Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder

Abstract

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD). In rats, ketamine selectively increased electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (REM) sleep and altered central brain-derived neurotrophic factor (BDNF) expression. Taken together, these findings suggest that higher SWA and BDNF levels may respectively represent electrophysiological and molecular correlates of mood improvement following ketamine treatment. This study investigated the acute effects of a single ketamine infusion on depressive symptoms, EEG SWA, individual slow wave parameters (surrogate markers of central synaptic plasticity) and plasma BDNF (a peripheral marker of plasticity) in 30 patients with treatment-resistant MDD. Montgomery-Åsberg Depression Rating Scale scores rapidly decreased following ketamine. Compared to baseline, BDNF levels and early sleep SWA (during the first non-REM episode) increased after ketamine. The occurrence of high amplitude waves increased during early sleep, accompanied by an increase in slow wave slope, consistent with increased synaptic strength. Changes in BDNF levels were proportional to changes in EEG parameters. Intriguingly, this link was present only in patients who responded to ketamine treatment, suggesting that enhanced synaptic plasticity - as reflected by increased SWA, individual slow wave parameters and plasma BDNF - is part of the physiological mechanism underlying the rapid antidepressant effects of NMDA antagonists. Further studies are required to confirm the link found here between behavioural and synaptic changes, as well as to test the reliability of these central and peripheral biomarkers of rapid antidepressant response.

Figures

Fig. 1

(a) Montgomery–Asberg Depression Rating Scale (MADRS) scores before (−60 min) and after ketamine infusion (230 min, day 1, day 2). Mixed analysis of variance (F3,84=29.48; p<0.00001) and simple effects tests (Bonferroni’s corrected) indicated that, compared to pre-infusion baseline, mood was significantly improved at 230 min post-infusion (41.46±6.62%; p<0.00001), at 1 d post-infusion (40.38±6.61%; p<0.00001) and at 2 d post-infusion (39.75±6.54%; p<0.00001). (b) Plasma log brain-derived neurotrophic factor (BDNF) levels measured before (−60 min) and after (230 min) ketamine infusion [actual means at −60 and 230 were 1948.1±402.2 (S.E.M.) and 2303.7±387.2 (S.E.M.), respectively]. The boxes indicate the 25th/75th percentile; the dashed line within the boxes marks the median. Whiskers above and below the box indicate the 90th and 10th percentiles, respectively. Empty dots represent outliers.

Fig. 2

(a) Slow wave activity (SWA) in the first three non-rapid eye movement (NREM) sleep episodes. Mixed analysis of variance (ANOVA) revealed a significant main effect for night (F2,56=7.55; p<0.01). Simple effects tests (Bonferroni’s corrected) indicated that SWA was significantly increased on the night of the infusion compared to baseline (p<0.01). Sleep cycle also significantly affected SWA (F2,56=39.9; p<0.0001). Simple effects tests (Bonferroni’s corrected) showed a progressive decline of SWA across the sleep cycles (cycle 1 vs. cycle 2: p<0.001; cycle 2 vs. cycle 3: p<0.00001; cycle 1 vs. cycle 3: p<0.0000001). Finally, a significant interaction was seen between night and sleep cycle (F4,112=2.81; p<0.05), demonstrating that SWA was increased during the first NREM sleep cycle on the night of ketamine infusion compared to baseline. (b) Normalized average power spectra for the first NREM episode of the baseline night (dashed line) and the night after ketamine infusion (solid line). Power values for each frequency bin have been normalized by the average power value of the corresponding bin across the whole baseline night NREM. Bars at the bottom represent significantly different bins (p<0.05, uncorrected). (c) Distribution of slow wave negative peak amplitude during the first NREM episode. Detected waves over the course of three nights were assigned to logarithmically increasing amplitude ranges based on their negative peak amplitude. Mixed ANOVA (F10,280=6.35; p<0.00001) and simple effects tests (Bonferroni’s corrected) demonstrated that, after the ketamine infusion, an overall increase in slow wave amplitude was observed, with a concomitant reduction in low-amplitude waves (10–20 μV negative peak) and increase in higher-amplitude waves (40–80 μV negative peak). (d) First and second-segment average slope of slow waves during the first NREM episode. Mixed ANOVA (F2,56=6.7569; p<0.01 and F2,56=5.6104, p<0.01, respectively) and simple effects tests (Bonferroni’s corrected) showed an increase of both segment slopes after ketamine infusion. Triangles indicate significance and direction of the simple effects test (p<0.01). * Indicate a trend toward significance (p<0.1). Baseline night is indicated by white bars (a, c and d). The night after the infusion (night 2) is indicated by black bars (a, c and d). Night 3 is indicated by grey bars (a, c and d).

Fig. 3

(a, left) The correlation between log brain-derived neurotrophic factor (BDNF) and slow wave activity (SWA) change scores (r=0.45, p=0.014). (a, right) The correlation between log BDNF and the incidence of high amplitude wave change scores (r=0.41, p=0.026). SWA and high amplitude slow waves incidence change scores were calculated as the difference between the night after ketamine infusion and the baseline electroencephalogram sleep night. (b, left) The correlation between SWA and BDNF in responders (r=0.595, p=0.032) and non-responders (r=0.215, p=0.424) to ketamine. Note the change in y axis scaling between responders and non-responders. (b, right) The correlation between slow wave incidence and BDNF in responders (r=0.626, p=0.022) and non-responders (r=0.033, p=0.904) to ketamine.