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Bipolar Affective Disorder Email to a Colleague

Last Updated: December 27, 2004
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Synonyms and related keywords: bipolar disorder, bipolar I, bipolar II, manic-depressive
disorder, MDI, BPI, BPII, schizophrenia, psychosis, mood disorders, cyclothymia, suicide, mania,
electroconvulsive therapy, ECT, electroshock, hypomania, psychomotor agitation, grandiosity,
inflated self-esteem, racing thoughts, flight of ideas, distractibility, hypersomnia, insomnia,
depression, Mental Status Examination, MSE, aggression
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Author: Stephen Soreff, MD, President of Education Initiatives, Nottingham, NH;

Faculty, Metropolitan College of Boston University, Boston, MA
Coauthor(s): Lynne Alison McInnes, MD, Director of Laboratory of
Neurobehavioral Disorders, Assistant Professor, Department of Psychiatry and
Human Genetics, Mount Sinai School of Medicine
Stephen Soreff, MD, is a member of the following medical societies: American
College of Mental Health Administration
Editor(s): Ronald C Albucher, MD, Assistant Chief, Psychiatry Service, VA Ann
Arbor Healthcare System; Clinical Assistant Professor, Department of Psychiatry,
University of Michigan School of Medicine; Francisco Talavera, PharmD, PhD,
Senior Pharmacy Editor, eMedicine; Iqbal Ahmed, MD, Program Director,
General and Geriatric Psychiatry Residency Programs, Vice Chair for Education,
Professor, Department of Psychiatry, John A Burns School of Medicine, University
of Hawaii; Harold H Harsch, MD, Program Director of Geropsychiatry,
Department of Geriatrics/Gerontology, Associate Professor, Department of
Psychiatry, Assistant Professor, Department of Medicine, Froedtert Hospital,
Medical College of Wisconsin; and Michael E Zevitz, MD, Clinical Assistant
Professor, Department of Medicine, Rosalind Franklin University of Medicine and


INTRODUCTION Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Manic-depressive illness (MDI) is one of the most common,

severe, and persistent mental illnesses. It is characterized by periods of deep,
prolonged, and profound depression that alternate with periods of excessively
elevated and/or irritable mood known as mania. The symptoms of mania include
a decreased need for sleep, pressured speech, increased libido, reckless
behavior without regard for consequences, grandiosity, and severe thought
disturbances, which may or may not include psychosis. Between these highs and
lows, patients usually experience periods of higher functionality and can lead a
productive life. MDI is a serious lifelong struggle and challenge (Bowden, 2003).

MDI has been recognized for a long time. Hippocrates described patients as
"amic" and "melancholic." In 1899, Emil Kraepelin defined MDI. He noted that
persons with this problem did not suffer the deterioration and dementia
associated with schizophrenia.

MDI constitutes one pole of a spectrum of mood disorders including bipolar I

(BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and major
depression. BPI also is referred to as classic manic-depression, characterized by
distinct episodes of major depression contrasting vividly with episodes of mania,
which lead to severe impairment of function. In comparison, BPII is a milder
disorder consisting of depression alternating with periods of hypomania.
Hypomania may be thought of as a less severe form of mania that does not
include psychotic symptoms or lead to major impairment of social or occupational

Pathophysiology: The etiology and pathophysiology of bipolar disorder have not

been determined, and no objective biological markers exist that correspond
definitively with the disease state. However, twin, family, and adoption studies all
indicate strongly that bipolar disorder has a genetic component. In fact, first-
degree relatives of a person with bipolar disorder are approximately 7 times more
likely to develop bipolar disorder than the rest of the population. Genetic studies
of patients with bipolar disorder are ongoing and are expected to be facilitated by
recent advances in information and technology developed, in part, by the Human
Genome Project.

Other molecular genetic approaches also are being used to gain insight into the
pathophysiology of bipolar disorder. For instance, investigators have
demonstrated recently that 2 chemically unrelated drugs used to treat bipolar
disorder, lithium and valproate, both up-regulate the expression of the
cytoprotective protein bcl-2 in the frontal cortex and the hippocampus of rat
brains. Neuroimaging studies of individuals with bipolar disorder or other mood
disorders also suggest evidence of cell loss in these same brain regions. Thus, a
suggested cause of bipolar disorder is abnormal programmed cell death, or
apoptosis, in critical brain circuitry that regulates emotion. According to this
hypothesis, mood stabilizers and antidepressants are thought to alter mood by
stimulating cell survival pathways and increasing levels of neurotrophic factors to
improve cellular resiliency.
Post and associates proposed a mechanism involving electrophysiological
kindling and behavioral sensitization processes, a method that also resonates
with the previous hypothesis based on neuronal injury. Post asserts that an
individual who is susceptible to bipolar disorder experiences an increasing
number of minor neurological insults, perhaps caused by drugs of abuse,
excessive glucocorticoid stimulation resulting from acute or chronic stress, or
other factors, which eventually result in mania. Subsequently, sufficient brain
damage might persist such that mania could recur even with no or minor
environmental or behavioral stressors. This type of formulation helps explain the
effective role of anticonvulsant medications, eg, carbamazepine and valproate, in
the prevention of the highs and lows of bipolar disorder. It also suggests that the
more episodes a person experiences, the more he or she will have in the future,
underscoring the need for long-term treatment.


 In the US: Lifelong prevalence rate of bipolar disorder in the United States
is 1-1.6%. The 2 types of disorders differ in adult populations, with
approximately 0.8% having BPI and 0.5% having BPII.

 Internationally: Lifelong prevalence rate is 0.3-1.5%.

Mortality/Morbidity: MDI has a very significant morbidity and mortality rate. In

terms of lost work, the cost of lost productivity resulting from this illness in the
United States during the early part of the 1990s was estimated at approximately
$15.5 billion annually. Approximately 25-50% of individuals with MDI attempt
suicide, and 11% actually commit suicide.

Race: No racial predilection exists. However, a point of historical interest is that

clinicians often tend to consider populations of African Americans and Hispanics
as more likely to be diagnosed with schizophrenia than with affective disorders
and MDI.

