself anxiety provoking, with the pres-
psychosis, delirium, and behavior dyscontrol, may produce ence of the significant illness that led to admission amplified
akathisia that may be manifest as disturbances in nocturnal by a strange environment and the attendant procedures, many
sleep/wake behavior. Typical neuroleptics may worsen sleep of which are painful and require preparation that may be
by exacerbating an underlying restless legs syndrome and peri- uncomfortable at least. In addition, care routines seldom con-
odic movements in sleep. The differential diagnosis between form to the patients home schedule, and new nursing person-
these two phenomena is often difficult. Distinguishing fea- nel appear at least three times a day. The cadre of laboratory
tures are that akathisia is not characteristically predominant workers, medical students, residents, fellows and attendings,
in the evening and at bedtime as is the syndrome of restless and consulting services have a schedule of their own that keep
legs. Restless legs are not commonly manifest in the morning days very active and often allow little time for rest and recu-
or midday hours, except in advanced cases. The differential peration from the previous tests or procedures.
diagnosis is important because of significant differences in The hospital day usually begins very early, as the patient
recommended treatment. Treatment for akathisia is reduc- is awakened from (usually) a restless nights sleep in a strange
tion of the neuroleptic (or rarely an SSRI), introduction of room with a strange bed. The first experience in the morn-
anticholinergic agents, or low-dose propranolol. Appropriate ing is often a needle stick for blood work, an opportunity for
treatment of restless legs syndrome is reduction of the exacer- a hurried bath, and preparations for tests that may include
bating agent, the addition of dopaminergic agents or clonaz- enemas and missed meals. The familiar bed partners absence
epam, or, in severe cases, narcotics. and changes in ambient noises and temperatures also contrib-
Another source of complexity in evaluating the sleep in ute to unsettled sleep patterns and sleep depth, resulting in
medical patients is the increasingly common use of unregu- fragmented sleep and disturbed circadian rhythms. The many
lated over-the-counter herbal preparations. Aside from the circadian, hormonal, and behavioral factors that contribute to
likelihood that these preparations may be contaminated with stable state of well-being are disrupted, and there is seldom
unknown substances (antiinflammatory agents, steroids, any exposure to ambient light of the right frequency, strength,
diuretics, antihistamines, tranquilizers, hormones, and heavy and duration to reset the important internal sleepwake cycle
I N T RODUC T IO N DI AG NO S T IC C R I T E R I A
The earliest three operationally qualified working definitions
Of every five patients seeking medical care, one complains of
for chronic fatigue syndrome are the CDC version (Fukuda
fatigue; this accounts for more than 7million office visits per
et al., 1994), the British version, and the Australian version
year (Epstein, 1995). Frequently no treatable cause is found.
(Bates et al., 1994; Wessely, 1995). The CDC version remains
Over 800 research articles reflect the scientific and medical
the most cited and the best validated although at least five
communitys vigorous efforts to uncover the etiology and
others have been added (Brurberg et al. [2014]; Johnston et al.
cure for a spectrum of complaints characterized globally as
[2013]). These criteria were designed as a basis for research into
chronic fatigue syndrome(CFS).
CFS to insure uniformity in patient selection. The CDC cri-
CFS denotes a syndrome of severe disabling physical and
teria differ by requiring multiple minor signs and symptoms.
mental fatigue lasting at least 6 months that substantially
The British criteria require a definite onset of the illness, and
impairs functioning, is exacerbated by minimal exertion,
the Australian criteria require the presence of post-exertional
and is unexplained by a conventional biomedical diagno-
fatigue (Bates et al., 1994).
sis (Fukuda et al., 1994; Sharpe et al., 1997). It is typically
The CDC guidelines describe the symptom of fatigue as
accompanied by other symptoms such as myalgias, sleep
severe mental and physical exhaustion. It is not somnolence
disturbances, and mood disorders. There is a high preva-
or lack of motivation and cannot be attributed to exertion or
lence of comorbid psychiatric illness (Katon et al., 1991;
diagnosable disease (Fukuda etal.,1994).
