in arousal seen in delirium may stem from dysfunction of the reticular activating system.

Hyperfunction in mesocorticolimbic dopaminergic pathways, leading to excess dopamine

release, may contribute to delusions and hallucinations observed in delirium and may explain
the salutary role of antipsychotic medication in management.
Diagnosis and Clinical Features
See Table 10.2-2, which lists DSM-IV-TR criteria for delirium, the cardinal symptoms
of which have been described earlier. The clinician must establish the presence of a general
medical condition or substance capable of causing delirium. A temporal association between
the initiation of the medical condition or substance and the development of a delirium is
highly suggestive of an etiological basis. Occasionally, delirium may be a harbinger of a
soon-to-be-diagnosed medical problem. As a result, its diagnosis should always herald a
vigorous search for cause.
Associated physical findings may assist with diagnosis of delirium. Hepatic
encephalopathy may be associated with a flapping movement of the hands called asterixis.
Autonomic hyperactivity may be observed in withdrawal from CNS depressants. Wernicke's
encephalopathy related to thiamine deficiency may be associated with paralysis of gaze.
Anticholinergic toxicity may be indicated by dry mucous membranes, tachycardia, and warm,
flushed skin.
Time course may be diagnostically helpful: Alcohol withdrawal delirium usually
commences within 24 to 72 hours of the cessation of alcohol use.
Five DSM-IV-TR diagnostic categories exist: delirium due to a general medical
condition, substance intoxication delirium, substance withdrawal delirium, delirium due to
multiple etiologies (when more that one medical origin, or a medical and substance origin,
are identified), and delirium not otherwise specified (when insufficient etiologic evidence is
present).
Recording procedures dictate that the etiology of delirium related to a general medical
condition is listed on Axis I and Axis III (e.g., delirium due to pneumonia). If several
etiologies are identified, all should be listed.
Laboratory Findings
Laboratory irregularities often point to the cause of delirium. Elevated white blood
count may suggest an infectious origin. Hemorrhagic stroke usually is seen on brain imaging.
Dehydration may be indicated by elevated serum sodium, blood urea nitrogen, and
hematocrit. Diagnosis of substance-induced delirium may be facilitated by examination of
urine toxicology and medication blood levels. In most deliria, electroencephalogram (EEG)
demonstrates nonfocal background slowing. In delirium due to withdrawal from a CNS
depressant, excess fast beta waves are observed. Severe slowing, including triphasic delta
waves, may be seen in hepatic encephalopathy.
Differential Diagnosis
Due to the fluctuating nature of delirium, symptoms may not all be present
concurrently, thereby confounding diagnosis, particularly in patients with incipient or lowgrade deliria. Acuity of onset, inattentiveness, and the fluctuating course of symptoms, all
within a medical context, assist in distinguishing delirium from slowly progressive cognitive
disorders, such as dementia and amnestic syndromes, and from mood, psychotic, anxiety, and
sleep disorders, all of which tend to have gradual onset and resolution. Distinguishing
substance-induced delirium from delirium due to a general medical condition may be assisted
by chronology of delirium symptoms and response to treatment of medical illness and
removal of suspect substances.

Course and Prognosis

Most individuals with delirium recover fully, despite the often dramatic fluctuations in
cognition, alertness, and mood encountered in this syndrome. Course usually is dictated by
the rapidity with which the offending cause (medical or substance) is removed. Yet, if the
clinician fails to make the diagnosis or to orchestrate the appropriate workup, severe
consequence, even death, may ensue (e.g., delirium due to expanding subdural hematoma and
alcohol withdrawal delirium). More than one-half of elderly in medical and surgical hospitals
may not achieve complete recovery from delirium at the time of discharge. This may account
for the finding that elderly hospitalized patients with delirium have a risk of nursing home
placement that is three times that of those without delirium.
Treatment
Management of delirium is threefold: identification and correction of the underlying
medical or substance cause, management of associated behavioral symptoms, and
implementation of strategies designed to ensure safety of the affected individual. An
aggressive search for offending medical conditions or substances should be undertaken with
an aim of rapid correction. Behavioral and mental symptoms (e.g., psychosis, aggression, and
psychomotor agitation) are best managed with antipsychotic medications. Increasingly, oral
atypical antipsychotic agents (e.g., risperidone [Risperdal], olanzapine [Zyprexa], and
quetiapine [Seroquel]) are used for this purpose. Another atypical agent, ziprasidone
(Geodon), may be administered by oral and intramuscular (IM) routes. One typical
antipsychotic agent, haloperidol (Haldol), has the unique advantage of three acceptable routes
of administration (oral, IM, and intravenous [IV]). Parenteral routes are especially useful in
noncompliant individuals or in those with malfunctioning gastrointestinal (GI) tracts.
Medications, such as benzodiazepines, that exacerbate disinhibition and memory disturbances
are best avoided, except in CNS depressant withdrawal delirium, in which benzodiazepines
are preferred. Minimizing environmental change and maximizing visual cues (e.g., familiar
photographs from home or the presence of a family member) also may be helpful in
containing the severity of delirium-related behavioral symptoms.
Safety of the affected individual is paramount, as delirious patients may inflict
deliberate or inadvertent injury on themselves (e.g., pulling out IV lines or catheters) or
others. Heightened attention to the delirious individual, through the use of constant
observation, may be indicated. Rarely, physical restraints may be used, although other
strategies for behavioral control almost always are preferable.

DEMENTIA DUE TO A GENERAL MEDICAL CONDITION

The syndrome of dementia is characterized by the gradual development of multiple
cognitive deficits. Relatively few cases occur before 65 years of age; early cases mostly are
due to traumatic brain injury. This section reviews dementias that are due to general medical
conditions (apart from Alzheimer's disease and cerebrovascular disease) and substances.
Definition
Dementia is characterized by widespread cognitive deficits, which include, but are not
limited to, memory impairment. The afflicted individual experiences significant impairment
in social or occupational functioning. Deterioration in cognition is gradual, extending over a
time span influenced by etiology of the dementia, efforts at treatment, and supervening
medical illness.

