1-Definition:

Bipolar disorder "manic depressive disorder or manic depression", It's a serious

mental illness, can lead to risky behavior, damaged relationships and careers, and even
suicidal tendencies, if it's not treated, Bipolar disorder is characterized by extreme
changes in mood (poles) from mania to depression, Between these mood swings, a
person with bipolar disorder may experience normal moods.

"Manic" describes an increasingly "restless, energetic, talkative, reckless, powerful,

euphoric period", Then, at some point, this high-flying mood can spiral into something
darker "irritation, confusion, anger, feeling trapped".

"Depression" describes the opposite mood "sadness, crying, sense of worthlessness,

loss of energy, loss of pleasure, sleep problems".

But because the pattern of highs and lows varies for each person, bipolar disorder is a
complex disease to diagnose. For some people, mania or depression can last for weeks
or months, even for years. For other people, bipolar disorder takes the form of frequent
and dramatic mood shifts (WebMD,2008).

2-Risk factors:
lifestyle habits increase the risk of bipolar disorder, that lack of sleep increases the
risk of having an episode of mania, In addition, antidepressant medications, particularly
when taken as the only medication, may also trigger a switch into a manic state.
Excessive use of alcohol or drugs can also trigger bipolar symptoms. Research has
shown that about 50% of bipolar sufferers have a substance abuse or alcohol problem.
Sufferers often use alcohol or drugs to self-medicate during their high and low moods.
Also environmental stress that include seasonal changes, holidays, and major life
changes such as starting a new job, losing a job, going to college, family disagreements,
marriage, or a death in the family, increase the risk of bipolar disorder (WebMD,2008).

3-Epidemiology:

Approximately 5% of the adult population has either bipolar I or II disorder, with the
full spectrum of recurrent mood disorders (American Psychiatric Association ,2000).

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The lifetime prevalence of bipolar I disorder (one or more manic or mixed episodes) is
0.4% to 1.6%; that for bipolar II disorder (recurrent major depressive episodes with
hypomanic episodes) is approximately 0.5%, Bipolar I disorder occurs equally in men
and women, whereas bipolar II disorder is more common in women (American Psychiatric
Association,2000 ; American Psychiatric Association,2002).

4-Etiology:
The exact etiology of bipolar disorder is unknown. Bipolar disorder is thought to be a
complex genetic disease that is environmentally influenced and caused by a wide range
of neurobiologic abnormalities. Stressful life events, alcohol or substance use, and
changes in the sleep-wake cycle can elicit the expression of genetic or biologic
vulnerabilities that cause dysregulation of neurotransmitters, neuroendocrine pathways,
and second messenger systems (Goldberg et al,1999).

4.1-Neurochemical theories:
Dysregulation between neurotransmitters, neuropeptides, hormones, and secondary
messenger systems can produce a cyclic rhythm disturbance in the central nervous
system (Torrey, Knable, 2002).
The "permissive serotonin hypothesis" proposes that serotonin (5-HT) plays a critical
role in modulating brain activity (e.g., stabilization of the catecholamine system and
inhibition of dopamine (DA) release), and is low in both mania and depression, The
type of affective state that is expressed with the permissive hypothesis is determined
secondarily by the level of norepinephrine (NE) (e.g., increased amounts of NE lead to
mania, decreased amounts lead to depression), 5-HT deficiency and changes in the
light–dark cycle may result in reduced melatonin secretion from the pineal gland that
disrupts the sleep wake cycle, alters circadian rhythms, and causes seasonal affective
changes (Goodnick et al, 1998; Mahmood et al, 2001).
The catecholamine hypothesis of mood disorders suggests that increased DA and NE
activity contribute to hyperactivity and psychosis associated with the severe stages of
mania, and reduced activity causes depression (Goodnick et al, 1998; Goldberg et al, 1999).
A γ-aminobutyric acid (GABA) deficiency theory has been proposed for mania as it
inhibits NE and DA activity (Goodnick et al, 1998; Goldberg et al, 1999).
Glutamate and aspartate, excitatory amino acid neurotransmitters, may be overactive
and involved in causing manic episodes (Manji et al, 2000).

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 Cholinergic under activity has been proposed to cause mania and over activity of
acetylcholine to cause depression (Goodnick et al, 1998; Manji et al, 2000).

4.2-Summarizes the etiologic theories of bipolar disorder:

4.2.1-Genetic factors:
• 80–90% of patients with bipolar disorder have a biologic relative with a mood
disorder (e.g., bipolar disorder, major depression, cyclothymia, or dysthymia).
• First-degree relatives of bipolar patients have a 15–35% lifetime risk of
developing any mood disorder and a 5–10% lifetime risk for developing bipolar
disorder.
• The concordance rate of mood disorders is 60–80% for monozygotic twins and
14–20% for dizygotic twins.
• Linkage studies suggest that certain loci on genes and the X chromosome may
contribute to genetic susceptibility of bipolar disorder.
4.2.2-Nongenetic factors:
• Perinatal insult.
• Head trauma.
• Environmental factors:
Deschronization of circadian or seasonal rhythms cause diurnal variations in
mood and sleep patterns and can result in seasonal recurrences of mood
episodes.
Changes in the sleep-wake cycle or light-dark cycle can precipitate episodes of
mania or depression.
Bright light therapy can be used for the treatment of winter depression and can
precipitate hypomania, mania, or mixed episodes.
• Psychosocial or physical stressors:
Stressful life events often precede mood episodes and can increase recurrence
rates and prolong time to recovery from mood episodes.
• Nutritional factors:
Deficiency of essential amino acid precursors in the diet can cause a
dysregulation of neurotransmitter activity (e.g., L-tryptophan deficiency causes a
decrease in 5-HT and melatonin synthesis and activity).