Manu, Matthews,& Lane, 1988)and comorbid fibromyalgia
Definitions for and clinical evaluation of prolonged
(Bombardier& Buchwald,1996).
fatigue and chronic fatigue according to the current CDC
To date, an identifiable etiology for CFS has not been
guidelines are as follows: prolonged fatigue is self-reported
reproducible. Physicians have very few proven treatments to
persistent fatigue lasting 1month or longer; chronic fatigue is
offer. Obviously, it is difficult to treat a syndrome of symp-
self-reported persistent or relapsing fatigue lasting 6 or more
toms effectively if the etiology is unknown.
consecutive months. Figure 34.1 describes the evaluation
Patients become disillusioned and angry if they perceive
and classification of unexplained chronic fatigue (Fukuda
that the authenticity of their suffering is questioned in light
etal.,1994).
of repeated negative findings. Many patients become dissatis-
Prolonged or chronic fatigue mandates a thorough clini-
fied with their physicians and seek alternative, nontraditional,
cal evaluation to identify potentially treatable underlying or
and nonscientific sources of care (Denz-Penhey& Murdoch,
contributing conditions. CFS as defined by the CDC cannot
1993; Murdoch, unpublished). This chapter is a guide for
be diagnosed without such an evaluation. This clinical evalu-
psychiatrists who are evaluating and managing chronically
ation should include the following:
fatigued patients.
1. Athorough history to evaluate the following:
a. the medical and psychosocial circumstances at the
DE S C R I P T ION OF C H RON IC onset of fatigue
FAT IGU E S Y N DROM E b. -past medical history (including history of thyroid
disease, anemia,etc.)
Chronic fatigue syndrome is a clinically defined condition c. the presence or history of depressive or other psychiat-
characterized by severe disabling fatigue and a combination ric disorders
of symptoms that prominently feature self-reported impair- d. any previous episodes of medically unexplained
ments in concentration and short-term memory, sleep distur- symptoms
bances, and musculoskeletal pain. The diagnosis of CFS can e. alcohol or other substanceabuse
be made only after medical and psychiatric causes of chronic f. current use of prescription and over-the-counter medi-
fatiguing illness have been excluded (Fukuda etal.,1994). cations and/or food supplements.
6 91
I. Clinically evaluate cases of prolonged or chronic fatigue by
A. History and physical examination;
B. Mental status examination (abnormalities require appropriate psychiatric, psychological, or
neurological examination)
C. Tests (abnormal results that strongly suggest an exclusionary condition must be resolved)
1. Screening laboratory test: CBC, ESR, ALT, total protein, albumin, globulin, alkaline
phosphatase, Ca, PO , glucose, BUN, electrolytes, creatinine, TSH, and UA
2. Additional tests as clinically indicated to exclude other diagnoses
III. Subgroup research cases by the presence or absence of the following essential
parameters:
1. Comorbid conditions (psychiatric conditions must be documented by use
of an instrument)
2. Current level of fatigue (measured by a scale)
3. Duration of fatigue
4. Current level of physical function (measured by an instrument)
2. Amental status examination should be performed, enzyme-linked immunosorbent assay (ELISA) and
searching for abnormalities in mood, intellectual func- Western blot for Borrelia burgdorferi, treponemal (fluo-
tion, memory, and/or personality. Particular attention rescent treponemal antibody absorption [FTA-Abs])
should be directed toward current symptoms of depres- or non-treponemal tests(VDRL or rapid plasma reagin
sion or anxiety, self-destructive thoughts, and observable [RPR] test for syphilis), sleep studies (polysomnography
signs such as psychomotor retardation. Evidence of a by a certified sleep laboratory), and reproductive/endo-
psychiatric or neurologic disorder requires an appropriate crine workup).
psychiatric, psychological, or neurologic evaluation.
Conditions that potentially explain chronic fatigue symp-
3. Athorough physical examination.
toms include the following:
4. Aminimum battery of laboratory screening tests includ-
ing complete blood count with leukocyte differential; 1. Any active medical condition that may explain the
erythrocyte sedimentation rate; serum levels of alanine presence of chronic fatigue (Kroenke, 1989), such as
aminotransferase, total protein, albumin, globulin, untreated hypothyroidism, cancer, sleep apnea, nar-
alkaline phosphatase, calcium, phosphorus, glucose, colepsy, and iatrogenic conditions such as side effects
blood urea nitrogen, electrolytes, and creatinine; deter- of medication(s). Unfortunately, much of the research
mination of thyroid-stimulating hormone (TSH); and describing CFS patients has included samples of patients
urinalysis (Fukuda etal., 1994). Further tests should be with these comorbid conditions.
judiciously included as warranted by suggestive findings
in the comprehensive history and physicalfor example, 2. Any previously diagnosed medical condition whose
human immunodeficiency virus (HIV), Epstein-Barr resolution has not been documented beyond reasonable
Virus (EBV) viral capsid antigen immunoglobulin M clinical doubt and whose continued activity may explain
(EBV VCA IgM) to consider acute mononucleosis -, the chronic fatiguing illness.
