Baseline delta sleep ratio predicts acute ketamine mood response in major depressive disorder

Abstract

Background: Electroencephalographic (EEG) sleep slow wave activity (SWA; EEG power between 0.6 and 4Hz) has been proposed as a marker of central synaptic plasticity. Decreased generation of sleep slow waves--a core feature of sleep in depression--indicates underlying plasticity changes in the disease. Various measures of SWA have previously been used to predict antidepressant treatment response. This study examined the relationship between baseline patterns of SWA in the first two NREM episodes and antidepressant response to an acute infusion of the N-methyl-d-aspartate (NMDA) antagonist ketamine.

Methods: Thirty patients (20M, 10F, 18-65) fulfilling DSM-IV criteria for treatment-resistant major depressive disorder (MDD) who had been drug-free for two weeks received a single open-label infusion of ketamine hydrochloride (.5mg/kg) over 40 min. Depressive symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) before and after ketamine infusion. Sleep recordings were obtained the night before the infusion and were visually scored. SWA was computed for individual artifact-free NREM sleep epochs, and averaged for each NREM episode. Delta sleep ratio (DSR) was calculated as SWA(NREM1)/SWA(NREM2).

Results: A significant positive correlation was observed between baseline DSR and reduced MADRS scores from baseline to Day 1 (r=.414, p=.02).

Limitations: The sample size was relatively small (N=30) and all subjects had treatment-resistant MDD, which may limit the generalizability of the findings. Further studies are needed to replicate and extend this observation to other patient groups.

Conclusions: DSR may be a useful baseline predictor of ketamine response in individuals with treatment-resistant MDD.

Figure 1

The delta sleep ratio (DSR: quotient of the SWA from the first to the second NREM episode) during the baseline night correlated with change in Montgomery Asberg Depression Rating Scale (MADRS) score from baseline to Day 1 (r=.414, p=.02) for MDD patients in the previously published studies investigating riluzole administration post-ketamine infusion. Ketamine responders are indicated by filled circles.

Figure 2

Average Montgomery Asberg Depression Rating Scale (MADRS) ratings from baseline until Day 7 for patients separated into two groups based on a baseline threshold value of delta sleep ratio (DSR) ≤ 1. MADRS ratings over the seven days showed a significant interaction between patients with low and high DSR scores (F=2.573; df =7, 195; p=.015); individuals with low DSR scores showed a greater and sustained clinical improvement in response to ketamine than individuals with higher DSR scores.