Bipolar Affective Disorder (Medscape)

Bipolar Affective Disorder
Contributor Information and Disclosures

Author
Stephen Soreff, MD President of Education Initiatives, Nottingham, NH; Faculty, Boston
University, Boston, MA and Daniel Webster College, Nashua, NH

Stephen Soreff, MD is a member of the following medical societies: American College of
Mental Health Administration

Disclosure: Nothing to disclose.
Coauthor(s)
Lynne Alison McInnes, MD, MS Associate Clinical Professor of Psychiatry, University of
California, San Francisco, School of Medicine

Lynne Alison McInnes, MD, MS is a member of the following medical societies: Alpha
Omega Alpha, American Psychiatric Association, and American Society of Human Genetics

Chief Editor
Iqbal Ahmed, MBBS, FRCPsych (UK) Faculty, Department of Psychiatry, Tripler Army
Medical Center; Clinical Professor of Psychiatry, Uniformed Services University of the
Health Sciences; Clinical Professor of Psychiatry, Clinical Professor of Geriatric Medicine,
University of Hawaii, John A Burns School of Medicine

Iqbal Ahmed, MBBS, FRCPsych (UK) is a member of the following medical societies:
Academy of Psychosomatic Medicine, American Association for Geriatric Psychiatry,
American Neuropsychiatric Association, American Psychiatric Association, American
Society of Clinical Psychopharmacology, and Royal College of Psychiatrists

Additional Contributors
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska
Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment

Practice Essentials
Bipolar disorder, or manic-depressive illness (MDI), is one of the most common, severe, and
persistent mental illnesses. It constitutes one pole of a spectrum of mood disorders that
includes bipolar I (BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and
major depression. The pathophysiology of bipolar disorder has not been determined, but
studies indicate that it has a substantial genetic component.
Essential update: Schizophrenia drug approved for bipolar depression
In June 2013, the FDA approved lurasidone (Latuda, Sunovion Pharmaceuticals), which is
already indicated for schizophrenia, to treat major depressive episodes in adults with bipolar
1 disorder. Lurasidone can be prescribed as monotherapy or with either lithium or valproate
for this new indication.
Approval was based on 2 clinical trials, one for lurasidone as an adjunctive therapy
(PREVAIL1), and the other for the drug as a monotherapy (PREVAIL2). In both studies,
patients taking lurasidone experienced a reduction in depressive symptoms as measured by
the Montgomery-Asberg Depression Rating Scale after 6 weeks compared with the group
taking placebo. Patients treated with lurasidone also showed significant improvements in
remission rates, anxiety symptoms, and enjoyment and quality of life. The most common
adverse effects associated with lurasidone monotherapy were akathisia, extrapyramidal
symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.
[1]

Signs and symptoms
The diagnosis of BPI requires the following:
A manic episode of at least 1 weeks duration that leads to hospitalization or other
significant impairment in occupational or social functioning
The episode cannot be caused by another medical illness or by substance abuse
Manic episodes also must include at least 3 of the following symptoms:
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 sexually
Excessive pleasurable activities, often with painful consequences
Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least
4 days duration, along with at least 3 of the following symptoms:
Grandiosity or inflated self-esteem
Pressured speech
Psychomotor agitation at home, at work, or sexually
Engaging in activities with a high potential for painful consequences
For major depressive episodes, the person experiences 5 or more of the following symptoms
for the same 2 weeks, with at least 1 of the symptoms being either of the first 2 listed:
Depressed mood
Markedly diminished pleasure or interest in nearly all activities
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 a plan or has attempted suicide
The symptoms cause significant impairment and distress
The mood is not the result of substance abuse or a medical condition
Mixed episodes are characterized by the following:
Persons must meet the criteria for both mania and major depression; the depressive
event is required to be present for 1 week only
The mood disturbance results in marked disruption in social or vocation function
The mood is not the result of substance abuse or a medical condition
Evaluation should address the following:
Appearance
Affect/mood
Thought content
Perceptions
Suicide/self-destruction
Homicide/violence/aggression
Judgment/insight
Cognition
Physical health
Complications (eg, suicide, homicide, and addictions)
History
Correct diagnosis of a disorder leads to proper effective treatment. Nowhere is that more
relevant than in diagnosing a patient with bipolar affective disorder. Wolkenstein et al have
pointed out the advantages of applying all DSM-specific criteria in order to make the correct
diagnosis.
[43]

The diagnosis of bipolar I (BPI) disorder requires the presence of a manic episode of at least
1 weeks 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).
[44]

Manic episodes are characterized by at least 1 week of profound mood disturbance,
characterized by elation, irritability, or expansiveness (referred to as gateway criteria). At
least 3 of the following symptoms must also be present:
Grandiosity
Excessive talking or pressured speech
Increased level of goal-focused activity at home, at work, or sexually
Excessive pleasurable activities, often with painful consequences
The mood disturbance is sufficient to cause impairment at work or danger to the patient or
others. The mood is not the result of substance abuse or a medical condition.
Hypomanic episodes are characterized by an elevated, expansive, or irritable mood of at least
4 days duration. At least 3 of the following symptoms are also present:
Grandiosity or inflated self-esteem
Pressured speech
Psychomotor agitation at home, at work, or sexually
Engaging in activities with a high potential for painful consequences
The mood disturbance is observable to others. The mood is not the result of substance abuse
or a medical condition.
Major depressive episodes are characterized by the following: 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 activities
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 a plan or has attempted suicide
The symptoms cause significant impairment and distress.
The mood is not the result of substance abuse or a medical condition.
Mixed episodes are characterized by the following:
Persons must meet both the criteria for mania and major depression; the depressive
event is required to be present for 1 week only.
The mood disturbance results in marked disruption in social or vocation function.
The mood is not the result of substance abuse or a medical condition.
The mixed symptomatology is quite common in patients presenting with bipolar
symptomatology. This often causes a diagnostic dilemma.
[45]

Refining the diagnosis of bipolar disorder
The fifth version of the DSM is underway, and efforts are being made to refine the diagnosis
based in part on data from the BRIDGE study (Bipolar Disorders: Improving Diagnosis,
Guidance and Education). For example, data from this study support revising the DSM-IV
concept of hypomanic episodes: specifically, the inclusion of increased activity in the
gateway criteria; the inclusion of 1 or 2 to 3-day episodes as clinically relevant; and the
elimination of all exclusion criteria such as hypomania/mania due to the use of
antidepressants or other substances.
[46]
If made official, these types of changes could have a
major impact on the prevalence of bipolar disorder. The data certainly suggest that more
careful screening of patients with depression for the presence of bipolarity is warranted.
[47]
Physical Examination
Use the Mental Status Examination (MSE) to diagnose bipolar disorder. This section
highlights the major findings for a person with bipolar disorder. Because the patients mental
status depends on whether he or she is depressed, hypomanic, manic, or mixed, the following
discussions of the various areas of the MSE include consideration of each of these particular
phases
Appearance
Persons experiencing a depressed episode may demonstrate poor to no eye contact. Their
clothes may be unkempt, unclean, holed, unironed, and ill-fitting. If the person has lost
significant weight, 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.
Persons experiencing a hypomanic episode 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.
In many ways, the behavior of a patient in the manic phase is the opposite of that 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 are often too bright, colorful, or garish. They stand out in a crowd
because their dress frequently attracts attention.
Affect/mood
In persons experiencing a depressed episode, sadness dominates the affect. These individuals
feel sad, depressed, lost, vacant, and isolated. The "2 Hs" h opeless and h elplessoften
accompany their mood. When in the presence of such patients, one comes away feeling sad
and down.
In persons experiencing a hypomanic episode, the mood is up, expansive, and often irritable.
In persons experiencing a manic episode, the mood is inappropriately joyous, elated, and
jubilant. These individuals are euphoric. They also may demonstrate annoyance and
irritability, especially if the mania has been present for a significant length of time.
Persons experiencing a mixed episode exhibit both depression and mania within a brief
period (1 wk or less).
Thought content
Patients experiencing a depressed episode have thoughts that reflect their sadness. They are
preoccupied with negative ideas and nihilistic concerns, and they tend to "see the glass as half
empty." They are likely to focus on death and morbid persons. Many think about suicide.
Patients experiencing a hypomanic episode are optimistic, forward thinking, and have a
positive attitude.
Patients experiencing a manic episode have very expansive and optimistic thinking. They
may be excessively self-confident 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
person to another.
Patients experiencing a mixed episode can oscillate dramatically between depression and
euphoria, and they often demonstrate marked irritability.
Perceptions
Two forms of a major depression are described, one with psychotic features and the other
without. With psychosis, the patient experiences delusions and hallucinations that are either
consistent or inconsistent with the mood.
In the former, the patients 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 mood. In the
latter, some patients experience delusions that are inconsistent with the depression, such as
paranoia or persecutory delusions.
Patients experiencing a hypomanic episode do not experience perceptual disturbances.
Approximately three fourths of patients experiencing a manic episode 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.
Patients experiencing a mixed episode might exhibit delusions and hallucinations consistent
with either depression or mania or congruent to both.
Suicide/self-destruction
Patients experiencing a depressed episode 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.
Dubovsky reports that the highest lifetime suicide risk (17.08%) is in men with bipolar
disorder and deliberate self-harm.
[48]

