Aetiology
The exact cause of bipolar disorder is unknown; in common with many psychiatric disorders, it is considered to be caused by the complex interaction of multiple genetic, cellular, and environmental factors.[37] Risk appears to be influenced by several genes.[38] Family history is the strongest individual risk factor for developing bipolar disorder, with first-degree relatives having an approximately eightfold higher risk of developing bipolar disorder compared with the baseline population risk (8% vs. 1%).[39] Twin and adoption studies suggest that the majority of this risk is genetic; heritability estimates are approximately 60% to 80%.[40][41] Environmental stressors or triggers are considered likely to contribute to the phenotypic expression of the underlying mood disorder.[42] Childhood maltreatment or abuse increase the risk of bipolar disorder, and are associated with earlier development of bipolar disorder, as well as with a more severe course of illness.[43][44][45][46]
Large-scale genome-wide association studies (GWAS) suggest that the genetic risk for bipolar disorder is spread across many common variants of small effect size.[47][48] The strongest association signals were detected at CACNA1C according to one GWAS, and at other genes encoding synaptic components, as well as immune and energy metabolism components.[49] However, the CACNA1C SNP finding also overlaps with other psychiatric conditions including schizophrenia, suggesting commonalities in the biological pathways in both conditions. One meta-analysis of GWAS found involvement of biological pathways that include hormonal regulation, calcium channels, second messenger systems, and glutamate signalling.[50] Elevated inflammatory markers, such as C-reactive protein, suggest that systemic inflammation may also be involved in the disease process.[51][52]
Pathophysiology
Studies utilising magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), positron emission tomography, and functional imaging (fMRI and fMRS) continue to bring insight into the pathophysiology of bipolar disorder. Structural MRI findings include increased foci of deep white matter hyperintensities, an increased corpus callosum cross-sectional area, and smaller hippocampus and basal ganglia in people with bipolar disorder compared with people with major depressive disorder, as well as increased lateral ventricle volumes and increased rates of subcortical grey matter hyperintensities compared with healthy controls.[53][54] Although several brain regions have been implicated as abnormal in bipolar disorder, the prefrontal cortex is of particular interest, with several studies reporting structural pathology in the prefrontal cortex in people with bipolar disorders.[55] Abnormalities also include reduced cortical grey matter thickness in the frontal, temporal, and parietal regions of both brain hemispheres.[56][57]
Functional MRI studies of emotional processing in bipolar disorder have identified alterations in patients' ability to identify, generate, and experience emotionally salient information on a neurophysiological basis.[58] The irregular patterns of prefrontal cortical processing and connectivity with subcortical responses, in bipolar compared with healthy individuals, may explain the difficulties with the regulation of emotional expression (such as inappropriate or labile affect) and behaviour (such as impulsivity or sexually inappropriate behaviours) observed clinically in people with bipolar disorder.[58] MRS studies, which can identify neurochemical information within specific brain regions, demonstrate alterations in N-acetylaspartate, choline, myoinositol, glutamate, and other critical substrates involved in regulation of mood in people with bipolar disorder compared to healthy controls.[59]
Inflammation has been also linked to several behaviours, including appetite, sleep, level of exercise, alcohol use, and smoking, and medical comorbidities such as type 2 diabetes, dyslipidaemia, obesity, osteoporosis, and pain that have been associated with bipolar disorder.[60][61] However, there is inconsistent evidence linking a variety of neuroinflammatory risk factors, including shared genetic polymorphisms and gene expression, increased pro-inflammatory cytokines, and decreased anti-inflammatory cytokines to bipolar disorder.[62][63] Disturbances in insulin signalling and function have also been implicated in the development of bipolar disorder, although it is unclear whether the established correlation between metabolic syndrome and bipolar disorder is causal, or whether it is the result of confounding factors such as exposure to psychotropic drugs and lifestyle factors.[64]
Low-level evidence studies suggest that bipolar disorder is associated with hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, including higher levels of baseline cortisol and adrenocorticotrophic hormone (ACTH).[65] Case-control differences in cortisol levels are positively associated with mania and older age, and negatively associated with antipsychotic use.[65]
Classification
Diagnostic and Statistical Manual of Mental Disorders, fifth edition, text revision (DSM-5-TR) for bipolar disorder[1]
Bipolar disorder, type I
At least 1 manic episode*
*Of note, DSM-IV required the presence of at least one manic or mixed episode for a bipolar disorder, type I diagnosis. DSM-5 amended the diagnostic requirements to at least one manic episode, while maintaining mixed features as a specifier that can be applied to both manic and depressive episodes.
