A study examined the effects of ketamine on sleep arousal metrics in individuals with treatment-resistant depression (TRD) vs. healthy volunteers, finding that ketamine increases certain sleep-related brain activities but does not significantly mediate its antidepressant effects through these sleep changes.
Highlights:
- Individuals with TRD had lower total sleep time and shorter REM latency compared to healthy volunteers.
- Ketamine increased delta power earlier in the night and alpha and delta power later in the night, indicating changes in sleep-related brain activity.
- The sleep changes observed did not mediate ketamine’s antidepressant or anti-suicidal effects.
- These results suggest that while ketamine affects sleep-related brain activity, these changes do not directly contribute to its therapeutic effects on depression and suicidal ideation.
Source: Translational Psychiatry (2024)
Major Findings: Ketamine’s Effect on Sleep in Depression & Healthy Adults (2024)
1. Baseline Sleep Differences (Depression vs. Healthy)
Total Sleep Time (TST): Individuals with treatment-resistant depression (TRD) had significantly lower total sleep time compared to healthy volunteers (HVs) (p = 0.006).
REM Latency: TRD participants exhibited shorter REM latency (time to first REM episode) compared to HVs (p = 0.04).
Sleep Architecture: There were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power between TRD and HV groups.
2. Effects of Ketamine on Sleep Metrics in Depression
Delta Power (Early in Night): Ketamine administration resulted in increased delta power earlier in the night. Delta power is typically associated with deep sleep, suggesting an enhancement in the quality of sleep stages involving restorative processes.
Alpha & Delta Power (Later in the Night): Both alpha (associated with quiet wakefulness) and delta power were elevated later in the night after ketamine administration compared to placebo. This indicates that ketamine induces specific temporal changes in sleep-related brain activity.
Beta Power (Middle of Night): There was a significant increase in beta power (associated with alert wakefulness) in the middle of the night post-ketamine administration.
3. No Significant Ketamine Effects on Sleep Macroarchitecture Arousal Metrics
Wakefulness After Sleep Onset (WASO): There were no significant differences in WASO between the ketamine and placebo conditions.
Total Sleep Time (TST): Ketamine did not significantly alter the TST in TRD participants when compared to placebo.
Post-Sleep Onset Sleep Efficiency (PSOSE): No significant changes were observed in PSOSE after ketamine administration.
REM Latency: Ketamine did not significantly affect REM latency compared to placebo.
4. Lack of Mediation Effects by Sleep Variables
Antidepressant and Anti-Suicidal Effects: The changes in sleep-related arousal metrics (alpha, beta, and delta power) did not mediate ketamine’s rapid antidepressant or anti-suicidal effects.
Temporal Dynamics: Although ketamine induced specific temporal changes in sleep-related brain activity, these changes did not significantly contribute to its therapeutic effects on depression and suicidal ideation.
Does Ketamine Impact Sleep of Depressed vs. Healthy Adults Differently?
Yes, ketamine impacts the sleep of depressed adults differently than healthy adults.
Baseline Sleep Differences: Depressed adults (TRD) sleep less and fall into REM sleep faster than healthy adults.
Changes in Deep Sleep (Delta Power)
Depressed Adults: Ketamine increases deep sleep earlier in the night.
Healthy Adults: No significant changes in deep sleep with ketamine.
Quiet Wakefulness (Alpha Power)
Depressed Adults: Ketamine increases alpha power later in the night, affecting periods of quiet wakefulness.
Healthy Adults: Alpha power remains unchanged with ketamine.
Alertness During Sleep (Beta Power)
Depressed Adults: Ketamine increases beta power, leading to more alertness during sleep periods.
Healthy Adults: Beta power is not affected by ketamine.
Overall Sleep Metrics
Depressed Adults: Ketamine does not significantly improve overall sleep duration, efficiency, or wakefulness after sleep onset.
Healthy Adults: These sleep metrics remain stable and unaffected by ketamine.
Ketamine-Related Sleep Changes Aren’t Responsible for its Antidepressant Effects
Researchers used a combination of rigorous study design, detailed data analysis, and specific findings to determine that the sleep changes induced by ketamine are not responsible for its antidepressant effects.
1. Rigorous Study Design
Participants received both ketamine and a placebo at different times, allowing a direct comparison of their effects within the same individuals.
2. No Mediation Effects (Sleep Stages vs. Depression Improvement)
The study specifically tested whether changes in sleep-related brain activity (delta, alpha, and beta power) mediated the antidepressant effects of ketamine.
The results showed no mediation, meaning that the sleep changes did not explain the improvements in depression symptoms.
3. No Significant Improvement in Overall Sleep Quality
Ketamine did not significantly improve key measures of sleep quality, such as total sleep time, wakefulness after sleep onset, or sleep efficiency.
If the sleep changes were responsible for the antidepressant effects, significant improvements in these overall sleep metrics would be expected.
4. Timing of Sleep Changes
The changes in sleep-related brain activity were specific to certain times during the night (e.g., increased deep sleep earlier, increased alertness in the middle of the night).
These specific timing changes did not align with the pattern of depression symptom improvement, which suggests that the sleep changes and antidepressant effects are not directly connected.
5. Direct Measurement of Depression Symptoms
Researchers used established clinical scales, such as the Montgomery-Asberg Depression Rating Scale, to measure depression symptoms before and after ketamine administration.
The significant improvements in these scores did not correlate directly with the sleep changes, indicating that other factors are responsible for the antidepressant effects.
Study Recap: Ketamine’s Effects on Sleep in Depression vs. Healthy Adults (2024)
The primary aim of the study was to evaluate the impact of ketamine on sleep-related arousal metrics in individuals with treatment-resistant depression (TRD) compared to healthy volunteers (HVs).
Sample
Participants: The study included 61 participants, consisting of 36 individuals with TRD and 25 HVs.
TRD Group:
- Age: Mean age 36.4 years (SD = 10.29)
- Gender: 61% female
- Diagnostic Criteria: Diagnosed with recurrent major depressive disorder (MDD) without psychotic features, characterized as non-responsive to at least one psychiatric medication during the current depressive episode.
- Medication: Free from psychiatric medications for at least two weeks prior to baseline assessment.
Healthy Volunteers (HVs):
- Age: Mean age 34.0 years (SD = 10.6)
- Gender: 64% female
- Diagnostic Criteria: No Axis I disorders and no first-degree relatives with Axis I disorders.
Methods
Design:
- A secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial.
- Participants received intravenous ketamine (0.5 mg/kg) and saline placebo in two crossover periods, separated by two weeks.
Polysomnography (PSG):
- Conducted one day before and one day after ketamine/placebo infusions.
- Measured sleep arousal using spectral power functions (alpha, beta, delta) and sleep macroarchitecture variables (WASO, TST, REM latency, PSOSE).
Data Analysis:
- Functional data analysis (FDA) to evaluate temporal patterns of alpha, beta, and delta power over the first five hours of sleep.
- Linear mixed models to assess diagnostic differences and the impact of ketamine on sleep macroarchitecture metrics.
- Mediation analysis to determine if sleep-related arousal mediates ketamine’s antidepressant and anti-suicidal effects.
Limitations
- Sample Size: The study was powered to detect large effect sizes, limiting the ability to detect small or medium effects.
- Inpatient vs. Outpatient: TRD participants were inpatients, whereas HVs were primarily outpatients, potentially leading to differences in daily schedules and sleep patterns.
- Sleep Measures: The study focused on objective PSG measures and did not include self-reported sleep quality metrics, which could provide additional insights.
- Generalizability: The sample consisted of individuals with severe TRD, limiting the generalizability of findings to other depression severities or psychiatric diagnoses.
- Transient Effects: The study measured sleep changes shortly after ketamine administration, and longer-term effects were not assessed.
Conclusion: Ketamine’s Effect on Sleep
This study demonstrates that while ketamine induces specific changes in sleep-related brain activity in individuals with treatment-resistant depression (TRD), these changes do not mediate its antidepressant effects.
Despite alterations in delta, alpha, and beta power during sleep, key sleep quality metrics such as total sleep time and sleep efficiency did not significantly improve with ketamine administration.
The improvements in depression symptoms observed are likely due to other mechanisms, such as ketamine’s impact on brain chemistry and neuroplasticity.
Therefore, the therapeutic effects of ketamine on depression are not directly linked to the sleep changes it induces, highlighting the need for further research to fully understand its complex mechanism of action.
References
- Study: Functional changes in sleep-related arousal after ketamine administration in individuals with treatment-resistant depression (2024)
- Authors: Elizabeth D Ballard et al.
