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

Ballard and colleagues situate their study within evidence that ketamine, a glutamatergic modulator, produces rapid reductions in depressive symptoms and suicidal ideation alongside transient changes in neurophysiological and molecular biomarkers. Previous work links ketamine to shifts in awake-state electrophysiology (for example gamma power) and to sleep-related measures such as increased slow wave activity in the first non-rapid eye movement (NREM) episode. Because sleep disturbances and nocturnal hyperarousal (indexed by higher nocturnal alpha and beta power and reduced delta power) are common in major depressive disorder (MDD) and have been implicated in suicide risk, the authors argue that sleep-related electrophysiology may be an important component of ketamine's system-level actions and a potential mediator of its clinical effects. This study therefore set out to characterise sleep-related arousal in individuals with treatment-resistant depression (TRD) versus healthy volunteers (HVs), to test whether a single 0.5 mg/kg intravenous ketamine infusion normalises arousal-related sleep metrics in TRD, and to evaluate whether ketamine-induced changes in sleep metrics mediate its antidepressant and anti-suicidal effects. The investigators emphasised a combined approach using both traditional macroarchitecture sleep measures (for example wakefulness after sleep onset, total sleep time, REM latency, and post-sleep onset sleep efficiency) and functional data analysis of spectral EEG power over time (alpha, beta, delta bands) to retain temporally resolved electrophysiological information.

The analysis used data from a previously published randomised, double-blind, placebo-controlled, crossover clinical trial of intravenous ketamine (0.5 mg/kg) versus saline. Participants included unmedicated adults aged 18–65 with recurrent MDD without psychotic features who met a minimal treatment-resistance definition (failure to respond to at least one medication during the current episode) and healthy volunteers with no Axis I disorders and no first-degree relatives with Axis I disorders. After medication washout, TRD participants (n = 36; 61% female; mean age 36.4 years, SD = 10.29) and HVs (n = 25; 64% female; mean age 34.0 years, SD = 10.6) underwent polysomnography (PSG). Five PSGs were excluded for technical problems, yielding the final sample reported. Each participant had an adaptation night; PSGs were recorded the night before (baseline) and the night after (post-infusion) each infusion. For ketamine-specific hypotheses, analyses were restricted to the TRD participants' baseline and post-infusion PSGs. PSG was performed in a sleep laboratory with standard EEG, electrooculogram and submental electromyogram channels, and 30-second epochs were scored blind to diagnosis and treatment using Rechtschaffen and Kales criteria. Macroarchitecture measures derived were wakefulness after sleep onset (WASO; hours awake between sleep onset and Lights-On), total sleep time (TST; hours asleep after sleep onset until Lights-On), REM latency (minutes from sleep onset to first REM epoch), and post-sleep onset sleep efficiency (PSOSE; TST divided by time between sleep onset and Lights-On). Functional spectral analyses measured normalised alpha, beta and delta power across 605 30-second epochs (approximately 5.04 hours) beginning at the first NREM Stage 2 epoch (defined as sleep onset here). For time-resolved spectral analyses, the investigators used multilevel function-on-scalar regression (FoSR) to model EEG power as a smooth function of time and to preserve temporal dynamics across the five-hour window; inference employed the Fast Univariate Inference (FUI) approach with 95% joint confidence bands (implemented via the R package fastFMM). Macroarchitecture comparisons used mixed-effects models: linear mixed models for WASO (log-transformed due to right skew) and TST (transformed by subtracting from eight then log-transforming), a beta-distributed generalised linear mixed model with logit link for PSOSE, and a Cox proportional hazards model for REM latency with robust standard errors to account for two nights per person. Ketamine effects in TRD were tested with analogous within-person mixed models including covariates (age, sex, infusion number, period-specific and average baseline values). Mediation analyses followed the Baron and Kenny approach: first testing ketamine's effect on outcomes (Day 1 suicidal ideation and MADRS*), then ketamine's effect on EEG spectral functions, and finally whether spectral functions predicted clinical outcomes via scalar-on-function mixed-effects regression. No correction for multiple comparisons was applied; all analyses were performed in R.