Comparative Nosology
DSM-III-R described primary degenerative dementia of the Alzheimer type, with
senile onset and with presenile onset, and multiinfarct dementia. Diagnoses of senile
dementia not otherwise specified and presenile dementia not otherwise specified were
available for dementia due to general medical conditions (e.g., Parkinson's disease). With the
advent of DSM-IV, the not otherwise specified category has been refined to include an array
of specific non-Alzheimer, nonvascular dementias.
For dementia due to medications or drugs of abuse, DSM-III-R offered a diagnosis of
psychoactive substance dementia. DSM-IV-TR offers a comparable diagnosis of substanceinduced persisting dementia.
ICD-10 offers diagnoses for dementia in Pick's disease, Creutzfeldt-Jakob disease,
Huntington's disease, Parkinson's disease, human immunodeficiency virus (HIV) disease, as
well as a category for dementia in other specified diseases (e.g., hypercalcemia, vitamin B12
deficiency, epilepsy, neurosyphilis, multiple sclerosis [MS], and intoxications with
nonpsychoactive substances). Also offered are categories for unspecified dementia, divided
into senile and presenile subcategories, and residual and late-onset psychotic disorder, which
includes dementia due to psychoactive substance use.
Epidemiology
Although Alzheimer's disease and cerebrovascular disease, individually and in combination,
account for 70 to 90 percent of all dementia cases, large numbers of patients with HIV
infection, Parkinson's disease, head trauma, and alcohol use disorders develop cognitive loss
often culminating in dementia.
Table 10.5-8 Causes of Dementia
Neurological
Degenerative
Alzheimer's disease
Pick's disease
Parkinson's disease
Huntington's disease
Wilson's disease
Cerebrovascular disease
Demyelinating disease
Multiple sclerosis
Head trauma
Posttraumatic dementia
Dementia pugilistica
Brain mass
Tumor
Subdural hematoma
Normal pressure hydrocephalus
Infectious and inflammatory
Human immunodeficiency virus
Slow viruses (e.g., Creutzfeldt-Jakob disease)
Neurosyphilis
System lupus erythematosus
Temporal arteritis
Metabolic and endocrine

Anemia
Organ failure
Heart
Lungs
Kidney
Liver
Thyroid
Parathyroid
Adrenal
Vitamin deficiency
Substance-induced
Medications
Sedative-hypnotic
Anxiolytic
Anticholinergic
Anticonvulsant
Cardiovascular
Other
Alcohol
Toxins
Lead
Mercury
Carbon monoxide

Etiology
Scientists postulate cholinergic deficit and inflammatory change as potential explanations for
changes in neurotransmission that eventually lead to dementia. General medical conditions
capable of causing dementia presumably exert their effects through one or more of these
mechanisms. Medical conditions and substances that may cause dementia are listed in Table
10.5-8.
Degenerative dementias may be categorized as cortical or subcortical. Individual
presentations often are mixed, particularly as dementia advances, with clinical and
neuroanatomical features of both categories. Cortical dementias, including Alzheimer's
disease and Pick's disease, are associated with defects in memory and executive functioning,
along with aphasia, agnosia, or apraxia, or a combination of these. Subcortical dementias,
including those due to HIV disease, Huntington's disease, and Parkinson's disease, involve
white and deep gray matter structures and their frontal lobe projections. Early in their course,
subcortical dementias present with psychomotor slowing and personality change,
occasionally in advance of overt cognitive impairment.
Diagnosis and Clinical Features
The essential feature in dementia, regardless of etiology, is the presence of multiple
cognitive deficits manifested by memory impairment and one or more of the following: (1)
aphasia, (2) apraxia, (3) agnosia, and (4) disturbance in executive functioning (Table 10.5-9).
These deficits compromise overall functioning and may be associated with change in
personality and withdrawal from usual activities. Depression, delusions, or aggressive
behavior may emerge as complications of dementia. Unless due to a single discrete (e.g.,

head injury) or reversible event, dementia tends to follow an inexorable, progressive course,
usually over the course of several years, until death ensues.
Table 10.5-9 DSM-IV-TR Criteria for Dementias Due to Other General Medical
Conditions
A. The development of multiple cognitive deficits manifested by
(1) Memory impairment (impaired ability to learn new information or to recall previously
learned information)
(2) One (or more) of the following cognitive disturbances:
(a) Aphasia (language disturbance)
(b) Apraxia (impaired ability to carry out motor activities, despite intact motor function)
(c) Agnosia (failure to recognize or to identify objects, despite intact sensory function)
(d) Disturbance in executive functioning (i.e., planning, organizing, sequencing, and
abstracting)
B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or
occupational functioning and represent a significant decline from a previous level of
functioning.
C. There is evidence from the history, physical examination, or laboratory findings that the
disturbance is the direct physiological consequence of a general medical condition other than
Alzheimer's disease or cerebrovascular disease (i.e., human immunodeficiency virus
infection, traumatic brain injury, Parkinson's disease, Huntington's disease, Pick's disease,
Creutzfeldt-Jakob disease, normal pressure hydrocephalus, hypothyroidism, brain tumor, or
vitamin B12 deficiency).
D. The deficits do not occur exclusively during the course of a delirium.
Specify:
Without behavioral disturbance
With behavioral disturbance
From American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Text rev. Washington, DC; American Psychiatric Association; 2000, with
permission.
In DSM-IV-TR's dementias due to other general medical conditions, there is evidence
from the history, physical examination, or laboratory findings of a cause distinct from
Alzheimer's disease or cerebrovascular disease. Factors supporting the diagnosis of dementia
due to a general medical condition include a temporal link between the onset of the medical
condition and the development of the dementia and a known link in the scientific literature
between the medical condition and dementia. Similar considerations apply to substanceinduced persisting dementia.
Two subtypes of dementia due to other general medical conditions exist: with
behavioral disturbance and without behavioral disturbance, based on whether the dementia is
accompanied by a clinically significant behavioral problem (e.g., aggression). In both cases,
the causative general medical condition is coded on Axes I and III (e.g., dementia due to
Pick's disease, with behavioral disturbance).
In substance-induced persisting dementia, the offending agent is listed on Axis I (e.g.,
alcohol-induced persisting dementia). In addition, DSM-IV-TR provides a category for
dementia due to multiple etiologies (e.g., the combination of Alzheimer's disease, head
trauma, and alcohol); each etiology should be listed on Axis I and, when indicated, on Axis
III. If specific etiology cannot be identified, dementia not otherwise specified is diagnosed.

When psychiatric syndromes in addition to dementia are attributable to a specific

