Etiology
Genetic influences may be important in the onset and course of bipolar disorder across the life span, although precise etiologic mechanisms have yet to be elucidated, and the data need to be replicated. No major bipolar locus has yet been found in adult bipolar disorder, but susceptible chromosomal loci of smaller effect contribute to the presence and variability of bipolar disorder; these data require replication. Neither is necessary nor sufficient for the development of bipolar disorder.[32][33]
Gene-environment interactions may shape the onset, course, and recurrence of bipolar disorder, as there is evidence of the involvement of many psychosocial factors, including maternal negativity (lack of maternal warmth/expressed emotion), physical and sexual abuse, low levels of family cohesion, and possible perinatal influences. As with all data in this area, it depends on how narrowly or broadly bipolar disorder is being defined.[34] A preliminary study has shown evidence for interaction effects of early life trauma with genes that are involved in calcium signaling.[35]
Pathophysiology
Due to the heterogeneity of samples within and across studies, interpretation of data is difficult. There are reports of amygdala volumes being smaller in children and adolescents with bipolar disorder compared with controls; these structural abnormalities do not appear to be present in adults with bipolar disorder, and abnormal amygdala activation during face processing appears to be more pervasive in children than in adults with bipolar disorder.[36][37][38] One meta-analysis has shown that amygdala, prefrontal, and visual system hyperactivation is important in the emotional dysfunction present in young people with bipolar disorder, and anterior cingulate cortex hypoactivation is relevant to the cognitive deficits in this population compared with adults.[39] One study looking at the effects of psychotherapy in pediatric patients at familial risk for bipolar disorder demonstrated a post-treatment activation decrease in the amygdala, and an increase in the dorsolateral prefrontal cortex that was significantly correlated with improvement in mania symptoms, suggesting that enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation.[40] There is some evidence that the effect on the amygdala may be mediated by independent life events in children and adolescents.[41]
Other structural brain abnormalities that have been found include hippocampal deficits and reduced gray matter in adolescents with bipolar disorder versus increased gray matter volume in healthy offspring of bipolar parents.[42][43][44] However, it remains unclear whether structural changes seen in bipolar disorder are specific or are indicative of more general pathology.[45] Functional magnetic resonance imaging in children and adolescents has shown impaired connectivity in brain regions involved with facial expressions and social stimuli, and differences have been found in the activation of circuitry implicated with memory and recognition and regulation of emotions.[46][47] Young people with bipolar disorder also display abnormal amygdala resting state network connections to regions that are critical for emotional processing and self-awareness.[48] Unaffected offspring at familial risk for bipolar disorder also appear to have alterations in the functioning of the frontolimbic system, which is implicated in emotion regulation, aberrant prefrontal activations and connectivity during reward processing, increased amygdala activity, as well as showing significant widespread white matter tract aberrations.[48][49][50][51] Preliminary evidence suggests that the differing patterns of amygdala activation between bipolar young people and healthy controls may be influenced by the DOK5 gene; increased amygdala activity may also be predictive of poor treatment response to medication.[52][53] There is some evidence to suggest that brain glutamate levels are elevated in bipolar patients when compared with healthy subjects, and that brain-derived neurotropic factor levels may be a marker for bipolar disorder in young people, but genetic studies have been conflicting.[54][55][56] Pro-inflammatory markers are elevated in young people with bipolar disorder; however, this effect is nonspecific, and larger prospective studies are needed to realize the goal of inflammatory markers informing clinical practice.[57] To date, there are no imaging tests or biomarkers that are diagnostic for bipolar disorder in children, adolescents, or adults. However, preliminary data have shown that face recognition neuroimaging techniques may predict those at-risk adolescents most likely to develop the disorder.[58] Children and adolescents with bipolar disorder have been found to suffer from cognitive deficits (e.g., verbal learning and memory, processing speed, or executive control) that are milder but similar in nature to those of children and adolescents with early onset schizophrenia. It has been suggested that the qualitative similarities between these neuropsychological profiles may represent a "continuum of psychosis" or reflect some degree of genetic biologic overlap.[59] However, a study of offspring of patients with schizophrenia and bipolar disorder reported that gray matter volume reduction in childhood and adolescence may be specific to offspring of patients with schizophrenia; this may index a greater neurodevelopmental impact of risk for schizophrenia relative to bipolar disorder during youth.[60]
Classification
Diagnostic and Statistical Manual of Mental Disorders, 5th edition, Text Revisions (DSM-5-TR): bipolar disorder[4]
Bipolar I disorder: occurrence of a manic episode lasting at least 1 week (or any duration if hospitalization is necessary). Core symptoms for mania include abnormally elevated, expansive, or irritable mood and persistently increased energy or activity. Major depressive episodes and hypomanic episodes are common in bipolar I disorder but are not required for the diagnosis.
Bipolar II disorder: at least one current or past episode of hypomania and at least one current or past episode of major depression. Core symptoms for hypomania include abnormally elevated, expansive, or irritable mood and persistently increased energy or activity, lasting at least 4 consecutive days. Core symptoms of a major depressive episode are depressed mood or loss of interest or pleasure, nearly every day for at least 2 weeks.
Cyclothymic disorder: numerous periods of hypomanic symptoms that do not meet criteria for a hypomanic episode, and numerous periods with depressive symptoms that do not meet criteria for a major depressive episode, for at least 1 year. During this time, the hypomanic and depressive periods have been present for at least half the time and the individual has not been without the symptoms for >2 months at a time.
Substance/medication-induced bipolar and related disorder: a manic episode that develops during or soon after substance intoxication or withdrawal, or after exposure to a medication.
Bipolar and related disorder due to another medical condition: a manic episode that is the direct pathophysiologic consequence of another medical condition.
Other specified bipolar and related disorder: used for cases that do not meet the full criteria for any of the disorders in the bipolar and related disorders diagnostic class, in which the clinician chooses to communicate the specific reason that the presentation does not meet the criteria for bipolar and related disorder.
Unspecified bipolar and related disorder: used for cases that do not meet the full criteria for any of the disorders in the bipolar and related disorders diagnostic class, in which the clinician chooses not to communicate the specific reason that the presentation does not meet the criteria for bipolar and related disorder. Includes presentations in which there is insufficient information to make a more specific diagnosis.
The specifier "with mixed features" may be added if episodes of mania/hypomania also present with depressive features, or if episodes of depression present with manic/hypomanic features.
International Classification of Diseases, 11th edition (ICD-11): bipolar disorder[7]
Recurrent episodes lasting at least 2 weeks (1 week for mania), unless treatment intervention shortens duration, where mood and activity levels are disturbed. These episodes will consist of mania or hypomania on some occasions and depression on others, although presence of one or more manic episodes alone is also classified as bipolar I disorder. A mixed episode occurs when there has been at least 1 manic, hypomanic, or mixed affective episode in the past, and the patient currently exhibits either a mixture or a rapid alternation of manic, hypomanic, and depressive symptoms. There is also a category for other bipolar disorders (includes bipolar II and cyclothymic disorder) and an unspecified category.
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