Bipolar Disorder

Updated: Feb 11, 2022
  • Author: Stephen Soreff, MD; Chief Editor: Glen L Xiong, MD  more...
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Practice Essentials

Bipolar disorder, which in the ICD-10 is classified as bipolar disorder, or manic-depressive illness (MDI), is a common, severe, and persistent mental illness. This condition is a serious lifelong struggle and challenge. [1]

Signs and symptoms

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.

Manic episodes are feature 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 [2] :

  • 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 consecutive days’ duration. The diagnosis of hypomania requires at least three of the symptoms above. The difference being that in hypomania these symptoms are not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization and are not associated with psychosis.

Major depressive episodes are characterized as, for the same 2 weeks, the person experiences 5 or more of the following symptoms, with at least 1 of the symptoms being either a depressed mood or characterized by a loss of pleasure or interest: [2]

  • 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

  • Feelings of worthlessness or excessive guilt

  • Decreased concentration ability or marked indecisiveness

  • Preoccupation with death or suicide; patient has a plan or has attempted suicide

See Clinical Presentation for more detail.


Examination of patients with suspected bipolar disorder includes evaluation using the Mental Status Examination as well as assessment of the following:

  • Appearance

  • Affect/mood

  • Thought content

  • Perception

  • Suicide/self-destruction

  • Homicide/violence/aggression

  • Judgment/insight

  • Cognition

  • Physical health


Although bipolar disorder is diagnosed based on the patient’s history and clinical course, laboratory studies may be necessary to rule out other potential causes of the patient’s signs and symptoms as well as to have baseline results before administering certain medications.

Laboratory tests that may be helpful include the following:

  • CBC count

  • ESR levels

  • Fasting glucose levels

  • Electrolyte levels

  • Protein levels

  • Thyroid hormone levels

  • Creatinine and blood urea nitrogen levels

  • Liver and lipid panel

  • Substance and alcohol screening

Depending on the patient’s presentation, other laboratory tests may be indicated, which may include the following:

  • Urinary copper levels

  • Antinuclear antibody testing

  • HIV testing

  • VDRL testing

Electrocardiography is important in elderly patients and before antidepressant therapy. Electroencephalography and/or MRI may be appropriate for selected patients.

See Workup for more detail.


The treatment of bipolar disorder is directly related to the phase of the episode (ie, depression or mania) and the severity of that phase, and it may involve a combination of psychotherapy and medication. Always evaluate patients with mania, hypomania, or mixed episode, and those with bipolar depression, for suicidality, homicidality, acute or chronic psychosis, or other unstable or dangerous conditions. [3]


Medications used to manage patients with bipolar disorder include the following:

  • Benzodiazepines - for acute agitation (eg, lorazepam, clonazepam)

  • Antimanic agents (eg, lithium)

  • Anticonvulsants (eg, carbamazepine, valproate sodium, valproic acid, divalproex sodium, lamotrigine)

  • First-generation antipsychotics (eg, inhaled loxapine, haloperidol)

  • Second-generation antipsychotics (eg, asenapine, ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, olanzapine and fluoxetine, cariprazine, clozapine, paliperidone, lurasidone)

  • Serotonin-dopamine activity modulators (SDAM) (eg, lumateperone, olanzapine/samidorphan) 

  • Phenothiazine antipsychotics (eg, chlorpromazine)

  • Dopamine agonists (eg, pramipexole)


Psychotherapy may help to decrease relapse rates, improve quality of life, and/or increase functioning, or more favorable symptom improvement. [4]

Electroconvulsive therapy may be useful in selected patients with bipolar disorder.

See Treatment and Medication for more detail.

What is bipolar disorder? Bipolar disorder, sometimes known as manic depression, is a type of mental disorder where people experience periods of extreme lows, known as depression, as well as periods of extreme highs, or manic episodes. Courtesy of (


Bipolar disorder, bipolar disorder, or manic-depressive illness (MDI), is a common, severe, and persistent mental illness. This condition is a serious lifelong struggle and challenge. [1] Other mental disorders and general medical conditions are more prevalent in patients with bipolar disorders than in patients in the general population. [5] Among the general comorbid 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. This pattern of alternating severe depression and periods of mania is characteristic of bipolar disorder type I (BPI), although in rarer cases, persons may only experience episodes of mania. In practice, symptoms of mania and depression can also occur together in what is termed a mixed state as the illness evolves. By contrast, bipolar disorder type II (BPII) is diagnosed when episodes of severe depression are punctuated with periods of hypomania, a less severe form of mania that does not include psychosis or lead to gross impairment in functioning. A diagnosis of cyclothymic disorder is given to individuals with periods of both hypomanic and depressive symptoms without meeting the full criteria for mania, hypomania or major depression.