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 Deficiency in essential fatty acids (e.g., omega-3 fatty acids) can cause a
dysregulation of neurotransmitter activity.
• Neurotransmitter/neuroendocrine/hormonal theories:
Dysregulation between excitatory and inhibitory neurotransmitter systems;
excitatory: NE, DA, glutamate, and aspartate; inhibitory: 5-HT and GABA.
• Monoamine hypothesis:
An excess of catecholamines (primarily NE and DA) cause mania.
Agents that decrease catecholamines are used for the treatment of mania (e.g.,
DA antagonists and α2-adrenergic agonists).
Deficit of neurotransmitters (primarily NE, DA, and/or 5-HT) cause depression.
Agents that increase neurotransmitter activity are used for the treatment of
depression (e.g., 5-HT and NE/DA reuptake inhibitors and MAOIs).
• Dysregulation of amino acid neurotransmitters:
Deficiency of GABA or excessive glutamate activity causes dysregulation of
neurotransmitters (e.g., increased DA and NE activity).
Agents that increase GABA activity or decrease glutamate activity are used for
the treatment of mania and for mood stabilization (e.g., benzodiazepines,
lamotrigine, lithium, or valproic acid).
• Cholinergic hypothesis:
Deficiency of acetylcholine causes an imbalance in cholinergic-adrenergic
activity and can increase the risk of manic episodes.
Agents that increase acetylcholine activity can decrease manic symptoms (e.g.,
use of cholinesterase inhibitors or augmentation of muscarinic cholinergic
activity).
Increased central acetylcholine levels can increase the risk of depressive
episodes.
Agents that decrease acetylcholine activity can alleviate depressive symptoms
(i.e., anticholinergic agents).
• Secondary messenger system dysregulation:
Abnormal G protein functioning dysregulates adenylate cyclase activity,
phosphoinositide responses, sodium/potassium/calcium channel exchange, and
activity of phospholipases.
Abnormal cyclic adenosine monophosphate and phosphoinositide secondary
messenger system activity.
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 Abnormal protein kinase C activity and signaling pathways.
• Hypothalamic-pituitary-thyroid axis dysregulation:
Hyperthyroidism can precipitate manic-like symptoms.
Hypothyroidism can precipitate a depression and be a risk factor for rapid
cycling; thyroid supplementation can be used for refractory rapid cycling and
augmentation of antidepressants in unipolar depression.
Positive antithyroid antibody titers reported in patients with bipolar disorder.
Hormonal changes during the female life cycle can cause dysregulation of
neurotransmitters (e.g., premenstrual, postpartum, and perimenopause).
• Membrane and cation theories:
Abnormal neuronal calcium and sodium activity and homeostasis cause
neurotransmitter dysregulation.
Hypocalcemia has been associated with causing anxiety, mood irritability,
mania, psychosis, and delirium.
Hypercalcemia has been associated with causing depression, stupor, and coma.
Extra cellular and intracellular calcium concentrations may affect the synthesis
and release of NE, DA, and 5-HT, as well as the excitability of neuronal firing.
• Sensitization and kindling theories:
Recurrences of mood episodes causes behavioral sensitivity and electro
physiologic kindling (similar to the amygdalakindling models for seizures in
animals) and can result in rapid or continuous mood cycling (Dipiro et al, 2008).

5-Clinical presentation:
The essential feature of bipolar spectrum disorders are a history of mania or hypomania
that is not caused by any other medical condition, substance, or psychiatric disorder.
Bipolar disorder is divided into four subtypes based on the identification of specific
mood episodes: bipolar I, bipolar II, cyclothymic disorder, and bipolar disorder not
otherwise specified.
Mood Disorders Defined by Episodes:
Disorder Subtype: Episode(s)
Major depressive disorder, Major depressive episode
single episode

Major depressive disorder, Two or more major

depressive episodes
Recurrent
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Bipolar disorder, type I Manic episode ± major
depressive or mixed
episode
Bipolar disorder, type II Major depressive episode +
hypomanic episode

Dysthymic disorder Chronic subsyndromal

depressive episodes

Cyclothymic disorder Chronic fluctuations between

subsyndromal depressive
and hypomanic episodes (2 years for adults
and 1 year
for children and adolescents)
Bipolar disorder not otherwise Mood states do not meet
criteria for any
Specified specific bipolar disorder