Sex: BPI occurs equally in both sexes; however, rapid-cycling bipolar disorder (4
or more episodes a year) is more common in women than in men. Incidence of
BPII is higher in females than in males.

Age: The age of onset of MDI varies greatly. The age range for both types of
bipolar disorders is from childhood to 50 years, with a mean age of approximately
21 years. Most cases commence when individuals are aged 15-19 years. The
second most frequent age of onset is 20-24 years. Some patients diagnosed as
having recurrent major depression may indeed have bipolar disorder and go on
to develop their first manic episode after age 50 years. They may have a family
history of bipolar disorder. However, for most patients, the onset of mania after
age 50 years should lead to an investigation for medical or neurological disorders
such as cerebrovascular disease.

CLINICAL Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History: The diagnosis of BPI disorder requires the presence of a manic episode
of at least 1 week's duration that leads to hospitalization or other significant
impairment in occupational or social functioning. The episode of mania cannot be
caused by another medical illness or by substance abuse. These criteria are
based on the specifications of the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision (DSM-IV-TR).

 Manic episodes are characterized by the following symptoms:

o At least 1 week of profound mood disturbance is present,

characterized by elation, irritability, or expansiveness

o Three or more of the following symptoms are present:

 Grandiosity
 Diminished need for sleep
 Excessive talking or pressured speech
 Racing thoughts or flight of ideas
 Clear evidence of distractibility
 Increased level of goal-focused activity at home, at work, or
 Excessive pleasurable activities, often with painful

o The mood disturbance is sufficient to cause impairment at work or

danger to the patient or others.

o The mood is not the result of substance abuse or a medical


 Hypomanic episodes are characterized by the following:

o The patient has an elevated, expansive, or irritable mood of at least

4 days' duration.

o Three or more of the following symptoms are present:

 Grandiosity or inflated self-esteem
 Diminished need for sleep
 Pressured speech
 Racing thoughts or flight of ideas
 Clear evidence of distractibility
 Psychomotor agitation at home, at work, or sexually
 Engaging in activities with a high potential for painful

o The mood disturbance is observable to others.

o The mood is not the result of substance abuse or a medical


 Major depressive episodes are characterized by the following:

o For the same 2 weeks, the person experiences 5 or more of the

following symptoms, with at least 1 of them being either a
depressed mood or characterized by a loss of pleasure or interest:
 Depressed mood
 Markedly diminished pleasure or interest in nearly all
 Significant weight loss or gain or significant loss or increase
in appetite
 Hypersomnia or insomnia
 Psychomotor retardation or agitation
 Loss of energy or fatigue
 Decreased concentration ability or marked indecisiveness
 Preoccupation with death or suicide; patient has either a
plan or has attempted suicide

o The symptoms cause significant impairment and distress.

o The mood is not the result of substance abuse or a medical


 Mixed episodes are characterized by the following:

o Persons must meet both the criteria for mania and major
depression; the depressive event is required to be present for 1
week only.

o The mood disturbance results in marked disruption in social or

vocation function.

o The mood is not the result of substance abuse or a medical

Physical: Use the Mental Status Examination (MSE) to diagnose a patient with
bipolar disorder. This section highlights the major findings for a person with
bipolar disorder. Because the patient's mental status is dependent on his
depressed state, eg, hypomanic, manic, or mixed, the various areas of the MSE
are labeled according to the particular phase of the patient.

 Appearance

o Depressed episode: Persons experiencing a depressed episode

demonstrate poor to no eye contact. Their clothes are unkempt,
unclean, holed, unironed, and ill fitting. If significant weight loss has
occurred, the garments may fit loosely.

The personal hygiene of individuals experiencing a depressed

episode reflects their low mood, as evidenced by poor grooming,
lack of shaving, and lack of washing. In women, fingernails may
show different layers of polish or one layer partially removed. They
may not have paid attention to their hair. Men may exhibit dirty
fingernails and hands.

When these individuals move, their depressed affect is

demonstrated. They move slowly and very little. They show
psychomotor retardation. They may talk in low tones or in a
depressed or monotone voice.

o Hypomanic episode: These patients are busy, active, and involved.

They have energy and are always on the go. They are always
planning and doing things. Others notice their energy levels and
mood changes (Keck, 2003).
o Manic episode: In many ways, the behavior of a patient in the
manic phase reflects behavior opposite of a person in the
depressed phase. Patients experiencing the manic phase are
hyperactive and might be hypervigilant. They are restless,
energized, and active. They talk and act fast.

Their attire reflects the mania. Their clothes might have been put on
in haste and are disorganized. Alternately, their garments often are
too bright, colorful, or garish. They stand out in a crowd because
their dress frequently attracts attention.

 Affect/mood

o Depressed episode: Sadness dominates the affect of individuals

experiencing a depressed episode. They feel sad, depressed, lost,
vacant, and isolated. The “2 Hs” command their mood, hopeless
and helpless. When in the presence of such patients, one comes
away feeling sad and down.
o Hypomanic episode: Their mood is up, expansive, and often
o Manic episode: The mood is inappropriately joyous, elated, and
jubilant. They are euphoric. They also may demonstrate annoyance
and irritability, especially if the mania has been present for a
significant length of time.
o Mixed episode: The patient exhibits both depression and mania
within a brief period of time (1 wk or less).

 Thought content

o Depressed episode: Patients experiencing a depression have

thoughts that reflect their sadness. They are preoccupied with
negative ideas and nihilistic concerns, and they metaphorically see
“the glass as half empty." They likely are to focus on death and
morbid subjects. Many think about suicide.
o Hypomanic episode: Patients in this state are optimistic, forward
thinking, and have a positive attitude.

o Manic episode: During the manic phase, patients have very

expansive and optimistic thinking. They may be excessively self-
confident and/or grandiose. They often have a very rapid
production of ideas and thoughts. They perceive their minds as
being very active and see themselves as being highly engaging and
creative. They are highly distractible and quickly shift from one
subject to another.
o Mixed episode: Patients in this state can oscillate dramatically
between depression and euphoria, and often they demonstrate
marked irritability.

