Effects of Ketamine on Brain Activity During Emotional Processing: Differential Findings in Depressed Versus Healthy Control Participants

Abstract

Background: In the search for novel treatments for depression, ketamine has emerged as a unique agent with rapid antidepressant effects. Experimental tasks involving emotional processing can be used during functional magnetic resonance imaging scanning to investigate ketamine's effects on brain function in major depressive disorder (MDD). This study examined ketamine's effects on functional magnetic resonance imaging activity during an emotional processing task.

Methods: A total of 33 individuals with treatment-resistant MDD and 24 healthy control participants (HCs) took part in this double-blind, placebo-controlled crossover study. Participants received ketamine and placebo infusions 2 weeks apart, and functional magnetic resonance imaging scans were conducted at baseline and 2 days after each infusion. Blood oxygen level-dependent signal was measured during an emotional processing task, and a linear mixed-effects model was used to analyze differences in activation among group, drug, and task-specific factors.

Results: A group-by-drug interaction was observed in several brain regions, including a right frontal cluster extending into the anterior cingulate cortex and insula. Participants with MDD had greater activity than HCs after placebo infusion but showed lower activity after ketamine infusion, which was similar to the activity in HCs after placebo. A group-by-drug-by-task condition interaction was also found, which showed further differences that varied between implicit and explicit emotional conditions.

Conclusions: The main results indicate that ketamine had differential effects on brain activity in participants with MDD versus HCs. The pattern of activation in participants with MDD after ketamine infusion resembled the activation in HCs after placebo infusion, suggesting a normalization of function during emotional processing. The findings contribute to a better understanding of ketamine's actions in the brain.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: Brain activity; Depression; Emotion; Face processing; Ketamine; fMRI.

Published by Elsevier Inc.

Figures

Figure 1:. Study design.

Representation of the double-blind, placebo-controlled, crossover protocol. Time points for the functional magnetic resonance imaging (fMRI) scans used in the current study are indicated in green. The number of participants with useable data for each time point is listed at the bottom.

Figure 2:. Drug effect in each group separately.

Regions of activity that differed between post-ketamine and post-placebo scan sessions in major depressive disorder (MDD) participants (top) and healthy controls (HCs) (bottom) (left=right). Contrast is post-ketamine minus post-placebo (with yellow indicating greater activity post-ketamine and blue indicating less activity post-ketamine).

Figure 3:. Drug (post-ketamine versus post-placebo) by group interaction.

Regions of activity for the drug-by-group interaction displayed on brain images (left=right). Extracted values from two clusters are graphed to visualize the directionality of interaction effects.

Figure 4:. Drug (post-ketamine versus post-placebo) by group by condition interaction.

Regions of activity for the drug-by-group-by-condition interaction displayed on brain images (left=right). Extracted values from two clusters are graphed to visualize the directionality of interaction effects.