The length and severity of a mood episode and the interval between episodes varies
from patient to patient. Manic episodes are usually briefer and end more abruptly than
major depressive episodes. The average length of untreated manic episodes ranges from
4 to 13 months. Episodes can occur regularly (at the same time or season of the year)
and often cluster at 12-month intervals. Women have more depressive episodes than
manic episodes, whereas men have a more even distribution of episodes. For bipolar I
disorder, 90% of individuals who experience a manic episode later have multiple
recurrent major depressive, manic, hypomanic, or mixed episodes alternating with a
normal mood state. Approximately 5–15% of patients with bipolar II disorder will
develop a manic episode over a 5-year period. If a manic or mixed episode develops in
a patient with bipolar II disorder, the diagnosis is changed to bipolar I disorder. Patients
with cyclothymic disorder have a 15–50% risk of later developing a bipolar I or II
disorder (American Psychiatric Association,2002).
5.1-Symptoms of the depressive phase of bipolar disorder may consist of the
following:

Depressed mood and low self-esteem.

Excessive crying spells.

Low energy levels and an apathetic view of life.

Sadness, loneliness, helplessness, feelings of guilt.

Slow speech, fatigue, and poor coordination and concentration.

Insomnia or oversleeping.

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 Thoughts of suicide or dying.

Changes in appetite (overeating/not eating).

Drug use: self-medication through illicit drugs.

Unexplainable aching.

Lack of interest or pleasure in usual activities.

5.2-Symptoms of bipolar mania or hypomania may contain:

Euphoria or irritability.

Excessive talking, racing thoughts.

Inflated self-esteem.

Unusual energy; less need for sleep.

Alcohol and illicit drug use - cocaine and methamphetamines.

Impulsiveness, a reckless pursuit of gratification, shopping sprees, impetuous travel,

more and sometimes promiscuous sex, high-risk business investments, fast driving.

Hallucinations and or delusions (in extreme cases of bipolar disorder with psychotic
features) (WebMD,2008).

But bipolar disorder can be sneaky, Symptoms can defy the expected manic-depressive
sequence, Infrequent episodes of mild mania can go undetected, Depression can
overshadow other aspects of the illness, And substance abuse can cloud the picture.
Taken together, these factors make bipolar disorder surprisingly difficult to diagnose.

5.3-A few facts about bipolar disorder:

As many as 20% of people complaining of depression to their doctor actually have

bipolar disorder.

About half of people with bipolar disorder have seen three professionals before
being diagnosed correctly.

It takes an average of 10 years for people to enter treatment for bipolar disorder after
symptoms begun. Partly, this is due to delays in diagnosis (WebMD,2008).

6-Diagnosis and difficulties:

The American Psychiatric Association has established a long list of specific criteria for
recognizing the disorder. Evaluation involves investigating the patient's history and any

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family history of mood swings or suicide. Other disorders must be ruled out particularly
such childhood problems as school phobia and attention deficit disorder, aging
problems of dementia, schizophrenia, schizoaffective disorder, and other psychotic
states induced solely by alcohol or drugs. Drug or alcohol abuse is common in persons
with bipolar disorder and can mask the symptoms, thus complicating diagnosis and
treatment. Recognizing and treating any drug abuse is a priority, since it is a strong
predictor of suicide, especially in men. Before treatment begins, the patient receives a
careful physical exam, and blood and urine are tested to detect conditions that could put
medical constraints on the choice of treatment. A thyroid analysis is particularly
important both because hyperthyroidism can look like mania and because lithium "the
principal drug treatment for bipolar disorder" is known to lower thyroid function and/or
impair kidney function. During treatment, frequent blood tests are necessary to see that
adequate drug levels have been reached and to detect adverse reactions at an early stage
(WebMD,2008).

Several medical, medication-induced, or substance-related causes of mania and

depression have been identified, A complete medical, psychiatric, and medication
history, physical examination, and laboratory testing are necessary to rule out any
organic causes of mania or depression (American Psychiatric Association,2002).

6.1-Secondary causes of mania:

• Medical conditions that induce mania:

