A. Biochemical Factors: Although many differences in biochemical indices have been described when patients with bipolar disorder are compared to normal control subjects, there is no agreement about which alterations have etiological significance and which are secondary effects or epiphenomena. Since the “switch” from depression into mania (and vice versa) can occur in minutes, attempts have been made to identify biochemical changes that might be associated with the switch. Specific changes in brain monoamine neurotransmitter metabolism and receptor function appear to be the most likely mechanisms. Although now regarded as too simplistic, the catecholamine hypothesis suggested that catecholamine (most specifically norepinephrine) deficiency was associated with motor retardation and depression, whereas catecholamine excess could result in excitement and euphoria.
Since all of the major neurotransmitter systems are functionally linked, it is not surprising that changes in other major neurotransmitter systems have also been documented. Changes in dopaminergic function, GABAergic regulation, and adrenergic-cholinergic system imbalance have been reported during manic episodes. Trait-dependent alterations in platelet serotonin uptake, in cerebrospinal fluid levels of serotonin metabolites, and in en-docrine response to serotonergic agonists have also been found in patients with bipolar illness. Neuroimaging studies have documented a number of abnormalities, including changes in amygdala, thalamus, hippocampus, and prefrontal cortex volume and increased white matter lesions in subcortical areas. Overall, however, there have been few biological studies of mania, since the nature of the syndrome makes compliance with research procedures difficult. Studies of the mechanism of action of lithium have pointed to the important regulatory functions of second messenger systems, particularly the phosphatidylinositol cycle, as well as modulation of glutamate activity.
Electrolyte disturbances have also been found in patients with bipolar disorders and may represent a defect of cellular membrane function. In general, sodium retention and potassium and water excretion increase during depression and decrease during manic intervals. Abnormal calcium homeostasis has also been reported. A variety of neuroendocrine changes have also been reported for patients with bipolar disorder who are in the depressed phase. About half of both bipolar and unipolar depressed patients show evidence of any or all of the follow-ing during a severe depressive episode: increased adrenal glucocorticoid function, decreased thyroid-stimulating hormone response to thyrotropin-releasing hormone, decreased basal prolactin levels, and de-creased growth hormone response to insulin challenge.
Because of pharmacological parallels to temporal lobe epilepsy and beneficial responses to several anticonvulsant agents, some investigators have hypothesized that recurrent bipolar mood episodes derive from an endogenous “kindling” of electrical discharges in limbic areas of the brain. Others have emphasized patterns in alteration of circadian rhythmicity.
Thus far, the results of studies in molecular genetics have been inconclusive. Regions on chromosome 18p and 18q and on chromosomes 4 and 21 have received the strongest support, although no specific gene has thus far been isolated for what is most certainly a complex multigenic disorder.
B. Psychosocial Factors: There is no reliable evidence that psychosocial factors cause bipolar disorder, although life stresses may precipitate manic or depressed bipolar states and may in fact be necessary for the expression of symptomatology in milder bipolar syndromes. The lifetime prevalence of comorbid substance abuse exceeds 60%. Recent research in biological circadian rhythmicity suggests that subtle changes in the light-dark cycle (eg, seasonal variations) are an additional predictor of risk.