general medical condition, these should be coded on Axis I as well. For example, an
individual with dementia due to hypothyroidism may also meet criteria for mood disorder due
to hypothyroidism, with depressive features.
Martha Jones is a 72-year-old woman without prior psychiatric history who,
over the course of 8 months, experienced a 20-lb weight gain and psychomotor
slowing. She stopped marketing for groceries, halted her participation in activities at
the local senior center, and failed to make rent payments for 2 months consecutively.
She was admitted to the hospital with lethargy of several weeks' duration. Psychiatry
was consulted to rule out depression.
Interview revealed a heavyset woman with bland and indifferent demeanor
and sleepiness. Physical examination revealed edematous facial features and thinning
hair, with delayed deep tendon reflexes. Ms. Jones denied that she was depressed. She
was oriented to place and year but not to month. Short-term recall was one of three
objects.
Laboratory studies were unremarkable, except for a thyroid-stimulating
hormone level of 112 (elevated).
The psychiatry consultant diagnosed dementia due to hypothyroidism. Thyroid
replacement therapy was initiated. Ms. Jones was discharged to a nursing home,
where qualities of withdrawal and inactivity were noted, despite gradual cognitive
improvement. A trial of methylphenidate (Ritalin) 5 mg twice daily was commenced.
Gradual improvement in cognition, alertness, and energy over the course of several
months allowed Ms. Jones to return home with the assistance of an aide.
In this case, factors suggesting a medical contribution to dementia include the
presence of lethargy, a well-established link between hypothyroidism and dementia, and the
improvement in dementia with the treatment of hypothyroidism. Psychotropic medication
was required to maximize clinical response.
Dementia Due to HIV Disease
One-third of asymptomatic individuals with HIV and one-half of individuals with
acquired immunodeficiency syndrome (AIDS) show evidence of cognitive impairment.
Those individuals with HIV-associated dementia complex appear apathetic and slowed. Gait
ataxia, tremor, and a decline in handwriting skills may be present. In some cases, the
dementia is not due to the effects of HIV on the CNS but rather to the effects of
accompanying opportunistic lesions of the brain (e.g., toxoplasmosis and lymphoma), in
which case dementia should be attributed to those lesions.
In HIV-associated dementia complex, brain magnetic resonance imaging (MRI) may
show demyelination of subcortical white matter. Functional brain imaging (e.g., positron
emission tomography [PET]) may demonstrate hyperactivity in the thalamus and basal
ganglia in early stage HIV-associated dementia complex and hypoactivity of the temporal
lobes in late stage HIV-associated dementia complex. Histopathologically, white matter and
subcortical destruction are described. Spinal fluid may show lymphocytosis or elevated
protein, or both; presence of white blood cells should prompt a search for a brain
opportunistic infection.
Dementia Due to Head Trauma
Occurring most commonly in young men, often with concurrent substance disorders,
dementia due to head trauma usually occurs as a consequence of a single injury to the head.
Head trauma is associated with abrupt acceleration or deceleration of the brain, an event that

deforms neurons. This leads to temporary or sustained neuronal dysfunction, the extent of
which influences the degree of recovery. If head trauma is associated with intracerebral
hemorrhage, neuronal function may be further compromised. Dementia resulting from head
trauma may be associated with labile affect, aggression, and irritability. This dementia rarely
is progressive, except in individuals with repeated blows to the head (e.g., boxers with
dementia pugilistica).
Dementia Due to Parkinson's Disease
More than one-half of patients with Parkinson's disease experience dementia. Onset of
Parkinson's disease is usually between 50 and 60 years of age. Depletion of dopaminergic and
serotonergic neurons in the substantia nigra and other subcortical structures appears to
underlie the movement disorder, which is characterized by bradykinesia, resting tremor, and
rigidity, all of which are progressive. Dysfunction of these same neurons likely contributes to
the cognitive, mood, and behavioral disturbances seen in Parkinson's disease. At autopsy,
Lewy bodies are found in the substantia nigra. Treatment of the movement disorder with
dopaminergic agents occasionally provokes or exacerbates psychiatric symptoms;
antipsychotic medications used to treat mental symptoms may exacerbate the movement
disorder. Dementia detected in elderly individuals with Parkinson's disease may be due to that
disorder or to other dementing disorders, including Alzheimer's disease and cerebrovascular
disease.
Dementia Due to Huntington's Disease
Huntington's disease is transmitted by a single autosomal dominant gene found on the
short arm of chromosome 4. Usually diagnosed in the late 30s or early 40s, Huntington's
disease affects men and women equally. Offspring of affected individuals have a 50 percent
chance of developing the disease. Interruption of corticostriatal connections leads to
characteristic motoric, emotional, and cognitive consequences. Emotional symptoms often
appear early and include irritability, depression, or psychosis. Later, cognitive disturbance
appears; this is marked by psychomotor slowing, loss of spontaneity, and memory defect.
Motoric abnormalities, which may present prior or subsequent to mental symptoms, include
the development of choreoathetotic movements, which eventually yield to profound
bradykinesia. In the striatum, reduction in levels of -aminobutyric acid (GABA) and
acetylcholine, both of which exert an inhibitory effect on movement, leads to the
characteristic movement disorder.
In late Huntington's disease, structural brain imaging, including computed
tomography (CT) and MRI, may show caudate atrophy and characteristic boxcar ventricles.
Functional imaging, such as PET, may show striatal hypometabolism.
Dementia Due to Pick's Disease
Pick's disease usually appears in the sixth decade of life and has a course of 2 to 5
years. The disorder affects the frontal and temporal lobes of the brain, making this one of
several forms of frontotemporal dementia. Pick's disease is characterized by personality
change, including disinhibited behavior and language abnormalities, later followed by
deterioration in memory. Structural brain imaging often reveals frontal atrophy. Even in the
absence of structural findings, functional imaging may demonstrate frontal hypometabolism.
At autopsy, intraneuronal argentophilic Pick inclusion bodies are identified.
Dementia Due to Creutzfeldt-Jakob Disease
Due to a transmissible prion, that is, a slow virus, Creutzfeldt-Jakob disease is
characterized by dementia; periodic bursts of EEG activity; involuntary movements, often

myoclonic or choreoathetotic in nature; and ataxia. Brain imaging may show nonspecific
atrophy. Postmortem microscopic examination of the brain demonstrates neuronal
degeneration in cortical and subcortical gray matter. Usually, the disease develops after 40
years of age and progresses rapidly over the course of several months.
Dementia Due to Other General Medical Conditions
The DSM-IV-TR residual category of dementia due to other general medical
conditions is used for dementias that may be reversible or irreversible and that do not fall into
one of the previous diagnostic categories. These dementias may present with features similar
to those seen in common dementing illnesses such as Alzheimer's disease and vascular
dementia, a fact that underscores the importance of performing an exhaustive laboratory and
pharmacological search for reversible causes of cognitive decline in all individuals presenting
with such complaints (Tables 10.5-7 and 10.5-8).
This residual category includes degenerative brain diseases such as progressive
supranuclear palsy and Lewy body disease (apart from Parkinson's disease). The former is
characterized by gaze paresis and axial rigidity; the latter is characterized by fluctuating
cognitive symptoms, psychosis, and extreme sensitivity to the extrapyramidal side effects of
antipsychotic medications.
Also included in this category is Wilson's disease. Transmitted by autosomal recessive
inheritance, this disorder manifests in late adolescence or early adulthood with personality
change, tremor, rigidity, and, eventually, dementia.
Dementia also may result from structural lesions and deformities of the brain (e.g.,
tumor, abscess, subdural hematoma, and normal pressure hydrocephalus [NPH]). Cognitive
loss due to subdural hematoma may occur days, weeks, or months after a causative head
injury. NPH may present with a triad of symptoms: dementia, sphincteric incontinence, and
gait disorder.
Other medical disorders capable of causing dementia include: metabolic and
endocrine abnormalities (e.g., hypothyroidism, hypercalcemia, liver failure, renal failure, and
cardiopulmonary failure), nutritional deficiencies (e.g., thiamine and vitamin B12), and
inflammatory and infectious states (e.g., neurosyphilis, chronic meningitis, and systemic
lupus erythematosus). Neurosyphilis, caused by Treponema pallidum, evolves over the course
of decades; one variant, general paresis, is characterized by pupillary abnormalities, action
tremor, dysarthria, seizures, and dementia that is occasionally associated with grandiose or
depressive features. Substances that may cause dementia include alcohol, anticonvulsants,
anticholinergic agents, sedative-hypnotic agents, mercury, and lead.
Pathophysiological mechanisms underlying the effect of general medical conditions
and substances on cognition are variable and often obscure. Slowly evolving cholinergic
hypofunction appears to be associated with neuronal dysfunction in a broad range of
dementing illnesses. This, too, likely explains the adverse impact on cognition of drugs with
anticholinergic potential.
Brain tumor and trauma directly distort neuronal structure and impede cerebral blood
flow. In NPH, neuronal dysfunction may be a consequence of insufficient blood flow
resulting from disruption of the pressure gradient between ventricular and subdural spaces.
In Wilson's disease, an enzymatic defect in the incorporation into ceruloplasmin of
copper leads to its toxic buildup in brain, liver, kidneys and cornea. In cardiopulmonary
failure and anemia, hypoperfusion or hypoxia presumably underlies impaired neuronal
activity. Alcohol causes neuronal loss and glial proliferation in several regions of the brain,
including the frontal lobes and temporal association areas.
Laboratory Examination

