Biological Theories of Bipolar Disorder
Bipolar disorder is fundamentally a genetic disorder with approximately 70% heritability, involving complex interactions between multiple susceptibility genes that disrupt neuronal-glial plasticity, monoaminergic signaling, inflammatory homeostasis, and mitochondrial function. 1
Genetic Mechanisms
The genetic architecture of bipolar disorder is robust and well-established:
First-degree relatives carry a 4-6 fold increased risk (5-10% lifetime risk versus 0.5-1.5% baseline population risk), with monozygotic twins showing 40-70% concordance rates. 2, 3, 4
Multiple genes interact epistatically rather than following simple Mendelian inheritance patterns, though occasional families may exist where a single gene plays a major role. 4
Shared genetic risk alleles exist between bipolar disorder and other psychiatric conditions, with bipolar I showing closer genetic association with schizophrenia, while bipolar II has closer genetic association with major depressive disorder. 1
Specific chromosomal regions of interest include 4p16, 12q23-q24, 16p13, 21q22, Xq24-q26, and chromosome 18, though no single gene has been definitively identified. 4
Early-onset and highly comorbid cases demonstrate even higher degrees of familiality than typical adult-onset presentations. 2, 3
Neurobiological Pathways
Multiple interconnected biological systems are disrupted in bipolar disorder:
Voltage-gated calcium channels have emerged as both part of the disease process and a potential drug target based on recent risk gene discoveries. 5
Disturbances in neuronal-glial plasticity represent a core pathophysiological mechanism, with impaired cellular processes leading to brain tissue loss identified in post-mortem and neuroimaging studies. 1, 6
Monoaminergic signaling dysfunction affects neurotransmitter systems, though candidate gene studies focusing on these systems have not yet yielded robust positive findings. 1, 4
Defects in multiple signaling pathways include apoptotic, immune-inflammatory, neurotransmitter, neurotrophin, and calcium-signaling cascades. 7
Cellular and Metabolic Dysfunction
Mitochondrial dysfunction and cellular bioenergetics are implicated as key pathophysiological processes, contributing to impaired neuronal function. 1, 7, 6
Oxidative and nitrosative stress damage cellular components and contribute to the systemic toxicity associated with recurrent mood episodes. 7, 6
Intracellular biochemical cascade dysfunctions impair processes linked to neuronal plasticity, leading to progressive cell damage. 6
Inflammatory and Immune Mechanisms
Inflammatory homeostasis disturbances play a significant role, with peripheral biomarkers related to inflammation being altered especially during acute mood episodes. 1, 6
Autoimmunity and cytokine dysregulation contribute to the pathophysiology, with these changes associated with systemic toxicity of the disease. 7, 6
Environmental Interactions
High prevalence of childhood maltreatment in people with bipolar disorder highlights the role of adverse environmental exposures, with childhood trauma associated with more complex presentations including increased suicidality. 1
Gene-environment interactions are critical, with genetic susceptibility requiring environmental triggers (stress, traumatic events) to manifest as clinical disease. 6
Certain temperamental patterns may presage bipolar disorder, including dysthymic, cyclothymic, or hyperthymic (irritable, driven) temperaments. 2
Neurodevelopmental and Chronobiological Factors
Disturbed brain development and chronobiology represent multiple associations with the disorder's pathophysiology. 7
Offspring of bipolar parents display prodromal symptoms including mood lability, anxiety, attention difficulties, hyperarousal, depression, and somatic complaints. 2, 3
The BDNF Val66Met polymorphism may be involved in seasonal affective patterns in bipolar disorder. 2
Clinical Implications
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. 2
Systemic toxicity from recurrent episodes influences brain anatomical changes and treatment response, emphasizing the progressive nature of the disorder. 6