1- CNS disorders: Brain tumor, Strokes, Head injuries, Subdural hematoma, Multiple
Sclerosis, Systemic Lupus Erythematosus, Temporal lobe seizures, Huntington’s
disease.
2- Infections: Encephalitis, Neurosyphilis, Sepsis, Human immunodeficiency virus.
3- Electrolyte or metabolic abnormalities: Calcium or Sodium fluctuations, Hyper
or Hypoglycemia.
4- Endocrine or hormonal dysregulation: Addison’s disease, Cushing’s disease,
Hyper or Hypothyroidism, Menstrual-related or Pregnancy-related or
Perimenopausal mood disorders.
• Medications or drugs that induce mania:
Alcohol intoxication.
Drug withdrawal states (alcohol, α2-adrenergic agonists, antidepressants,
barbiturates, benzodiazepines, opiates).
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 Antidepressants (MAOIs, TCAs, 5-HT and/or NE and/or DA reuptake inhibitors,
5-HT antagonists).
DA-augmenting agents (CNS stimulants: amphetamines, cocaine,
sympathomimetics, DA agonists, releasers, and reuptake inhibitors).
Hallucinogens (LSD, PCP).
Marijuana intoxication precipitates psychosis, paranoid thoughts, anxiety, and
restlessness.
NE-augmenting agents (α2-adrenergic antagonists, β-agonists, NE reuptake
inhibitors).
Steroids (anabolic, adrenocorticotropic hormone, corticosteroids).
Thyroid preparations.
Xanthines (caffeine, theophylline).
Over-the-counter weight loss agents and decongestants (ephedra, pseudo
ephedrine).
Herbal products (St. John’s wort).
• Somatic therapies that induce mania:
Bright light therapy.
Sleep deprivation.
6.2-Secondary causes of depression:
• General medical conditions:
1-Endocrine diseases: Hypothyroidism, Addison or Cushing disease.
2-Deficiency states: Pernicious anemia, Wernicke encephalopathy , Severe anemia.
3-Infections: AIDS, Encephalitis, Human immunodeficiency virus, Mononucleosis.
Sexually transmitted diseases , Tuberculosis.
4-Collagen disorder: Systemic lupus erythematosus.
5-Metabolic disorders: Electrolyte imbalance,(Hypokalemia, Hyponatremia), Hepatic
encephalopathy.
6-Cardiovascular disease: Coronary artery disease, Congestive heart failure,
Myocardial infarction.
7-Neurologic disorders: Alzheimer’s disease, Epilepsy, Huntington’s disease, Multiple
sclerosis, Pain, Parkinson’s disease, Post stroke.
8-Malignant disease.
• Medications or drugs that induce depression:
Substance use disorders (including intoxication and withdrawal):
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 Alcoholism.
Marijuana abuse and dependence.
Nicotine dependence.
Opiate abuse and dependence (e.g., heroin).
Psychostimulant abuse and dependence (e.g., cocaine).
Drug therapy:
Antihypertensives: Clonidine, Diuretics, Guanethidine sulfate, Hydralazine
hydrochloride, Methyldopa, Propranolol, Reserpine.
Hormonal therapy:
Oral contraceptives.
Steroids/adrenocorticotropic hormone.
Acne therapy:
Isotretinoin.
Other:
Interferon-β1a.
An accurate diagnosis is important because some psychiatric and neurologic disorders
present with manic-like or depressive-like symptoms, For example, attention-
deficit/hyperactivity disorder and a manic episode have similar characteristics; thus
individuals with bipolar disorder can be misdiagnosed and prescribed central nervous
system stimulants.
Another disease state that has a similar presentation to bipolar disorder is
schizoaffective disorder. This disease is a mix between schizophrenia and bipolar
disorder. Patients with schizoaffective disorder have mood episodes, but the
distinguishing factor from bipolar disorder is that these patients experience psychosis
even between mood episodes during periods of euthymia (Dipiro et al, 2008).
6.3-Diagnostic criteria of mood episodes:
1. Mental status examination.
2. Psychiatric, medical, and medication history.
3. Physical and neurologic examination.
4. Basic laboratory tests: complete blood count, blood chemistry screen, thyroid
function, urinalysis, urine drug screen.
5. Psychological testing.
6. Brain imaging: magnetic resonance imaging and functional scan; alternative:
computed tomography scan, positron emission tomography scan.

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 7. Lumbar puncture.
8. Electroencephalogram.

7-Course of illness:
The average age of onset of a first manic episode is 21 years. More than 80% of bipolar
patients have more than four episodes during their lifetime. Usually there is normal
functioning between episodes. Rapid cyclers (10% to 20% of bipolar patients) have four
or more episodes per year (major depressive, manic, mixed, or hypomanic). Rapid-
cycling and mixed states are associated with a poorer prognosis and nonresponse to
antimanic agents. Risk factors for rapid cycling include biologic rhythm dysregulation,
antidepressant or stimulant use, hypothyroidism, and premenstrual and postpartum
states.
Suicide attempts occur in up to 50% of patients with bipolar disorder, and
approximately 10% to 19% of individuals with bipolar I disorder commit suicide.
Bipolar II patients may be more likely than bipolar I patients to attempt suicide. Bipolar
patients with substance abuse disorders are more likely to have an earlier onset of
illness, mixed states, higher relapse rates, poorer response to treatment, higher suicide
risk, and more hospitalizations. Episodes may become longer in duration and more
frequent with aging (American Psychiatric Association,2002).

8-Treatment:
8.1-General principles for the management of bipolar disorder:
Goals of treatment:
• Eliminate mood episode with complete remission of symptoms (i.e., acute
treatment).
• Prevent recurrences or relapses of mood episodes (i.e., continuation phase
treatment).
• Return to complete psychosocial functioning.
• Maximize adherence with therapy.
• Minimize adverse effects.
• Use medications with the best tolerability and fewest drug interactions.
• Treat comorbid substance use and abuse.
• Eliminate alcohol, marijuana, cocaine, amphetamines, and hallucinogens.
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 • Minimize nicotine use and stop caffeine intake at least 8 hours prior to bedtime.
• Avoidance of stressors or substances that precipitate an acute episode.

