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Int J Neuropsychopharmacol. 2018 Apr 13. doi: 10.1093/ijnp/pyy041. [Epub ahead of print]

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

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Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.



The glutamatergic modulator ketamine has rapid antidepressant effects in individuals with major depressive disorder (MDD) 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.


This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free MDD subjects and 18 heathy controls who received a single intravenous infusion of ketamine hydrochloride (0.5 mg/kg) as well as an intravenous saline placebo. Magnetoencephalographic (MEG) recordings were collected prior to the first infusion and six to nine 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 (MADRS). Dynamic causal modeling (DCM) was used to measure changes in -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates in MDD subjects and controls using a simple model of somatosensory evoked responses.


Both MDD and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with MDD subjects showing enhanced NMDA connectivity estimates in backward connections, and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our MDD 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.


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


[Available on 2019-04-13]

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