Patients presenting with evidence of progressive cognitive loss should have routine
blood work, including complete blood count, electrolytes, glucose, blood urea nitrogen,
creatinine, liver function tests, thyroid function tests, calcium, magnesium, phosphorus,
vitamin B12 and folate levels, and reactive plasma reagin (RPR) or Venereal Disease Research
Laboratory (VDRL) tests. The last two assist in identifying neurosyphilis. Erythrocyte
sedimentation rate (ESR) should be requested if inflammatory, infectious, or oncological
disease is suspected. Urinalysis should be examined. Urine and serum toxicology are
indicated if substance use disorders are suspected. Electrocardiogram (ECG) and arterial
blood gases (ABG) may be diagnostically useful in individuals with known or suspected
cardiopulmonary disease. Structural brain imaging and, occasionally, lumbar puncture and
EEG should be obtained. In selected cases, special examinations are indicated (e.g., if
Wilson's disease is suspected based on family history, serum ceruloplasmin will be low;
ophthalmological examination will reveal the pathognomonic Kayser-Fleischer ring of the
cornea). Neuropsychological testing may assist in distinguishing among different forms of
dementia.
Differential Diagnosis
Differential diagnosis includes Alzheimer's disease and vascular dementia, which may
present similarly to, or may overlap with, dementia due to a general medical condition. When
patients present with multiple possible factors contributing to dementia, the relative
importance of each factor may be difficult to discern.
Also within the differential diagnosis are pseudodementia of depression, amnestic
syndromes, delirium, and age-related cognitive decline. Depression and dementia both may
be associated with loss of interest, appetite, and spontaneity. Clues suggestive of depression
are the presence of a prior history of mood disorder, multiple unsubstantiated somatic
complaints, feelings of worthlessness, and suicidal ideation. In contrast to dementia, delirium
has a fluctuating, acute quality. Amnestic syndromes do not encompass the global cognitive
decline typical of dementia. Age-related cognitive decline does not cause the impairment in
functioning characteristic of dementia.
When attempting to discern the relative contributions of various medical or
neurological illnesses or substances in the evolution of dementia in an individual case,
diagnosis may be assisted by examination of chronology of dementia symptoms and response
to correction of medical illness or removal of suspect substances.
Course and Prognosis
The course of dementia due to a general medical condition is highly variable,
depending on etiology. If dementia is attributable to a reversible cause (e.g., hypothyroidism),
gradual improvement may be possible; however, if the insult has been of long duration (e.g.,
neurosyphilis), recovery may be incomplete or imperceptible. If dementia is attributable to an
irreversible cause (e.g., Pick's disease), progressive worsening is inevitable. Substanceinduced persisting dementia often improves after cessation of substance use, although some
forms (e.g., alcohol-induced) may endure indefinitely.
Treatment
Management techniques are most successful when a reversible dementia of short
duration is identified. If dementia is due to correctable intracranial pathology, improvement
may follow neurosurgical intervention (e.g., ventriculoperitoneal shunting in NPH and
evacuation of subdural hematoma). Nutritional, infectious, endocrine, and cardiopulmonary
conditions should be optimized. In rare cases, special pharmacotherapy may be required (e.g.,

symptoms of Wilson's disease respond to management with copper-chelating agents, such as

penicillamine [Cuprimine]).
Regardless of etiology of dementia, psychotropic medications often are indicated in
the presence of prominent behavioral or mood symptoms. Antipsychotic agents, usually
atypical, commonly are used for symptoms of aggression or psychosis. Antidepressant
medications and mood stabilizers (e.g., divalproex [Depakote]) may assist with labile affect,
disinhibition, and tearfulness. Rarely, hormonal interventions (e.g., medroxyprogesterone
[Depo-Provera]) may be considered in men with dementia who demonstrate sexually
disinhibited or aggressive behavior patterns. Medications with high anticholinergic potential
(e.g., thioridazine [Mellaril] and amitriptyline [Elavil]) tend to worsen cognitive loss and are
best avoided. Drugs with prominent amnestic properties (e.g., benzodiazepines), too, should
be avoided. The use of cholinesterase inhibitors (e.g., donepezil [Aricept] and galantamine
[Reminyl]) and N-methyl-D-aspartate (NMDA)-receptor antagonists (e.g., memantine
[Namenda]) is controversial. Complications of psychotropic agents include gait disturbance,
drug-induced parkinsonism, and oversedation. These are best minimized by using the lowest
effective dosages of selected agents and avoiding polypharmacy.