Treatment of bipolar disorder must be individualized because the clinical presentation,

severity, and frequency of episodes vary widely among patients. Treatment approaches
should include both nonpharmacologic and pharmacologic strategies (Goldberg et al,1999).
Patients and family members should be educated about bipolar disorder (e.g.,
symptoms, causes, and course) and treatment options. Long-term adherence to
treatment is the most important factor in achieving stabilization of the disorder. The
treatment of bipolar disorder can vary depending on what type of episode a patient is
experiencing. Once diagnosed with bipolar disorder patients should remain on a mood
stabilizer (e.g. lithium, valproate) for life. During acute episodes medications can be
added and then tapered once a patient is stabilized and euthymic. For example, when
treating a patient for mania with psychotic features, the patient should be on a mood
stabilizer and antipsychotic. If the antipsychotic is the patient’s maintenance therapy,
the dose should be increased or perhaps changed altogether. If treating a patient for a
severe depressive episode, add an antidepressant to the mood stabilizer and an
antipsychotic if psychosis is also present (Dipiro et al, 2008).
8.2-Nonpharmacologic therapy:
The basics of nonpharmacologic approaches are of adequate nutrition, sleep, exercise,
and stress reduction. Sleep deprivation, high stress, and deficiencies in dietary essential
amino acids, fatty acids, vitamins, and minerals can exacerbate mood episodes and
result in poorer outcomes (Goldberg et al,1999).
Another effective treatment is to combine medications with adjunctive psycho
educational programs, supportive counseling, insight-oriented psychotherapy
(individual or group), couples or family therapy, cognitive behavioral therapy, and
communication enhancement training.
8.2.1-Types of psychotherapy used to treat bipolar disorder include:

Behavioral therapy: This focuses on behaviors that decrease stress.

Cognitive therapy: This type of approach involves learning to identify and modify the
patterns of thinking that accompany mood shifts.

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 Interpersonal therapy: This involves relationships and aims to reduce strains that the
illness may place upon them.

Social rhythm therapy: This helps them develop and maintain daily routines.

Support groups also help patients with bipolar disorder, that receive encouragement,
learn coping skills, and share concerns, they may feel less isolated as a result. Family
members and friends may also benefit from a support group. They can gain a better
understanding of the illness, share their concerns, and learn how to best support loved
ones with bipolar disorder (WebMD,2008).

8.2.2-Electroconvulsive therapy (ECT) is sometimes used for severely manic or

depressed patients and for those who don't respond to medication or for those women
who, while pregnant, experience symptoms. Because it acts quickly, it can also help
patients who are considered to be at high risk for committing suicide. ECT fell out of
favor in the 1960s, but the procedure has been greatly refined since then. The patient is
first anesthetized and a drug to prevent muscle contraction is given. Then an electric
current is passed through the brain to produce a grand mal seizure of short duration " no
more than a few seconds". During the course of ECT treatments usually two to three
weeks lithium and other mood stabilizers are discontinued to ensure an adequate
response to the electrical stimulation.

The newer types of non-pharmocological treatments of depression are:

• VNS (Vagal Nerve Stimulation).

• TMS (Transcranial Magnetic Stimulation).

Light therapy has proved effective as an additional treatment when bipolar disorder has
a connection to the winter depression condition seasonal affective disorder. For those
people who usually become depressed in winter, sitting for 20-30 minutes a day in front
of a special light box with a full-spectrum light can effectively treat their depression
(WebMD,2008).

The use of ECT for severe episodes of mania, depression, psychotic features (e.g.,
hallucinations or delusions), mixed episodes, or rapid cycling is still considered the best
acute treatment approach for those patients who do not respond to first-line mood
stabilizers such as lithium and valproate (Goldberg et al,1999).

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8.2.3-Dietary intake:
Disturbances in 5-HT neurotransmission secondary to inadequate dietary L-tryptophan
or abnormalities in tryptophan hydroxylase, 5-HT transporters, and 5-HT receptors was
implicated in the pathophysiology of manic depressive illness as early as 1958, If
available 5-HT is low, the synthesis and secretion of melatonin can be disrupted, thus
causing circadian rhythm changes (Goodnick et al, 1998).
A dietary deficiency in essential fatty acids (found in certain fish oils and flaxseed oil
that contains α-linolenic acid) has been proposed as a potential cause of mood
disorders, Omega-3 fatty acids have been shown to suppress neuronal pathways and
inhibit kindling processes by several mechanisms (e.g., inhibition of
phosphatidylinositol and G-protein secondary messengers and blocking L-type calcium
channels). Seafood and fish are rich dietary sources of omega-3 essential fatty acids,
specifically docosahexaenoic acid and eicosapentaenoic acid (Parker et al, 2006).
8.3-Pharmacologic therapy:

Pharmacotherapy is crucial for the acute and maintenance treatment of bipolar disorder
and includes lithium, valproate, carbamazepine, lamotrigine, atypical antipsychotics,
and adjunctive agents such as antidepressants and benzodiazepines (Dipiro et al, 2008).
The term mood stabilizer is often used to describe the class of medications used in the
treatment of bipolar disorder, but this may not be accurate as some medications are
more effective for acute mania, some for the depressive episode, and others for the
maintenance phase. Lithium, valproate (or divalproex sodium), aripiprazole,
olanzapine, quetiapine, risperidone, and ziprasidone are currently approved by the Food
and Drug Administration (FDA) for the treatment of acute mania in bipolar disorder;
only lithium, olanzapine, and lamotrigine are approved for the maintenance treatment of
bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar
depression. Lithium is the drug of choice for bipolar disorder with euphoric mania,
whereas valproate has better efficacy for mixed states, irritable/dysphoric mania, and
rapid cycling compared to lithium (American Psychiatric Association,2002).
Combination therapies (e.g., lithium plus valproate or carbamazepine; lithium or
valproate plus an atypical antipsychotic) can provide better acute response and long-
term prevention of relapse and recurrence than monotherapy in some bipolar patients
particularly those with mixed states or rapid cycling. There are few controlled studies in
children and adolescents with bipolar disorder, thus little is known about the long-term

14
efficacy and safety of specific agents or for combination therapies in this population
(American Psychiatric Association,2002; Goldberg et al,1999).