The symptoms of mania include decreased sleep time accompanied by 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, many patients, if adequately medicated, 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 of 1.8%–4% for BPI and BPII disorder combined 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]

In the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, (DSM-5), bipolar disorder constitutes a spectrum of mood disorders that includes BPI, BPII, cyclothymia and are thought to be a “bridge” between schizophrenia spectrum disorders and depressive disorders in terms of the symptomology, family history and genetics. [2]



The pathophysiology of bipolar disorder, or manic-depressive illness (MDI), has not been determined, and no objective biologic markers correspond definitively with the disease state. However, twin, family, and adoption studies all indicate that bipolar disorder has a significant 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, and the heritability of bipolar I disorder (BPI) has recently been estimated at 0.73. [7]


The genetic component of bipolar disorder appears to be complex: The condition is likely to be caused by multiple different common disease alleles, 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.

When the genetics of bipolar disorder were first being studied, less precise tools were available, but they still yielded interesting information. Many loci are now known to be associated with the development of bipolar disorder. These loci are grouped as major affective disorder (MAFD) loci and numbered in the order of their discovery.

MAFD loci

MAFD1 is located at 18p and was originally described in a group of 22 patients with bipolar disorder. [8] MAFD2 is located at Xq28 and, as such, is associated with an X-linked inheritance pattern. The notion of an X-linked form of bipolar disorder is not a new one, and at least one paper from the pregenetic era discusses this very possibility. [9] MAFD3 is located at 21q22.13, and the association appears to be with the TRPM2 gene. [10, 11] MAFD4 is located at 16p12 and has been associated with susceptibility to bipolar disease in a cohort of 41 Finnish families. [12]

MAFD5 is located at 2q22-q24, and MAFD6 is located at 6q23-24. Interestingly, evidence suggests a strong interaction between genes located in these 2 regions. It has been concluded that the candidate gene in the MAFD5 locus shows epistatic interaction with the MAFD6 risk locus. [13] MAFD7 is located at 22q12.1 and was detected using microsatellite markers in a North American population; a large region on 22q12 was associated with bipolar disorder in this study. [14] Further study in this region showed a polymorphism in the promoter region of the XBP1 gene, which also showed susceptibility to bipolar disorder in a Japanese cohort. [15] XBP1 appears to be involved mainly in immune system function; thus,its influence on the susceptibility of bipolar disorder is not understood.

MAFD8 is located at 10q21, and its discovery is the result of a large analysis of over 1.8 million variants in 4387 cases of bipolar disorder. [16] The association in this study appears to be with the ANK3 gene, which is a gene of marked interest and is therefore discussed at length below. [16] MAFD9 is located at 12p13.3, and its discovery is the result of the same large analysis as MAFD8. The association in this study appears to be with the CACNA1C gene. [16] Like ANK3, it remains a gene of interest [17] and is also mentioned below.

Genome-wide association studies

The first series of genome-wide association studies (GWASs) for bipolar disorder were published in 2007 and 2008, [18, 19, 20, 16] 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 4387 cases and 6209 controls. [16] 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 downregulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action of one of the most effective treatments for bipolar disorder. [21]

Further evidence for association of bipolar disorder to CACNA1C was reported in 2011 in an ever-growing sample (numbering 11,974 bipolar disorder cases and 51,792 controls at the time of the report), providing overwhelming support for this gene as a bipolar susceptibility locus. [17]

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 GWASs also underscored that bipolar disorder and schizophrenia could indeed share common susceptibility genes on chromosome 6. [22]