AMNESTIC DISORDER DUE TO A GENERAL MEDICAL CONDITION

In contrast to the multiple cognitive deficiencies demonstrated in dementia,
individuals with amnestic disorders demonstrate impairment only in their ability to learn new
information or to recall old information. Aphasia, agnosia, apraxia, and disturbance in
executive functioning are not pronounced or, if present, do not substantially intrude on
functioning. Amnestic disorders may be transient or chronic.
Comparative Nosology
In DSM-III-R, amnestic syndrome was categorized as an organic mental disorder. It
required a finding of long- and short-term memory deficits and was attributable to the effects
of a general medical condition or substance. DSM-IV and DSM-IV-TR diagnoses include:
amnestic disorder due to a general medical condition, substance-induced persisting amnestic
disorder, and amnestic disorder not otherwise specified.
ICD-10 offers the diagnoses of organic amnestic syndrome for states due to medical
conditions and nonpsychoactive substance use and amnestic syndrome, psychoactive
substance-induced.
Epidemiology
Amnestic disorders due to general medical conditions and substances apparently are
uncommon.
Etiology
Injuries to brain regions involved with memory (e.g., middle temporal lobe structures,
including hippocampus and mammillary bodies), regardless of etiology, may cause amnestic
disorder. Such injuries may be due to head trauma, cerebrovascular event, hypoxia, and
infections such as herpes simplex encephalitis. Transient amnestic disorder may result from
disease in the vertebrobasilar system. Limbic encephalopathy, a nonmetastatic complication
of carcinoma (usually small cell lung cancer), which may precede its diagnosis, is
characterized by amnestic disorder and occasionally by mood and psychotic symptoms. Of
substance-induced persisting amnestic disorders, the most common is due to alcohol
(Korsakoff's psychosis). This syndrome results from thiamine deficiency associated with
prolonged consumption of alcohol. The preceding acute state, Wernicke's encephalopathy, is
characterized by confusion, ataxia, and gaze palsies. Unless thiamine is administered in the

acute state, alcohol-induced persisting amnestic disorder results. Other substances that may
induce amnestic disorder include anticonvulsants, lead, mercury, and carbon monoxide.
Diagnosis and Clinical Features
The critical feature in amnestic disorder, whether the result of a general medical
condition or substance, is impairment in the ability to learn new information or to recall
previously learned information (Table 10.5-10). The afflicted individual may confabulate,
that is, create imagined experiences to fill in gaps in memory. Unlike delusions, which are
fixed, confabulated stories tend to be variable. Apathy, altered personality, lack of initiative,
and impairment in functioning also are aspects of amnestic disorder. As with other mental
disorders due to general medical conditions and substances, a temporal association and a
known link in the literature enhance the likelihood that the general medical condition or
substance has caused the amnestic disorder.
The general medical condition or substance is indicated on Axis I. Etiological general
medical conditions also are indicated on Axis III.
If amnestic disorder is due to a general medical condition and a substance (e.g., head
injury and alcohol in an individual with alcohol dependence), amnestic disorder due to a
general medical condition and substance-induced persisting amnestic disorder are diagnosed.
When evidence of specific etiology is lacking, the diagnosis is amnestic disorder not
otherwise specified.
Table 10.5-10 DSM-IV-TR Diagnostic Criteria for Amnestic Disorder Due to a General
Medical Condition
A. The development of memory impairment as manifested by impairment in the ability to
learn new information or the inability to recall previously learned information.
B. The memory disturbance causes significant impairment in social or occupational
functioning and represents a significant decline from a previous level of functioning.
C. The memory disturbance does not occur exclusively during the course of a delirium or a
dementia.
D. There is evidence from the history, physical examination, or laboratory findings that the
disturbance is the direct physiological consequence of a general medical condition (including
physical trauma).
Specify:
Transient: if memory impairment lasts for 1 month or less
Chronic: if memory impairment lasts for more than 1 month
Coding note: Include the name of the general medical condition on Axis I, e.g., Amnestic
disorder due to head trauma; also code the general medical condition on Axis III.
From American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Text rev. Washington, DC: American Psychiatric Association; copyright
2000, with permission.
Laboratory Evaluation
Structural brain imaging may reveal atrophy or enlargement of third ventricle or
lateral horns related to damage to mediotemporal lobe structures. Neuropsychological testing
may assist in defining the specific degree and type of memory impairment.
Differential Diagnosis

Dementia, in contrast to amnestic disorder, by definition, requires more global

cognitive deficits, although both disorders impair functioning. Delirium is a more acute
phenomenon and is associated with deficits in consciousness not characteristic of amnestic
disorders. Predictable amnesia occurring during the course of acute substance (e.g., alcohol)
intoxication or withdrawal should not be diagnosed as amnestic disorder. Dissociative
amnesia usually involves inability to recall previous memories, with no deficits in recalling
new information, and usually is related to emotional trauma, not a general medical condition
or substance.
When medical illness and substances capable of inducing amnestic disorder coexist,
differential diagnosis may be assisted by careful examination of the chronology of amnestic
symptoms and the response to correction of medical disorders or removal of potentially
offending substances.
Course and Prognosis
Course and prognosis of amnestic disorder due to a general medical condition are
highly variable. Onset may be sudden if due to head injury or cerebrovascular event, with
recovery limited by the extent of brain injury. Alcohol-induced persisting amnestic disorder
improves little or not at all. In contrast, amnestic syndromes resulting from sustained heavy
sedative-hypnotic use often slowly subside with cessation of substance use. Transient
amnesia due to cerebrovascular insufficiency is by definition short lived but may be
recurrent.
Treatment
Treatment is similar to that for dementia. Pharmacotherapy may be indicated for
psychosis or mood disturbance. Psychotherapy may be limited by the core memory defect.
Guidance in matters of personal hygiene, nutrition, and finance may be indicated. The
affected individual should be encouraged to avoid substances that may have contributed to
amnestic disorder; in some cases, formal substance treatment is indicated.

COGNITIVE DISORDERS NOT OTHERWISE SPECIFIED

Not all cognitive disorders due to general medical conditions meet criteria for
dementia, delirium, or amnestic disorders. DSM-III-R placed these remaining disorders
within the category organic mental syndrome not otherwise specified. DSM-IV-TR uses the
somewhat more precise diagnosis cognitive disorder not otherwise specified for cognitive
disorders not meeting criteria for any of the dementia, delirium, or amnestic disorders. DSMIV-TR specifically describes two syndromes that meet research criteria for cognitive disorder
not otherwise specified: postconcussional disorder (Table 10.5-11) and mild neurocognitive
disorder (Table 10.5-12). ICD-10 offers comparable diagnoses of postconcussional syndrome
and mild cognitive disorder.
Table 10.5-11 DSM-IV-TR Research Criteria for Postconcussional Disorder
A. A history of head trauma that has caused significant cerebral concussion.
Note: The manifestations of concussion include loss of consciousness, posttraumatic
amnesia, and, less commonly, posttraumatic onset of seizures. The specific method of
defining this criterion needs to be established by further research.
B. Evidence from neuropsychological testing or quantified cognitive assessment of difficulty
in attention (concentrating, shifting focus of attention, or performing simultaneous cognitive
tasks) or memory (learning or recalling information).
C. Three (or more) of the following occur shortly after the trauma and last at least 3 months:

(1) Becoming easily fatigued

(2) Disordered sleep
(3) Headache
(4) Vertigo or dizziness
(5) Irritability or aggression on little or no provocation
(6) Anxiety, depression, or affective lability
(7) Changes in personality (e.g., social or sexual inappropriateness)
(8) Apathy or lack of spontaneity.
D. The symptoms in Criteria B and C have their onset after head trauma or else represent a
substantial worsening of preexisting symptoms.
E. The disturbance causes significant impairment in social or occupational functioning and
represents a significant decline from a previous level of functioning. In school-age children,
the impairment may be manifested by a significant worsening in school or academic
performance dating from the trauma.
F. The symptoms do not meet criteria for dementia due to head trauma and are not better
accounted for by another mental disorder (e.g., amnestic disorder due to head trauma or
personality change due to head trauma).
From American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Text rev. Washington, DC; American Psychiatric Association; 2000, with
permission.
Table 10.5-12 DSM-IV-TR Research Criteria for Mild Neurocognitive Disorder
A. The presence of two (or more) of the following impairments in cognitive functioning,
lasting most of the time for a period of at least 2 weeks (as reported by the individual or a
reliable informant):
(1) Memory impairment as identified by a reduced ability to learn or to recall information
(2) Disturbance in executive functioning (i.e., planning, organizing, sequencing, and
abstracting)
(3) Disturbance in attention or speed of information processing
(4) Impairment in perceptual-motor abilities
(5) Impairment in language (e.g., comprehension and word finding).
B. There is objective evidence from physical examination or laboratory findings (including
neuroimaging techniques) of a neurological or general medical condition that is judged to be
etiologically related to the cognitive disturbance.
C. There is evidence from neuropsychological testing or quantified cognitive assessment of
an abnormality or decline in performance.
D. The cognitive deficits cause marked distress or impairment in social, occupational, or
other important areas of functioning and represent a decline from a previous level of
functioning.
E. The cognitive disturbance does not meet criteria for a delirium, a dementia, or an amnestic
disorder and is not better accounted for by another mental disorder (e.g., substance-related
disorder or major depressive disorder).
From American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Text rev. Washington, DC; American Psychiatric Association; 2000, with
permission.
Postconcussional Disorder

In postconcussional disorder, head injury leads to an impairment in cognitive

functioning after cerebral concussion. The latter is characterized by loss of consciousness and
posttraumatic amnesia and, occasionally, posttraumatic seizures, according to DSM-IV-TR
research criteria. Cognitive deficiencies may exist in attention or memory. In addition, the
individual may experience a series of behavioral and mood changes. Impairment in the
individual's usual level of functioning is significant, yet affected individuals do not meet
cognitive criteria for dementia. In addition, they demonstrate somatic and behavioral
complaints not present in amnestic disorder due to head trauma.

Differential Diagnosis
Postconcussional disorder must be distinguished from malingering, especially in
circumstances in which legal action is contemplated (e.g., subsequent to an automobile
accident). Individuals who, after head injury, complain of fatigue, sleep impairment, or
concentration impairment may meet the criteria for major depressive disorder or,
occasionally, posttraumatic stress disorder (PTSD) and should be so diagnosed. Not
uncommonly, head injury occurs in young men with concurrent substance disorders, which
may require independent attention.
Treatment
In individuals with postconcussional disorder, mood and anxiety symptoms may be
managed psychotherapeutically and psychopharmacologically. Medications with high
anticholinergic side effects (e.g., amitriptyline and diphenhydramine [Benadryl]) or amnestic
potential (e.g., benzodiazepines) should be used with caution. Cognitive remediation
techniques occasionally may be useful. Individuals should be encouraged to conclude
litigation as rapidly as is feasible.

Mild Neurocognitive Disorder

In mild neurocognitive disorder, a general medical condition results in cognitive
deficits, which, by definition, are mild, but which nonetheless intrude on prior levels of
functioning. The affected individual may be able to compensate for such deficits. Yet, if the
causative medical condition is progressive, an individual with this disorder eventually may
meet criteria for dementia or amnestic disorder. Examples of general medical conditions
capable of causing mild cognitive loss include chronic hypoxia due to cardiopulmonary
disease; hypothyroidism; early stage Alzheimer's disease; early stage HIV infection of the
CNS, causing HIV-associated minor cognitive-motor disorder; and Parkinson's disease.
Structural brain imaging may be completely normal, although functional brain imaging (e.g.,
PET) occasionally may demonstrate abnormalities suggestive of one of the more advanced
cognitive disorders into which mild neurocognitive disorder may evolve.
Differential Diagnosis
Early delirium may resemble mild neurocognitive loss but progresses in a more rapid
and fluctuating manner. Individuals with age-related cognitive decline, with cognitive
complaints due to substance use, or with cognitive complaints occurring in the absence of
demonstrated findings on neuropsychological testing should not be diagnosed with mild
neurocognitive disorder. Individuals in the last group occasionally meet criteria for a mood
disorder.
Treatment

Correction of the underlying medical disorder, when possible, may not always result
in complete eradication of cognitive loss but may slow or halt further deterioration.

MOOD DISORDER DUE TO A GENERAL MEDICAL CONDITION

Mood disorders, particularly depression, accompany a range of medical problems.
Often in question is the link between a medical illness and associated mood symptoms: Is the
mood disturbance a physiological or psychological reaction to the medical condition? Are the
two conditions (medical and psychiatric) concurrent sequelae of another factor? Is the mood
syndrome responsible for exacerbation of the limitations associated with the medical
condition, as might be seen in depressed individuals with fatigue and somatic complaints?
Definition
To meet criteria for mood disorder due to a general medical condition, the
diagnostician must identify mood symptoms that are a direct physiological product of a
general medical condition. The mood syndrome may be depressive, manic, or mixed in
presentation. The mood disturbance need not meet precise criteria for a major depressive,
manic, mixed, or hypomanic episode. Mental symptoms must not be better accounted for by a
primary mental disorder, for example, adjustment disorder with depressed mood, occurring as
psychological response to the medical condition. The diagnosis is not made if mood
symptoms occur during the course of delirium, a clinical syndrome commonly accompanied
by transitory shifts in mood.
A diagnosis of substance-induced mood disorder relies on the appearance of mood
symptoms during intoxication or withdrawal. These mood symptoms must be in excess of
those usually associated with intoxication with, or withdrawal from, the substance or must be
severe enough to warrant independent clinical attention.
History and Comparative Nosology
DSM-III-R offered a diagnosis of organic mood syndrome in its section on organic
mental syndromes and disorders. Seemingly more restrictive in terms of mood symptoms
than the DSM-IV-TR corresponding diagnoses, organic mood syndrome was defined by
symptoms similar to either a manic or major depressive episode. Mild cognitive impairment
often was said to be present. Diagnosis was not made in the presence of delirium.
Commencing with DSM-IV, organic mood syndrome was bifurcated into mood
disorder due to a general medical condition and substance-induced mood disorder. Apart from
the etiological difference, the diagnostic criteria for the disorders are nearly identical.
ICD-10 offers the diagnosis organic mood (affective) disorder for depressive,
hypomanic, manic, or bipolar symptoms due to a medical condition or nonpsychoactive
substance. Mood symptoms with onset during psychoactive substance use and persisting
beyond the period during which a direct psychoactive substance-related effect might
reasonably be assumed to be operating may be diagnosed as residual or late-onset psychotic
disorder, a term rooted in a more historical view of psychosis as a state of severe psychiatric
impairment, not simply one in which delusions or hallucinations are present. Alternatively,
the clinician may code ICD-10's harmful use diagnosis, which applies to a pattern of
psychoactive substance use that is causing damage to health, whether physical or mental.
Epidemiology
Mood disorder due to a general medical condition, with depressive features, appears
to affect men and women equally, in contrast to major depressive disorder, which
predominates in women. As much as 50 percent of all poststroke patients experience
depressive illness. A similar prevalence pertains to individuals with pancreatic cancer. Forty