8.3.1-General information regarding efficacy and safety:

Lithium was first used in 1949 as a treatment for mania and was approved in 1972 in
the United States for the treatment of acute mania and for maintenance therapy. Lithium
was the first established mood stabilizer, and is still considered a first-line agent for
acute mania and continuation treatment of bipolar I and II disorders (Goldberg et al,1999).
Lithium is the only bipolar medication approved for children and adults aged 12 years
and older. Long-term lithium treatment has been shown to reduce suicide risk in several
studies, Patients with rapid cycling or mixed states may not respond as well to lithium
monotherapy compared to some anticonvulsants Lithium requires regular assessment of
renal and thyroid functioning and lithium blood level monitoring to minimize adverse
effects (American Psychiatric Association,2002).
Divalproex sodium (known as sodium valproate) was marketed in 1995 for the acute
treatment of mania in adults and is now the most prescribed mood stabilizer in the
United States. Divalproex sodium is FDA approved only for the treatment of acute
manic or mixed episodes; however it is commonly used in clinical practice as
maintenance monotherapy for bipolar disorder. Although carbamazepine is commonly
used for both acute and maintenance therapy, it is not approved in the United States for
bipolar disorder. There are some data to support the use of oxcarbazepine, a 10-keto
analogue of carbamazepine, in the treatment of bipolar disorder, however it is not
approved for the treatment of bipolar disorder in the United States. Valproate,
carbamazepine, and oxcarbazepine each have a wide range of neurologic,
gastrointestinal, electrolyte, and hematologic adverse effects that requires regular
assessment and routine blood test (Dipiro et al, 2008).
Lamotrigine, a newer anticonvulsant, was approved in 2003 in the United States for the
maintenance treatment of bipolar I disorder (Calabrese et al, 2002; Hurley SC, 2002),
Lamotrigine add-on or monotherapy has been used for treatment refractory bipolar
depression (American Psychiatric Association,2002; Calabrese et al, 2002), Lamotrigine is associated
with causing hypersensitivity reactions and rare life-threatening skin rashes and requires
slow dosage titration (American Psychiatric Association,2002).
Atypical antipsychotics such as aripiprazole, olanzapine, quetiapine, risperidone, and
ziprasidone are effective as monotherapy or adjunctive therapy with lithium and
valproate in the treatment of acute mania (Perlis et al, 2006), Some antipsychotics have the

15
potential to cause adverse effects such as extrapyramidal reactions, sedation, emotional
blunting, sexual dysfunction, metabolic syndrome, and orthostatic hypotension (Goodnick
et al, 1998; Yatham LN, 2002).

8.3.2-Alternative drug treatments:

Benzodiazepines: High potency benzodiazepines such as clonazepam and lorazepam
are commonly used as an alternative to or in combination with antipsychotics when
patients are experiencing acute mania, agitation, anxiety, panic, and insomnia, or cannot
take mood stabilizers (e.g., during the first trimester of pregnancy) (American Psychiatric
Association,2002; Goldberg et al,1999).

Benzodiazepines cause minimal adverse effects compared to antipsychotics, and at

higher doses, rapidly sedate agitated patients (Goldberg et al,1999), Benzodiazepines can
cause central nervous system depression, sedation, cognitive and motor impairment,
dependence, and withdrawal reactions. Relative contraindications for long-term therapy
with benzodiazepines are drug or alcohol abuse or dependency. When no longer
required, benzodiazepines should be gradually tapered and discontinued to avoid
withdrawal symptoms (Dipiro et al, 2008).
Antidepressants: Antidepressants are routinely added for the treatment of acute
depression, but some studies have reported that specific classes such as the tricyclic
antidepressants can carry an increased risk of inducing mania in bipolar I disorder and
possibly cause rapid cycling (American Psychiatric Association,2002; Goldberg et al,1999).
Some guidelines recommend avoiding antidepressants in the treatment of bipolar
depression or limiting their use to brief intervals, but recent evidence suggests that the
coadministration of mood stabilizers can reduce the risk of antidepressant induced
switching (Keck et al, 2003).
In general, the antidepressant should be gradually withdrawn 2 to 6 months after
remission, and the patient maintained on a moodstabilizing agent (Sachs et al, 2000), For
patients with recurrent depressive episodes, long-term adjunctive treatment with
antidepressants can be required to avoid relapses, particularly in bipolar II disorder
(American Psychiatric Association,2002; Goldberg et al,1999).

