The sleep-circadian interface: A window into mental disorders

Abstract

Sleep, circadian rhythms, and mental health are reciprocally interlinked. Disruption to the quality, continuity, and timing of sleep can precipitate or exacerbate psychiatric symptoms in susceptible individuals, while treatments that target sleep-circadian disturbances can alleviate psychopathology. Conversely, psychiatric symptoms can reciprocally exacerbate poor sleep and disrupt clock-controlled processes. Despite progress in elucidating underlying mechanisms, a cohesive approach that integrates the dynamic interactions between psychiatric disorder with both sleep and circadian processes is lacking. This review synthesizes recent evidence for sleep-circadian dysfunction as a transdiagnostic contributor to a range of psychiatric disorders, with an emphasis on biological mechanisms. We highlight observations from adolescent and young adults, who are at greatest risk of developing mental disorders, and for whom early detection and intervention promise the greatest benefit. In particular, we aim to a) integrate sleep and circadian factors implicated in the pathophysiology and treatment of mood, anxiety, and psychosis spectrum disorders, with a transdiagnostic perspective; b) highlight the need to reframe existing knowledge and adopt an integrated approach which recognizes the interaction between sleep and circadian factors; and c) identify important gaps and opportunities for further research.

Keywords: chronobiology; mental disorder; mood disorder; psychosis; sleep.

Fig. 1.

Contribution of sleep and circadian factors to diurnal mood variation and greater probability of adverse psychiatric outcomes during the morning hours. Field studies in patient populations demonstrate (A) lower mood (8), (B) greater anxiety symptoms (9), and (C) elevated suicide risk, after adjusting for population sleep/wake timing (solid line) and greater proportion of suicides per hour (dotted line) (10) in the morning, indicating a diurnal rhythm in these variables when sampled under real-world conditions. Note that these time courses are likely to be underpinned by multiple additional factors (e.g., alcohol use and social isolation may contribute to elevated suicide risk) and show significant individual differences. Measures of outcomes such as suicide differ depending on the type of study and assumptions of the analysis. Stringently controlled laboratory protocols allow the contribution of sleep homeostasis and circadian factors on mood to be disentangled from environmental and behavioral influences. (D) Constant routine (CR) study illustrating the modulation of mood by sleep homeostatic and circadian processes across the 24-h cycle, in women with depression (11). (E and F) Forced desynchrony (FD) protocol revealing the relative contribution of the endogenous circadian and sleep homeostatic process on mood in healthy control participants (12). These are representative, and not definitive, time-courses. (G) the two-process model posits that sleep and alertness are regulated by the close interaction of two counterpoised processes—homeostatic sleep pressure and the circadian system. Although alertness, (black line) and not mood, is predicted by the mathematical model, note that the time-course for alertness is similar to that for the circadian component of mood in the forced desynchrony study.

Fig. 2.

Conceptual framework of circadian (Left) and sleep (Right) mechanisms in mental disorders. (A) Nonvisual light information is conveyed from the retina to areas involved in arousal, emotion, and cognition through an indirect pathway via the SCN, but also through direct pathways which bypass the SCN. Mis-timed or low-amplitude light exposure can therefore exert widespread effects on sleep, alertness, and mood. (B) Circadian rhythmicity is generated by the transcription of core clock genes and their suppression by their protein products. (C) Misalignment between the endogenous circadian timing system and behavioral or environmental cycles can negatively affect mood. (D) Physical activity and eating that occurs at a nonoptimal circadian phase, leading to misalignment between central and peripheral clocks, have been implicated in the pathogenesis of mood disorder. Preliminary findings in healthy humans also suggest that alterations in the gut microbiome influence mood via circadian mechanisms (5, 61) and increase depression and anxiety-like symptoms in healthy participants (62). (E–G) Sleep disturbances, particularly insomnia, are implicated in mood dysregulation through several pathways including maladaptive emotional processing, aberrant neuroplasticity and memory consolidation, and dysregulated neurotransmitter signaling (63). For instance, depression reduces both increase in synaptic density build up during wakefulness and increase synaptic pruning during sleep (black arrow, F). We emphasize, however, the many points of interaction and synergy between sleep and circadian systems. Abbreviations: RHT, retino hypothalamic tract; RGC, retinal ganglion cells; SCN, suprachiasmatic nucleus; SCG, superior cervical ganglion; ACC, anterior cingulate cortex; PFC, prefrontal cortex.