What causes bipolar disorder?

What Causes Bipolar Disorder

Bipolar disorder is primarily caused by strong genetic factors, with a four- to sixfold increased risk in first-degree relatives of affected individuals, though the exact mechanisms involve complex interactions between multiple genes and environmental factors. 1

Genetic Factors

The genetic contribution to bipolar disorder is substantial and well-established:

• Twin, adoption, and family history studies demonstrate a major genetic component, with monozygotic twins showing 40-70% concordance rates. 2
• First-degree relatives have a 5-10% lifetime risk compared to 0.5-1.5% in the general population. 2
• Early-onset and highly comorbid cases show even higher degrees of familiality than typical adult-onset cases. 1
• Multiple genes are involved rather than a single causative gene in most cases, with complex interactions (epistasis) or mechanisms like dynamic mutation or imprinting playing roles. 2
• Promising chromosomal regions identified include 4p16, 12q23-q24, 16p13, 21q22, Xq24-q26, and chromosome 18, though no specific genes have been definitively confirmed. 2

Biological Mechanisms

Multiple biological pathways contribute to the disorder's development:

• Disturbances in neurotransmitter systems, neurotrophin signaling, and calcium-signaling pathways are implicated in the pathophysiology. 3
• Defects in immune-inflammatory pathways, oxidative and nitrosative stress, and cellular bioenergetics contribute to disease development. 3
• Abnormalities in brain development, neuroplasticity, and chronobiology result from the interaction of genetic and environmental factors. 3
• The BDNF Val66Met polymorphism may be involved in seasonal affective patterns in bipolar disorder. 4

Environmental and Developmental Risk Factors

While genetics play the primary role, environmental factors interact with genetic vulnerability:

• Certain temperamental patterns may presage bipolar disorder, including dysthymic, cyclothymic, or hyperthymic (irritable, driven) temperaments. 1
• Offspring of parents with bipolar disorder display early warning symptoms including mood lability, anxiety, attention difficulties, hyperarousal, depression, and somatic complaints. 1
• Premorbid psychiatric problems are common, especially disruptive behavior disorders, irritability, and behavioral dyscontrol in early-onset cases. 1
• Approximately 20% of youths with major depression eventually develop manic episodes by adulthood, particularly those with rapid onset, psychomotor retardation, psychotic features, family history of affective disorders, or antidepressant-induced hypomania. 1

Gene-Environment Interactions

The current understanding is that bipolar disorder results from gene-environment interactions rather than genetics or environment alone. 5, 6

• Individual risk factors often have small attributable risk, and most are not specific to bipolar disorder but associated with several mental illnesses. 5
• The mechanisms by which multiple risk factors interact to produce bipolar disorder remain under investigation, with increasing focus on specific gene-environment interactions. 5

Clinical Implications

The multifactorial nature means no single biomarker exists for diagnosis, requiring careful clinical assessment as the cornerstone of diagnosis. 6 The strong genetic component makes family history assessment critical in evaluating at-risk individuals. 1