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. ### Competing Interest Statement T.R. and S.K. are listed as co-inventors on a patent application wherein new tools enabling the development of rapid-acting antidepressants and the efficacy monitors thereof are disclosed based on the basic principles of ENCORE-D. T.R. and S.K. have assigned their patent rights to the University of Helsinki but will share a percentage of any royalties that may be received by the University of Helsinki. C.Z. is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. C.Z. is listed as co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereo-isomeric dehydro- and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. C.Z. has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. All other authors declare no conflict of interest. ### Funding Statement Funding for this work was provided in part by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH; ZIAMH002927) to Dr. Zarate (C.Z.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Not applicable to current study All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All the data are available upon request.