Misattunement
Immune
Failure of Affective and
System
Self-Consolidation Physiological Instability
CFS
Defective Capacity
Symptoms
for Self-Regulation
2. Perform thorough physical and psychiatric examinations Family and personal history
to rule out common causes of chronic fatigue (Epstein, Past medical and psychiatric history
1995). See Box34.3. Premorbid personality and lifestyle
Review Findings
Review the positive and negative findings from the history, much worse in the long run. The most useful treatments
physical examination, and laboratory testing, teaching how include maximizing your overall health (this allows
each finding relates to fatigue. Treat any underlying medical your body to heal itself naturally), normalizing your
and/or psychiatric conditions appropriately. If no explanation sleep, and increasing your activity level extremely slowly
is identified for the fatigue, patients may be reassured and within a structured cognitive behavioral therapy pro-
educated aboutCFS: gram forCFS.
You have an illness called chronic fatigue syndrome. It It is important to observe the patients reactions to this
is not an illness that leads to death. Despite a great deal news (Salit, 1985), including nonverbal communications
of research, there is no single cause; many factors may (Ekman& Friesen, 1975), and to inquire as to thoughts, feel-
contribute. There are no scientifically proven cures, but ings, questions, and concerns.
there are many claims for cure. You must be extremely
cautious not to fall prey to particularly expensive treat- Plan Comprehensive Treatment Strategy
ment programs promising spectacular results.
It will take a lot of work to fight this illness and Iwill Design the treatment strategy tailored for each unique patient,
continue to help you in this long uphill battle. What we maximizing overall positive health behaviors (Denz-Penhey&
do know is that strategies of strict inactivity make CFS Murdoch,1993).
DEPRESSION
FATIGUE
and related symptomatology
Distorted perception of
Belief in physical illness how much was achieved.
and need to rest Ehnanced perception of
feelings of fatigue and pain
Deconditioning
INACTIVITY
FAILURE TO REACH
DESIRED GOAL
EXPECTATION FOR FUTURE
PERFORMANCE REDUCED.
BURST OF
ACTIVITY
Discrepancy between
expected and desired goal
Belief in necessity
to achieve high standard
Figure 34.3 A cognitive model of chronic fatigue syndrome and the pathways that perpetuate it. From Fry& Martin,1996.
Novel pharmacologic agents are available, but they are not group studied was atypical in that they were severely affected
yet proven to be clinically efficacious by reproducible double- (many subjects were bedbound), and the magnitude of the
blind randomized placebo-controlled trials. A recent review therapeutic effect was small (Wilson etal., 1994). Adouble
of the effect of treatments for CFS (Reid et al., 2011) con- blind placebo controlled randomized clinical trial of this
cluded that the effectiveness of corticosteroids and intramus- toll-like receptor 3 agonist and inducer of innate immune
cular magnesium are unknown. Dietary supplements, evening responses involved 234 subjects with long-standing debili-
primrose oil, oral nicotinamide adenine dinucleotide, home- tating CFS at 12 sites. The outcome of exercise tolerance was
opathy, and prolonged rest have not been studied in enough improved in the drug-treated group (Strayer et al., 2012);
detail to draw conclusions. In one single randomized control however, this orphan drug has not been approved.
study galantamine was no better than placebo. For gamma- 9. Recognize countertransference. Recognize that it is
globulin, two double blind placebo controlled trials were con- normal to experience frustration and helplessness in treat-
ducted utilizing intravenous gammaglobulin in adults with ing patients with CFS. Be cautious not to base professional
CFS. One study showed a significant improvement, but results gratification on patient improvement. Patients often need
were not replicated in the second study. A third study of 99 unconditional empathy whether they are fatigued or ener-
adults showed side effects but no benefit; therefore, gamma- getic. Empathy, however, must be balanced with active efforts
globulin in the management of CFS cannot be recommended to mobilize these patients from sick and disability roles they
(Vollmer-Conna et al., 1997; Wilson et al., 1994). may have adopted. In our present state of knowledge it is just
Rintatolimod (trade name ampligen), known as PolyI; as likely for clinicians to reinforce symptoms of CFS, includ-
poly C12U, is an experimental immunomodulatory ing sick role behaviors, versus diminishing their severity.
