Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment-resistant major depression

Abstract

Background: Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine.

Methods: Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores.

Results: Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders.

Conclusions: These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.

Trial registration: ClinicalTrials.gov NCT00088699.

Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Timeline of ketamine session. Patients received a single open-label infusion of ketamine (.5 mg/kg) over 40 m (Ket). Patients' depressive, dissociative and psychotic symptoms were assessed before the infusion and at several time points afterwards (indicated by arrows). Depressive symptom change at 230 m was used to define responder and non-responder groups. Blood draws to measure plasma metabolite concentrations were taken around the same times following the infusion. Post-ketamine MEG recordings (MEG) were made ≈6.5 h after the start of infusion. An oral dose of riluzole (50 mg) or placebo was administered ≈1 h before MEG recordings.

Figure 2

Depressive symptoms improve after ketamine. A, Depressive symptoms measured by the Montgomery-Asberg Depressive Rating Scale (MADRS) decrease 40 m following the infusion and remain low through 230 m. B, Patients were divided into responders (Resp, N = 9) and non-responders (Non-Resp, N = 11) based on percent change in MADRS scores. C, Psychotic symptoms measured by the Brief Psychiatric Rating Scale-positive symptoms subscale (BPRS-pos) decrease after 80 m and remain low through 230 m. D, Dissociative symptoms measured by the Clinician Administered Dissociative States Scale (CADSS) spike at 40 m but return to baseline by 80 m post-infusion. *significantly different than baseline (−60 m, Bonferroni-corrected)

Figure 3

Tactile stimulation of the left and right finger elicits an early stimulus-evoked response that is localized to left and right primary SS ctx. A, Grand-averaged (N = 20) Stockwell time-frequency plots before (Pre-Ket) and after ketamine administration (Post-Ket) show robust stimulus-evoked power to the tactile stimulus (relative to a pre-stimulus baseline) in sensors overlying the contralateral hemisphere (colored circles). B, Source analyses of evoked power (relative to pre-stimulus power) revealed peaks in left and right central sulci (BA 3/4). Whole brain maps of evoked power are statistically thresholded based on one-sample t tests (false discovery rate = .001) and overlayed on a standardized brain template.

Figure 4

Rapid improvement in depressive symptoms following ketamine is linked to increased SS ctx excitability. A, Stimulus-evoked SS ctx gamma-band responses from pre- to post-ketamine infusion, collapsed across left and right hemispheres and contralateral and ipsilateral stimulation, were selectively increased in responders (N = 9, right) but not non-responders (N= 11, left). Solid lines represent individual patients, and the dotted lines represent the group means. B, Post-ketamine SS ctx responses were positively correlated with plasma norketamine levels (40 m relative to the start of infusion) in responders (right) but not non-responders (left).