Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling

Abstract

Background: The glutamatergic modulator ketamine has rapid antidepressant effects in individuals with major depressive disorder and bipolar depression. Thus, modulating glutamatergic transmission may be critical to effectively treating depression, though the mechanisms by which this occurs are not fully understood.

Methods: This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free major depressive disorder subjects and 18 heathy controls who received a single i.v. infusion of ketamine hydrochloride (0.5 mg/kg) as well as an i.v. saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6 to 9 hours after both ketamine and placebo infusions. During scanning, participants passively received tactile stimulation to the right index finger. Antidepressant response was assessed across timepoints using the Montgomery-Asberg Depression Rating Scale. Dynamic causal modeling was used to measure changes in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates in major depressive disorder subjects and controls using a simple model of somatosensory evoked responses.

Results: Both major depressive disorder and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with major depressive disorder subjects showing enhanced NMDA connectivity estimates in backward connections and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our major depressive disorder subject group, ketamine efficacy, as measured by improved mood ratings, correlated with reduced NMDA and AMPA connectivity estimates in discrete extrinsic connections within the somatosensory cortical network.

Conclusions: These findings suggest that AMPA- and NMDA-mediated glutamatergic signaling play a key role in antidepressant response to ketamine and, further, that dynamic causal modeling is a powerful tool for modeling AMPA- and NMDA-mediated connectivity in vivo.

Clinicaltrials.gov: NCT#00088699.

Keywords: dynamic causal modeling; ketamine; magnetoencephalography; major depressive disorder.

Published by Oxford University Press on behalf of CINP 2018. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Figures

Figure 1.

Source locations, model architecture, and example model fits. (A) Evoked gamma frequency (30–58 Hz) source-localized estimates of the main effect of ketamine for all participants, thresholded at P<.05 corrected. (B) A simple model architecture was used that included subcortical inputs to left primary somatosensory cortex and lateral connections to right primary somatosensory cortex. Forward and backward recurrent extrinsic connections carried signals from S1 to frontal cortex, bilaterally. (C) Example model fits showing measured wide-band (1–42 Hz) virtual electrode signals (observed) from left S1 (blue), right S1 (red), left frontal (orange), and right frontal (purple) sources compared with the estimated signal from the fitted model (predicted).

Figure 2.

Dynamic causal modeling (DCM) model and NMDA-mediated effects in vivo. (A) The CMM_NMDA model included four distinct cell layers: superficial pyramidal cells, spiny stellates, inhibitory interneurons, and deep pyramidal cells. Superficial pyramidal cells carry forward extrinsic signals to excitatory spiny stellate cells. Deep pyramidal cells carry backward extrinsic signals to both superficial pyramidal cells and inhibitory interneurons. B. A comparison of between-subject differences in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates found significantly increased NMDA-mediated connectivity following ketamine administration in the backward connection from right frontal cortex to right S1 in subjects with major depressive disorder (MDD) compared to controls. C. A comparison of within-subject differences in AMPA- and NMDA-mediated connectivity estimates found significantly increased NMDA-mediated connectivity following ketamine administration compared to placebo administration in the forward connection from right S1 to right frontal cortex in our controls.

Figure 3.

N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) estimates following ketamine administration and improved mood. (A) NMDA estimates following ketamine administration were compared with change in Montgomery-Asberg Depression Rating Scale (MADRS) scores at several timepoints: ketamine minus baseline, ketamine minus placebo, and 11 days post-ketamine minus baseline. A significant correlation was observed between the NMDA parameter estimate from the lateral connection between right S1 and left S1 and change in MADRS scores from baseline to ketamine and placebo to ketamine. (B) Post-ketamine administration, AMPA estimates were compared with change in MADRS score at the same timepoints. A significant correlation was observed between the AMPA parameter estimate from the forward connection between left S1 and left frontal cortex and change in MADRS scores from baseline to ketamine and placebo to ketamine. This same parameter estimate approached significance with change in MADRS score from baseline to 11 days post-ketamine infusion (P=.05).