Calcium channel antagonists: Calcium channel antagonists inactivate voltage-

sensitive calcium channels, thus inhibiting neurotransmitter synthesis and release and
neuronal signal transmission (Manji et al, 2000; Goodnick et al, 1998).

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Nimodipine, a dihydropyridine, can be more effective than verapamil for rapid-cycling
bipolar disorder because of its anticonvulsant properties, high lipid solubility, and good
penetration into the brain (American Psychiatric Association,2002; Goldberg et al,1999; Manji et al, 2000;
Goodnick et al, 1998).

Calcium channel blockers are generally well tolerated, and the most common adverse
effects are bradycardia and hypotension. The low teratogenic effects of these agents can
make them a preferable choice over lithium or anticonvulsants during pregnancy and
breastfeeding (Goodnick et al, 1998).

9-Evaluation of therapeutic outcomes:

The establishment and maintenance of a therapeutic alliance with a clinician is essential

in monitoring a patient’s psychiatric status and safety; enhancing treatment adherence,
promoting good nutrition, sleep, and exercise, identifying stressors, recognizing new
mood episodes, and minimizing adverse reactions and drug interactions (Torrey, Knable,
2002).

Patients who have a partial response or nonresponse to established bipolar therapies

should be reassessed for an accurate diagnosis, concomitant medical or psychiatric
conditions, and medications or substances that exacerbate mood symptoms.
Nonadherence to medication treatment, delusional symptoms, alcohol or substance
abuse, rapid cycling, or mixed states are often associated with poorer treatment
outcomes. The evaluation of therapeutic outcomes for bipolar disorder requires regular
monitoring by a clinician. More frequent office visits, telephone calls, and intensive
outpatient programs are first-line strategies to prevent hospitalization during the acute
treatment phase of a manic or depressive episode (American Psychiatric Association,2002).

10-Women with bipolar disorder:

In general, research shows that women tend to experience more periods of depression
than men. In bipolar disorder, women are more likely to develop the type bipolar II
meaning they never develop severe mania, but instead have milder episodes of
hypomania that alternate with depression. Women are also at higher risk for rapid
cycling, which means having four or more mood episodes in one year (WebMD,2008).

10.1-Bipolar disorder drugs and reproduction:

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Mood stabilizing drugs for bipolar disorder have been linked with reproductive
problems in women, specifically polycystic ovarian syndrome, a problem related to
female hormones. This condition puts women at risk for infertility, diabetes, and
possibly heart disease and cancer of the uterus. However, the condition is treatable with
medications.

Before and during pregnancy, women should not take lithium and other bipolar
medications, says Michael Aronson, a clinical psychiatrist and consultant for WebMD.
"The interesting thing is, sometimes pregnancy by itself will stabilize someone with
bipolar disorder. At other times, it can destabilize them. The best alternative for
someone who is pregnant, who is having problems with depression or mania and cannot
be placed on an adequate dose of medication, is using ECT (electroconvulsive therapy).
It's very effective and it's safe." (WebMD,2008).

10.2-Bipolar disorder drugs and menopause:

The hormone fluctuations of perimenopause and menopause can cause mood disorders
in any woman not just those with bipolar disorder. However, for those already having
troubles with major depression, bipolar, or anxiety disorders there usually is an increase
in symptoms during this time. Especially during perimenopause, women may be
especially vulnerable to depressive symptoms because of declining estrogen levels,
During menopause, hormone therapy may help. A change in antidepressant or mood
stabilizing drug also may be the answer (WebMD,2008).

11-Related news:

11.1-Study shows symptoms of bipolar disorder may continue in adulthood:

Oct. 6, 2008 Children who are diagnosed with bipolar disorder can continue to suffer
from the disease as they develop into young adults.

Barbara Geller, and her colleagues at Washington University followed a sample of

children diagnosed with pediatric bipolar disorder into adulthood.

Beginning in 1995 to 1998, the researchers examined 115 children diagnosed with
bipolar disorder with an average age of 11. At the beginning of the study and again
during nine follow-up visits conducted over eight years, the children and their parents
were interviewed separately about their symptoms, diagnoses, daily cycles of mania and
depression, and interactions with others.
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During the eight-year follow-up, the researchers found that the children's first, second,
and third episodes of mania included psychosis and daily cycling between mania and
depression for long periods of time. Many of them recovered from these episodes, but
about 73% of them relapsed.

After the follow-up period, Geller and her colleagues found that about 44% of those
who had bipolar disorder as children and who turned 18 by the end of the study period
continue to have manic episodes as young adults. 35% of them had substance use
disorders, a rate similar to those diagnosed with bipolar disorder as adults.

"The study provides validation that the illness continues into adulthood in a very large
proportion of the children, and unfortunately like adults with the disease, they have a
high rate of substance dependence," says Geller.

The study concluded that the severity and chronic nature of this disorder highlights the
need for a greater effort toward understanding the neurobiology behind the disease and
for developing prevention and intervention strategies.

11.2-Study shows age of dad is a factor in risk of child developing bipolar disorder:
Sept. 2, 2008 A new study suggests that children born from older fathers are at
increased risk of developing bipolar disorder.

