Bipolar 1 disorder is known as being the sixth leading cause of disability in the world, and it

is a condition which is characterized by recurrent episodes of mania and depression. As well,

many bipolar 1 disorder episodes are characterized by elated mood, over-talkative or
heightened talking speed, hyperactivity and agitation.

Introduction

Background
Bipolar disorder, or manic-depressive illness (MDI), is one of the most common, severe, and persistent
mental illnesses. Bipolar disorder is characterized by periods of deep, prolonged, and
profound depression that alternate with periods of an 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. Bipolar disorder is a serious lifelong struggle and
challenge.1

Bipolar disorder, or manic-depressive illness, has been recognized since at least the time of Hippocrates,
who described such patients as "amic" and "melancholic." In 1899, Emil Kraepelin defined manic-
depressive illness and noted that persons with manic-depressive illness lacked deterioration and
dementia, which he associated with schizophrenia.

Bipolar disorder 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. Bipolar I disorder is also
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,
bipolar II disorder 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 function.

For related information, see Medscape's Bipolar Disorder Resource Center.

Pathophysiology
The etiology and pathophysiology of bipolar disorder have not been determined, and no objective
biological markers 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.

Bipolar disorder is a complex genetic disorder however, meaning that it is likely caused by multiple
different common disease alleles, each contributing relatively low risk for the disorder on their own. It can
be difficult to find such disease genes without very large sample sizes, on the order of thousands of
subjects.

Fortunately, four genome-wide association studies of large samples of subjects with bipolar disorder have
now been published2,3,4,5 and a collaborative analysis of the latter 3 studies give combined support for two
particular genes, ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium
channel) in a sample of 4,387 case and 6,209 controls. 5 ANK3 is an adaptor protein found at axon initial
segments that regulates the assembly of voltage-gated sodium channels and both ANK3 and subunits of
the calcium channel are down-regulated in mouse brain in response to lithium, indicating a possible
therapeutic mechanism of action of one of the most effective treatments for bipolar disorder. 6 

The first genome-wide association study of bipolar disorder used a much smaller sample size 2 , an initial
sample of 461 patients with bipolar disorder from the NIMH consortium and a follow-up sample of 563
patients collected in Germany, however it 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 (GSK3β). Lithium-mediated inhibition of GSK3β is
thought to result in down-regulation of molecules involved in cell death and upregulation of
neuroprotective factors (see below). Additionally, GSK3β is a central regulator of the circadian clock and
lithium-mediated modulation of circadian periodicity is thought to be a critical component of its 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
manic-like behavior in mice.7

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 biological 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 specifically in the ventral tegmental area of the mouse brain. This area is rich in D2
receptors. Joseph Coyle hypothesizes in his commentary in the paper on 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.

Findings from gene expression studies of postmortem brain tissue from persons with bipolar disorder
versus controls have yielded exciting new insights into the pathophysiology of the disorder. In particular,
levels of expression of oligodendrocyte-myelin-related genes appear to be decreased in brain tissue from
persons with bipolar disorder.8,9,10

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.

Interestingly, gene expression and neuroimaging studies of persons with schizophrenia and major
depression also demonstrate similar findings, indicating that mood disorders and schizophrenia, may
share some biological underpinnings, possibly related to psychosis. 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.
The national institutes of health report on recent genome-wide association studies demonstrated that
bipolar disorder and schizophrenia could indeed share common susceptibility genes on chromosome 6.
These genes are located in a section of the chromosome containing genes involved in immunity and
controlling how and when genes turn on and off. This connection can help explain the link between
environmental stress and schizophrenia and possibly bipolar disorder. 11 

Another approach to delineating the pathophysiology of bipolar disorder involves studying changes in
gene expression induced in rodent brains after administration of pharmacologic agents used to treat
bipolar disorder. For example, investigators have demonstrated that 2 chemically unrelated drugs (lithium
and valproate) used to treat bipolar disorder 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 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.

For a review of novel drugs and therapeutic targets for severe mood disorders that focus on increasing
neuroplasticity and cellular resiliency please see Mathew et al, 2008. 12
Post and associates proposed a mechanism involving electrophysiologic 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 neurologic insults, perhaps caused by drugs of abuse, excessive glucocorticoid
stimulation resulting from acute or chronic stress, or other factors, which eventually result in
mania.13 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 supports clinical observations that the more episodes a person experiences, the
more he or she will have in the future, underscoring the need for long-term treatment.

Frequency
United States

The lifelong prevalence of bipolar disorder in the United States has been noted to range from 1-1.6%.
Studies indicate differences in lifetime prevalence estimates for bipolar I, bipolar II, and subthreshold
bipolar disorders: 1.0% for bipolar I disorder, 1.1% for bipolar II disorder, and 2.4-4.7% for subthreshold
bipolar disorders.8

International

Lifelong prevalence rate is 0.3-1.5%.