In 2013, the Cross-Disorder Group of the Psychiatric Genomics Consortium published results of their large GWAS study of psychiatric disorders, reporting that specific single-nucleotide polymorphisms (SNPs) are associated with range of childhood- or adult-onset psychiatric disorders. [23] The study comprised a combined sample of 33,332 persons with schizophrenia, bipolar disorder, major depression, attention deficit disorder and autism spectrum disorders and 27,888 controls of European ancestry. [23]

Specific expression of common genetic variants at different times during development, or in different regions of the brain, and in concert with other genetic variants could help to explain differences in disease phenotypes. Genetic markers in 4 regions were associated with all 5 disorders, including variants in the CACNA1C gene, another gene for an L-type voltage-gated calcium channel subunit, CACNB2, and markers on chromosomes 3p21 and 10q24. [23] Although specific variants from CACNA1C showed the strongest association when only samples from individuals with bipolar disorder, major depression and schizophrenia were evaluated, the majority of regions seemed to be associated with all 5 disorders, suggesting that common risk alleles contribute to each phenotype, an effect described as pleiotropy. As noted by the authors, although CACNB2 was not identified in previous GWASs of a combined bipolar and schizophrenia sample, it was one of the main signals detected in an independentGWASs of Han Chinese individuals with bipolar disorder. [23]

Although the first GWAS of bipolar disorder used a much smaller sample size than subsequent attempts, 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, it still yielded interesting observations that will need to be followed up in the larger samples mentioned earlier. [18] For example, 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 downregulation of molecules involved in cell death and upregulation of neuroprotective factors.

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 lithium’s 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 maniclike behavior in mice, [24] including 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 specifically in the ventral tegmental area of the mouse brain. [25] This area is rich in D2 receptors. Joseph Coyle hypothesized 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. [26]

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. [27] Such promising measures for bipolar disorder include structural brain phenotypes, sleep and activity measures, neurocognitive measures, and gene expression studies. [28] This collaborative research effort under the aegis of the National Institute of Mental Health (NIMH) has been termed the Bipolar Phenome Project. [29]

Newer GWASs continue to find additional genes of interest which appear to be associated with an increased risk of bipolar disorder. One study showed an association between bipolar disorder and the NCAN gene. [30] This gene is expressed in the brain and is involved in the migration of cells within the brain. In a mouse model, it was observed that the NCAN product is most prevalent in the hippocampus. There was no phenotypic defect in NCAN -deficient mice, but subtle effects could not be excluded. [30]

Although most of the present research does not stratify by sex, a recent study looked at association between estrogen receptor binding site variation with bipolar disorder in females. In particular, the association is with the transglutaminase 2 (TGM2) gene, which is known to be under estrogenic control. [31] This is further evidence of the heterogeneity of bipolar disorder and also presents evidence to explain the differences in the epidemiology of bipolar disorder between women and men.

Of additional interest, a number of studies suggest that certain large copy number variants (greater than 100 kb) (includes both deletions and duplications) are associated with psychiatric disease, with bipolar disease and schizophrenia being the most commonly associated. [32] The implication is that possession of one of these copy number variants may modify the phenotype to those who are at risk of psychiatric disease. [32]

When investigators looked at microarray results for 1001 patients with bipolar disorder and 1033 controls to quantify the risk of deletions throughout the genome for patients with bipolar disorder, they found that 16.2% of patients with bipolar disorder had deletions, whereas 12.3% of controls had deletions. In addition, patients who had bipolar disorder and deletions more frequently had onset of mania before age 18 years. [4]

Gene expression studies

Gene expression studies are one way of measuring the relative activity or inactivity of genes, and they have already been proven useful for illuminating the pathophysiology of psychiatric disorders, including bipolar disorder. For example, 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-myelin–related genes appear to be decreased in brain tissue from persons with bipolar disorder. [33, 34, 35, 36] 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. [37, 38] 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. [37, 38] Of note, many widely used psychotropic treatments including those for bipolar disorder share signaling pathways that affect myelination, its plasticity, andrepair;such pathways may promote myelination of neurons. [39]

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 biologic 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.

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 upregulate the expression of the cytoprotective protein Bcl-2 in the frontal cortex and the hippocampus of rat brains. [40] These types of studies are also performed on human tissue by exposing cultured monocytes from peripheral blood to lithium and other factors.

