Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder

Abstract

Conventional antidepressants require 2–8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation (SD) therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder (MDD) patients. Evidence that MDD may be a circadian-related illness is based, in part, on a large set of clinical data showing that diurnal rhythmicity (sleep, temperature, mood and hormone secretion) is altered during depressive episodes. In a microarray study, we observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death (TOD). We screened 12 000 transcripts and observed that the core clock genes, essential for controlling virtually all rhythms in the body, showed robust 24-h sinusoidal expression patterns in six brain regions in control subjects. In MDD patients matched for TOD with controls, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in anterior cingulate (ACC). These findings suggest that in addition to structural abnormalities, lesion studies, and the large body of functional brain imaging studies reporting increased activation in the ACC of depressed patients who respond to a wide range of therapies, there may be a circadian dysregulation in clock gene expression in a subgroup of MDDs. Here, we review human, animal and neuronal cell culture data suggesting that both low-dose ketamine and SD can modulate circadian rhythms. We hypothesize that the rapid antidepressant actions of ketamine and SD may act, in part, to reset abnormal clock genes in MDD to restore and stabilize circadian rhythmicity. Conversely, clinical relapse may reflect a desynchronization of the clock, indicative of a reactivation of abnormal clock gene function. Future work could involve identifying specific small molecules capable of resetting and stabilizing clock genes to evaluate if they can rapidly relieve symptoms and sustain improvement.

Depressive disorders: Processes leading to neurogeneration and potential novel treatments

“…However, when supplemented with both medication and sleep phase advance by bright light therapy (SPA) the response may be continued for up to several months. In one study in post-mortem brain tissue it was shown that core clock gene expression shows robust 24 hr rhythms in six brain regions in control subjects that were significantly disrupted in patients with MDD (Bunney et al, 2015). Most robust changes were seen in the ACC.…”

Sex differences in the circadian regulation of sleep and waking cognition in humans

“…In view of the pervasiveness of circadian rhythms, it is not surprising that they affect many aspects of physiology, behavior, and cognition in health and in disease. Indeed, circadian abnormalities have been implicated in disorders of sleep, mood, and cognition (6), in deleterious responses to shift work (7), depression (8), and Alzheimer's disease (9). The prevalence of most of these disorders is higher in women than in men (10), and their impact on psychological functions and quality of life of patients differs between the sexes (11).…”

The Underrated Circadian System and Its Contribution to Neurodegeneration in Mood Disorders

“…The disruption of circadian oscillator functions in depression has been recently discussed 4 . Such findings were also demonstrated in post-mortem brain tissue: while core clock gene expression exhibited robust 24 hr-rhythms in six brain regions of control subjects, the oscillations of 11 clock genes were significantly disrupted in MDD, as shown in 34 patients 53 . In the brains of depressive patients, structural changes were clearly apparent, especially in the anterior cingulate cortex, in which the volume of grey matter was reduced 53,54 .…”