Overall, children born to fathers in their mid-50s and older were found to have a 37%
higher risk for bipolar disorder than children born to dads in their early 20s.

The risk of developing the mood disorder before the age of 20 was roughly 2.5-times
greater for children born to men age 50 and older than for children born to men between
the ages of 20 and 24.

According to the National Institute of Mental Health, about 5.7 million American adults
have bipolar disorder, a serious mental illness characterized by dramatic, episodic mood
swings. While the mood disorder tends to run in families, suggesting a genetic link,
little else is known about the causes of bipolar disorder.

Older maternal age was associated with a slight, but nonsignificant, overall increase in
risk, but no association was seen between maternal age and the risk for a bipolar
diagnosis before age 20.

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The fact that paternal age appears to be a more important risk factor for bipolar disorder
than maternal age suggests that genetic mutations in sperm may be to blame. Men add
more mutations to the gene pool than women because their reproductive cells continue
to divide throughout their lives. Women have only about 23 divisions in the cells that
produce their eggs, and these divisions occur before birth, More divisions mean more
potential mutations or DNA damage that could be driving the increased risk for bipolar
disorder and other genetically influenced mental disorders.

11.3-Study shows family connections for bipolar disorder and schizophrenia:

Jan. 15, 2009 The largest study ever to track bipolar disorder and schizophrenia within
families offers evidence that the two psychiatric disorders share a common genetic
cause.

For more than a century the psychiatric community has debated whether schizophrenia
and bipolar disorder were two distinct disorders or were more connected.

Over the course of their illnesses, many patients experience similarities in certain
symptoms characteristic of both, such as manic mood swings in bipolar disorder and
psychosis in schizophrenia.

Recent genetic studies suggest a common genetic cause for the two conditions. But
earlier studies in families have not supported this conclusion, finding no increase in
bipolar disorder in family members of schizophrenics and vice versa (WebMD,2008).

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12-References:

American Psychiatric Association. Diagnostic and Statistical Manual of Mental

Disorders, Fourth Edition, Text Revision. Washington, American Psychiatric
Association, 2000:382–401.

American Psychiatric Association. Practice Guideline for the Treatment of Patients with
Bipolar Disorder (Revision). Am J Psychiatry 2002;159:1–50.

Calabrese JR, Shelton MD, Rapport DJ, et al. Long-term treatment of bipolar disorder
with lamotrigine. J Clin Psychiatry 2002;63(Suppl10):18–22.

DiPiro J., Talbert R., Yee G., Matzke G., Wells B., Posey L., Pharmacotherapy A
Pathophysiological Approach, seven edition, 2008.

Goldberg JF, Harrow M, eds. Bipolar Disorders: Clinical Course and Outcome.
Washington, DC: American Psychiatric Press, 1999.

Goodnick PJ, ed. Mania: Clinical and Research Perspectives. Washington, DC:
American Psychiatric Press, 1998.

Hurley SC. Lamotrigine update and its use in mood disorders. Ann Pharmacother
2002;36:860–873.

Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the
U.S. population: Re-analysis of the ECA database taking into account sub threshold
cases. J Affect Disord 2003;73:123–131.

Keck PE Jr., Nelson EB, McElroy SL. Advances in the pharmacologic treatment of
bipolar depression. Biol Psychiatry 2003;53:671–679.

Mahmood T, Silverstone T. Serotonin and bipolar disorder. J Affect Disord 2001;66:1–

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Manji HK, Bowden CL, Belmaker RH, eds. Bipolar Medications: Mechanisms of
Action. Washington, DC: American Psychiatric Press, 2000.

Parker F, Gibson NA, Brotchie H, et al. Omega-3 fatty acids and mood disorders. Am J
Psychiatry 2006;163:969–978.

Perlis RH, Welge JA, Vornik LA, et al. Atypical antipsychotics in the treatment of
mania: a meta-analysis of randomized, placebo-controlled trials. J Clin Psychiatry
2006;67:509–516.

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Sachs GS, Koslow CL, Ghaemi SN. The treatment of bipolar depression. Bipolar
Disord 2000;2:256–260.

Taylor L, Farone SV, Tsuang MT. Family, twin, and adoption studies of bipolar disease.
Curr Psychiatry Rep 2002;4:130–133.

Torrey EF, Knable MB. Surviving Manic Depression: A Manual on Bipolar Disorder for
Patients, Families, and Providers. New York: Basic Books, 2002.

WebMD Medical Reference with The Cleveland Clinic: "Bipolar Disorder (Manic
Depressive Disorder)." WebMD Assess Plus: Bipolar Disorder Assessment. National
Institute for Mental Health: "Step-BD Women’s Studies." Massachusetts General
Hospital Bipolar Clinic & Research Program. MedicineNet.com: "Bipolar Disorder
(Mania)." WebMD Medical Reference with The Cleveland Clinic: "Effects of Untreated
Depression." American Psychiatric Association: "Practice Guideline for the Treatment
of Patients With Bipolar Disorder." Reviewed by Amal Chakraburtty, MD on July 22,
2008.

Yatham LN. The role of novel antipsychotics in bipolar disorders. J Clin Psychiatry
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