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. [41] 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. [42]

Post et al had previously proposed a mechanism involving electrophysiologic kindling and behavioral sensitization processes, which resonates with the neuronal injury hypothesis. [24] They asserted that a person who is susceptible to bipolar disorder experiences an increasing number of minor neurologic insults—such as those induced by drugs of abuse, stress-related excessive glucocorticoid stimulation, oxidative or immune-mediated damage—that eventually resulting in mania that further compromises the injured neurons. [24] Sufficient brain damage might persist to cause mania to recur even with no or minor environmental or behavioral stressors.

Post et al’s 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.

For more information, see the Medscape Reference topic Genetics of Bipolar Disorder.



A number of factors contribute to bipolar disorder, or manic-depressive illness (MDI), including genetic, biochemical, psychodynamic, and environmental factors.

Genetic factors

Bipolar disorder, especially bipolar type I (BPI) disorder, has a major genetic component, with the involvement of the ANK3,CACNA1C, and CLOCK genes. [18, 19, 20, 16, 17, 25, 43] 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. One logitudinal study found that subthreshold manic or hypomanic episodes were a diagnostic risk factor for the development of subsequent manic, mixed, or hypomanic episodes in the offspring of parents with bipolar disorder. High-risk offspring, compared with offspring of parents without bipolar disorder, also had higher rates of ADHD, disruptive behavior disorders, anxiety disorders, and substance use disorders. [44]

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 disorder, even if they are reared in a home with adopted parents who are not affected. Frey and colleagues’ work supports the genetic contributions in bipolar disorder. [45, 46]

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. [47] This finding suggests an independent genetic liability for psychosis shared by both mood and schizophrenia spectrum disorders, as Berrettini [48] previously speculated and that has been confirmed in the recent large-scale GWAS studies mentioned above. [17]

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.

Duffy et al. described the emergent course of bipolar disorder in offspring of affected parents. They assessed 279 high-risk children and 87 control subjects and found the cumulative incidence of bipolar disorder was 24.5%, and the median age at onset was 20.7 years. The clinical course of the affected parent was associated with that of the affected child. In addition, childhood sleep and anxiety disorders significantly predicted 1.6-fold and 1.8-fold increases in risk of mood disorder, respectively. Depressive and manic symptoms predicted 2.7-fold and 2.3-fold increases in risk, respectively. [49]

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.

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

One study found that as many as a third of all patients with substance use-induced psychosis may go on to develop schizophrenia or bipolar disorder within five years. Researchers studied 6,788 patients who received a diagnosis of substance-induced psychosis over a 20-year period and who did not have any previous record of treatment for schizophrenia spectrum disorders or bipolar disorder. Overall, 32.2% of all patients with substance use-induced psychosis converted to either schizophrenia or bipolar disorder. Cannabis-induced psychosis carried the highest risk of conversion for patients at a rate of 47.4%. [50]

Evidence is mounting of the contribution of glutamate to both bipolar disorder and major depression. A postmortem study of the frontal lobes of individuals with these disorders revealed that the glutamate levels were increased. [51]

Calcium channel blockers have been used to treat mania, which may also result from a disruption of intracellular 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 upregulates 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.

Neurophysiologic 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. [52] 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 anatomic alterations in bipolar disorder in brain networks associated with the experience and regulation of emotions. [52]

White matter hyperintensities(WMH) are more common in individuals with bipolar disorder than in those without, and one study found that WMH burden appears to be associated with familiality and type of BP. The study used MRIs to measure total volume of all WMH in 45 individuals with bipolar disorder (bipolar I disorder (BP-I) with psychotic features, BP-I without psychotic features, or bipolar II disorder (BP-II)) and 7 of their unaffected relatives compared to 32 healthy subjects. Results show that BP-I patients had a significantly higher mean total volume of WMH (p < 0.05) than that of healthy subjects. In addition, researchers observed a positive linear trend by familiality and type of affectedness when comparing mean total WMH volume of all participants. [53] These findings suggest a possible structural marker for bipolar disorder.

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. [54]

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. For example, pregnancy is a particular stress for women with a manic-depressive illness history and increases the possibility of postpartum psychosis. [55]

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 who was busy in the spring, summer, and fall became relatively inactive during the winter, except for plowing snow. Consequently, he appeared manic for a good part of the year, and then he would crash and hibernate during the cold months.