 Perceptions

o Depression episode: Two forms of a major depression are

described. One has psychotic features and the other does not. With
psychosis, the patient experiences delusions and hallucinations
that are either consistent or inconsistent with the mood. In the
former, the patient's delusions of having sinned are accompanied
by guilt and remorse or the patient feels he or she is utterly
worthless and should live in total deprivation and degradation.
Hence, the delusional content remains consistent with the
depressed affect.
In contrast, some patients experience delusions that are
inconsistent with the depression. For example, the individual feels
that he is the Messiah in the presence of his very depressed affect.

o Hypomanic episode: Patients in this state do not experience

perceptual disturbances.
o Manic episode: Approximately three fourths of patients in the manic
phase have delusions. As in major depression, the delusional
content is either consistent or inconsistent with the mania. Manic
delusions reflect perceptions of power, prestige, position, self-
worth, and glory.
o Mixed episode: Patients might exhibit delusions and hallucinations
consistent with either depression or mania or congruent to both.

 Suicide/self-destruction

o Depressed episode: Depressed patients have a very high rate of

suicide. They are the individuals who attempt and succeed at killing
themselves. Query patients to determine if they have any thoughts
of hurting themselves (suicidal ideation) and any plans to do so.
The more specific the plan, the higher the danger. As patients
emerge from a period of depression, their suicide risk may
increase. This may be because, as the illness remits, executive
functions are improved such that the person is again capable of
making and carrying out a plan.
o Hypomanic episode: Incidence of suicide is low.
o Manic episode: Incidence of suicide is low.
o Mixed episode: The depressed phases put the patient at risk for

 Homicide/violence/aggression

o Depressed episode: Generally, suicide remains the paramount

issue. However, certain persons in the depths of a depression not
only see the world as hopeless and helpless for themselves but
also for others. Frequently, that perspective can create and lead to
a homicide followed by a suicide. One example of this occurred
when a 42-year-old mother of 2 was experiencing a significant
depression as part of her bipolar disorder. She believed the earth
was doomed and was a terrible place to dwell. Furthermore, she
thought that if she died, her children would be left in a wretched
place. Because of this view, she planned to kill her 2 children and
then herself. Fortunately, her family recognized the state of affairs,
which led to an emergency intervention and her hospitalization.
o Hypomanic episode: Patients who are hypomanic frequently show
evidence of irritability and aggressiveness. They can be pushy and
impatient with others.
o Manic episode: Persons in mania can be openly combative and
aggressive. They have no patience or tolerance for others. They
can be highly demanding, violently assertive, and highly irritable.
The homicidal element particularly emerges if these individuals
have a delusional content to their mania. They are acting out of the
grandiose belief that others must obey their commands, wishes,
and directives. If their delusions become persecutory in nature, they
may defend themselves against others in a homicidal fashion.
o Mixed episode: Persons in a mixed episode may exhibit
aggression, especially in the manic phases.

 Judgment/insight

o Depressed episode: Depression clouds and dims these individuals'

judgment and colors their insights. They fail to make important
actions because they are so down and preoccupied with their own
plight. They see no tomorrow; therefore, planning for it is very
difficult. Frequently, persons in the middle of a depression have
done things such as forgetting to pay their income taxes. At that
time, they have little insight into their behavior. Often, others have
to persuade them to seek therapy because of their lack of insight.
o Hypomanic episode: Generally, these people have good but
expansive judgment. They may take on too many tasks or become
over-involved. Often, their distractibility impairs their judgment, and
they have little insight into their driven qualities. They see
themselves as productive and conscientious, not as hypomanic.

o Manic episode: The hallmark of this phase is seriously impaired

judgment. They make terrible decisions in terms of their work and
family. They may invest the family fortune in very questionable
programs. They may become professionally over-involved in work
activities or with coworkers. They start a series of dramatic very
unsound fiscal or professional ventures. They do not listen to any
feedback, suggestions, or advice from friends, family, or colleagues.
They have no insight into the extreme nature of their demands,
plans, and behavior. Often, commitment proves the only way to
contain them.
o Mixed episode: Major shifts in affect during short lengths of time
severely impair their judgment and interfere with their insight.

 Sensorium: Impairments in orientation and memory are seldom observed

in patients with bipolar disorder unless they are very psychotic. They know
the time and their location, and they recognize people. They can
remember immediate, recent, and distant events. In some cases of
hypomanic and even manic episodes, their ability to recall information can
be extremely vivid and expanded. In extremes of depression and mania,
they may experience difficulty in concentrating and focusing.

Causes: Bipolar disorder has a number of contributing factors, including genetic,

biochemical, psychodynamic, and environmental elements.

 Genetics

o Bipolar disorder, especially BPI, has a major genetic component.

The evidence indicating a genetic role in bipolar disorder takes
several forms.

o First-degree relatives of people with BPI are approximately 7 times

more likely to develop BPI than the general population.
Remarkably, offspring of a parent with bipolar disorder have a 50%
chance of having another major psychiatric disorder.

o Twin studies demonstrate a concordance of 33-90% for BPI in

identical twins.

o Adoption studies prove that a common environment is not the only

factor that makes bipolar disorder occur in families. Children whose
biologic parents have either BPI disorder or a major depressive
disorder remain at increased risk of developing an affective
disorder, even if they are reared in a home with adopted parents
who are not affected.

o Numerous genetic studies of BPI disorder suggest multiple different

genetic loci, but, as yet, no genes have been definitively identified.
This is, in part, because many genes contribute small effects to the
disorder in different individuals and, partly, because no objective
means of identifying a particular genetic subtype is available.
However, studies are ongoing, and technological and statistical
advances may lead to a breakthrough in the next decade.
o A very interesting new finding in psychiatric genetics heralds the
future revision of DSM-IV-TR according to an etiological rather than
descriptive basis. Using probands from the Maudsley Twin Register
in London, Cardno and colleagues showed that schizophrenic,
schizoaffective, and manic syndromes share genetic risk factors
and that the genetic liability for schizoaffective disorder was entirely
shared in common with the other two syndromes. This finding
suggests an independent genetic liability for psychosis shared by
both mood and schizophrenia spectrum disorders as Berrettini
previously speculated.
o A recent study by Tsuang et al further indicates the genetic
contribution to MDI with psychotic features. Their findings show the
link between schizophrenia and bipolar disorder (Tsuang, 2004).