Baseline diagnostic comparisons. Function-on-scalar regression suggested a general pattern of lower alpha, beta and delta power in the TRD group during the earlier part of the five-hour post-sleep onset interval, but 95% joint confidence bands included zero throughout and these spectral differences were therefore not statistically significant. In contrast, macroarchitecture showed significant diagnostic differences: total sleep time was lower in TRD than HVs (b = 0.36, SE = 0.12, p = 0.006; approximated Cohen's f2 = 0.14). REM latency was shorter in TRD with a greater event hazard (b = 0.48, SE = 0.20, p = 0.04); the median time to first REM epoch in TRD was 55 minutes, while the extracted text did not clearly report the corresponding HV median. No baseline diagnostic differences were observed for WASO (b = 0.005, SE = 0.19, p = 0.98) or PSOSE (b = 0.01, SE = 0.18, p = 0.94). Ketamine effects on spectral dynamics in TRD. Comparing post-ketamine to post-placebo nights within TRD participants, multilevel FoSR analyses with 95% joint confidence bands supported significant increases in EEG power across all three frequency bands, with temporally specific patterns. Delta power showed recurring significant increases at multiple intervals across the five-hour window. Alpha power increases were detected primarily at the end of the five-hour period. Beta power increases were observed in the middle portion of the night. These spectral effects were detected despite no concurrent effects on macroarchitecture. Macroarchitecture, clinical response and mediation. Ketamine produced the expected clinical effects in this subset: Day 1 suicidal ideation decreased (p = 0.01) and Day 1 MADRS* scores declined (p < 0.01). However, ketamine did not produce detectable changes in macroarchitecture measures (WASO, TST, PSOSE, REM latency) relative to placebo in the TRD sample, and interaction terms testing whether post-infusion macroarchitecture mediated ketamine's clinical effects were non-significant (p > 0.05 for all). Mediation testing of functional spectral variables likewise did not support mediation of ketamine's antidepressant or anti-suicidal effects by post-infusion alpha, beta or delta power functions; there was a trend for delta power mediating antidepressant effects (p = 0.06) but this did not reach conventional significance. The extracted text reports no significant mediation effects for macroarchitecture measures either.

Ballard and colleagues interpret their findings as evidence that ketamine produces temporally specific changes in sleep-related electrophysiology in individuals with TRD without appreciably altering conventional sleep macroarchitecture measures in the night following infusion. The study replicated baseline features of depression in PSG macroarchitecture—reduced total sleep time and shortened REM latency—but baseline spectral differences were smaller than hypothesised and directionally inconsistent with some expectations, a result the authors note was not statistically significant. They highlight that ketamine increased delta power at recurring intervals during the recorded night and produced later-night increases in alpha and mid-night increases in beta power; these latter spectral effects were contrary to the initial hypotheses but are framed as plausible indicators of altered cortical excitability or plasticity. The authors position the temporal spectral findings relative to prior literature showing ketamine-linked increases in slow wave activity during the first NREM episode and parallels with recovery sleep after sleep deprivation, suggesting possible shared mechanisms between ketamine and sleep-deprivation therapy. They also note relationships with circadian and clock-gene effects reported for both ketamine and sleep deprivation, arguing for a systemic, 24-hour perspective on ketamine's neurobiology. Methodologically, the investigators emphasise the value of functional data analysis for preserving temporally rich EEG information across the night, arguing that this approach captures dynamics lost when PSG is reduced to stage-based summary metrics. Key limitations acknowledged by the authors include sample size and power constraints (the parent trial was powered to detect large effects), the inpatient status of TRD participants versus greater schedule flexibility among HVs (a potential confound with group), the absence of comprehensive self-report sleep measures beyond insomnia items in depression scales, and the focus on a severe TRD sample which limits generalisability. The authors further observe that mediation and moderator analyses of ketamine response face statistical challenges and that larger samples may be required to detect small-to-moderate neurobiological mediators. Strengths highlighted include the placebo-controlled, double-blind, crossover design with within-person comparisons, medication washout prior to PSG in TRD participants, and inclusion of HV PSG data for contextualising diagnostic differences. Finally, the authors recommend replication of these FDA-based findings, investigation of whether the spectral signatures are ketamine-specific or common to rapid-acting antidepressant interventions, and extension to broader clinical samples and complementary self-report measures of sleep quality.