There have been a number of studies linking bipolar disorder and increased amount of sunlight during the day (aka, springtime). In one study, researchers collected data from 5536 patients at 50 sites in 32 countries on six continents; onset of bipolar disorder occurred at 456 locations in 57 countries. Results show a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. The study suggests that a large increase in springtime solar insolation may impact the onset of bipolar disorder, particularly in those patients with a family history of mood disorders. [56]

Futhermore, another study assessed psychiatric admission of 730 patients and found the admission rate for patients with bipolar disorder was significantly higher during May, June, and July; months with maximum sunlight exposure. These findings suggest photoperiod is a key element in bipolar disorder. [57]

Pharmacological factors

There is the risk that antidepressant treatment may propel the patient into a manic episode. Researchers investigated the association between antidepressant therapy and the later onset of mania/bipolar disorder. They analyzed the electronic records of 21,012 adults presenting to South London and Maudsley National Health Service (NHS) Trust (SLaM), a large provider of inpatient and community mental healthcare in the United Kingdom, between April 1, 2006 and March 31, 2013 with unipolar depression. The overall incidence rate of mania/bipolar disorder was 10.9 per 1000 person-years. The peak incidence of mania/bipolar disorder was seen in patients aged between 26 and 35 years (12.3 per 1000 person-years). Prior antidepressant treatment was associated with an increased incidence of mania/bipolar disorder ranging from 13.1 to 19.1 per 1000 person-years. Results suggest that in people with unipolar depression, antidepressant treatment is associated with an increased risk of subsequent mania/bipolar disorder. These findings highlight the importance of considering risk factors for mania when treating people with depression. [58]



United States statistics

The lifelong prevalence of bipolar disorder, or manic-depressive illness (MDI), including subsyndromal forms in the United States has been noted to range from 0.9% to 2.1%. [59] Studies also indicate differences in lifetime prevalence estimates for bipolar disorder type I (BPI) (1.0%), bipolar disorder type II (BPII) (1.1%), and subthreshold bipolar disorders (2.4–4.7%). [60]

International statistics

Globally, the lifelong prevalence rate of bipolar disorder 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 BPI, 0.4% for BPII, 1.4% for subthreshold bipolar disorder, and 2.4% for bipolar spectrum. [61] Yutzy and colleagues reported an increase in the prevalence of BPI and BPII in recent years. [62] This prevalence ranged from 0.4% to 1.6% between the mid 1970s and 2000; by the late 1990s to the 2000s, the prevalence had the climbed from approximately 5% to 7%. [62]

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 of bipolar disorder 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. These individuals 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.

For more information, see the Medscape Reference article Pediatric Bipolar Affective Disorder.

Sex-related differences in incidence

BPI occurs equally in both sexes; however, rapid-cycling bipolar disorder (≥4 episodes/y) 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 also report an increased risk in women for BPII/hypomania, rapid cycling, and mixed episodes. [63]



Bipolar disorder, or manic-depressive illness (MDI), 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 disorder was estimated at approximately $15.5 billion annually. Approximately 25-50% of individuals with bipolar disorder attempt suicide, and 11% successfully commit suicide.

Additionally, a 2011 study from the United Kingdom suggested that for patients with bipolar disorder, mortality 1 year after hospital discharge was also higher than that of the general population for natural causes, chiefly respiratory and circulatory disorders. [64]

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

  • Substance abuse

  • Psychotic features

  • Depressive features between periods of mania and depression

  • Evidence of depression

  • Male sex

  • Pattern of depression-mania-euthymia

Factors suggesting a better prognosis include the following:

  • Length of manic phases (short duration)

  • Late age of onset

  • Few thoughts of suicide

  • Few psychotic symptoms

  • Few medical problems


Patient Education

Treatment of patients with bipolar disorder, or manic-depressive illness (MDI), 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. [65]

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. The National Institute of Mental Health (NIMH) has a story of a person with manic-depressive illness that can help the patient see the struggle and challenge from another perspective. [66] Others have written about their family struggles and challenges. [67]

Important resources for patients and families to gain information on dealing with manic-depressive illness include the following: