Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder

Abstract

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg(-1)). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.

Figure 1

Differences in brain activation between patients with treatment-resistant depression and healthy volunteers during positive emotion task. Left: analysis yielded activation cluster centered on the right caudate (Peak MNI coordinates: 12,24,6; uncorrected P<0.05, k>170, FWE P<0.05). Right: percent signal change extracted from activation cluster at left depicting neural responses to each condition in depressed individuals and healthy volunteers. BOLD, blood oxygen level-dependent; FWE, family-wise error; MNI, Montreal Neurological Institute.

Figure 2

Regulation of brain responses to positive emotion by ketamine in patients with treatment-resistant depression following ketamine. Left: analysis yielded a single large cluster centered on the right caudate (peak MNI coordinates: 12,21,3; FWE P<0.05). Right: percent signal change extracted from activation cluster at left depicting neural responses to each condition pre- and post-ketamine. BOLD, blood oxygen level-dependent; FWE, family-wise error; MNI, Montreal Neurological Institute.

Figure 3

Correlations between functional connectivity of the right caudate and improvement in depressive symptoms following ketamine. Significant clusters indicate brain regions displaying a positive correlation between connectivity of the right caudate and percent improvement in MADRS score. Results are based on psychophysiological interaction analysis using the functionally defined right caudate as the seed region (peak MNI coordinates: 12,21,3) and are corrected for multiple comparisons (FWE P<0.05). FWE, family-wise error; MADRS, Montgomery–Asberg Depression Scale; MNI, Montreal Neurological Institute.