Mortality/Morbidity
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.
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 bipolar disorder.

Sex
Bipolar I disorder 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 bipolar II disorder is higher in
females than in males.

Age
The age of onset of bipolar disorder varies greatly. The age range for both bipolar I and bipolar II 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.

Clinical

History
The diagnosis of bipolar I 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 theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition,
Text Revision (DSM-IV-TR).9

Manic episodes are characterized by at least 1 week of profound mood disturbance, characterized by
elation, irritability, or expansiveness. Three or more of the following symptoms must also be 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 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. Three or more of the following symptoms are also 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 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 symptomology is quite common in patients presenting with bipolar symptomology.
This often causes a diagnostic dilemma.10

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

Appearance

Depressed episode: 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.

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.

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
are often too bright, colorful, or garish. They stand out in a crowd because their dress frequently attracts
attention.

Affect/mood

Depressed episode: Sadness dominates the affect of individuals experiencing a depressed episode. They
feel sad, depressed, lost, vacant, and isolated. The "2 Hs" often accompany their mood, hopeless and
helpless. When in the presence of such patients, one comes away feeling sad and down.

Hypomanic episode: Their mood is up, expansive, and often irritable.

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.

Mixed episode: The patient exhibits both depression and mania within a brief period (1 wk or less).

Thought content

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 are likely to focus on death and morbid persons. Many think about suicide.

Hypomanic episode: Patients in this state are optimistic, forward thinking, and have a positive attitude.

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 person to another.

Mixed episode: Patients in this state can oscillate dramatically between depression and euphoria, and
they often demonstrate marked irritability.

Perceptions

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
mood. In contrast, some patients experience delusions that are inconsistent with the depression, such as
paranoia or persecutory delusions.

Hypomanic episode: Patients in this state do not experience perceptual disturbances.

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.

Mixed episode: Patients might exhibit delusions and hallucinations consistent with either depression or
mania or congruent to both.

Suicide/self-destruction

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 while the subjective feeling of depression and accompanying suicidal
thoughts may persist.

Hypomanic episode: Incidence of suicide is low.

Manic episode: Incidence of suicide is low.

Mixed episode: The depressed phases put the patient at risk for suicide.

Homicide/violence/aggression

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.

Hypomanic episode: Patients who are hypomanic frequently show evidence of irritability and
aggressiveness. They can be pushy and impatient with others.

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.

Mixed episode: Persons in a mixed episode may exhibit aggression, especially in the manic phases.

Judgment/insight

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 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.

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.

Manic episode: The hallmark of this phase is seriously impaired judgment. They make terrible decisions in
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.

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.

Although the Mental Status has been used here to highlight key aspects of the examination, the clinician
must pay particular attention to the patient's physical health. As Fagiolini points out, patients with bipolar
disorder have a high incidence of endocrine disorders, cardiovascular disorders, and obesity. These
factors must be considerations when prescribing any medications. 13,14

Causes
Bipolar disorder has a number of contributing factors, including genetic, biochemical, psychodynamic, and
environmental elements.

Genetics

Bipolar disorder, especially bipolar I, has a major genetic component. 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.

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 bipolar I 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
Medscape's CME Activity New Findings in Childhood Bipolar Disorder.

Numerous genetic studies of BPI suggest that multiple different genetic loci, each of small effect,
contribute to the affected phenotype. Four genome-wide association studies of bipolar disorder have now
been published and a collaborative analysis of the 3 largest studies implicate 2 genes coding for proteins
that either regulate or are subunits of ion channels ANK3 and CACNA1C.2,3,4,5 These findings suggest that
bipolar disorder might be, in part, an ion channelopathy, similar to epilepsy. Another interesting candidate
gene for mania is the CLOCK gene involved in circadian periodicity.7 A mouse CLOCK mutant was
recently shown to exhibit features of mania.

An interesting 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 the same as the other 2
syndromes.15 This finding suggests an independent genetic liability for psychosis shared by both mood
and schizophrenia spectrum disorders as Berrettini16 previously speculated.

A study by Tsuang et al further indicates the genetic contribution to manic-depressive illness with
psychotic features. Their findings show the link between schizophrenia and bipolar disorder. 17

As discussed above, 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 causes

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.

Evidence is mounting of the contribution of glutamate to both bipolar and major depressions. A
postmortem study of the frontal lobes with both these disorders revealed that the glutamate levels were
increased.18 

The blood pressure drug reserpine, which depletes catecholamines from nerve terminals, 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 depression.

Drugs like cocaine, which also act on this neurotransmitter system, exacerbate mania.

Other agents that exacerbate mania include L-dopa, which implicates dopamine and serotonin-reuptake
inhibitors, which, in turn, implicate serotonin.

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 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.

Tricyclic antidepressants can trigger mania.19

Psychodynamic

Many practitioners see the dynamics of manic-depressive illness as being linked through one common
pathway.

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

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.20

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 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.