Bellivier and collogues found in a European study of adults with bipolar disorder that 29.9%
had a history of at least 1 attempt of suicide (663 of 2219 patients who provided data on
lifetime history of suicide attempts). Female sex, history of alcohol abuse, history of
substance abuse, young age at first treatment for a mood episode, longer disease duration,
greater depressive symptom severity (5-item Hamilton Depression Rating Scale [HAMD-5]
total score), current benzodiazepine use, higher overall symptom severity (Clinical Global
Impression-Bipolar Disorder [CGI-BP] scale: mania and overall score), and poor compliance
were the baseline factors associated with a history of suicidal behavior.
[49]

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 to the point where the person
is again capable of making and carrying out a plan while the subjective feeling of depression
and accompanying suicidal thoughts persist.
Patients experiencing a hypomanic or manic episode have a low incidence of suicide.
In mixed episodes, the depressed phases put the patient at risk for suicide.
For more information see the Medscape Reference article Suicide.
Homicide/violence/aggression
In patients experiencing a depressed episode, suicide generally remains the paramount issue.
However, certain persons in the depths of a depression see the world as hopeless and helpless
not only for themselves but also for others. Frequently, that perspective can create and lead to
a homicide followed by a suicide.
As an example, 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.
Patients who are hypomanic frequently show evidence of irritability and aggressiveness.
They can be pushy and impatient with others.
Persons experiencing a manic episode 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 is particularly likely to emerge 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. The patient may become violent
toward those "disordent" subjects. If their delusions become persecutory in nature, they may
defend themselves against others in a homicidal fashion.
Persons experiencing a mixed episode may exhibit aggression, especially in the manic
phases.
Judgment/insight
In persons experiencing a depressed episode, the depression clouds and dims their 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
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.
Persons experiencing a hypomanic episode generally have good but expansive judgment.
They may take on too many tasks or become overinvolved. 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.
In patients experiencing a manic episode, judgment is seriously impaired. These persons
make terrible decisions in their work and family. They may invest the family fortune in very
questionable programs, become professionally overinvolved in work activities or with
coworkers, or start dramatically unsound fiscal or professional ventures. They ignore
feedback, suggestions, and advice from friends, family, and colleagues. They have no insight
into the extreme nature of their demands, plans, and behavior. Often, commitment proves the
only way to contain them.
In persons experiencing a mixed episode, major shifts in affect during short lengths of time
severely impair their judgment and interfere with their insight.
Cognition
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.
Physical health
Although the MSE has been used here to highlight key aspects of the examination, the
clinician must pay particular attention to the patients physical health. As Fagiolini points out,
patients with bipolar disorder have a high incidence of endocrine disorders, cardiovascular
disorders, and obesity, and these factors must be considered when medications are
prescribed.
[50, 51]

Diagnosis
Laboratory studies that may be helpful include the following:
Complete blood count (CBC) with differential
Erythrocyte sedimentation rate (ESR)
Fasting glucose level
Serum electrolyte concentrations
Serum calcium concentration
Serum protein levels
Thyroid tests
Serum creatinine and blood urea nitrogen (BUN) levels
Substance and alcohol screening
Other laboratory tests: Urine copper levels, antinuclear antibody (ANA) testing, HIV
testing, or Venereal Disease Research Laboratory (VDRL) testing
Other diagnostic modalities that may be helpful include the following:
Magnetic resonance imaging
Electrocardiography
Electroencephalography
Diagnostic Considerations
Other conditions to be considered include the following:
Cancer
Epilepsy
Fahr disease
AIDS
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, procyclidine)
Circadian rhythm desynchronization
Cyclothymic disorder
Multiple personality disorder
Oppositional defiant disorder (in children)
Substance abuse disorders (eg, with alcohol, amphetamines, cocaine, hallucinogens,
opiates)
Differential Diagnoses
Anxiety Disorders
Cushing Syndrome
Head Trauma
Hyperthyroidism
Hypothyroidism
Multiple Sclerosis
Neuro-ophthalmic Perspective Migraine Headache
Neurosyphilis
Pediatric Attention Deficit Hyperactivity Disorder
Posttraumatic Stress Disorder
Schizoaffective Disorder
Schizophrenia
Seasonal Affective Disorder
Systemic Lupus Erythematosus
Approach Considerations
A number of reasons exist for obtaining selected 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 condition necessitates use of 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 medications.
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.
For more information, see Pediatric Bipolar Affective Disorder.
Management
Treatment of bipolar disorder is directly related to the phase of the episode and the severity of
that phase. It may involve inpatient care, outpatient care, or partial hospitalization or day
treatment. Indications for inpatient treatment include the following:
Danger to self
Danger to others
Total inability to function
Total loss of control
Medical conditions that warrant medication monitoring
Pharmacologic agents approved by the FDA for use in treating bipolar disorder are as
follows:
Valproate (manic)
Carbamazepine, extended-release (manic, mixed)
Lamotrigine (maintenance; risk of aseptic meningitis
[2]
)
Lithium (manic, maintenance)
Aripiprazole (manic, mixed, maintenance)
Ziprasidone (manic, mixed)
Risperidone (manic, mixed)
Asenapine (manic, mixed)
Quetiapine (manic, depression)
Chlorpromazine (manic)
Olanzapine (manic, mixed, maintenance)
Olanzapine-fluoxetine (depression)
Electroconvulsive therapy (ECT) has proved to be highly effective in the treatment of acute
mania. Other measures that may be considered include the following:
Diet: Unless the patient is on monoamine oxidase inhibitors (MAOIs), no special diet
is required; no significant changes should be made in salt intake; adjunctive use of
omega-3 may improve bipolar depressive symptoms, though not bipolar mania
[3]

Regular exercise
Prevention (medication and psychoeducation)
The treatment of bipolar disorder is directly related to the phase of the episode (ie,
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. Fortunately, most patients recover from the first manic
episode, but their course beyond that is variable.
[58]

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 order. If the patient is
in a depressed or manic phase and is not responding to medications, transfer the
patient to a facility where electroconvulsive therapy (ECT) can be administered.
A consultation with a psychiatric colleague or a psychopharmacologist is always
appropriate if the patient does not respond to conventional treatment and medication.
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.
No surgical care is indicated for bipolar disorder. Historically, treatment was
attempted with psychosurgical procedures, such as prefrontal lobotomy. Lobotomy is
no longer used in the clinical care of patients with bipolar disorder.

