Circadian Rhythm Hypotheses of Mixed Features, Antidepressant Treatment Resistance, and Manic Switching in Bipolar Disorder

Abstract

Numerous hypotheses have been put forth over the years to explain the development of bipolar disorder. Of these, circadian rhythm hypotheses have gained much importance of late. While the hypothalamus-pituitary-adrenal (HPA) axis hyperactivation hypothesis and the monoamine hypothesis somewhat explain the pathogenic mechanism of depression, they do not provide an explanation for the development of mania/hypomania. Interestingly, all patients with bipolar disorder display significant disruption of circadian rhythms and sleep/wake cycles throughout their mood cycles. Indeed, mice carrying the Clock gene mutation exhibit an overall behavioral profile that is similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, and lower anxiety. It was recently reported that monoamine signaling is in fact regulated by the circadian system. Thus, circadian rhythm instability, imposed on the dysregulation of HPA axis and monoamine system, may in turn increase individual susceptibility for switching from depression to mania/hypomania. In addition to addressing the pathophysiologic mechanism underlying the manic switch, circadian rhythm hypotheses can explain other bipolar disorder-related phenomena such as treatment resistant depression and mixed features.

Association ofCLOCK, ARNTL, andNPAS2gene polymorphisms and seasonal variations in mood and behavior

“…To date, genetic variations in circadian genes have been associated with sleep, mood, and metabolic disorders (Takahashi et al, 2008), and numerous human genetic studies have implicated polymorphisms in the individual genes of the molecular clock in the manifestation of mood disorders -particularly SAD, and also bipolar disorder and major depression (Benedetti et al, , 2008Johansson et al, 2003Johansson et al, , 2004Kishi et al, 2008Kishi et al, , 2009Kripke et al, 2009;Lavebratt et al, 2010;Lee et al, 2005aLee et al, , 2006Lee et al, , 2010Lee et al, , 2013Mansour et al, 2006Mansour et al, , 2009McGrath et al, 2009;Paik et al, 2007;Partonen et al, 2007;Shi et al, 2008;Sjoholm et al, 2010;Soria et al, 2010). Polymorphisms in the NPAS2, PER2, ARNTL, and GNB3 genes are associated with the development of SAD (Johansson et al, 2003;Lee et al, 2005a;Partonen et al, 2007).…”

Analysis of genetic association and epistasis interactions between circadian clock genes and symptom dimensions of bipolar affective disorder

“…Animal (mice) models showed Clock gene important in depression-mania switch (Lee et al, 2013;van Enkhuizen et al, 2013). Mutations (ClockD19) in its protein result in behavioural abnormalities resembling mania.…”

“…Several clinical reports described circadian rhythms in BD (Lee et al, 2013). For example increase risk for anxiety and depressive symptoms and disorders are observed in ''evening owls'' group (Gaspar-Barba et al, 2009;Kitamura et al, 2010).…”

Towards Personalized Treatment of Depression

“…Учение о ритмах получило завершенную форму в результате крепелиновского синтеза, с выделени-ем маниакально-депрессивного психоза ("manicdepressive illness", Goodwin) [28]. Многократные эпизоды заболевания встречаются значительно чаще, чем одиночные.…”