 Biochemical causes

o Multiple biochemical pathways likely contribute to bipolar disorder,

which is why detecting one particular abnormality is difficult.

o A number of neurotransmitters have been linked to this disorder,

largely based on patients' responses to psychoactive agents.

o For instance, the blood pressure drug reserpine, which dampens

catecholaminergic transmission, was noted incidentally to cause
depression. This led to the catecholamine hypothesis, which holds
that an increase in epinephrine and norepinephrine causes mania
and a decrease in epinephrine and norepinephrine causes

o Drugs like cocaine, which also act on this neurotransmitter system,

exacerbate mania.

o Other agents that exacerbate mania include L-dopa, which

implicates dopamine and serotonin-reuptake inhibitors, which, in
turn, implicate serotonin.

o Calcium channel blockers have been used to treat mania, which

also may result from a disruption of calcium regulation in neurons.
The proposed disruption of calcium regulation may be caused by a
variety of neurologic insults such as excessive glutaminergic
transmission or ischemia. Interestingly, valproate specifically up-
regulates expression of a calcium chaperone protein, GRP 78,
which may be one of its chief mechanisms of cellular protection.

o Hormonal imbalances and disruptions of the hypothalamic-pituitary-

adrenal axis involved in homeostasis and the stress response also
may contribute to the clinical picture of bipolar disorder.

 Psychodynamic

o Many practitioners see the dynamics of MDI as being linked

through one common pathway.

o They see the depression as the manifestation of the losses, ie, the
loss of self-esteem and the sense of worthlessness. Therefore, that
mania serves as a defense against the feelings of depression.
(Melanie Klein was one of the major proponents of this formulation.)

 Environmental

o In some instances, the cycle either may be directly linked to

external stresses or the external pressures may serve to
exacerbate some underlying genetic or biochemical predisposition.
o Pregnancy is a particular stress for women with an MDI history and
increases the possibility of postpartum psychosis (Chaudron,

o Because of the nature of their work, certain individuals have

periods of high demands followed by periods of few requirements.
For example, one person was a landscaper and gardener. In the
spring, summer, and fall, he was very busy. During the winter, he
was relatively inactive except for plowing snow. Thus, he appeared
manic for a good part of the year, and then he would crash and
hibernate for the cold months.

DIFFERENTIALS Section 4 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Anxiety Disorders
Cushing Syndrome
Head Trauma
Posttraumatic Stress Disorder
Schizoaffective Disorder
Systemic Lupus Erythematosus

Other Problems to be Considered:

 Cancer

 Neurosyphilis
 Epilepsy
 Fahr disease
 Multiple sclerosis
 Medications (eg, antidepressants can propel a patient into mania; other
medications may include baclofen, bromide, bromocriptine, captopril,
cimetidine, corticosteroids, cyclosporine, disulfiram, hydralazine, isoniazid,
levodopa, methylphenidate, metrizamide, procarbazine, and procyclidine)
 Circadian rhythm desynchronization
 Attention-deficit/hyperactivity disorder (ADHD), especially in children and
 Cyclothymic disorder
 Multiple personality disorder
 Oppositional defiant disorder (in children)
 Substance abuse disorders (eg, with alcohol, amphetamines, cocaine,
hallucinogens, opiates)

WORKUP Section 5 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Lab Studies:

 Standard laboratory studies: A number of reasons exist to obtain the

following laboratory studies. First, the practitioner needs to perform the
tests to determine the diagnosis. Because bipolar disorder encompasses
both depression and mania and because a significant number of medical
causes for each state exists, an extensive range of tests is indicated. The
basic principle remains, "do not miss a treatable medical cause for the
mental status." Second, the physician employs a number of medications
that require certain body systems to be working properly; for example,
lithium requires an intact genitourinary (GU) system and can affect certain
other systems, and certain anticonvulsants can suppress bone marrow.
Third, because bipolar illness is a lifelong disorder, performing certain
baseline studies is important to establish any long-term effects of the

o CBC count with differential: This test is used to rule out anemia as a
cause of depression. Treatment, especially with certain
anticonvulsants, may depress the bone marrow, hence, the need to
check the red and white blood counts for signs of bone marrow
suppression. Lithium may cause a reversible increase in the WBC

o Sedimentation rate: This test is used to look for any underlying

disease process such a lupus or an infection. An elevated
sedimentation rate would indicate such a disease process.

o Glucose-level fasting: This test is used to rule out diabetes. Atypical

antipsychotics have been associated with weight gain and
problems with blood glucose regulation in patients with diabetes.
o Electrolytes: This test is used to diagnose electrolyte problems,
especially with sodium, that are related to depression.
Hyponatremia, ie, low sodium can manifest as a depression.
Treatment with lithium can lead to renal problems and electrolyte
problems. Low sodium levels can lead to higher lithium levels and
lithium toxicity. Hence, in screening candidates for lithium therapy
as well as those on lithium therapy, checking electrolytes is

o Serum calcium: This test is used to diagnose hypercalcium and

hypocalcium levels associated with mental status changes, eg,
hyperparathyroidism. Hyperparathyroidism, as evidenced by an
elevated calcium blood level, produces depression. Certain
antidepressants, such as nortriptyline, affect the heart; therefore,
checking calcium levels is important.

o Serum proteins: Low serum proteins found in patients who are

depressed may be a result of not eating. Low serum proteins
increase the availability of certain medications because they have
less protein to which to bind.

o Thyroid studies: Perform thyroid tests to rule out hyperthyroidism

(mania) and hypothyroidism (depression). Treatment with lithium
can cause hypothyroidism.

o Substance and alcohol screen: Alcohol abuse and abuse of a wide

variety of drugs can present as either mania or depression. For
example, speed (ie, amphetamines) and cocaine abuse can
present as a manialike disorder, and barbiturate abuse can present
as a depressionlike disorder. A number of patients with bipolar
affective disorder also have a drug or alcohol addiction; therefore,
they have dual diagnoses. Performing a substance screen helps
make this dual diagnosis. If the patient has a dual diagnosis,
monitoring for these substances is important.

o Urine copper level: This test is used to rule out Wilson disease,
which produces mental changes. It is a rare disease that can be
missed easily.

o Antinuclear antibody: This test is used to rule out lupus.