Medication Summary
Appropriate medication depends on the stage of the bipolar disorder the patient is
experiencing. The choice of agent depends on the presence of symptoms such as psychotic
symptoms, agitation, aggression, and sleep disturbance. Drug categories include mood
stabilizers, anticonvulsants, and antipsychotics.
Anxiolytics, Benzodiazepines
Class Summary
By binding to specific receptor sites, these agents appear to potentiate the effects of GABA
and facilitate inhibitory GABA neurotransmission and the action of other inhibitory
transmitters.
Lorazepam (Ativan)
Lorazepam is a sedative hypnotic with a short onset of effects and a relatively long half-life.
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain,
it may depress all levels of the CNS, including the limbic and reticular formation. Monitor
the patient's blood pressure after administering a dose of lorazepam. Adjust the dose as
necessary.
Clonazepam (Klonopin)
Clonazepam is a long-acting benzodiazepine that increases presynaptic GABA inhibition and
reduces monosynaptic and polysynaptic reflexes. It suppresses muscle contractions by
facilitating inhibitory GABA neurotransmission and other inhibitory transmitters.
Mood stabilizers
Class Summary
Clinical experiences have shown that patients with bipolar disorder have fewer episodes of
mania and depression when treated with mood-stabilizing drugs.
[77]
These medications serve
to stabilize the patients mood, as the name implies. They also can dampen extremes of mania
or depression.
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.
[70]
However, it is also
associated with increased risk of reduced urinary concentrating ability, hypothyroidism,
hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of
hyperparathyroidism should prompt physicians to check patient calcium concentrations
before and during treatment. Lithium is not associated with a significant reduction in renal
function in most patients, and the risk of end-stage renal failure is low.
[71]
Lithium therapy
may serve to protect and preserve the hippocampal volumes, in contrast to patients with
major depression (ie, unipolar), who show diminished hippocampal volumes.
[72]

Lithium carbonate (Lithobid)
Lithium is considered a first-line agent for long-term prophylaxis in bipolar illness, especially
for classic bipolar disorder with euphoric mania. It also can be used to treat acute mania,
though it cannot be titrated up to an effective level as quickly as valproate can. Evidence
suggests that lithium, unlike any other mood stabilizer, may have a specific antisuicide effect.
Monitoring blood levels is critical with this medication.
Anticonvulsants
Class Summary
Anticonvulsants have been effective in preventing mood swings associated with bipolar
disorder, especially in those 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 anxiolytic properties.
The most widely used anticonvulsants have been carbamazepine, valproate, and lamotrigine.
More recently, topiramate and oxcarbazepine also are being tried.
Carbamazepine (Equetro)
Carbamazepine is effective in patients who have not responded to lithium therapy. It also can
act to inhibit seizures induced through the kindling effect, which is thought to occur by way
of repeated limbic stimulation. Carbamazepine has been effective in treating patients who
have rapid-cycling bipolar disorder or those who have not been responsive to lithium therapy.
Valproate sodium, valproic acid, divalproex sodium (Depakene, Depakote,
Depakote ER, Depacon, Stavzor)

Valproate has proven effectiveness in treating and preventing mania. It is classified as a
mood stabilizer and can be used alone or in combination with lithium. It is useful in treating
patients 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%.
Lamotrigine (Lamictal, Lamictal ODT)
Lamotrigine is an anticonvulsant that appears to be effective in the treatment of the depressed
phase in bipolar disorders. It is used for the maintenance treatment of bipolar I disorder to
delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed
episodes) in adults treated for acute mood episodes with standard therapy.
Atypical Antipsychotics
Class Summary
Atypical antipsychotics are being used increasingly for treatment of both acute mania and
mood stabilization.
Asenapine (Saphris)
Asenapine's mechanism of action is unknown. It is indicated as monotherapy for the acute
treatment of manic or mixed episodes that are associated with bipolar I disorder. Asenapine is
also indicated as adjunctive therapy with lithium or valproate. Its efficacy thought to be
mediated through a combination of antagonist activity at dopamine 2 and serotonin (5-HT2)
receptors. Asenapine exhibits high affinity for serotonin 5-HT1A, 5-HT1B, 5-HT2A, 5-
HT2B, 5-HT2C, 5-HT5, 5-HT6, and 5-HT7 receptors; dopamine D2, D3, D4, and D1
receptors; alpha-1 and alpha-2 adrenergic receptors; and histamine H1 receptors, with
moderate affinity for H2 receptors.
In vitro assays suggest antagonistic activity elicited at these receptors. Asenapine is indicated
for acute treatment of manic or mixed episodes associated with bipolar I disorder (with or
without psychotic features).
The prescribing information was updated in September 2011 to include data from 52 reports
of type 1 hypersensitivity reactions.
Ziprasidone (Geodon)
Ziprasidone is an atypical antipsychotic that is approved for the treatment of acute or mixed
episodes that are associated with bipolar disorder. It can be used as maintenance treatment as
an adjunct to lithium or valproate.
Quetiapine (Seroquel, Seroquel XR)
Quetiapine is indicated for acute treatment of manic episodes that are associated with bipolar
I disorder. It can be used as monotherapy or adjunctively with agents such as lithium or
divalproex.
Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)
Risperidone is indicated for short-term treatment of acute manic or mixed episodes that are
associated with bipolar I disorder. It can be used alone or in combination with lithium or
valproate. Risperidone can be used in adults and adolescents aged 10-17 years with bipolar I
disorder.
Aripiprazole (Abilify, Abilify Discmelt)
Aripiprazole is an atypical antipsychotic used for the acute and maintenance treatment of
manic or mixed episodes associated with bipolar I disorder. It can be used alone or in
combination with lithium or valproate.
Olanzapine (Zyprexa, Zyprexa Zydis)
Olanzapine is used for the acute and maintenance treatment of manic or mixed episodes
associated with bipolar I disorder. It can be used alone or in combination with lithium or
valproate. It can be used in adults and adolescents aged 13-17 years with bipolar I disorder.
Olanzapine and fluoxetine (Symbyax)
The drug combination includes olanzapine, an atypical antipsychotic, and fluoxetine, a
selective serotonin reuptake inhibitor. This drug is indicated for the acute treatment of
depressive episodes associated with bipolar I disorder in adults. The clinical effects of this
agent have not been studied in patients younger than 18 years.
Antipsychotics, 1st Generation
Class Summary
First-generation antipsychotics, also known as conventional or typical antipsychotics, are
strong dopamine D2 antagonists. However, each drug in this class has various effects on
other receptors, such as 5-HT2 serotonin, alpha1, histaminic, and muscarinic receptors.
Loxapine inhaled (Adasuve)
Loxapine's mechanism of action is unknown, but is theorized to antagonize central dopamine
D2 and serotonin 5-HT2a receptors. The inhaled dosage form is indicated for acute treatment
of agitation associated with schizophrenia or bipolar I disorder in adults.

