Functional changes in sleep-related arousal after ketamine administration in individuals with treatment-resistant depression.

Ketamine, a drug that modulates the glutamate system, is linked to changes in sleep, depression, and suicidal thoughts. In a randomized, double-blind, crossover trial, 36 people with treatment-resistant major depression and 25 healthy volunteers underwent polysomnography before and after receiving ketamine or placebo. At baseline, those with depression had less total sleep time and shorter REM latency. Ketamine increased slow-wave (delta) brain activity early in the night and both alpha and delta activity later, compared to placebo. However, ketamine did not significantly alter sleep arousal metrics or mediate its antidepressant or anti-suicidal effects through sleep changes. The findings suggest sleep-related variables are part of broader neurobiological shifts after ketamine.

Study at a glance

Abstract

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.