percent of patients with Parkinson's disease are depressed. Depressive disorders associated
with terminal or painful conditions carry the greatest risk of suicide.
Etiology
The array of medical illnesses that physiologically are capable of inducing a mood
syndrome includes neurological disorders (e.g., Parkinson's disease, Huntington's disease,
Wilson's disease, MS, cerebrovascular disease, brain tumor, temporal lobe epilepsy, and
neurosyphilis); metabolic and endocrine conditions (e.g., hypo- and hyperthyroidism,
hypercalcemia, hypo- and hyperadrenocorticism, hypo- and hyperparathyroidism, and
vitamin B12 deficiency); hematological and oncological disorders (anemia and pancreatic
cancer); and infectious and inflammatory states (e.g., systemic lupus erythematosus and
HIV).
Prescribed substances capable of inducing mood syndromes include agents from the
following categories: stimulant and sympathomimetic (e.g., methylphenidate and
theophylline [Asmalix]); corticosteroid; antiparkinsonian (e.g., L-dopa [Larodopa] and
bromocriptine [Parlodel]); antidepressant (inducing manic symptoms); immunosuppressant
(e.g., cyclosporine [Neoral] and tacrolimus [Prograf]); antihypertensive (e.g., -blockers and
methyldopa [Aldomet]); cancer chemotherapy (e.g., vincristine [Oncovin], vinblastine
[Velban], interferon, and procarbazine [Matulane]); oral contraceptives; CNS depressant (e.g.,
benzodiazepines and barbiturates); heavy metals; and toxins (e.g., paint and carbon
monoxide).
Substances of abuse that may produce mood symptoms in intoxication include
stimulants (e.g., cocaine), opioids, hallucinogens, phencyclidine (PCP), and CNS depressants
(e.g., alcohol).
Substances of abuse that may produce mood symptoms in withdrawal include
stimulants (e.g., cocaine) and CNS depressants (e.g., alcohol).
As in primary mood disorders, pathophysiological mechanisms by which general
medical conditions and substances induce mood syndromes likely involve impact on
noradrenergic, dopaminergic, serotonergic, and cholinergic neurotransmission. Substances
(e.g., reserpine [Serpalan]) and medical conditions (e.g., hypoxia) capable of depleting
noradrenergic function may induce depression; agents (e.g., amphetamine) that stimulate
noradrenergic activity may cause mania. Many metabolic and endocrine disorders appear to
induce mood syndromes by impact on the hypothalamic-pituitary-adrenal axis.
Demyelinating disorders, such as MS, may cause mania associated with lesions to the
hypothalamus and temporal lobes of the brain. Patchy demyelination of the CNS associated
with depression is observed in vitamin B12 deficiency. Cerebrovascular injury may induce
depression through physiological means, although precise neuroanatomical correlates require
further study.
Diagnosis and Clinical Features
Patients with depression may experience psychological symptoms (e.g., sad mood,
lack of pleasure or interest in usual activities, tearfulness, concentration disturbance, and
suicidal ideation) or somatic symptoms (e.g., fatigue, sleep disturbance, and appetite
disturbance), or both. Diagnosis in the medically ill may be confounded by the presence of
somatic symptoms related purely to medical illness, not to depression. In an effort to
overcome the underdiagnosis of depression in the medically ill, most practitioners favor
including somatic symptoms in identifying mood syndromes.
In contrast to depressed individuals, those with mania present with irritable or
euphoric mood, heightened energy, reduced need for sleep, and accelerated rate of thoughts.

Occasionally, manic patients may engage in reckless activities with little consideration of the
consequences of such behavior, such as excessive spending or risky sexual adventures.
The likelihood that a mood disorder is due to a general medical condition is increased
if a temporal relationship exists between the onset, exacerbation, or remission of the medical
condition and the mood disorder. Atypical features (e.g., unusual age of onset, lack of family
history, and lack of prior episodes of mood disorder) also raise the likelihood of a medical
basis to mood symptoms. A further supporting factor is evidence from the literature of a link
between the medical condition and the development of specific mood symptoms.
Similar diagnostic considerations apply to substance-induced mood disorder. A
primary mood disorder, or a mood disorder stemming from a general medical condition, is
more likely if the mood symptoms develop in advance of the use of the suspect substance,
persist for more than 4 weeks after cessation of use of the substance, are substantially in
excess of what one would expect from the substance, or occur in an individual who
previously experienced episodes of similar mood symptoms not attributable to the substance.
DSM-IV-TR provides diagnostic criteria for mood disorder due to a general medical
condition with depressive features, with major depressivelike episode, with manic features,
or with mixed features. In general, these criteria are less strict than for corresponding primary
mood disorders. The subtype with major depressivelike episode is not available for
substance-induced mood disorder (Table 10.5-13).
Table 10.5-13 DSM-IV-TR Criteria for Mood Disorder Due to a General Medical
Condition
A. A prominent and persistent disturbance in mood predominates in the clinical picture and is
characterized by either (or both) of the following:
(1) Depressed mood or markedly diminished pleasure in all, or almost all, activities
(2) Elevated, expansive, or irritable mood.
B. There is evidence from the history, physical examination, or laboratory findings that the
disturbance is the direct physiological consequence of a general medical condition.
C. The disturbance is not better accounted for by another mental disorder (e.g., adjustment
disorder with depressed mood in response to the stress of having a general medical
condition).
D. The disturbance does not occur exclusively during the course of a delirium.
E. The symptoms cause clinically significant distress or impairment in social, occupational,
or other important areas of functioning.
Specify:
With depressive features: if the predominant mood is depressed, but the full criteria are
not met for a major depressive disorder
With major depressivelike episode: if all criteria for major depressive episode are met,
except, clearly, for the criterion that the symptoms are not due to the physiological effects of
a substance or a general medical condition
With manic features: if the predominant mood is elevated, euphoric, or irritable
With mixed features: if the symptoms of mania and depression are present, but neither
predominates
From American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Text rev. Washington, DC; American Psychiatric Association; 2000, with
permission.