Table. FDA-Approved Bipolar Treatment Regimens
Generic Name Trade Name Manic Mixed Maintenance Depression
Valproate Depakote X
Carbamazepine extended release Equetro X X
Lamotrigine Lamictal X
Lithium X X
Aripiprazole Abilify X X X
Ziprasidone Geodon X X
Risperidone Risperdal X X
Asenapine Saphris X X
Quetiapine Seroquel X X
Chlorpromazine Thorazine X
Olanzapine Zyprexa X X X
Olanzapine/fluoxetine combination Symbyax X
Lurasidone Latuda X

Background
Bipolar disorder, or manic-depressive illness (MDI), is one of the most common, severe, and
persistent mental illnesses. Bipolar disorder is a serious lifelong struggle and challenge.
[4]

It is also useful to note that other mental health disorders and general medical conditions are
more prevalent in patients with bipolar disorders.
[5]
Among the general medical conditions,
cardiometabolic conditions such as cardiovascular disease, diabetes, and obesity are a
common source of morbidity and mortality for persons with bipolar disorder.
Bipolar disorder is characterized by periods of deep, prolonged, and profound depression that
alternate with periods of an excessively elevated 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.
Unipolar major depressive disorder and bipolar disorder share depressive symptoms, but
bipolar disorder is defined by episodes of mania or hypomania. A community lifetime
prevalence (in its broadest measure) of 4% has been suggested. The costs of bipolar disorder
include the direct costs of treatment along with the even more significant indirect costs of
excess unemployment, decreased productivity, and excess mortality; it is a severely impairing
illness that affects many aspects of patients' lives.
[6]

Bipolar disorder constitutes 1 pole of a spectrum of mood disorders that includes including
bipolar I (BPI), bipolar II (BPII), cyclothymia (oscillating high and low moods), and major
depression.
BPI, also referred to as classic manic-depression, is 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 that consists 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 function.
Pathophysiology
The pathophysiology of bipolar disorder has not been determined, and no objective biologic
markers have yet been found to correspond definitively with the disease state. However, twin,
family, and adoption studies all indicate 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.
The genetic component of bipolar disorder appears to be complex: the disorder is likely to be
caused by multiple different common disease alleles, on the order of hundreds to thousands,
each of which contributes a relatively low degree of risk on its own. Such disease genes can
be difficult to find without very large sample sizes, on the order of thousands of subjects.
The first series of genome-wide association studies (GWAS) for bipolar disorder were
published in 2007 and 2008,
[7, 8, 9, 10]
and a collaborative analysis of the last 3 studies gave
combined support for 2 particular genes, ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit
of the L-type voltage-gated calcium channel) in a sample of 4,387 cases and 6,209
controls.
[10]
ANK3 is an adaptor protein found at axon initial segments that regulates the
assembly of voltage-gated sodium channels. Both ANK3 and subunits of the calcium channel
are down-regulated in mouse brain in response to lithium, which indicates a possible
therapeutic mechanism of action of 1 of the most effective treatments for bipolar disorder.
[11]

Further evidence for association of bipolar disorder to CACNA1C was reported in 2011 in an
ever-growing sample (now numbering 11,974 bipolar disorder cases and 51,792 controls),
providing overwhelming support for this gene as a bipolar susceptibility locus.
[12]

CACNA1C, on chromosome 12, encodes the alpha subunit of the L-type voltage-gated
calcium ion channel found in the brain. L-type calcium channel blockers have been used to
treat bipolar disorder, and there has been speculation that at least some mood stabilizers may
mediate their effects via modulating calcium channel signaling in bipolar illness.
A joint analysis of the bipolar GWAS data was carried out, including GWAS data from
another large-scale study of schizophrenia published in the same issue. Again, both ANK3
and CACNA1C came up positive in the combined data set, suggesting a shared genetic basis
for these disorders. A previous National Institutes of Health (NIH) report on recent genome-
wide association studies also underscored that bipolar disorder and schizophrenia could
indeed share common susceptibility genes on chromosome 6.
[13]
These data herald future
revision of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision (DSM-IV-TR) according to an etiologic rather than descriptive basis.
The first GWAS of bipolar disorder used a much smaller sample size than subsequent
attempts
[7]
, including an initial sample of 461 patients with bipolar disorder from the
National Institute of Mental Health (NIMH) consortium and a follow-up sample of 563
patients collected in Germany. This gene was not highlighted in the most recent and largest
bipolar GWAS published by Sklar et al 2011.
[12]
Nevertheless, this study remains of interest,
in that the strongest association signals were detected in genes also involved in biochemical
pathways regulated by lithium. The strongest hit was at a marker within the first intron of
diacylglycerol kinase eta (DGKH) gene. DGKH is a key protein in the lithium-sensitive
phosphatidyl inositol pathway.
Three of the other associated genes in this study also interact with the Wnt signaling pathway
upstream and downstream of glycogen synthase kinase 3-beta (GSK3). Lithium-mediated
inhibition of GSK3 is thought to result in downregulation of molecules involved in cell
death and upregulation of neuroprotective factors.
Additionally, GSK3 is a central regulator of the circadian clock, and lithium-mediated
modulation of circadian periodicity is thought to be a critical component of lithiums
therapeutic effect. In fact, another major coup for bipolar disorder research has been the
finding that a dominant-negative mutation in the CLOCK gene normally contributing to
circadian periodicity in humans results in behavior mimicking mania in mice.
[14]

Manic behavior in CLOCK mutant mice includes hyperactivity, decreased sleep, reduced
anxiety, and an increased response to cocaine. The latter finding also provides a shared
biologic basis for the high rate of substance abuse observed in clinical populations of subjects
with bipolar disorder.
Furthermore, the experimenters were able to abolish the manic behaviors by rescuing
expression of normal CLOCK gene product specifically in the ventral tegmental area of the
mouse brain.
[15]
This area is rich in D2 (dopamine) receptors. Joseph Coyle hypothesizes in
his commentary in the paper in the same issue that the efficacy of atypical antipsychotics in
acute mania might, in part, be achieved by their ability to lower activity in neurons
specifically within the ventral tegmental area.
Although large-scale association studies of bipolar disorder are beginning to yield results, one
of the greatest obstacles to finding genes for such complex behavior is the imprecision
inherent in diagnosis of the disorder itself; objective criteria are lacking. Therefore, some of
the most exciting recent research is focused on defining heritable, quantitative diagnostic
measures that capture specific features of bipolar disorder (termed endophenotypes) to refine
the search for responsible genes.
[16]
Such promising measures for bipolar disorder include
structural brain phenotypes, sleep and activity measures, neurocognitive measures, and gene
expression studies.
[17]
This collaborative research effort under the aegis of the National
Institute of Mental Health (NIMH) has been termed the Bipolar Phenome Project; more
information is available in the links provided below.
Gene expression studies, one way of measuring the relative activity or inactivity of genes,
have already been proven useful for illuminating the pathophysiology of psychiatric
disorders, including bipolar disorder. For instance, studies comparing specific regions of
postmortem brain tissue from persons with bipolar disorder with tissue from control subjects
have consistently shown that levels of expression of oligodendrocyte-myelinrelated genes
appear to be decreased in brain tissue from persons with bipolar disorder.
[18, 19, 20, 21]
As with
genetic studies, gene expression profiling studies require very large sample sizes to produce
replicable data. Furthermore, they must focus on the correct brain region(s) thought to be
functioning differently in bipolar disorder, a point still under some debate. Therefore,
research in this area is ongoing and frequently subject to update.
Oligodendrocytes produce myelin membranes that wrap around and insulate axons to permit
the efficient conduction of nerve impulses in the brain. Therefore, loss of myelin is thought to
disrupt communication between neurons, leading to some of the thought disturbances
observed in bipolar disorder and related illnesses. Brain imaging studies of persons with
bipolar disorder also show abnormal myelination in several brain regions associated with this
illness. It can be useful to compare data from gene expression studies with brain imaging
studies of persons with bipolar disorder to determine whether abnormalities of structure or
function correlate with changes in gene expression. In this case, structural neuroimaging
studies also show abnormal myelination in several brain regions associated with bipolar
disorder.
[22, 23]

