Circadian abnormalities as markers of susceptibility in bipolar disorders.

Chronobiological models have contributed to a better understanding of the pathophysiology of bipolar disorders. Circadian functions dysregulations are associated with bipolar disorders, including biochemical (melatonin and cortisol profiles), actigraphic (sleep/wake patterns), and dimensional (chronotypes) circadian markers. These associations are observed not only during acute episodes but also during euthymic periods. Most markers that are associated with bipolar disorders are also found in the healthy relatives of patients, suggesting a strong degree of heritability. As such, they may serve as trait markers of the disorder. Several circadian genes have been found to be associated with bipolar disorders: at least three studies have reported positive associations for each of CLOCK, NPAS2, ARNTL1, NR1D1, PER3, RORB and CSNK1epsilon. Thus the clock machinery may contribute to the genetic susceptibility to bipolar disorders. The circadian model theory has also led to the development of novel therapeutic strategies such as InterPersonal and Social Rhythms Therapy and chronotherapeutics. Additionally, the circadian model theory may help explain how mood stabilizers (in particular lithium carbonate) bring about their therapeutic effects.