 Infectious screening tests: A number of infections, especially chronic

infections, can produce a presentation of depression in the patient. Any of
the encephalitides can dramatically manifest as changes in mental status.
o HIV test: AIDS causes changes in mental status, including
dementia and depression.

o VDRL test: Syphilis, especially in its later stage, alters mental


 Serum creatinine and BUN: Kidney failure can present as depression.

Treatment with lithium can affect urinary clearances, and serum creatinine
and BUN can increase. Therefore, carefully and regularly monitor these

 ECG: Many of the antidepressants, especially the tricyclics and some of

the antipsychotics, can affect the heart and cause conduction problems.
Lithium also can lead to changes such as reversible flattening or inversion
of T waves. A pretreatment ECG is important.

Imaging Studies:

 The total value of performing an MRI in a patient with bipolar disorder

remains unclear; however, a couple of reasons do exist for performing an
imaging study.

o Because MDI is a lifelong disease, a strong battery of studies rules

out any other medical etiology and establishes a baseline.

o Some investigators report that patients with mania have

hyperintensity in their temporal lobes.

Other Tests:

 The reasons for ordering an electroencephalogram (EEG) in patients with

bipolar illness are as follows:

o EEG provides a baseline and helps rule out any neurologic

problems. Use this test to rule out a seizure disorder and brain

o If electroconvulsive therapy (ECT) is contemplated, an EEG is


o Some studies have shown that EEG abnormalities have been

indicative of anticonvulsant effectiveness. Specifically, an abnormal
EEG predicts the response to divalproex.

o Some patients may have seizures when on medications, especially

antidepressants. Also, lithium can cause diffuse slowing.
TREATMENT Section 6 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical Care: The treatment of bipolar disorder is directly related to the phase of
the episode, eg, depression or mania, and the severity of that phase. For
example, a person who is extremely depressed and exhibits suicidal behavior
requires inpatient treatment. In contrast, an individual with a moderate
depression who still can work would be treated as an outpatient.

 Inpatient hospital treatment: The indications for hospitalization in a person

with bipolar disorder include the following:

o Danger to self: A patient, especially one in a depressive episode,

may present with a significant risk for suicide. Serious suicide
attempts and specific ideation with plans constitute clear evidence
of the need for constant observation and preventive protection;
however, in other situations, the danger to the person may come
from other aspects of the disease. For example, a person who is
depressed enough to not eat might be at risk of death. Alternately, a
person in extreme mania, who foregoes rest, sleep, or food, may be
in a state of serious exhaustion.
o Danger to others: Patients with bipolar disorder can become a
threat to others. For example, a patient experiencing a severe
depression believed the world was so bleak that she planned to kill
her children to spare them from the world's misery. In the other
extreme, a delusional patient having a manic episode believed
everyone was against him; he searched for a rifle in order to defend
himself and to get them before they got him.
o Total inability to function: Occasionally, depression is so profound
that the person cannot function at all. Leaving such a person alone
would be dangerous and not therapeutic.
o Totally out of control: This is true especially during a manic episode.
In this situation, a person's behavior is so beyond limits, they are
destroying their career and can be harmful to those around them.
o Medical conditions that warrant medication monitoring: For
example, patients with certain cardiac conditions should be in a
medical environment where the effects of the psychotropic
medications can be monitored and observed closely.

 Partial hospitalization or a day-treatment program

o In general, these patients have severe symptoms but have a level

of control and a stable living environment.
o For example, a patient with severe depression who has thoughts of
suicide but no plans to act upon them and who has a high degree
of motivation can get well when given a great deal of interpersonal
support, especially during the day, and with the help of a very
involved and supportive family. The family needs to be home every
night and should be very concerned with the patient's care. Partial
hospitalization also offers a bridge to return to work. Returning
directly to work often is difficult for patients with severe symptoms,
and partial hospitalization provides support and interpersonal
 Outpatient treatment

o Outpatient treatment has 4 major goals.

o First, look at areas of stress and find ways to handle them. The
stresses can stem from family or work, but if they accumulate, they
propel the person into mania or depression. This is a form of
o Second, monitor and support the medication. Medications make an
incredible difference. The key is to get the benefits and avoid
adverse effects. Patients are ambivalent about their medications.
They recognize that the drugs help and prevent hospitalizations, yet
they also resent that they need them. The job is to address their
feelings and allow them to continue with the medications.
o Third, develop and maintain the therapeutic alliance. This is one of
the many reasons for the practitioner to deal with the patient's
ambivalence about the medications. Over time, the strength of the
alliance helps keep the patient's symptoms at a minimum and helps
the patient remain in the community.

o The fourth aspect involves education. The clinician must help

educate both the patient and the family about bipolar illness. They
need to be aware of the dangers of substance abuse, the situations
that would lead to relapse, and the essential role of medications.
Support groups for patients and families are of tremendous

Surgical Care: No surgical procedure is indicated, except historically when

treatment was attempted with psychosurgery, such as prefrontal lobotomy.
Lobotomy currently is outdated and not used in the clinical care of patients with
bipolar disorder.

Consultations: A consultation with a psychiatric colleague or a

psychopharmacologist always is appropriate if the patient does not respond to
conventional treatment and medication.

Diet: Unless the patient is on monoamine oxidase inhibitors (MAOIs), no special

diet is required. Patients should be advised to not make significant changes in
their salt intake because increased salt intake may lead to reduced serum lithium
levels and reduced efficacy and reduced intake may lead to increased levels and

Activity: Patients in the depressed phase are encouraged to exercise. Propose

a regular exercise schedule for all patients, especially those with bipolar disorder.
Both the exercise and the regular schedule are keys to surviving this illness.
However, increases in exercise level, with increased perspiration, can lead to
increased serum lithium levels and lithium toxicity.