Interestingly, gene expression and neuroimaging studies of persons with schizophrenia and
major depression also demonstrate abnormalities of myelination in various brain regions,
indicating that mood disorders and schizophrenia may share some biologic underpinnings,
possibly related to psychosis, which can be a symptom of all 3 disorders. These types of data
may also lead to the future revision of psychiatric diagnostic manuals based on a new
understanding of the etiology of these disorders.
In addition to structural neuroimaging studies that look for volumetric changes in brain
regions regardless of brain activity, functional neuroimaging studies are performed to find
regions of the brain, or specific cortical networks, that are either hypoactive or hyperactive in
a particular illness. For example, a meta-analysis by Houenou et al found decreased
activation and diminution of gray matter in a cortical-cognitive brain network, which has
been associated with the regulation of emotions in patients with bipolar disorder.
[24]
An
increased activation in ventral limbic brain regions that mediate the experience of emotions
and generation of emotional responses was also discovered. This provides evidence for
functional and anatomical alterations in bipolar disorder in brain networks associated with the
experience and regulation of emotions.
Another source of knowledge regarding the pathophysiology of bipolar disorder comes from
studies done using animal models.
For instance, investigators can study changes in gene expression/activation, induced in rodent
brains after administration of pharmacologic agents used to treat bipolar disorder to look at
the mechanism of action of these drugs. For example, investigators have demonstrated that 2
chemically unrelated drugs (lithium and valproate) used to treat bipolar disorder both increase
the cytoprotective protein Bcl-2 in the frontal cortex and the hippocampus of rat brains.
[25]
These types of studies are also performed on human tissue by exposing cultured human
monocytes from peripheral blood to lithium and other factors and then measuring changes in
gene expression.
A postmortem study by Konradi et al of the hippocampus in both patients with bipolar
disorder and healthy persons found that the 2 groups did not differ in the total number of
hippocampal neurons.
[26]
However, patients with bipolar disorder had reduced volume of
nonpyramidal cell layers, a reduced number of somatostatin-positive and parvalbumin
positive neurons, a reduced somal volume in cornu ammonis sector 2/3, and reduced
messenger RNA levels for somatostatin, parvalbumin, and glutamic acid decarboxylase 1.
These findings suggest alteration of hippocampal interneurons in patients with bipolar
disorder that might lead to hippocampal dysfunction.
Neuroimaging studies of individuals with bipolar disorder or other mood disorders also
suggest evidence of cell loss or atrophy in these same brain regions. Thus, another suggested
cause of bipolar disorder is damage to cells in the 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.
In 2008, Mathew et al published a review of novel drugs and therapeutic targets for severe
mood disorders that focus on increasing neuroplasticity and cellular resiliency.
[27]

Post et al had previously proposed a mechanism involving electrophysiologic kindling and
behavioral sensitization processes, which resonates with the neuronal injury hypothesis.
[14]
They asserted that a person who is susceptible to bipolar disorder experiences an increasing
number of minor neurologic insultssuch as those induced by drugs of abuse, stress-related
excessive glucocorticoid stimulation, oxidative or immune-mediated damageeventually
resulting in mania that further compromises the injured neurons.
[14]
Sufficient brain damage
might persist to cause mania to recur even with no or minor environmental or behavioral
stressors.
Post et als 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 supports the clinical observation that the more episodes a person experiences, the more
he or she will have in the future, underscoring the need for long-term treatment.
Updated research Web sites
Research on bipolar disorder is proceeding at a rapid rate, and the traditionally referenced
peer-reviewed publications provided in this article may become rapidly outdated. To keep
current with research into bipolar disorder, search the following Web sites, which are
continually updated.
For information about clinical trials, including both traditional pharmacotherapies and
nutritional supplements, please consult http://clinicaltrials.gov and enter the search term
"bipolar affective disorder".
For information about the research aims and priorities of the NIMH, please consult
http://www.nimh.nih.gov/about/strategic-planning-reports/index.shtml.
For those interested in following refinements in the diagnosis of bipolar disorder, please
consult www.dsm5.org.
The International Society for Bipolar Disorders (ISBD) also sponsors a yearly conference
where the worlds experts present their research findings on all aspects of bipolar disorder.
For more about the ISBD, see http://www.isbd.org/EdCenter/aboutisbd/mission.asp; their
findings are published yearly in the Annals of the New York Academy of Sciences.
Etiology
A number of factors contribute to bipolar disorder, including genetic, biochemical,
psychodynamic, and environmental factors.
Genetic factors
Bipolar disorder, especially BPI, has a major genetic component, with the involvement of the
ANK3,CACNA1C, and CLOCK genes.
[7, 8, 9, 10, 12, 15, 28]
The evidence indicating a genetic role
in bipolar disorder takes several forms.
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. Twin studies demonstrate a
concordance of 33-90% for BPI in identical twins. As identical twins share 100% of their
DNA, these studies also show that environmental factors are involved and there is no
guarantee that a person will develop bipolar disorder, even if they carry susceptibility genes.
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 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. For more information on
bipolar disorder in children, see New Findings in Childhood Bipolar Disorder.
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 was the same for schizoaffective disorder as for the other 2 syndromes.
[29]
This finding suggests an independent genetic liability for psychosis shared by both mood and
schizophrenia spectrum disorders, as Berrettini
[30]
previously speculated and as has been
confirmed in the recent large-scale GWAS studies mentioned above.
[12]

Gene expression studies also demonstrate that persons with bipolar disorder, major
depression, and schizophrenia share similar decreases in the expression of oligodendrocyte-
myelin-related genes and abnormalities of white matter in various brain regions.
Biochemical factors
Multiple biochemical pathways likely contribute to bipolar disorder, which is why detecting
one particular abnormality is difficult.
A number of neurotransmitters have been linked to this disorder, largely based on patients
responses to psychoactive agents as in the following examples.
Drugs used to treat depression and drugs of abuse (eg, cocaine) that increase levels of
monoamines, including serotonin, norepinephrine or dopamine, can all potentially trigger
mania, implicating all these neurotransmitters in its etiology.
Evidence is mounting on the contribution of glutamate to both bipolar disorder and major
depression. A postmortem study of the frontal lobes from persons with both these disorders
revealed that the glutamate levels were increased.
[31]

Calcium channel blockers have been used to treat mania, which also may result from a
disruption of calcium regulation in neurons as suggested by experimental and genetic data.
The proposed disruption of calcium regulation may be caused by various 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.
Hormonal imbalances and disruptions of the hypothalamic-pituitary-adrenal axis involved in
homeostasis and the stress response may also contribute to the clinical picture of bipolar
disorder.
Neurophysiological factors
In addition to structural neuroimaging studies that look for volumetric changes in brain
regions regardless of brain activity, functional neuroimaging studies are performed to find
regions of the brain, or specific cortical networks, that are either hypoactive or hyperactive in
a particular illness. For example, a meta-analysis by Houenou et al found decreased
activation and diminution of gray matter in a cortical-cognitive brain network, which has
been associated with the regulation of emotions in patients with bipolar disorder.
[24]
An
increased activation in ventral limbic brain regions that mediate the experience of emotions
and generation of emotional responses was also discovered. This provides evidence for
functional and anatomical alterations in bipolar disorder in brain networks associated with the
experience and regulation of emotions.
Psychodynamic factors
Many practitioners see the dynamics of manic-depressive illness as being linked through a
single common pathway. They see the depression as the manifestation of losses (ie, the loss
of self-esteem and the sense of worthlessness). Therefore, the mania serves as a defense
against the feelings of depression. Melanie Klein was one of the major proponents of this
formulation. A study by Barnett et al found that personality disturbances in extraversion,
neuroticism, and openness are often noted in patients with bipolar disorder and may be
enduring characteristics.
[32]

Environmental factors
In some instances, the cycle may be directly linked to external stresses or the external
pressures may serve to exacerbate some underlying genetic or biochemical predisposition.
Pregnancy is a particular stress for women with a manic-depressive illness history and
increases the possibility of postpartum psychosis.
[33]

Because of the nature of their work, certain individuals have periods of high demands
followed by periods of few requirements. For example, a landscaper and gardener would be
busy in the spring, summer, and fall but relatively inactive during the winter, except for
plowing snow. Thus, he or she might appear manic for a good part of the year and then would
crash and hibernate for the cold months.
Epidemiology
United States statistics
The lifelong prevalence of bipolar disorder in the United States has been noted to range from
1% to 1.6%. Studies indicate differences in lifetime prevalence estimates for BPI, BPII, and
subthreshold bipolar disorders: 1.0% for BPI, 1.1% for BPII, and 2.4-4.7% for subthreshold
bipolar disorders.
[34]

