This double-blind, placebo-controlled study (n=57) investigated ketamine’s effects on brain activity (BOLD) during an emotional processing task where fMRI of participants with depression (MDD) showed greater activity than healthy participants. After ketamine treatment, the depressed participants showed similar levels of brain activity, suggesting a normalization of function during emotional processing.

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.”

Authors: Jessica L. Reed, Allison C. Nugent, Maura L.Furey, Joanna E. Szczepanik, Jennifer W. Evans & Carlos A. Zarate Jr.

Notes

This paper was originally published a year earlier by Reed and colleagues (2018).

Summary

Ketamine has emerged as a unique agent with rapid antidepressant effects. This study examined ketamine’s effects on brain function during an emotional processing task.

Depression affects more than 300 million people worldwide, but most treatments are ineffective. Ketamine, a glutamatergic modulator, has rapid antidepressant effects in MDD and treatment-resistant depression.

Neuroimaging research has found that individuals with MDD have increased activation in prefrontal and limbic regions during emotion regulation, along with differences in areas of the anterior cingulate cortex (ACC). These differences may represent a bias toward negative emotional stimuli and away from positive emotional stimuli.

fMRI has been used to study the effects of antidepressants on brain activation, and has shown that antidepressants normalize brain function in areas of under- or overactivation in participants with MDD.

Neuroimaging studies using fMRI are a valuable way to explore how ketamine affects brain function in MDD. The study by our research group found that ketamine normalized brain activity in several regions and that the activation in HCs post-ketamine was also similar to the activation in participants with MDD post-placebo.

We used an emotional processing task to examine the effects of ketamine versus placebo on BOLD signal in participants with MDD and healthy controls. We found that ketamine decreased activation across the brain in participants with MDD, but increased activation in healthy controls. We expected that participants with MDD would be more attuned to emotional expressions, and that HCs would be less sensitive to emotional expressions, and that ketamine would normalize brain activity during emotional processing.

Participants

In total, 33 participants with treatment-resistant MDD and 24 healthy controls were included in the analyses for this study. Diagnoses were ascertained using the Structured Clinical Interview for DSM-IV-TR.

Participants with MDD were tapered off medications and had a drug-free period of at least 2 weeks before they took part in the study.

Study Design

A randomized, double-blind, placebo-controlled crossover study was conducted to explore the mechanism of action of ketamine. Participants’ depressive symptoms were measured at several time points and were compared between groups and between pre-infusion and scan day time points.

Some participants did not complete all scans or had scans excluded for too much motion, poor alignment of functional data with structural data, or low accuracy on the task.

Experimental Task

In an emotional processing task, participants were presented with faces with emotional expressions and were asked to judge the emotion of the face. Ketamine was found to affect multiple factors, including valence of emotion and explicit versus implicit processing, with upside-down faces included to examine any such effects.

For the first-level analyses, regressors were created for each participant to model individual trial types. A whole-brain analysis was conducted using a linear mixed-effects model to analyze activation estimates from the event-related findings from each participant’s first-level analysis. We used F-tests to examine the effects of ketamine on the brain, and then used general linear tests to examine the directionality of significant results.

Behavioral Data Analysis

Accuracy and reaction time on the task were analyzed using SPSS version 24.0 (IBM Corp., Armonk, NY). Participants with less than 50% accuracy were excluded from both imaging and behavioral analyses, and only correct trials were included in the reaction time analysis.

Participants

Participants with MDD had a significant group-by-time-by-drug interaction, with MADRS scores decreasing significantly from 60 minutes pre-ketamine infusion to the day of the scan.

Neuroimaging Results

The main effects of session and condition were found, but not for group, emotion, or face direction. Participants with MDD showed greater activity than HCs in several regions, including the bilateral cuneus/lingual gyrus, left temporal and medial frontal gyrus, and right parietal cortex.

The drug effect was examined separately in each group across all task-related factors. In the MDD group, large areas showing less activation after ketamine were observed, while no areas showing greater activation were found.

A significant group-by-drug interaction was found in a large cluster of brain regions, including the right frontal gyri, ACC, insula, bilateral posterior cingulate, and numerous other regions.

Significant group-by-drug-by-condition interaction was also observed, including clusters in bilateral medial/superior frontal gyri, temporal gyri, and precuneus/posterior cingulate. The amount of activation varied according to explicit versus implicit condition, with greater differences between conditions in participants with MDD.

Behavioral Results

Participants with MDD had higher accuracy and faster reaction times in responding to the gender versus emotion condition, to positive versus negative faces, and to right-side-up versus upside-down faces. There was a trend toward a group-by-session interaction for accuracy but not for reaction time.

DISCUSSION

In this double-blind, placebo-controlled crossover study, ketamine affected several regions across the brain in participants with MDD and healthy controls, but the effects were often opposite in the MDD versus HC groups.

Ketamine decreased activation in several regions of the brain during emotional processing in participants with MDD compared to placebo. This result may suggest greater efficiency in such brain function post-ketamine, or that more deactivation of the default mode network during the task may be related to better engagement of task-related processing.

Statistically significant differences in drug effects between groups were shown in the drug-by-group interaction findings. Ketamine normalized BOLD activation in MDD, and this may be different from the effects of traditional antidepressants, which have been shown to increase and decrease fMRI activity during emotional processing in MDD.

A group-by-drug-by-condition interaction was also found in multiple clusters. Participants with MDD showed less differentiation in BOLD response between explicit and implicit emotion processing conditions post-ketamine versus participants without MDD.

Results showed that participants with MDD were more accurate than HCs across sessions, and that performance- versus brain-based analyses may be differentially sensitive to particular factors explored in this study.

The current study was associated with several limitations and unexpected findings, including fewer data in the analyses and a complex analysis model. We found no effect for emotional valence on brain activation, which would typically be predicted in MDD. However, the study design did not include a baseline condition for each arm (ketamine and placebo), and participants with MDD were not more attuned to emotional stimuli across task conditions.

Ketamine normalized brain function in MDD versus healthy controls in an fMRI study. Ketamine altered brain activity in different ways in MDD versus healthy controls, significantly expanding our knowledge of ketamine’s impact on brain function.