double-stranded RNA preparation thought to have both
antiviral and immunomodulatory properties. When admin-
istered to CFS patients in a randomized multicenter placebo C L I N IC A L PE A R L S
controlled double blind study for 24 weeks it was found
to significantly improve global performance and perceived The risk of CFS is increased in patients with a history
cognition (Strayer et al., 1994). Unfortunately, the patient of depression. Rates of comorbid psychiatric syndromes
708
patient has not been sexually active recently or has not recently traumatic event? Is the lack of an interest in sex due to a
experienced sexual desire. The medical psychiatrist can deter- belief of some kind? For example, does the patient who
mine what aspects of the sexual experience are most related has no sexual partner feel undesirable to a potential
to the patients satisfaction; this will influence the focus of partner because of their age, appearance, or health status?
treatment. For some patients having an orgasm is less impor- Does the patient feel masturbation is wrong or harmful?
tant than physical closeness to or the satisfaction of a spouse Or, does the patient simply not care about sexuality at
or partner. For others, arousal without orgasm is an intensely this particular point in their life? Is there any distress or
unpleasant experience. The mechanical aspects of sexphysi- perplexity associated with the loss of interest in sex? If the
cal arousal, erection or lubrication, and orgasmoften are the patient does not wish to be sexual because the spouse or
easiest ones to address. For each there is a reasonable base of partner is not interested, why does the spouse or partner
evidence for differential diagnosis and for treatment. In the lack interest? What is the recent history of the couples
15years since the last edition of this volume was written, accu- sexual relationship? Does the spouse or partner find the
rate diagnosis and effective treatment for mechanical aspects lack of a sexual relationship to be acceptable?
of sex have become more widely available, and information
3. Assess desire. If the patient wishes to be sexual but feels
about almost any sexual topic has become easy to find on
no desire, is that loss of interest generalized or specific to
the Internet (though not always accurate). Notwithstanding,
the current spouse or partner? Desire can be viewed as a
even now patients with addressable physical impediments to
balance of impulse and inhibition. It can be assessed over
sexual satisfaction do not necessarily seek treatment for them,
days or over hours. General medical illness, medications,
and this is true even when the patients sexual issues cause
and emotional reactions to illness can affect either impulse,
them emotional distress or adversely affect the quality of their
inhibition, or both. Fatigue reduces the impulse, while the
marital relationship.
irritability that comes with fatigue increases the power of
While there is much written about the workup of sexual
environmental effects to inhibit desire. How would the
dysfunction, the authors find it useful to think about the
patient describe the interplay of impulse and inhibition in
sexuality of medical-psychiatric patients in a broader context.
their own experience? Can they offer examples where they
This chapter offers a framework for conceptualizing sexual
noticed a lack of response to circumstances that they would
issues in patients with general medical illness. Detailed dis-
expect to find arousing? Can they recall specific reasons
cussion of physiological aspects of male sexual function and
why sexual activity didnt take place because something
dysfunction can be found in this books chapters on urology
interfered? Does the patient have a problem with sleep or
and on spinal cord injury.
with sleepiness? Sleep disorders are common. Lack of sleep
is associated with reduced desire, greater vulnerability
of desire to inhibition by distraction or discomfort, and
A N ALY Z I NG S EX UAL I T Y I N decreased physical arousal. Snoring, restless legs or a dis-
M E DIC AL P S YC H I AT R IC PAT I E N T S turbing parasomnia can inhibit the arousal of the partner.
The following sequence of questions describes the scope of 4. Assess arousal. If the patient or partner is a woman, does
an ideal inquiry into the sexual issues of a medical-psychiatric she experience emotional arousal? If so, is there associated
patient. The actual questions the clinician will ask will depend lubrication or does the vagina remain dry? If the patient
on the reason for the consultation, the amount of time available, or partner is a man, does he have an erection? Is the erec-
the setting of the interview, the patients current mental sta- tion persistent? Is it firm enough for penetration?
tus, and, importantly, the scope of the clinicians license. 5. Assess sexually related pain. Does the patient have, anticipate
The latter will be quite different when the medical psychiatrist having, or fear having some form of physical discomfort
is intervening in a crisis where a patient is resistant to medically during sexual activity? In the medical psychiatric contexts
necessary care versus when he or she is responding to a patients sexually related discomfort encompasses much more than
personal request for help in coping with the emotional impact dyspareunia. Sexually related discomforts range broadly
of a serious illness. from dyspnea on exertion to muscle pain to neuropathic
dysesthesia of the pelvis or thighs to postcoital migraine.