International statistics
Lifelong prevalence rate is 0.3-1.5%. In cross-sectional, face-to-face household surveys of
more than 61,000 adults across 11 countries, Merikangas et al, using the World Mental
Health version of the World Health Organization Composite International Diagnostic
Interview, version 3.0, determined that the aggregate lifetime prevalences were 0.6% for
bipolar I disorder, 0.4% for bipolar II disorder, 1.4% for subthreshold bipolar disorder, and
2.4% for bipolar spectrum.
[35]
Yutzy and colleagues report an increase in the prevalence
bipolar affective disorders I and II in recent years. They noted the prevalence from mid 1970s
to 2000 ranged from 0.4% to 1.6%. By the late 1990s to the 2000s, it had the climbed from
approximately 5% to 7%.
[36]

Age-related differences in incidence
The age of onset of bipolar disorder varies greatly. For both BPI and BPII, the age range 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 range of
onset is 20-24 years.
Some patients diagnosed with recurrent major depression may indeed have bipolar disorder
and go on to develop their first manic episode when older than 50 years. They may have a
family history of bipolar disorder. However, for most patients, the onset of mania in people
older than 50 years should lead to an investigation for medical or neurologic disorders, such
as cerebrovascular disease.
Sex-related differences in incidence
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. The incidence of BPII is higher in
females than in males. , Most studies report a nearly equal male-to-female ratio in the
prevalence of bipolar disorder; however, most studies report an increased risk in women for
BPII/hypomania, rapid cycling, and mixed episodes.
[37]

Race-related differences in incidence
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 bipolar disorder.
Prognosis
Bipolar disorder has significant morbidity and mortality rates. In the United States during the
early part of the 1990s, the cost of lost productivity resulting from this bipolar disorder was
estimated at approximately $15.5 billion annually. Approximately 25-50% of individuals
with bipolar disorder attempt suicide, and 11% actually commit suicide.
Additionally, a study from the United Kingdom suggests that for patients with bipolar
disorder, mortality one year after hospital discharge was also higher than that of the general
population for natural causes, chiefly respiratory and circulatory disorders.
[38]

Furthermore, bipolar disorder has long been associated with premature death. In a national
cohort study of 6,587,036 Swedish adults, including 6618 with bipolar disorder, Crump and
colleagues found that women and men with bipolar disorder died 9 years and 8.5 years earlier
on average than the rest of the population, respectively.
[39]
They concluded that patients with
bipolar disorder died prematurely from multiple causes, including cardiovascular disease,
diabetes, chronic obstructive pulmonary disease, influenza or pneumonia, unintentional
injuries, and suicide.
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, 45% 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:
Poor job history
Alcohol abuse
Psychotic features
Depressive features between periods of mania and depression
Evidence of depression
Male sex
Factors suggesting a better prognosis include the following:
Length of manic phases (short in duration)
Late age of onset
Few thoughts of suicide
Few psychotic symptoms
Few medical problems
Patient Education
Treatment of patients with bipolar disorder involves initial and ongoing patient education. To
this end, a strong therapeutic alliance is essential.
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.
[40]

An explanation of the biology of the disease must be provided. This decreases feelings of
guilt and promotes medication compliance. Information should be provided on 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.
Education must also encompass the dangers of stressors. Helping the individual identify and
work with stressors provides a critical aspect of patient and family awareness. Efforts should
be made to educate the patient about relapses within the total context of the disorder.
Individual stories help patients and families. NIMH has a story of a person with manic-
depressive illness that can help the patient see the struggle and challenge from another
perspective.
[41]
Others have written about their family struggles and challenges.
[42]

Important resources for patients and families to gain information on dealing with manic-
depressive illness include the following:
National Institute of Mental Health (NIMH) - Public Information and
Communications Branch, 6001 Executive Blvd, Rm 8184, MSC 9663, Bethesda, MD
20892-9663; phone, 301-443-4513 (local) or 866-615-6464 (toll-free); fax, 301-443-
4279
Fax Back System, Mental Health FAX4U 301-443-5158; e-mail:
nimhinfo@nih.gov
Child & Adolescent Bipolar Foundation - 1000 Skokie Blvd, Suite 570, Wilmette, IL
60091; phone, 847-256-8525; e-mail, cabf@bpkids.org
Depression and Related Affective Disorders Association (DRADA) - 2330 West
Joppa Rd, Suite 100, Lutherville, MD 21093; phone, 410-583-2919; e-mail,
drada@jhmi.edu
National Alliance on Mental Illness (NAMI) - Colonial Place Three, 2107 Wilson
Blvd, Suite 300, Arlington, VA 22201-3042; phone, 703-524-7600 (local) or 800-
950-NAMI (6264) (toll-free); fax, 703-524-9094
Depression & Bipolar Support Alliance (DBSA) - 730 North Franklin St, Suite 501,
Chicago, IL 60610-7224; phone, 312-642-0049 (local) or 800-826-3632 (toll-free);
fax, 312-642-7243
International Foundation for Research and Education on Depression (iFred) - 2017-D
Renard Court, Annapolis, MD 21401; phone, 401-268-0044; fax, 443-782-0739; e-
mail, info@ifred.org
Mental Health America (MHA) - 2000 North Beauregard St, 6th Floor, Alexandria,
VA 22311; phone, 703-684-7722 (local) or 800-969-6642 (toll-free); TTY, 800-443-
5959; fax, 703-684-7722
Bipolar Disorder Support Groups

