Sleep and circadian rhythms in bipolar disorders

Multiple lines of evidence support the conceptualization of bipolar disorder (BD) as a disorder of circadian rhythms, linking the disease with an abnormal internal timing (Harvey, 2008; McClung, 2013). Altered rhythmicity of circadian functions before and during mood episodes of illness, both mania and depression, has long been demonstrated. More recently, circadian abnormalities have been considered trait markers of the disorder and have been proposed to play a pathogenetic role (Singh and Rose, 2009), since the persistence of abnormal circadian rhythms has also been shown during euthymic periods. In addition, it is very common for symptoms to be seasonal, in that patients are more likely to have depressive symptoms in the winter and manic symptoms during the summer(Mitterauer, 2000), thus suggesting a relationship between bipolar symptomatology and circadian changes of the photoperiod. Moreover, genetic polymorphisms affecting the function of genes involved in the genesis of circadian rhythms not only show an association with the disorder but also seem to influence core clinical features, including onset and recurrence of illness episode and response to treatment. Finally, some of the treatments that are currently used to treat mood disorder (total sleep deprivation, light therapy, sleep phase advance) are chronobiological interventions and are thought to act by shifting or resetting the circadian clock. Based on all these findings, BD has been suspected to arise in part from a malfunction of the circadian system. However, the exact mechanism of circadian disruption and its relationship to disease development are not still clearly understood. Circadian rhythms in bipolar disorder Circadian rhythms include all physiological processes (biological and behavioral) displaying a period around 24 hours. In mammals they are mainly generated by the primary circadian pacemaker which is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus (Klein et al., 1991). The accepted model for the molecular machinery that generates circadian rhythms involves a number of clock genes and their products. The mechanism is based on self-regulated oscillations in expression of a set of genes. The circadian oscillations are driven by feedback mechanisms, where the protein products of some clock genes inhibit (Per1, Per2, Cry1, Cry2, and Nr1d1/Rev-erba) or activate (Clock and Bmal1) the transcription of other clock genes.