MEDICATION Section 7 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Appropriate medication depends on the stage of the bipolar disorder the patient
is experiencing. Thus, a number of drugs are indicated for an acute manic
episode, primarily the antipsychotics and benzodiazepines (eg, lorazepam,
clonazepam). The choice of agent depends on the presence of symptoms such
as psychotic symptoms, agitation, aggression, and sleep disturbance. Atypical
antipsychotics are being used increasingly for treatment of both acute mania and
mood stabilization. The broad range of antidepressants and ECT are used for an
acute depressive episode (ie, major depression). Finally, another set of
medications is chosen for the maintenance and preventive phases of treatment.

Clinical experiences have shown that, if treated with mood-stabilizing drugs,

patients with bipolar disorder have fewer episodes of mania and depression.
These medications serve to stabilize the patient's mood, as the name implies.
They also can dampen extremes of mania or depression.

Drug Category: Mood stabilizers -- Lithium is the drug commonly used for
prophylaxis and treatment of manic episodes. A recent study suggests that lithium may
also have a neuroprotective role (Bauer, 2003).

Lithium carbonate (Duralith, Eskalith,

Lithobid) -- Considered a first-line agent
for long-term prophylaxis in bipolar
illness, especially for classic bipolar
disorder with euphoric mania. Also can
be used to treat acute mania, although
Drug Name
cannot be titrated up to an effective level
as quickly as valproic acid. Evidence
suggests that lithium, unlike any other
mood stabilizer, may have a specific
antisuicide effect. Monitoring blood levels
is critical with this medication.
Adult Dose Maintenance, preventive use: 400-1200
mg (0.6-1 mmol/L) PO qd
Acute manic episode: 600-2400 mg PO
(0.8-1.2 mmol/L) qd
<6 years: Not established
6-12 years: 15-60 mg/kg/d PO divided
Pediatric Dose
tid/qid; not to exceed adult dose
>12 years: Administer as in adults
Documented hypersensitivity; renal
disease or damage (renal function and
clearance are critical in maintaining
proper levels); history or evidence of
brain damage; cardiovascular disease;
generalized severe debilitation
Increases toxicity of thiazide diuretics,
haloperidol, phenothiazines,
neuromuscular blockers, carbamazepine,
fluoxetine, and ACE inhibitors
Pregnancy D - Unsafe in pregnancy
Patient should have adequate renal
function as evidenced by elevated
creatinine levels or BUN levels, and they
should drink plenty of fluids to prevent
dehydration; excessive sodium loss can
produce lithium toxicity (avoid excessive
sweating); use lower doses in elderly
individuals; do not perform ECT when
being administered; avoid rapid
increases in dosing
Anything causing hyponatremia
increases levels and could cause toxicity;
toxicity is closely related to serum levels
and can occur at therapeutic doses;
serum lithium determinations are
required to monitor therapy