The name of the general medical condition is coded on Axis I (e.g., mood disorder
due to hypothyroidism, with depressive features) and on Axis III.
If the mood disorder is substance-induced, the diagnostician may select with onset
during intoxication or with onset during withdrawal, if the criteria for intoxication or
withdrawal syndromes are met and if mood symptoms appear during one of those syndromes.
The name of the causative substance is indicated on Axis I (e.g., cocaine-induced mood
disorder, with depressive features, and with onset during withdrawal).
If mood symptoms are due to a general medical condition and a substance, both
diagnoses are indicated. If mood symptoms cannot readily be attributed to a general medical
condition, substance, or primary mood disorder, the clinician should diagnose mood disorder
not otherwise specified.
A 45-year-old toy designer was admitted to the hospital after a series of
suicidal gestures culminating in an attempt to strangle himself with a piece of wire.
Four months before admission, his family had observed that he was becoming
depressed: when at home, he spent long periods sitting in a chair, he slept more than
usual, and he had given up his habits of reading the evening paper and puttering
around the house. Within 1 month, he was unable to get out of bed in the morning to
go to work. He expressed considerable guilt but could not make up his mind to seek
help until forced to do so by his family. He had not responded to 2 months of
outpatient antidepressant drug therapy and had made several half-hearted attempts to
cut his wrists before the serious attempt that precipitated the admission.
Physical examination revealed signs of increased intracranial pressure, and a
CT scan showed a large frontal-lobe tumor. (Reprinted with permission from DSMIV-TR Casebook.)
In this case, provisional diagnosis recorded on Axis I is mood disorder due to brain
tumor, with major depressivelike episode. Frontal lobe tumor is recorded on Axis III. This
diagnosis would be supported if mood disturbance resolves after tumor resection. If it fails to
do so, major depressive episode unrelated to brain tumor would also merit diagnostic
consideration, especially if the individual had experienced previous such episodes earlier in
life or had a family history of depression. In either case, antidepressant treatment would be
appropriate for mood symptoms that fail to resolve after tumor resection.
Laboratory Evaluation
Complete blood count and chemistries, thyroid function tests, serum vitamin B12 level,
and urinalysis should be examined in all individuals with new-onset or atypical mood
symptoms. Urine toxicology often is appropriate, particularly if abuse of substances is
suspected. In selected cases, added laboratory studies, such as ESR, RPR, urinalysis, or
lumbar puncture may be indicated. EEG or structural brain imaging, or both, should be
considered in the absence of an overt medical or substance cause, the presence of cognitive
impairment, or the report or presence of neurological symptoms (e.g., headache, motor or
sensory loss, visual disturbance, or lethargy).
Differential Diagnosis
Mood changes occurring during the course of delirium are acute and fluctuating and
should be attributed to that disorder, not to mood disorder due to a general medical condition
or to substance-induced mood disorder. Pain syndromes may depress mood but do so through
psychological, not physiological means, and may appropriately lead to a diagnosis of primary
mood disorder. In the medically ill, somatic complaints, such as sleep disturbance, anorexia,
and fatigue, may be counted toward a diagnosis of major depressive episode or mood

disorder due to a general medical condition, unless those complaints are purely attributable to
the medical illness.
Mood disorder due to a general medical condition may be distinguished from
substance-induced mood disorder by examination of time course of symptoms, response to
correction of suspect medical conditions or discontinuation of substances, and, occasionally,
by urine or blood toxicology results.
Course and Prognosis
The course of mood disorder due to a general medical condition largely depends on
the course of the underlying medical state, as well as the extent of concurrent psychiatric
intervention. Similar considerations apply to substance-induced mood disorder. Prognosis for
mood symptoms is best when etiological medical illnesses or medications are most
susceptible to correction (e.g., treatment of hypothyroidism and cessation of alcohol use).
When such intervention is not possible (e.g., halting immunosuppressant use in an
individual after kidney transplant) or fails to lead to prompt remission of mood symptoms,
formal psychiatric treatment is indicated.
Treatment
Pharmacotherapies should be designed to address mood symptoms while minimizing
adverse interactions of prescribed antidepressant or mood-stabilizing medications with other
concurrently prescribed medications. Selective serotonin reuptake inhibitors (SSRIs) used in
depressive syndromes variably impact the cytochrome P450 enzyme system, thereby
affecting the metabolism of other medications. Sertraline (Zoloft), citalopram (Celexa), and
escitalopram (Lexapro) have a more limited impact on metabolism of other medications than
do paroxetine (Paxil) and fluoxetine (Prozac). Bupropion (Wellbutrin) has stimulant
properties that may be useful in the depressed, debilitated, medically ill individual. This drug
must not be used in individuals with history of seizure. Mirtazapine (Remeron) may be
especially useful in stimulating appetite in the anorectic or debilitated individual with
depression. Similar benefit may be derived from psychostimulants, such as methylphenidate.
The clinician must recognize that medically ill individuals often are exquisitely
sensitive to medication side effects and toxicities. For this reason, tricyclic antidepressants,
which typically have a higher incidence of orthostatic hypotensive, anticholinergic, and
cardiac conduction effects, rarely are preferred to SSRIs in the management of depression in
the medically ill.
In manic or mixed mood states, divalproex is preferred to lithium (Eskalith); the latter
has a low therapeutic index, with major toxicity considerations in medically ill patients at risk
for dehydration or electrolyte imbalance. Other anticonvulsant agents potentially useful in
mood stabilization include lamotrigine (Lamictal), carbamazepine (Tegretol), oxcarbazepine
(Trileptal), and topiramate (Topamax). Drug interactions may complicate the use of
anticonvulsants, particularly divalproex and carbamazepine.
In the anxious, depressed individual, caution must be exercised in the use of
benzodiazepines, as these agents possess amnestic qualities that may exacerbate cognitive
loss commonly present in the medically ill and elderly. When the use of benzodiazepines
seems essential, agents with short half-lives (e.g., lorazepam [Ativan] and alprazolam
[Xanax]) are preferred over agents with long half-lives (e.g., clonazepam [Klonopin] and
diazepam [Valium]), particularly in individuals with impaired hepatic function.
In the elderly and in individuals with hepatic or renal impairment, psychotropic
medications should be initiated at low dosages. Yet, if mood symptoms persist in the absence
of serious toxicity or side effects, the clinician should titrate dosing upward until symptom
relief is achieved, lest a premature diagnosis of treatment refractoriness be entertained.

Interestingly, medically ill individuals often require psychopharmacological doses similar to

those used in medically healthy individuals.
ECT, useful in severe depression (especially if associated with intense suicidal
ideation), mania, and catatonia, has the advantage of being safe, highly effective, and
arguably more rapid in onset than pharmacological modalities, a point of considerable
importance in the debilitated, bedridden, anorectic patient for whom a feeding tube