No abstract

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 behavioural 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 antidepressant effects of ketamine 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 behavioural 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.

Nitrous oxide (N2O) has shown promise as a putative rapid acting antidepressant but little is known about the underlying mechanisms. We have here performed transcriptomics and electrophysiological studies to dissect shared signatures acutely induced by 1-hour inhalation of 50% N2O and single subanesthetic dose of ketamine, a well-established antidepressant, in the adult mouse medial prefrontal cortex. Unbiased quantitative RNA sequencing demonstrated that several transcripts belonging to the mitogen-activated protein kinase (MAPK) pathway are similarly regulated by N2O and ketamine. In particular, both treatments increased the expression of the dual specificity phosphatases (DUSPs), negative regulators of MAPKs. N2O also rapidly reduced saccharine preference and induced expression of Dusp1 and Dusp6 in animals subjected to chronic treatment with stress hormone corticosterone. Interestingly, overall, the effects of N2O on the mRNA expression were more prominent and widespread compared to ketamine. Ketamine and to lesser extent nitrous oxide caused elevation of gamma-activity (30-100 Hz) of cortical local field potential, however firing rate and phase locking of spike-to-LFPs of neurons of this brain area showed no uniform changes across the treatments. These findings provide support for the antidepressant properties of N2O and further highlight the involvement of MAPK regulation in the mechanism of action of rapid-acting antidepressants.

We show that both pharmacological and non-pharmacological treatments of depression activate TrkB receptors - a well-established target of antidepressants - by inducing a physiological response coupled to sedation. Several rapid-acting antidepressants trigger TrkB signaling by evoking a state associated with electroencephalographic slow-wave activity, behavioral immobility, reduced cerebral glucose utilization, and lowered body temperature. Remarkably, antidepressant-induced TrkB signaling was not compromised in animals exhibiting reduced activity-dependent release of BDNF but was diminished by maintaining animals in warm ambient temperature. Most importantly, prevention of the hypothermic response attenuated the behavioral effects produced by rapid-acting antidepressant nitrous oxide. Our results suggest that the phenomenon underlying TrkB transactivation - changes in energy expenditure and thermoregulation - is essential, but not sufficient, for antidepressant responses. Indeed, regardless of differential clinical and pharmacodynamic properties, all drugs that disrupt energy metabolism and induce hypothermia activated TrkB. This study challenges pharmacology-centric hypotheses regarding antidepressant effects and highlight the role of complex changes in bioenergetics and thermoregulation.