Bipolar disorder and genetics

• ALSO KNOWN AS: Bipolar affective disorder; manic-depressive illness; manic depression; manic disorder; manic affective disorder

DEFINITION: Bipolar disorder results in extreme swings in mood, energy, and ability to function. The mood changes of bipolar disorder are more dramatic than normal ups and downs; they can hurt relationships and cause poor job or school performance. Bipolar disorder can be treated. Individuals should contact their doctors if they think they may have this condition.

The two extremes of the illness are mania and depression. In mania, energy peaks; an individual’s mood may be overly happy or irritable. In depression, lethargy takes over; the mood may be very blue. There are three forms of this condition. Bipolar I disorder involves recurrent episodes of mania and depression. Bipolar II disorder involves milder episodes of mania (called hypomania) that alternate with episodes of depression. Cyclothymic disorder may be diagnosed in patients who experience frequent depressive symptoms and hypomanic symptoms that do not meet full episode criteria for at least two years and who have been without symptoms for no more than two months.

Risk Factors

A family history of bipolar disorder increases an individual’s chance of developing this condition. Patients should tell their doctors if they have a family member with bipolar disorder.

Etiology and Genetics

Bipolar affective disorder is a complex condition in which the etiology most often depends on a combination of genetic and environmental factors. While specific genetic factors and their interactions are not well understood, it is clear from twin, family, and adoption studies that there is a strong genetic component. One study suggests that children of individuals with bipolar affective disorder are significantly more likely to develop the disorder than are children whose parents are unaffected, but there is otherwise no predictable pattern of inheritance. Twin studies suggest a substantially higher concordance rate for identical twins than for fraternal twins.

Although dozens of genes may play small roles in the development of bipolar affective disorder, two specific genes have been identified that may be major contributors. The ANK3 gene, found at position 10q21 on the long arm of chromosome 10, encodes a protein known as ankyrin G. This is an adapter protein that regulates the assembly of ion channels on neuronal axons. A second gene, CACNA1C, found on the short arm of chromosome 12 at position 12p13.3, specifies the alpha subunit of a specific calcium channel in neurons. Studies in mice suggest that the levels of the mouse versions of both of these proteins are depressed in the brains of mice in response to lithium treatment. These studies suggest that mutant alleles may affect the production of these proteins and provide a possible explanation for the effectiveness of lithium treatment in some patients. A 2015 study published in Proceedings of the National Academy of Sciences  found that rare variants in neuronal excitability genes may also contribute to the risk of bipolar disorder. Further research identified genes involved in neuronal signaling and synaptic plasticity, including ODZ4, TRANK1, and ADCY2. Researchers have also increasingly used polygenic risk scores (PRS) to estimate an individual’s genetic liability based on the cumulative effect of thousands of variants. This marked a trend in genome research in bipolar disorder away from single-gene models toward integrative frameworks that consider gene-environment interplay.

Symptoms

Symptoms of bipolar affective disorder include dramatic mood swings, ranging from elated excitement to severe depression; periods of normal mood in between ups and downs; and extreme changes in energy and behavior.

Signs and symptoms of mania include persistent and inexplicable elevation in mood, increased energy and effort toward goal-directed activities, restlessness and agitation, racing thoughts, jumping from one idea to another, and rapid speech or pressure to continue talking. Trouble concentrating; a decreased need for sleep; overconfidence or inflated self-esteem; and poor judgment, often involving spending sprees and sexual indiscretions, are other signs and symptoms of mania.

Signs and symptoms of depression include a prolonged sad, hopeless, or empty mood; feelings of guilt, worthlessness, or helplessness; and a loss of interest or pleasure in activities once enjoyed, including sex. Decreased energy or fatigue; trouble concentrating, remembering, and/or making decisions; restlessness or diminished movements; agitation; sleeping too much or too little; unintended weight loss or gain; and thoughts of death or suicide with or without suicide attempts are other signs and symptoms of depression.

Severe episodes of mania or depression may sometimes be associated with psychotic symptoms, such as hallucinations, delusions, and disorders of thought.

Screening and Diagnosis

A doctor will ask patients about their symptoms and medical history, and a physical exam may be done. In some cases, lab tests are ordered; they will help to rule out other causes of mood and behavior symptoms. Patients may also be referred to a mental health specialist who may use tools like the Mood Disorder Questionnaire (MDQ).

Diagnosis of bipolar disorder is based on the presence of symptoms over time, the absence of other causes, such as some medications, thyroid disease, Parkinson’s disease, and a family history of bipolar disorder. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), is the standard reference used for diagnosing bipolar and related disorders.

Mania is diagnosed if a patient’s mood is elevated and there are three or more of the mania symptoms listed above. If the mood is irritable, not elevated, four symptoms must be present for a diagnosis of mania. Symptoms last for most of the day, nearly every day, for one week or longer.

A depressive episode is diagnosed if there are five or more of the depressive symptoms listed above. Symptoms last for most of the day, nearly every day, for two weeks or longer.

Some medicines and other medical issues, such as corticosteroids, thyroid disease, and multiple sclerosis, may show similar features. The diagnosis is made only when none of these other causes are present.

Treatment and Therapy

Individuals should talk with their doctors about the best plans for them. Medications are among the treatment options. Many patients are treated with a combination of two or more of these medications: lithium, a mood stabilizer, often used as initial treatment to help prevent manic and depressive episodes from returning; antiseizure medications, also used as mood stabilizers instead of or in combination with lithium; valproate (Depakote); carbamazepine (Tegretol); and lamotrigine (Lamictal).

Benzodiazepines, including clonazepam (Klonopin) and lorazepam (Ativan), can be used to treat agitation or insomnia; zolpidem (Ambien) can be used to treat insomnia. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or bupropion (Wellbutrin), are used to treat depression.

Antipsychotic medications are used for acute manic or mixed episodes and maintenance treatment. Classic antipsychotic medications, such as haloperidol (Haldol), are not often used because of risks of tardive dyskinesia (uncontrollable movements); atypical antipsychotic medications (risperidone, olanzapine, aripiprazole, ziprasidone, and quetiapine) are more effective with less risk of tardive dyskinesia. Lurasidone (Latuda) and cariprazine (Vraylar) are among the atypical antipsychotic medications used in the treatment of bipolar depression. Lumateperone (Caplyta) is also used to treat depressive episodes associated with bipolar disorder.

The treatment plan is based on the pattern of the patient’s illness. Treatment may need to be continued indefinitely, and it should prevent significant mood swings.

Psychotherapy is another treatment option and may include cognitive-behavioral therapy, counseling, family therapy, and interpersonal and social rhythm therapy—a form of therapy designed to treat bipolar disorder. Electroconvulsive therapy may be effective when medications fail; it can be used for both mania and depression.

Prevention and Outcomes

While the disorder cannot be prevented, early intervention strategies and monitoring at-risk individuals with a family history may reduce symptom severity or delay onset. Early intervention, sustained treatment, psychoeducation, and support systems improve long-term outcomes.

Bibliography

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