Conventional antidepressants require 2-8 weeks for a full clinical response. In contrast, two rapidly acting antidepressant interventions, low-dose ketamine and sleep deprivation therapy, act within hours to robustly decrease depressive symptoms in a subgroup of major depressive disorder patients. Evidence that major depressive disorder 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, the authors observed widespread changes in cyclic gene expression in six regions of postmortem brain tissue of depressed patients matched with controls for time-of-death. 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 major depressive disorder patients, the expression patterns of the clock genes in brain were significantly dysregulated. Some of the most robust changes were seen in the anterior cingulate. 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 anterior cingulate 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 major depressive disorder patients. Here, the authors review data suggesting that both low-dose ketamine and sleep deprivation can modulate circadian rhythms. They hypothesize that the rapid antidepressant actions of ketamine and sleep deprivation may act, in part, to reset abnormal clock genes 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.
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Bunney BG, Li JZ, Walsh DM, Stein R, Vawter MP, Cartagena P, Barchas JD, Schatzberg AF, Myers RM, Watson SJ, Akil H, Bunney WE: Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder. Molecular Psychiatry 20(1): 48-55 (2015).
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http://www.ncbi.nlm.nih.gov/pubmed/25349171