Abstract
Depression is frequently associated with sleep problems, and clinical improvement often coincides with the normalization of sleep architecture and realignment of circadian rhythm. The effectiveness of treatments targeting sleep in depressed patients, such as sleep deprivation, further demonstrates the confluence of sleep and mood. Moreover, recent studies showing that the rapid-acting antidepressant ketamine influences processes related to sleep-wake neurobiology have led to novel hypotheses explaining rapid and sustained antidepressant effects. Despite the available evidence, studies addressing ketamine’s antidepressant effects have focused on pharmacology and often overlooked the role of physiology. To explore this discrepancy in research on rapid-acting antidepressants, we examined articles published between 2009–2019. A keyword search algorithm indicated that vast majority of the articles completely ignored sleep. Out of the 100 most frequently cited preclinical and clinical research papers, 89 % and 71 %, respectively, did not mention sleep at all. Furthermore, only a handful of these articles disclosed key experimental variables, such as the times of treatment administration or behavioral testing, let alone considered the potential association between these variables and experimental observations. Notably, in preclinical studies, treatments were preferentially administered during the inactive period, which is the polar opposite of clinical practice and research. We discuss the potential impact of this practice on the results in the field. Our hope is that this perspective will serve as a wake-up call to (re)-examine rapid-acting antidepressant effects with more appreciation for the role of sleep and chronobiology.
Highlights
The discovery of ketamine’s rapid antidepressant effects is arguably one of the most substantial advances in modern psychiatry
It should be noted that the most widely used clinical guide lines (CONSORT, SPIRIT, and TIDieR) do not clearly state the necessity of disclosing time of day and focus instead on other time-associated variables, such as treatment duration and frequency (Chan et al, 2013; Hoffmann et al, 2014; Schulz et al, 2010). These guidelines were initially issued to enhance the quality of research because it was found that important details that enable replication of clinical trials, including time-associated variables, were missing from half of the publications (Chan et al, 2013; Glasziou et al, 2008)
To the best of our knowledge, the impact of sleep or circadian time of drug administration has not been systematically evaluated in the context of treatment efficacy or potential translational bias in studies involving ketamine or other rapid-acting antidepressants
Summary
The discovery of ketamine’s rapid antidepressant effects is arguably one of the most substantial advances in modern psychiatry. Another study has suggested that baseline delta sleep ratio is a useful predictor for the antidepressant effects of ketamine (Duncan et al, 2013a) These and other observations have led to hypotheses proposing that the interplay of increased synaptic strength and the neurobiological processes that occur during SWA is important for the emergence of rapid antidepressant effects as well as their sustainability (Duncan et al, 2019; Goldschmied and Gehrman, 2019; Rantamaki and Kohtala, 2020; Wolf et al, 2016). It is tempting to speculate that some of the effects attributed to ketamine and other putative antidepressants in preclinical research may originate from unaccounted effects associated with the prolonged wakefulness of experimental animals resulting from the administration of stimulatory treatments in the early inactive period This possibility further emphasizes the need to disclose the circadian time of treatment while reporting research in order to enable replication and proper comparison of results. These guidelines were initially issued to enhance the quality of research because it was found that important details that enable replication of clinical trials, including time-associated variables, were missing from half of the publications (Chan et al, 2013; Glasziou et al, 2008)
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