Bipolar Affective Disorder 

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.^[1]

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.

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.

Go to Pediatric Bipolar Affective Disorder for complete information on this topic.

Case history

At the age of 25, D.A.K., a postgraduate student in chemistry, found himself at the emergency department (ED) of the university hospital, where the campus police had brought him. He had been working late at the laboratory alone when the police came. He had been awake for the past 4 days working on an experiment that he believed would save the world.

D.A.K.’s professors had voiced concerns as the often quiet and well-mannered student had recently begun to take over the class discussions and interrupt lectures. More remarkable than the behavior itself was the change it represented. In the preceding semester, D.A.K. had been uncharacteristically quiet and withdrawn. Many suspected that he was depressed, but they could find no apparent reason for his behavior. Then he isolated himself from friends and family and stopped seeing his girlfriend of 2 years.

D.A.K. had a family history of depression on his mother’s side, with a grandmother who had received electroconvulsive therapy (ECT) years ago in a state hospital. On his father’s side, his uncle had received lithium and had been diagnosed with manic depression. A vague history of colorblindness was also noted. D.A.K. had a younger sister who was often described as moody.

In the ED, D.A.K. was belligerent, talked rapidly but coherently, and demanded to return to the laboratory so that he could save his experiment and thus the world. He wanted a lawyer and denied being suicidal but threatened those who, he claimed, were standing in his way. He accused the faculty of being against him, threatened legal action against those incarcerating him, denied hallucinations but clearly saw himself in highly grandiose terms, was orientated times 3, had good recall, and was colorful and verbose in his response to proverbs.

No history of drug or alcohol use was noted, except for a large consumption of coffee in the preceding several weeks. He had no obvious medical problems.

D.A.K. kept demanding to leave and return to the laboratory to save everyone. He was a huge challenge to the emergency physicians, who could not wait for the psychiatric resident to arrive.

The pathophysiology of bipolar disorder 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 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,^{[2, 3, 4, 5]} 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.^[5] 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.^[6]

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.^[7]

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.^[8] 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^[2] , 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.^[7] 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 (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.^[9]

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 specifically in the ventral tegmental area of the mouse brain.^[10] 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.

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.^[11] Such promising measures for bipolar disorder include structural brain phenotypes, sleep and activity measures, neurocognitive measures, and gene expression studies.^[12]

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-myelin–related genes appear to be decreased in brain tissue from persons with bipolar disorder.^{[13, 14, 15, 16]} 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.^{[17, 18]}

A meta-analyses 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. 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.^[19]

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 up-regulate the expression of the cytoprotective protein Bcl-2 in the frontal cortex and the hippocampus of rat brains.^[20] 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.^[21] 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.^[22]

Post et al proposed a mechanism involving electrophysiologic kindling and behavioral sensitization processes, which resonates with the neuronal injury hypothesis.^[9] They asserted that a person who is susceptible to bipolar disorder experiences an increasing number of minor neurologic insults—from drugs of abuse, stress-related excessive glucocorticoid stimulation, or other factors—that eventually result in mania.^[9] Sufficient brain damage might persist to cause mania to 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.

A number of factors contribute to bipolar disorder, including genetic, biochemical, psychodynamic, and environmental factors.

Genetic factors

As noted (see Pathophysiology), bipolar disorder, especially BPI, has a major genetic component, with the involvement of the ANK3,CACNA1C, and CLOCK genes.^{[2, 3, 4, 5, 7, 10]} 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.^[23] This finding suggests an independent genetic liability for psychosis shared by both mood and schizophrenia spectrum disorders, as Berrettini^[24] previously speculated and as has been confirmed in the recent large-scale GWAS studies mentioned above.^[7]

As noted (see Pathophysiology), 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.

Evidence is mounting of the contribution of glutamate to both bipolar disorder and major depression. A postmortem study of the frontal lobes with both these disorders revealed that the glutamate levels were increased.^[25]

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 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.

Tricyclic antidepressants can trigger mania.^[26]

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 again

st 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.^[27]

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.^[28]

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

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.^[29]

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.^[30]

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.

Go to Pediatric Bipolar Affective Disorder for complete information on this topic.

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.

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.

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 recent 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.^[31]

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:

• Manic phases (short in duration)
• Late age of onset
• Few thoughts of suicide
• Few psychotic symptoms
• Few medical problems

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.^[32]

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.^[33] Others have written about their family struggles and challenges.^[34]

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

For patient education resources, see the Depression Center, as well as Depression and Bipolar Disorder.