Default Mode Connectivity in Major Depressive Disorder Measured Up to 10 Days After Ketamine Administration

Abstract

Background: The symptoms of major depressive disorder (MDD) are rapidly alleviated by administration of a single dose of the glutamatergic modulator ketamine. However, few studies have investigated the potential sustained neural effects of this agent beyond immediate infusion. This study used functional magnetic resonance imaging to examine the effect of a single ketamine infusion on the resting state default mode network (DMN) at 2 and 10 days after a single ketamine infusion in unmedicated subjects with MDD as well as healthy control subjects (HCs).

Methods: Data were drawn from a double-blind, placebo-controlled crossover study of 58 participants (33 with MDD and 25 HCs) who received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 separate test days spaced 2 weeks apart. Eight minutes of functional magnetic resonance imaging resting state data was acquired at baseline and at about 2 and 10 days after both infusions. The DMN was defined using seed-based correlation and was compared across groups and scans.

Results: In subjects with MDD, connectivity between the insula and the DMN was normalized compared with HCs 2 days postketamine infusion. This change was reversed after 10 days and did not appear in either of the placebo scans. Group-specific connectivity differences in drug response were observed, most notably in the insula in subjects with MDD and in the thalamus in HCs.

Conclusions: Connectivity changes in the insula in subjects with MDD suggest that ketamine may normalize the interaction between the DMN and salience networks, supporting the triple network dysfunction model of MDD.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: Default mode network; Functional magnetic resonance imaging (fMRI); Glutamatergic modulator; Ketamine; Major depressive disorder; Resting state.

Conflict of interest statement

Financial Disclosures

Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a coinventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors report no biomedical financial interests or potential conflicts of interest.

Published by Elsevier Inc.

Figures

Figure 1

Summary of the study’s double-blind, placebo-controlled, crossover design showing the medication taper and drug-free period in relation to the imaging scans (green circles), infusions (red triangles), and rating scales (blue rectangles) in both the placebo and ketamine study arms.

Figure 2

Change in Montgomery-Asberg Depression Rating Scale (MADRS) total score for the healthy control (HC) and major depressive disorder (MDD) groups for both ketamine (red) and placebo (blue) infusions over the course of the study. The group mean is shown as a circle, and the error bars are the standard error. The linear timescale indicates the timing of the imaging scans (green circles), infusions (red triangle), and rating scale administrations (blue rectangles).

Figure 3

Group (healthy control (HC), major depressive disorder (MDD)) differences in connectivity with the posterior cingulate cortex (PCC) seed of the default mode network (DMN) across scans at each scan day. The mean Z-score maps are shown at a threshold of p

Figure 4

Group-specific differences for connectivity with the posterior cingulate cortex (PCC) seed of the default mode network (DMN) across scans for the major depressive disorder (MDD) and healthy control (HC) groups. The mean Z-score maps illustrate the contrast between ketamine and placebo scans at two and 10 days post-infusion, respectively, and are shown at a threshold of p

Figure 5

Mean connectivity for regions of interest (ROIs) with significant differences across scans for both healthy control (HC; red) and major depressive disorder (MDD; blue) groups for the bilateral anterior (first row), posterior insula (second row), and thalamus (third row). Error bars represent standard deviation.