Motor-Activity Markers of Circadian Timekeeping Are Related to Ketamine’s Rapid Antidepressant Properties

Abstract

Background The rapid clinical antidepressant effects of the glutamatergic modulator ketamine may be due to its ability to restore synaptic plasticity and related effects on sleep-wake and circadian systems. Preclinical studies indicate that ketamine alters expression of circadian clock-associated molecules, and clinical studies of ketamine on plasticity-related biomarkers further suggest an association with sleep slow waves and sleep homeostasis. Methods Wrist activity monitors were used to examine the pharmacologic and rapid antidepressant effects of ketamine on markers of circadian timekeeping (amplitude and timing) in mood disorders. Circadian amplitude and timing of activity at baseline, post-infusion Day1 (D1), and Day3 (D3) were measured in 51 patients with major depressive disorder (MDD) or bipolar disorder (BD). Results Compared with either placebo or baseline, a mood-independent decrease of the central circadian value (mesor) was present on D1 after ketamine treatment. Mood-associated circadian effects between rapid (D1) responders and non-responders were found at baseline, D1, and D3. At baseline, a phase-advanced activity pattern and lower mesor distinguished subsequent responders from non-responders. On D1, ketamine non-responders had a lower mesor and a blunted 24-hour amplitude relative to baseline. On D3, patients with a persisting clinical response exhibited a higher amplitude and mesor compared with non-responders. Conclusions The findings are the first to demonstrate an association between ketamine’s clinical antidepressant effects and circadian timekeeping. The results suggest that trait-like circadian activity patterns indicate rapid mood response to ketamine, and that mediators of continuing ketamine-induced mood changes include altered timing and amplitude of the circadian system.

24-h Activity Rhythms and Health in Older Adults

“…There is evidence that these associations are independent of medication use [56], but we also know that some 24-h activity rhythm disturbances are related to medication use. For example, eveningness and phase delay potentially hamper the efficacy of antidepressants [58, 59•], and ketamine might improve 24-h activity rhythms, independent of its effect on mood [60].…”

Circadian Misalignment and Bipolar Disorder

“…This may be due to the time required to normalize the whole-body circadian rhythm, which is the reason why antidepressants have a delayed therapeutic response. Recently, three antidepressant modalities have become the focus of research because of their very rapid antidepressant effect: sleep deprivation, electroconvulsive therapy, and ketamine therapy [19][20][21]. Previous evidence suggests that the mechanism underlying the antidepressant effect is a process in which the delayed circadian rhythm is restored to normal by treatment [22].…”

Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment‐resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans

“…Several studies have demonstrated that ketamine enhanced rapid eye movement (REM) sleep and significantly increased levels of brain-derived neurotrophic factor (BDNF), a synaptic protein correlated strongly with slow-wave activity (SWA), to improve BDNFmediated synaptic plasticity and depressive symptoms (Ballard et al, 2016;Duncan et al, 2017;Evans et al, 2018;Monteggia & Zarate, 2015;Zarate & Machado-Vieira, 2017). These findings suggest the involvement of circadian and sleep rhythms in the rapid, antidepressant response to ketamine.…”

“…Further comparative transcriptomics analyses revealed that several key rhythmic genes (e.g., Ciart, Per2, Npas4, Dbp, and Rorb) were differentially expressed in the brain in response to ketamine treatment in mice (Orozco‐Solis et al, ). Several studies have demonstrated that ketamine enhanced rapid eye movement (REM) sleep and significantly increased levels of brain‐derived neurotrophic factor (BDNF), a synaptic protein correlated strongly with slow‐wave activity (SWA), to improve BDNF‐mediated synaptic plasticity and depressive symptoms (Ballard et al, ; Duncan et al, ; Evans et al, ; Monteggia & Zarate, ; Zarate & Machado‐Vieira, ). These findings suggest the involvement of circadian and sleep rhythms in the rapid, antidepressant response to ketamine.…”