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, postinfusion day 1 (D1), and day 3 (D3) were measured in 51 patients with major depressive disorder or bipolar disorder.

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 nonresponders were found at baseline, D1, and D3. At baseline, a phase-advanced activity pattern and lower mesor distinguished subsequent responders from nonresponders. On D1, ketamine nonresponders 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 nonresponders.

Conclusions: The findings are the first to demonstrate an association between ketamine's clinical antidepressant effects and circadian timekeeping. The results suggest that traitlike 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.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: Clock genes; Neuroplasticity; Sleep deprivation; Slow wave sleep; Wrist activity.

Published by Elsevier Inc.

Figures

Figure 1

A) Baseline circadian parameter estimates of amplitude, time of peak phase (acrophase), and mesor in ketamine responders and non-responders. Phase-advanced 24-hour activity and decreased central value (mesor) were associated with rapid antidepressant response to ketamine. B) Ketamine’s effects on the 24-hour pattern of wrist activity for ketamine-treated patients on Day 1 (D1) after infusion compared with placebo. Ketamine decreased the mesor without changing the amplitude or phase of activity. The mesor of the 24-hour activity pattern was lower for ketamine versus placebo treatment (p=.0317). C) Baseline (BL), D1, and D3 patterns of wrist activity for ketamine-treated patients who responded (> 50% decrease in MADRS scores) within one day of ketamine infusion compared with patterns of non-responders. Raw MADRS scores for each cohort are shown as bar chart inserts for each day. Left panel: At baseline prior to infusion, subsequent D1 responders (Rs) are compared with D1 Non-responders (NRs). During baseline, the mesor (p=.006) and the phase (p=.019) of the baseline 24-hour activity patterns are different in D1 responders versus non-responders. Middle Panel: Responders compared with Non-Responders on D1 after ketamine infusion. On D1, the phase of the 24-hour pattern of activity in ketamine responders differed from non-responders (p=.0038). Right Panel: Responders who maintained the 50% decrease in MADRS score on D3 compared with patients who did not meet response criteria on D3. On D3, the mesor (p=.0202) and amplitude (p =.0488) of the 24-hour pattern significantly differed between responders and non-responders. Filled circles correspond to mean activity counts/minute in hourly bins ± SEM. The dotted sinusoidal curves correspond to the best fit line to the 24-hour data for each group. The dotted horizontal line (mesor) corresponds to the estimated 24-hour average (mesor) of the curve fits to each group. Group sizes are: baseline and D1 (responders=21, non-responders=30) and D3 (responders=13, non-responders=35).

Figure 2

A model of rapid mood response to ketamine is shown that incorporates the temporal interactions of sleep, plasticity, and clock-associated genes. In this schematic, ketamine’s rapid antidepressant effects and individuals’ subsequent relapse are related to the interaction of sleep homeostasis (process S) and circadian (process C) processes. While depressed (1), sleep loss, stress, environmental, and genetic factors are associated with diminished sleep homeostatic (S) and circadian (C) mechanisms, weakening S-C interactions, and promoting depressed mood (M-). (2) Acutely (four to 24 hours) after ketamine infusion, ketamine rapidly increases plasticity and improves mood (M+), as well as increases sleep slow waves (SWS) and sleep quality. Simultaneously, ketamine acts on clock controlled gene (CCG) associated molecules to alter timing and diminish circadian output, thus weakening the S-C interaction and lessening the circadian mood component. (3) During a continued antidepressant response, the interaction between S and C is strengthened as increased S acts on C, thus facilitating and re-establishing a more functional S-C interaction, greater temporal organization of the transcriptome, continued mood improvement (M+), and potentially contributing to a durable response (4). Alternatively a weakened S-C interaction is associated with relapse.