1. Set the context. Is the patient sexually active in any way These symptoms or avoidance of them not only can
with a partner or solo? If not, does the patient wish to cause conscious avoidance of sex but can also inhibit
be? If there is a wish but no activity, what is the reason? the patients desire. Eventually yes but becomes not
When was the patient last sexually active and what was tonight and then just no.
the sexual experience like at that time? If there is no wish
6. Assess orgasm, including its qualitative aspects. Does the
to be sexually active, when did they last have such a wish?
patient have orgasms, and if so, is it qualitatively the same
If the patient has a regular sexual relationship how
as in times past? If the patient is a woman, has she ever
frequently do they have sex? Who usually initiates
had an orgasm? If so has she had one with intercourse? If
the sexual encounter?
she does not have orgasms does she come close to having
2. Assess sexual interest. If the patient does not wish to be one? Is the experience of arousal without orgasm pleasant
sexual at all, what is the reason? Is it related to a specific or unpleasant? If the patient is a man and he does not now
35 . S e x ua l Dy s f unction 709
have orgasms does he get close to having one? Is the S C R EE N I N G PAT I E N T S F OR
experience of arousal without orgasm pleasant or S EX UAL DY S F U N C T ION
unpleasant? If he has an orgasm does he ejaculate
normally? Does he ejaculate earlier than he desires? Studies of sexual dysfunction in medical patients have led to the
And with how much stimulation? Does he have a sense development of efficient screening questions for detecting the
of control over his ejaculation? most common sexual issues. Questions can be asked in writing
via questionnaires to be completed by the patient or asked orally
7. Assess the patients view of the spouse or partners sexual
by the physician as part of the overall history and examination.
function.
Questionnaires and self-rated instruments sometimes will
8. Assess satisfaction and frustration of the patient and elicit information about sexual concerns that would not
partner, qualitatively and quantitatively. How does the come out in a face-to-face interview. When they are available
patients sexual dysfunction affect the quality of the and applicable, sexuality related rating scales specific to the
sexual relationship? How distressing does the patient patients medical illness or condition can be more informative
find the sexual dysfunction? Does the patient find than general scales of sexual function and dysfunction.
intimacy with their spouse or partner to be satisfying
despite the sexual dysfunction? What is the spouse or
partners point of view on these matters? I N T E RV I E W QU E S T ION S S C R E E N I NG
FOR S E X UA L DY S F U NC T ION
9. Explore consideration of sexual alternatives:Is the patient
willing to consider alternatives to their customary sexual The following short list of sexuality related questions was
repertoire before illness? For example, willingness to recommended by Shafer (2008) for inclusion in a general
consider alternatives to vaginal intercourse varies greatly diagnostic interview. Questions can be reworded if this would
with patients cultural background and openness to make the interview more comfortable for the patient.
new experiences. Even with the greater permissiveness
of mainstream culture in Western countries, many 1. Are you active sexually? With men, women, or both?
patients come from a cultural or religious background 2. In your sex life:
that restricts the acceptable forms of sexual expression. a. is there anything you would like to change?
Patients with such issues vary in their acceptance of b. have there been any changes recently?
permission to experiment when the permission is given c. are you satisfied?
by a physician. The patients personality is relevant as
well; those patients with personalities that are high Additional screening questions have been suggested by Althof
on the openness factor are more likely to accept and colleagues (2013):
alternative forms of sexual expression. For both men and women:
10. Consider specialist referral. Is the patient open to
referral to a specialist in sexual medicine? Such a 1. Do you identify yourself as heterosexual, homosexual,
referral would be a second or third referral, following or bisexual?
the referral to the medical psychiatrist, which in itself 2. Are you satisfied with the level of your sexual desire or
might have come through another medical specialist interest?
or through a nonphysician mental health professional.
3. Are you satisfied with the frequency of lovemaking?
Accepting this referral, which is based on an explicitly
sex-related reason, requires that a patient believes that 4. Do you experience pain during lovemaking?
the sexual issue is important enough to deserve an 5. Are you satisfied with the overall quality of your sexual
investment of time and resources, that there is some life?
hope of a good outcome, and that the specialist is com-
petent, trustworthy, and will maintain confidentiality. For men:
Furthermore, it may require the approvalor at least
the nonoppositionof a spouse or significant other. A 1. Are you satisfied with your ability to achieve and main-
referral to a specialist in sexual medicine may be more tain an erection?
acceptable to a patient if the medical psychiatrist takes
2.