References
1. Lowes R. Lurasidone Approved for Bipolar Depression. Medscape Medical News.
Available at http://www.medscape.com/viewarticle/807204. Accessed July 30, 2013.
2. Susan Jeffrey. FDA Warns of Aseptic Meningitis Risk With Lamotrigine. FDA
Warns of Aseptic Meningitis Risk With Lamotrigine. Available at
http://www.medscape.com/viewarticle/726845. Accessed August 12, 2010.
3. Sarris J, Mischoulon D, Schweiter I. Omega-3 for Bipolar Disorder: Meta-Analyses of
Use in Mania and Bipolar Depression. J Clin Psychiatry. 2011;Online ahead of print..
4. Bowden C, Singh V. Long-term Management of Bipolar Disorder. Available at
http://www.medscape.com/viewprogram/2686. Accessed Dec 31, 2003.
5. Price AL, Marzani-Nissen GR. Bipolar disorders: a review. Am Fam Physician. Mar 1
2012;85(5):483-93. [Medline].
6. Ketter TA. Diagnostic features, prevalence, and impact of bipolar disorder. J Clin
Psychiatry. Jun 2010;71(6):e14. [Medline].
7. Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, et al. A genome-
wide association study implicates diacylglycerol kinase eta (DGKH) and several other
genes in the etiology of bipolar disorder. Mol Psychiatry. Feb 2008;13(2):197-207.
[Medline]. [Full Text].
8. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000
cases of seven common diseases and 3,000 shared controls. Nature. Jun 7
2007;447(7145):661-78. [Medline]. [Full Text].
9. Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K, et al. Whole-
genome association study of bipolar disorder. Mol Psychiatry. Jun 2008;13(6):558-69.
[Medline].
10. Ferreira MA, O'Donovan MC, et al. Collaborative genome-wide association analysis
supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. Sep
11. McQuillin A, Rizig M, Gurling HM. A microarray gene expression study of the
molecular pharmacology of lithium carbonate on mouse brain mRNA to understand
the neurobiology of mood stabilization and treatment of bipolar affective disorder.
Pharmacogenet Genomics. Aug 2007;17(8):605-17. [Medline].
12. Sklar P, Ripke S, Scott LJ, et al. Large-scale genome-wide association analysis of
bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet. Sep 18
2011;43(10):977-83. [Medline].
13. NIH News. Schizophrenia and Bipolar Disorder Share Genetic Roots. National
Institutes of Health. Available at http://www.nih.gov/news/health/jul2009/nimh-
01.htm. Accessed August 26, 2009.
14. Post RM, Speer AM, Hough CJ, Xing G. Neurobiology of bipolar illness:
implications for future study and therapeutics. Ann Clin Psychiatry. Jun
2003;15(2):85-94. [Medline].
15. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, et al. Mania-
like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A. Apr 10
16. Bearden CE, Freimer NB. Endophenotypes for psychiatric disorders: ready for
primetime?. Trends Genet. Jun 2006;22(6):306-13. [Medline].
17. American College of Neuropsychopharmacology. American College of
Neuropsychopharmacology 2010 Annual Meeting Abstracts. December 5-9, 2010;
Miami Beach, Florida.
18. Aston C, Jiang L, Sokolov BP. Transcriptional profiling reveals evidence for
signaling and oligodendroglial abnormalities in the temporal cortex from patients with
major depressive disorder. Mol Psychiatry. Mar 2005;10(3):309-22. [Medline].
19. Davis KL, Haroutunian V. Global expression-profiling studies and oligodendrocyte
dysfunction in schizophrenia and bipolar disorder. Lancet. Sep 6 2003;362(9386):758.
[Medline].
20. Prabakaran S, Swatton JE, Ryan MM, et al. Mitochondrial dysfunction in
schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol
Psychiatry. Jul 2004;9(7):684-97, 643. [Medline].
21. Tkachev D, Mimmack ML, Ryan MM, et al. Oligodendrocyte dysfunction in
schizophrenia and bipolar disorder. Lancet. Sep 6 2003;362(9386):798-805.
[Medline].
22. Adler CM, Holland SK, Schmithorst V, Wilke M, Weiss KL, Pan H, et al. Abnormal
frontal white matter tracts in bipolar disorder: a diffusion tensor imaging study.
Bipolar Disord. Jun 2004;6(3):197-203. [Medline].
23. Adler CM, Adams J, DelBello MP, et al. Evidence of white matter pathology in
bipolar disorder adolescents experiencing their first episode of mania: a diffusion
tensor imaging study. Am J Psychiatry. Feb 2006;163(2):322-4. [Medline].
24. Houenou J, Frommberger J, Carde S, et al. Neuroimaging-based markers of bipolar
disorder: Evidence from two meta-analyses. J Affect Disord. Aug 2011;132(3):344-
55. [Medline].
25. Chen G, Zeng WZ, Yuan PX, et al. The mood-stabilizing agents lithium and valproate
robustly increase the levels of the neuroprotective protein bcl-2 in the CNS. J
Neurochem. Feb 1999;72(2):879-82. [Medline].
26. Konradi C, Zimmerman EI, Yang CK, Lohmann KM, Gresch P, Pantazopoulos H, et
al. Hippocampal interneurons in bipolar disorder. Arch Gen Psychiatry. Apr
2011;68(4):340-50. [Medline].
27. Mathew SJ, Manji HK, Charney DS. Novel drugs and therapeutic targets for severe
mood disorders. Neuropsychopharmacology. Aug 2008;33(9):2300. [Medline].
28. The HUGE Project; Research Program on Genes, Environment, and Health. Multi-
Ethnic Genome Wide Association Study of Bipolar Disorder. Kaiser Permanente.
[Full Text].
29. Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. A twin study of genetic
relationships between psychotic symptoms. Am J Psychiatry. Apr 2002;159(4):539-
45. [Medline].
30. Berrettini WH. Are schizophrenic and bipolar disorders related? A review of family
and molecular studies. Biol Psychiatry. Sep 15 2000;48(6):531-8. [Medline].
31. Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients
with mood disorders. Biol Psychiatry. Dec 1 2007;62(11):1310-6. [Medline].
32. Barnett JH, Huang J, Perlis RH, et al. Personality and bipolar disorder: dissecting
state and trait associations between mood and personality. Psychol Med. Aug
2011;41(8):1593-604. [Medline].
33. Chaudron LH, Pies RW. The relationship between postpartum psychosis and bipolar
disorder: a review. J Clin Psychiatry. Nov 2003;64(11):1284-92. [Medline].
34. Calabrese JR. Overview of patient care issues and treatment in bipolar spectrum and
bipolar II disorder. J Clin Psychiatry. Jun 2008;69(6):e18. [Medline].
35. Merikangas KR, Jin R, He J-P, et al. Prevalence and correlates of bipolar spectrum
disorder in the World Mental Health Survey Initiative. Arch Gen Psychiatry.
2011;68(3):241-251.
36. Yutzy SH, Woofter CR, Abbott CC, Melhem IM, Parish BS. The increasing
frequency of mania and bipolar disorder: causes and potential negative impacts. J
Nerv Ment Dis. May 2012;200(5):380-7. [Medline].
37. Diflorio A, Jones I. Is sex important? Gender differences in bipolar disorder. Int Rev
Psychiatry. 2010;22(5):437-52. [Medline].
38. Hoang U, Stewart R, Goldacre MJ. Mortality after hospital discharge for people with
schizophrenia or bipolar disorder: retrospective study of linked English hospital
episode statistics, 1999-2006. BMJ. Sep 13 2011;343:d5422. [Medline].
39. Crump C, Sundquist K, Winkleby MA, Sundquist J. Comorbidities and Mortality in
Bipolar Disorder: A Swedish National Cohort Study. JAMA Psychiatry. Jul 17
2013;[Medline].
40. Dogan S, Sabanciogullari S. The effects of patient education in lithium therapy on
quality of life and compliance. Arch Psychiatr Nurs. Dec 2003;17(6):270-5.
[Medline].
41. National Institute of Mental Health. A story of bipolar disorder (manic-depressive
illness). [Full Text].
42. Webb M. The Years of Silence Are Past: My Father's Life With Bipolar Disorder. Am
J Psychiatry. Dec 1 2003;160(12):2257.
43. Journal of Affective Disorders. Misdiagnosing bipolar disorder - Do clinicians show
heuristic biases?. May 2011;130(3):405-12. [Medline].
44. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision, DSM-IV-TR. Washington, DC: 2000.
45. Frye MA. Diagnostic dilemmas and clinical correlates of mixed states in bipolar
disorder. J Clin Psychiatry. May 2008;69(5):e13. [Medline].
46. Angst J, Gamma A, Bowden CL, et al. Diagnostic criteria for bipolarity based on an
international sample of 5,635 patients with DSM-IV major depressive episodes. Eur
Arch Psychiatry Clin Neurosci. Feb 2012;262(1):3-11. [Medline].
47. Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Gamma A, et al. Prevalence and
characteristics of undiagnosed bipolar disorders in patients with a major depressive