Bipolar disorder, type II
Never had a full manic episode; at least 1 hypomanic episode and at least 1 major depressive episode
Substance-/medication-induced bipolar and related disorder
Prominent and persistent disturbance of mood characterised by elevated, expansive, or irritable mood and abnormally increased activity or energy that develops during substance intoxication or withdrawal, and the substance/medication is capable of producing disturbance of mood
Bipolar and related disorder due to another medical condition
Prominent and persistent disturbance of mood characterised by elevated, expansive, or irritable mood and abnormally increased activity or energy that develops as the direct pathophysiological consequence of another medical condition (e.g., hyperthyroidism, Cushing syndrome)
Cyclothymic disorder
Persistent (at least 2 years for adults) mood disturbance characterised by numerous periods of hypomanic symptoms and numerous periods of depressive symptoms; the symptomatic periods are of insufficient severity, pervasiveness, or duration to meet full criteria for a hypomanic, manic, or major depressive episode.
Other specified bipolar and related disorder and unspecified bipolar and related disorder
Clinically significant impairment in social, occupational, or other important areas of functioning caused by symptoms characteristic of bipolar and related disorder but symptoms are not severe enough to meet full criteria for any of the above disorders. The other specified type is diagnosed when significant symptoms are clearly identifiable but do not align completely with the standard diagnostic criteria for bipolar I, bipolar II, or cyclothymic disorder. This category is applied when the clinician chooses to communicate the specific reason that the criteria for any specific bipolar and related disorder are not met or when there is insufficient information to make a more specific diagnosis.
International Classification of Diseases, 11th edition (ICD-11): bipolar affective disorder[2]
Bipolar and related disorders are episodic mood disorders defined by the occurrence of manic, mixed, or hypomanic episodes or symptoms. These episodes typically alternate over the course of these disorders with depressive episodes or periods of depressive symptoms.
Bipolar type I disorder
A history of at least one manic or mixed episode. Although a single manic or mixed episode is sufficient for a diagnosis of bipolar type I disorder, the typical course of the disorder is characterised by recurrent depressive and manic or mixed episodes. Although some episodes may be hypomanic, there must be a history of at least one manic or mixed episode.
Bipolar type II disorder
A history of at least one hypomanic episode and at least one depressive episode. The typical course of the disorder is characterised by recurrent depressive and hypomanic episodes.
There is no history of manic or mixed episodes.
Cyclothymic disorder
Mood instability over an extended period (2 years or more) characterised by numerous hypomanic and depressive periods.
Hypomanic periods may or may not have been sufficiently severe or prolonged to meet the diagnostic requirements for a hypomanic episode.
Mood symptoms are present for more days than not. While brief symptom-free intervals are consistent with the diagnosis, there have never been any prolonged symptom-free periods (e.g., lasting 2 months or more) since the onset of the disorder.
There is no history of manic or mixed episodes.
During the first 2 years of the disorder, there has never been a 2-week period during which the number and duration of symptoms were sufficient to meet the diagnostic requirements for a depressive episode.
The symptoms are not a manifestation of another medical condition (e.g., hyperthyroidism) and are not due to the effects of a substance or medication on the central nervous system (e.g., stimulants), including withdrawal effects.
The symptoms result in significant distress about experiencing persistent mood instability or significant impairment in personal, family, social, educational, occupational, or other important areas of functioning. If functioning is maintained, it is only through significant additional effort.
Other specified bipolar or related disorders
The presentation is characterised by manic or hypomanic symptoms (with or without depressive symptoms) that share primary clinical features with other bipolar or related disorders (e.g., persistent elevation of mood).
The symptoms do not fulfil the diagnostic requirements for any other disorder in the bipolar or related disorders grouping.
The symptoms are not better accounted for by another mental, behavioural, or neurodevelopmental disorder (e.g., schizoaffective disorder; a disorder due to addictive behaviours; a personality disorder).
The symptoms and behaviors are not a manifestation of another medical condition and are not due to the effects of a substance or medication (e.g., alcohol, cocaine) on the central nervous system, including withdrawal effects.
The symptoms result in significant distress or significant impairment in personal, family, social, educational, occupational, or other important areas of functioning. If functioning is maintained, it is only through significant additional effort.
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