A wake-up call - revealing the oversight of sleep physiology and related translational discrepancies in studies of rapid-acting antidepressants

Depression and sleep problems go hand-in-hand, while clinical improvement often emerges along the normalization of sleep architecture and realignment of the circadian rhythm. Antidepressant effects of sleep deprivation and cognitive behavioral therapy targeted at insomnia further demonstrate the confluence of sleep and mood. Moreover, recent literature showing that ketamine influences many processes related to sleep-wake neurobiology, have led to novel hypotheses explaining rapid and sustained antidepressant effects. Surprisingly, studies addressing ketamine’s antidepressant effects have had a narrow focus on solely on pharmacological aspects and often ignore the role of physiology. To illustrate this discrepancy, we conducted a literature review on articles around rapid-acting antidepressants published between 2009-2019. A gross keyword check indicated overall ignorance of sleep in most studies. To investigate the topic closer, we focused on the most cited preclinical and clinical research papers. Circadian rhythm, timing of drug administration and behavioral tests relative to light cycles, sleep, and their potential association with experimental observations were mentioned only in a handful of the papers. Most importantly, in preclinical reports the treatments have been preferentially delivered during the inactive period, which is polar opposite to clinical practice and research. We hope this report serves as a wake-up call for sleep in the field and urges (re)examining rapid-acting antidepressant effects from the perspective of wake-sleep physiology.