episode: the BRIDGE study. Arch Gen Psychiatry. Aug 2011;68(8):791-8. [Medline].
48. Dubovsky S. The Real Risk for Suicide in Mental Disorders. Medscape News Today.
Available at
http://www.medscape.com/viewarticle/754885?sssdmh=dm1.779217&src=journalnl
%20accessed. Accessed April 26, 2012.
49. Bellivier F, Yon L, Luquiens A, et al. Suicidal attempts in bipolar disorder: results
from an observational study (EMBLEM). Bipolar Disord. Jun 2011;13(4):377-386.
[Medline].
50. Fagiolini A. Medical monitoring in patients with bipolar disorder: a review of data. J
Clin Psychiatry. Jun 2008;69(6):e16. [Medline].
51. Keck PE Jr. Evaluating Treatment Decisions in Bipolar Depression. Available at
http://www.medscape.com/viewprogram/2571. Accessed Dec 30, 2003.
52. Hong CJ, Huo SJ, Yen FC, Tung CL, Pan GM, Tsai SJ. Association study of a brain-
derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset
and suicidal behavior. Neuropsychobiology. 2003;48(4):186-9. [Medline].
53. Ilgen MA, Bohnert AS, Ignacio RV, McCarthy JF, Valenstein MM, Kim HM, et al.
Psychiatric diagnoses and risk of suicide in veterans. Arch Gen Psychiatry. Nov
2010;67(11):1152-8. [Medline].
54. Fazel S, Lichtenstein P, Grann M, Goodwin GM, Lngstrm N. Bipolar disorder and
violent crime: new evidence from population-based longitudinal studies and
systematic review. Arch Gen Psychiatry. Sep 2010;67(9):931-8. [Medline].
55. Saarni SI, Vierti S, Perl J, Koskinen S, Lnnqvist J, Suvisaari J. Quality of life of
people with schizophrenia, bipolar disorder and other psychotic disorders. Br J
Psychiatry. Nov 2010;197:386-94. [Medline].
56. Fiedorowicz JG, Endicott J, Leon AC, Solomon DA, Keller MB, Coryell WH.
Subthreshold hypomanic symptoms in progression from unipolar major depression to
bipolar disorder. Am J Psychiatry. Jan 2011;168(1):40-8. [Medline]. [Full Text].
57. Leibenluft E. Severe mood dysregulation, irritability, and the diagnostic boundaries of
bipolar disorder in youths. Am J Psychiatry. Feb 2011;168(2):129-42. [Medline].
58. Tohen M, Zarate CA Jr, Hennen J, Khalsa HM, Strakowski SM, Gebre-Medhin P, et
al. The McLean-Harvard First-Episode Mania Study: prediction of recovery and first
recurrence. Am J Psychiatry. Dec 2003;160(12):2099-107. [Medline].
59. Goldstein TR, Ha W, Axelson DA, et al. Predictors of Prospectively Examined
Suicide Attempts Among Youth With Bipolar Disorder. Arch Gen Psychiatry. Jul 2
2012;1-10. [Medline].
60. Schottle D, Huber CG, Bock T, Meyer TD. Psychotherapy for bipolar disorder: a
review of the most recent studies. Curr Opin Psychiatry. Nov 2011;24(6):549-55.
[Medline].
61. McIntyre RS, Soczynska JK, Beyer JL, Woldeyohannes HO, Law CW, Miranda A, et
al. Medical comorbidity in bipolar disorder: re-prioritizing unmet needs. Curr Opin
Psychiatry. Jul 2007;20(4):406-16. [Medline].
62. Bradford DW, Kim MM, Braxton LE, Marx CE, Butterfield M, Elbogen EB. Access
to medical care among persons with psychotic and major affective disorders.
Psychiatr Serv. Aug 2008;59(8):847-52. [Medline].
63. Bartels SJ, Pratt SI, Aschbrenner KA, et al. Clinically Significant Improved Fitness
and Weight Loss Among Overweight Persons With Serious Mental Illness. Psychiatr
Serv. May 15 2013;[Medline].
64. Woltmann E, Grogan-Kaylor A, Perron B, Georges H, Kilbourne AM, Bauer MS.
Comparative effectiveness of collaborative chronic care models for mental health
conditions across primary, specialty, and behavioral health care settings: systematic
review and meta-analysis. Am J Psychiatry. Aug 1 2012;169(8):790-804. [Medline].
65. Bauer M, Ritter P, Grunze H, Pfennig A. Treatment options for acute depression in
bipolar disorder. Bipolar Disord. May 2012;14 Suppl 2:37-50. [Medline].
66. Lowry F. New Recs for Antidepressant Use in Bipolar Patients Released. Medscape
Medical News. Available at http://www.medscape.com/viewarticle/806788. Accessed
July 2, 2013.
67. Post RM, Leverich GS, Altshuler LL, et al. Relationship of prior antidepressant
exposure to long-term prospective outcome in bipolar I disorder outpatients. J Clin
Psychiatry. Mar 20 2012;[Medline].
68. Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, et al.
Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter,
randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord.
Feb 2012;14(1):31-40. [Medline].
69. Lesem MD, Tran-Johnson TK, Riesenberg RA, Feifel D, Allen MH, Fishman R, et al.
Rapid acute treatment of agitation in individuals with schizophrenia: multicentre,
randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. Jan
70. Bauer M, Alda M, Priller J, Young LT. Implications of the neuroprotective effects of
lithium for the treatment of bipolar and neurodegenerative disorders.
Pharmacopsychiatry. Nov 2003;36 Suppl 3:S250-4. [Medline].
71. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium
toxicity profile: a systematic review and meta-analysis. Lancet. Feb 25
2012;379(9817):721-8. [Medline].
72. Hajek T, Kopecek M, Hschl C, Alda M. Smaller hippocampal volumes in patients
with bipolar disorder are masked by exposure to lithium: a meta-analysis. J
Psychiatry Neurosci. Apr 16 2012;37(3):110143. [Medline].
73. Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard
South Shore Program: an update on bipolar depression. Harv Rev Psychiatry.
2010;18(1):36-55. [Medline].
74. Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S, et al.
A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-
resistant bipolar depression. Arch Gen Psychiatry. Aug 2010;67(8):793-802.
[Medline]. [Full Text].
75. Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar
depression: a systematic review and meta-analysis. J Clin Psychiatry. Feb
2011;72(2):156-67. [Medline].
76. Kessing LV, Hellmund G, Geddes JR, Goodwin GM, Andersen PK. Valproate v.
lithium in the treatment of bipolar disorder in clinical practice: observational
nationwide register-based cohort study. Br J Psychiatry. Jul 2011;199:57-63.
[Medline].
77. Geddes JR, Goodwin GM, Rendell J, et al. Lithium plus valproate combination
therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE):
a randomised open-label trial. Lancet. Jan 30 2010;375(9712):385-95. [Medline].
78. Pappadopulos E, Newcomer JW, Kolluri S. Changes in weight, plasma lipids, and
glucose in adults treated with ziprasidone: a comprehensive analysis of pfizer-initiated
clinical trials. J Clin Psychiatry. Jun 2012;73(6):e742-8. [Medline].
79. Findling RL, Correll CU, Nyilas M, Forbes RA, McQuade RD, Jin N, et al.
Aripiprazole for the treatment of pediatric bipolar I disorder: a 30-week, randomized,
placebo-controlled study. Bipolar Disord. Mar 2013;15(2):138-149. [Medline].
80. Smith LA, Cornelius V, Warnock A, Bell A, Young AH. Effectiveness of mood
stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a
systematic review of randomized controlled trials. Bipolar Disord. Jun 2007;9(4):394-
412. [Medline].
81. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of
antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. Aug 16
2011;[Medline].
82. Swartz HA, Thase ME. Pharmacotherapy for the treatment of acute bipolar II
depression: current evidence. J Clin Psychiatry. Mar 2011;72(3):356-66. [Medline].
83. [Guideline] Hirschfeld RMA (Chair); Work Group on Bipolar Disorder. Practice
Guideline for the Treatment of Patients With Bipolar Disorder, Second Edition.
Review and Synthesis of Available Evidence. Somatic Treatments of Acute Manic
and Mixed Episodes. American Psychiatric Association. [Full Text].
84. Hamrin V, Iennaco JD. Psychopharmacology of pediatric bipolar disorder. Expert Rev
Neurother. Jul 2010;10(7):1053-88. [Medline].
85. Gutman DA, Nemeroff C. Atypical Antipsychotics in Bipolar Disorder. Medscape.
Available at http://www.medscape.com/viewarticle/554128. Accessed June 27, 2007.
86. Brooks JO 3rd, Goldberg JF, Ketter TA, Miklowitz DJ, Calabrese JR, Bowden CL, et
al. Safety and tolerability associated with second-generation antipsychotic
polytherapy in bipolar disorder: findings from the Systematic Treatment Enhancement
Program for Bipolar Disorder. J Clin Psychiatry. Feb 2011;72(2):240-7. [Medline].
87. Keller DM. Biomarker Effectively Stages Bipolar Disorder. Available at
http://www.medscape.com/viewarticle/782184. Accessed April 16, 2013.

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