Drug Category: Anticonvulsants -- Have been effective in preventing mood

swings associated with bipolar disorder, especially in patients known as rapid cyclers. For
the depressed phase, mood stabilizers, such as lithium and lamotrigine, are preferred
because antidepressants may propel a patient into a manic episode or exacerbate
irritability in mixed-symptom mania. Gabapentin, although not a mood stabilizer, also
may have antidepressant and anxiolytic properties. The most widely used anticonvulsants
have been carbamazepine, divalproex sodium, and lamotrigine. More recently, topiramate
and tiagabine also are being tried.
Carbamazepine (Tegretol) -- Effective in
patients who have not responded to
lithium therapy. Also can act to inhibit
seizures induced through the kindling
effect, which is thought to occur by way
Drug Name
of repeated limbic stimulation. Has been
effective in treating patients who have
rapid-cycling bipolar disorder or those
who have not been responsive to lithium
Initial: 200 mg PO qd in divided doses
with increments of 100 mg 2 times/wk; if
adverse effects occur, decrease dose by
200 mg
Adult Dose Dose range: 300-1600 mg PO qd
Serum level range: 17-50 mmol/L (4-12
Manic episode: 200-1800 mg PO qd
Plasma level: 4-12 mcg/mL
<6 years: Not established
6-12 years: 100 mg PO bid or 10 mg/kg/d
divided bid initially, then increase to 100
mg/d every wk
Pediatric Dose
Maintenance: 20-30 mg/kg/d PO divided
bid/qid; not to exceed 1000 mg/d
>12 years: Administer as in adults to
achieve 4-12 mcg/mL plasma level
Documented hypersensitivity;
administration of MAOIs within last 14 d;
history of liver disease, cardiovascular
disease, and blood dyscrasias
Interactions Halothane coadministration may cause
hepatocellular damage; grapefruit juice,
influenza vaccine, isoniazid, cimetidine,
erythromycin, and phenelzine increase
plasma levels; phenytoin, alprazolam,
clonazepam, primidone, and
phenobarbital decrease both CBZ level
and levels of interacting agents;
fluoxetine increases level; decreases
levels of imipramine, phenothiazines,
haloperidol, theophylline, thyroid
hormones, ritonavir, saquinavir,
contraceptives, risperidone, thiothixene,
cyclosporine, corticosteroids,
doxycycline, trazodone, doxepin, and
amitriptyline; increases plasma levels of
diltiazem and verapamil; can reduce its
own level by "autoinduction;"
coadministration with lithium or loxapine
increases toxicity of both CBZ and the
interacting agents; coadministration with
clozapine further increases bone marrow
toxicity and resulting agranulocytosis
Pregnancy D - Unsafe in pregnancy
There is a very small, but significant, risk
of causing agranulocytosis or aplastic
During drug initiation, avoid using
hazardous equipment or driving; other
depressants and alcohol may lead to
increased dizziness and sleepiness;
keep in a dry place; drinking grapefruit
juice while taking CBZ elevates blood
levels; report any indications of blood
dyscrasias (eg, easy bruising, sore
throats, fever, rash)
Valproate sodium, valproic acid
(Depakene, Depakote) -- Has proven
effectiveness in treating and preventing
mania. Classified as a mood stabilizer
and can be used alone or in combination
with lithium. Useful in treating patients
Drug Name
with rapid-cycling bipolar disorders and
has been used to treat aggressive or
behavioral disorders. A combination of
valproic acid and valproate has been
effective in treating persons in manic
phase, with a success rate of 49%.
Adult Dose 250 mg PO tid, initially in increments until
a serum level of 350-700 mmol/L (50-100
mcg/mL) has been achieved
Maintenance: 750-3000 mg PO qd in
divided doses
Manic episode: Loading dose of 20
mg/kg/d PO
Stat dose: 20 mg/kg PO, with next dose
in 12 h; then 10 mg/kg bid
Maintenance: 500-3500 mg PO qd to
achieve plasma level of 50-125 mcg/mL
10-15 mg/kg/d PO initially in 1-3 divided
doses; increase by 5-10 mg/kg/d PO
every wk until therapeutic plasma level
Pediatric Dose
Maintenance: 30-60 mg/kg/d PO divided
Documented hypersensitivity, hepatic
Coadministration with cimetidine,
salicylates, felbamate, and erythromycin
may increase toxicity; rifampin may
significantly reduce valproate levels; in
pediatric patients, protein binding and
metabolism of valproate decrease when
taken concomitantly with salicylates;
coadministration with carbamazepine
may result in variable changes of
carbamazepine concentrations, with
possible loss of seizure control; valproate
may increase diazepam and
ethosuximide toxicity (monitor closely);
valproate may increase phenobarbital
and phenytoin levels, while either one
may decrease valproate levels; valproate
may displace warfarin from protein
binding sites (monitor coagulation tests);
may increase zidovudine levels in patient
seropositive for HIV
Pregnancy D - Unsafe in pregnancy
Monitor for hepatic toxicity (obtain liver
function tests prior to initiating therapy
and thereafter); serum ammonia levels
may increase independently of other liver
functions and may cause altered mental
status; check platelet count and bleeding
times prior to therapy and during
treatment; valproic acid inhibits
cytochrome P-450 metabolism system
(pay attention to any drugs that use this
system); monitor for symptoms of
pancreatitis and pancreatic enzymes
because hemorrhagic pancreatitis has
been reported
Gabapentin (Neurontin) -- Not a mood
stabilizer and cannot be used to treat
mania. May have useful antidepressant
Drug Name
and anxiolytic effects in depressed or
irritable patients. Has few drug-to-drug
900-1800 mg PO in divided doses, not to
Adult Dose
exceed 3600 mg/d
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Antacids may significantly reduce
bioavailability (administer at least 2 h
following antacids); may increase
norethindrone levels significantly; can
potentiate sedating effects of other CNS
depressant drugs
C - Safety for use during pregnancy has
not been established.
Precautions Caution in severe renal disease
Lamotrigine (Lamictal) -- Anticonvulsant
that appears to be effective in the
Drug Name
treatment of the depressed-phase in
bipolar disorders.
12.5-37.5 mg/d PO, initially, gradually
titrated in 25-mg increments not more
Adult Dose
often than weekly; effective dose usually
100-400 mg/d qd or divided bid
Pediatric Dose 2-15 mg/kg/d PO divided bid initially
Documented hypersensitivity; lactation;
Contraindications renal impairment; hepatic and cardiac
Acetaminophen increases renal
clearance and decreases effects;
similarly, phenobarbital and phenytoin
Interactions increase metabolism, causing a
decrease in levels; concurrent
administration with valproic acid
increases lamotrigine levels
C - Safety for use during pregnancy has
not been established.
Precautions Can cause adverse CNS effects,
including dizziness, sedation, ataxia,
nystagmus, and diplopia; dermatological
problems include hypersensitivity rash,
Stevens-Johnson syndrome, and
angioedema; renal involvement can
produce hematuria; caution in impaired
renal or hepatic function; fatal
hypersensitivity reactions to lamotrigine
are more likely to occur with rapid dose
increments (caution when
coadministered with valproate)

Drug Category: Antipsychotic agents -- Atypical antipsychotics are being used

increasingly for treatment of both acute mania and mood stabilization.

Ziprasidone (Geodon) -- Indicated to

treat acute bipolar mania, including
manic and mixed episodes. Antagonizes
dopamine D2, D3, 5-HT2A, 5-HT2C, 5-HT1A,
5-HT1D, and alpha1adrenergic. Has
Drug Name moderate antagonistic effect for
histamine H1. Moderately inhibits
reuptake of serotonin and
norepinephrine. Although effective for
bipolar disorder, the mechanism of action
in bipolar disorder is unknown.
40 mg PO bid with food on day 1, then
increase to 60-80 mg PO bid on day 2;
Adult Dose adjust dose according to tolerance and
efficacy within range of 40-80 mg PO bid;
not to exceed 3-wk treatment duration
Pediatric Dose Not established
Documented hypersensitivity; history of
prolonged QT interval
Interactions CYP450-3A4 inhibitors (eg,
erythromycin, ketoconazole) may
increase serum levels; CYP450-3A4
inducers (eg, carbamazepine, rifampin)
may decrease serum levels;
coadministration with drugs that increase
QT/QTc interval (eg, amiodarone,
fluoroquinolones) increases risk of life-
threatening arrhythmias; amphetamines
may decrease efficacy of ziprasidone;
ziprasidone may decrease efficacy of
C - Safety for use during pregnancy has
not been established.
Prolongs QT/QTc interval (caution in
patients with known risk factors, eg,
hypomagnesemia, hypokalemia); caution
in seizure disorders; may cause
Precautions hypotension, extrapyramidal symptoms,
and somnolence; hyperglycemia may
occur and in some cases be extreme,
resulting in ketoacidosis, hyperosmolar
coma, or death
FOLLOW-UP Section 8 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Further Inpatient Care:

 ECT is useful in a number of instances. ECT has proven to be highly

effective in the treatment of acute mania. Often, the severity of the
symptoms, the lack of response to medications, or the contradiction of
certain medications necessitates the use of ECT. In one study of 400
patients with acute mania who received ECT, 313 showed significant
clinical improvement.

Further Outpatient Care:

 All patients with bipolar disorder need outpatient monitoring for both
medications and psychotherapy. In addition, they need education. The
schedule must be regular, with great flexibility if they need extra sessions.

