Sleep and circadian rhythm disturbances: plausible pathways to major mental disorders?

Abstract

The Mental Health Priority Area of the Wellcome Trust recently posited that sleep and circadian rhythm disturbances (SCRDs) are a plausible nexus for linking aspects of the biology, phenomenology, course and treatment of major mood, anxiety and psychotic disorders1. This emphasis fits well with the currently spreading trend to develop more effective and scalable forms of indicated prevention, early intervention, and secondary prevention (of both primary illness progression and physical illness). This focus on SCRDs also aligns with broader studies as to why some specific periods of life (e.g., adolescence, postnatal, menopause, late life), accompanied by large shifts in the 24-hour patterns of the sleep-wake cycle, are also associated with elevated risk of major mood disorders2. Along the same line, several research groups have now prioritized understanding of chronobiology to advance the management of all phases of major mood disorders (e.g., the Chronobiology Task Force of the International Society for Bipolar Disorders)3. Developments in this area have been greatly assisted by increased understanding of the basic biology of the homeostatic circadian system – recognized by the Nobel Prize in Medicine or Physiology in 2017. Of note has been the delineation of the molecular architecture of the core circadian clock, along with the revelation that the circadian system's stability is fundamentally regulated by common environmental factors, such as the timing, intensity and spectrum of light exposure4. It appears that there are specific brain circuits in mammals by which light regulates mood, learning and activity, which are not wholly dependent on mediation by the master circadian timekeeper (the suprachiasmatic nucleus), including a recently identified region in the perihabenular nucleus. The discovery of new light-sensitive brain circuits is of extreme interest to clinical psychiatry and psychiatric epidemiology. An intriguing finding from over 80,000 adults in the UK Biobank was that more exposure to artificial light at night was associated not only with increased rates of major depression, but also with an increased incidence of several other mental disorders, including bipolar disorder, generalized anxiety disorder and post-traumatic stress disorder, as well as with higher rates of self-harm behavior and psychosis-like experiences4. As predicted on the basis of the evidence that day-time light exposure is the primary synchronizer of the circadian clock in mammals, as well as the success of bright light therapy in the treatment of mood disorders, more light exposure during the day was also associated with lower rates of mental disorders4. Triangulation of evidence from animal models, experimental studies in humans, and epidemiology has provided strong evidence for a major role of daily light exposure to good mental health. A focus on a possible causative role of SCRDs in the etiology and pathophysiology of at least some major mood disorders may surprise those who think of these disturbances as epiphenomena that accompany most mental disorders. However, recent discoveries regarding the regulation of many physiologic and behavioral parameters by the circadian system2, 3, alongside major developments in longitudinal psychiatric epidemiology5, have challenged that assumption. Indeed, it is now strongly established by studies across clinical, laboratory and field-based settings that mood disorders such as bipolar disorder are related to SCRD-relevant features, including stable trait-like profiles of delayed sleep phase, long sleep time, and preference for eveningness2, 3; delayed melatonin and core body temperature rhythms; and abnormal time relationships between circadian phase markers and the 24-hour sleep-wake cycle6. Accumulating evidence suggests that circadian dysregulation is likely to be cross-diagnostic rather than disorder-specific3, and to be especially related to key mood (e.g., affective instability), behavioral (e.g., impulsivity), cognitive (e.g., disinhibition), and immune-metabolic (e.g., insulin resistance, raised C-reactive protein blood levels) phenotypes2. Empirical advances regarding the predictive significance of prior SCRDs for the first major episode have been most evident in the mood disorders domain. SCRD-related factors such as preference for eveningness and dysregulation of social rhythms are observed in at-risk groups (e.g., offspring of a parent with bipolar disorder) as well as in youth with early bipolar disorder, and meta-analytic evidence from prospective studies suggests that a pre-existing SCRD is associated with a 40% higher risk of onset of bipolar disorder7. A study of over 2,000 adolescents and young adults seeking help from early-intervention clinics found that prior circadian disturbance predicted the transition from an earlier to a later clinical stage of major mood, anxiety or psychotic disorders8. Studies focusing on intensive longitudinal measurement of within- and between-day dynamics of mood, sleep and motor activity in adults with mood disorders – which appear to be more dysregulated and cross-reactive than those of control populations – have highlighted the need to investigate biological interfaces linking these systems, of which the homeostatic circadian system is one plausible candidate3. The circadian system appears to be a potentially important target for more personalized treatment of at least a major subgroup of those with mood disorders. The discovery that treatments such as selective serotonin reuptake inhibitors (SSRIs) may increase sensitivity to light, and thereby destabilize the circadian system in at-risk individuals, is a major concern9. This finding requires urgent replication and extension to an examination of the possible positive or negative impacts of exposures to other common interventions, such as behavioral activation, sleep restriction, mood stabilizers, antipsychotic agents, and other antidepressants. Some new agents (e.g., orexin antagonists, melatonin-based antidepressants) and older pharmacotherapies (e.g., lithium) do appear to enhance the stabilization of these systems in several animal models as well as in small studies of patients with mood disorders3. Further testing of the circadian effects of such medications, and the potential for treatment-relevant subtyping, is highly warranted2, 9. There are major hurdles to the wider application of these new insights. Accurate, real-time, and repeated detection of the true timing of the internal circadian clock, and its alignment with the external light-dark cycle, remains a major goal. Current measures are largely limited to either intensive, expensive, in-lab methods, or indirect inferences from wearable recordings of the 24-hour patterns of motor activity and sleep. Hence, a clear research focus is the development of novel methods based on 24-hour patterns of gene expression, metabolic activity, and peripheral blood or urinary markers. More sophisticated modelling techniques, based on tracking symptom clusters and objective markers earlier in the course of illness, and then longitudinally, are also required to unpick the direction of causation between these phenomena. Increased and coordinated global investment in this research area is timely, and may well lead to genuine new therapeutic insights.

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