 Fortunately, most patients recover from the first manic episode, but their
course beyond that is variable (Tohen, 2003).

In/Out Patient Meds:

 The same medications are applicable in both settings.


 If the patient is in a short-term inpatient care unit and has not made
significant progress, transfer to a long-term inpatient care unit might be in
 If the patient is in a depressed or manic phase and is not responding to
medications, transfer the patient to a facility where ECT can be


 Prevention is the key to the long-term treatment of bipolar disorders. It

takes several forms, as follows:

o First, medications such as lithium serve as mood stabilizers.

o Second, psychoeducation is instituted for the patient and the

patient's family. Both the patient and the patient's family must
understand and recognize the importance of medication
compliance and the early signs of mania and depression. This is


 The complications are suicide, homicide, and addictions. These are

discussed in Special Concerns.


 Patients with BPI fare worse than patients with a major depression. Within
the first 2 years after the initial episode, 40-50% of patients experience
another manic attack.

 Only 50-60% of patients with BPI who are on lithium gain control of their
symptoms. In 7% of these patients, symptoms do not recur. Forty-five
percent of patients experience more episodes and 40% go on to have a
persistent disorder.

 Often, the cycling between depression and mania accelerates with age.

 Factors suggesting a worse prognosis include the following:

o Poor job history

o Alcohol abuse
o Psychotic features

o Depressive features between periods of mania and depression

o Evidence of depression
o Male sex
 Indicators of a better prognosis include the following:

o Manic phases (short in duration)

o Late age of onset
o Few thoughts of suicide
o Few psychotic symptoms

o Few medical problems

Patient Education:

 Treatment of patients with bipolar disorder involves initial and ongoing

patient education. The educational efforts must be directed not only
toward the patient but also toward their family and support system.
Furthermore, evidence continues to mount that these educational efforts
not only increase patient compliance and their knowledge of the disease,
but also their quality of life (Dogan, 2003).

o First, an explanation of the biology of the disease must be provided.

This lessens the guilt and promotes medication compliance.

o Second, include information about how to monitor the illness in

terms of an appreciation of the early warning signs, reemergence,
and symptoms. Recognition of changes can serve as a powerful
preventive step.

o A strong therapeutic alliance remains an essential part of treatment

and education.

o Education also must encompass the dangers of stressors. Helping

the individual identify and work with stressors provides a critical
aspect of patient and family awareness.

o Finally, inform the patient about relapses within the total context of
the disorder.

o Individual stories help patients and families. The National Institute

of Mental Health (NIMH) has a story of a person with MDI that can
help the patient see the struggle and challenge from another
perspective (NIMH, 2003). Others have written about their family
struggles and challenges (Webb, 2003).

 Important resources for patients and families to gain information on

dealing with MDI include the following (NIMH, 2001):
o National Institute of Mental Health (NIMH)
Office of Communications
Information Resources and Inquiries Branch
6001 Executive Blvd, Rm 8184, MSC 9663
Bethesda, MD 20892-9663
Phone: (301) 443-4513; Fax: (301) 43-4279
Fax Back System, Mental Health FAX4U: (301) 443-5158
E-mail:; Web site:
o Child & Adolescent Bipolar Foundation
1187 Wilmette Ave, PMB #331
Wilmette, IL 60091
Phone: (847) 256-8525
Web site:
o Depression and Related Affective Disorders Association (DRADA)
Johns Hopkins Hospital, Meyer 3-181
600 North Wolfe St
Baltimore, MD 21287-7381
Phone: (410) 955-4647 or (202) 955-5800 (Washington, DC)
E-mail:; Web site:
o National Alliance for the Mentally Ill (NAMI)
Colonial Place Three
2107 Wilson Blvd, 3rd Floor
Arlington, VA 22201-3042
Toll-Free: 1-800-950-NAMI (6264)
Phone: (703) 524-7600; Fax: (703) 524-9094
o Depression & Bipolar Support Alliance (DBSA)
730 North Franklin St, Ste 501
Chicago, IL 60610-7204
Toll-Free: 1-800-826-3632
Phone: (312) 642-0049; Fax: (312) 642-7243
o National Foundation for Depressive Illness, Inc (NAFDI)
PO Box 2257
New York, NY 10116
Toll-Free: 1-800-239-1265
Web site:
o National Mental Health Association (NMHA)
2001 North Beauregard St, 12th Floor
Alexandria, VA 22314-2971
Phone: 1-800-969-6642 or (703) 684-7722
 For excellent patient education resources, visit eMedicine's Depression
Center. Also, see eMedicine's patient education articles Depression and
Bipolar Disorder.

MISCELLANEOUS Section 9 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Medical/Legal Pitfalls:

 Involuntary hospitalization for depression: In the clearest case of the

bipolar/depressed phase, the patient is suicidal and homicidal in a few
situations (this can result in homicide followed by suicide). In these
scenarios, commitment is in order and indicated. In other situations, the
depression has led to an inability to work, eat, and function; hospitalization
also is indicated in these cases.

 Involuntary hospitalization for mania: In the situation of a patient in

bipolar/manic phase, often, less clear and dramatic evidence of homicide
or suicide is present, but a pattern of very poor judgment and impairment
emerges. Because of the behavior during the manic phase, the person
often does major damage to their finances, career, and position in the
community. This type of self-destructive mania calls for containment with
good documentation and family support.

Special Concerns:

 Several special concerns accompany patients with bipolar disorder,

including suicide, homicide, and addiction.

o Suicidal patients remain at risk for suicide. Patients emerging from

a depression are thought to be at an increased risk for suicide. The
risk of self-destructive behavior and death is lifelong. Hong's 2003
study demonstrates a genetic link between bipolar disorder and
suicidal behavior, especially in white individuals.

o Homicidal patients, often in the manic phase, can be very

demanding and grandiose. In this context, they will be angered if
others do not immediately comply with their wishes. This can make
them turn dramatically violent. Also, they can become homicidal by
acting on delusions.

o Individuals with bipolar disorder are at risk for an addiction. This

creates the problem of a dual diagnosis and, therefore, complicates