This double-blind, placebo-controlled, crossover study (n=59) investigated how ketamine (35mg/70kg) affects the brain function of patients with depression compared to healthy controls, during the attentional processing of emotional stimuli. They found that depressed patients and healthy controls exhibited differences in the activation of the fronto-cingulate area during emotional processing and that this variation was normalized by ketamine, such that post-infusion brain activity in patients depression resembled that of healthy controls under the influence of placebo.

Abstract

“Background: An urgent need exists for faster-acting pharmacological treatments in major depressive disorder (MDD). The glutamatergic modulator ketamine has been shown to have rapid antidepressant effects, but much remains unknown about its mechanism of action. Functional MRI (fMRI) can be used to investigate how ketamine impacts brain activity during cognitive and emotional processing.

Methods: This double-blind, placebo-controlled, crossover study of 33 unmedicated participants with MDD and 26 healthy controls (HCs) examined how ketamine affected fMRI activation during an attentional bias dot probe task with emotional face stimuli across multiple time points. A whole brain analysis was conducted to find regions with differential activation associated with group, drug session, or dot probe task-specific factors (emotional valence and congruency of stimuli).

Results: A drug session by group interaction was observed in several brain regions, such that ketamine had opposite effects on brain activation in MDD versus HC participants. Additionally, there was a similar finding related to emotional valence (a drug session by group by emotion interaction) in a large cluster in the anterior cingulate and medial frontal cortex.

Conclusions: The findings show a pattern of brain activity in MDD participants following ketamine infusion that is similar to activity observed in HCs after placebo. This suggests that ketamine may act as an antidepressant by normalizing brain function during emotionally valenced attentional processing.”

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

Notes

This paper was also published a year later by Reed and colleagues (2019).

Summary

An urgent need exists for faster-acting treatments in major depressive disorder.

Introduction

Currently available FDA-approved pharmacological treatments for major depressive disorder (MDD) take several weeks to achieve their full antidepressant effects, which significantly impacts patient function and well-being. Ketamine has rapid antidepressant effects, but much remains unknown about its precise mechanism of action in the brain.

Dot probe tasks have been used to assess cognitive biases in depressed participants, and can span both attentional and emotional processing domains. Using dot probe tasks, researchers have shown that the left middle cingulum and left insula are associated with attentional bias towards or away from certain emotional stimuli, and that the anterior cingulate cortex is also associated with attentional bias towards incongruent trials.

Dot probe tasks can be used to investigate changes in the brain associated with treatment, such as the effects of anxiolytics on attentional biases.

Ketamine is uniquely suited to study antidepressant response using cognitive tasks and fMRI, and has been shown to affect individuals with treatment-resistant MDD in a variety of ways, including increased activation in the right caudate in response to positive emotion and decreased activation in the anterior cingulate cortex in response to negative emotion.

The current study used a dot probe task to investigate whether ketamine altered brain activity in regions associated with emotional processing and depression in treatment-resistant participants with MDD and healthy individuals.

2.1. Participants

In this study, 33 individuals with treatment-resistant MDD (12 M/21 F, mean age = 36.1 9.5 years) and 26 healthy controls (10 M/16 F, mean age = 33.9 10.4 years) were included. All participants had no serious, unstable illnesses, and a negative drug screen was required throughout the study.

MDD participants were tapered off medications and given a drug-free period before the study began. All participants gave written informed consent to participate.

2.2. Study design

This study was part of a randomized, double-blind, placebo-controlled, crossover protocol. Participants received either a ketamine or placebo infusion and crossed over two weeks later to receive the other treatment condition.

We performed fMRI scans one to three days after each infusion to examine drug effects in each treatment phase. We compared MADRS scores between pre-infusion and day two post-infusion and between groups at each of these time points.

We included 52 participants at baseline, 44 post-ketamine, 40 interim-ketamine, 42 post-placebo, and 35 interim-placebo. Some participants did not have usable data for all five scan sessions, but the analysis models allowed for missing data and enabled us to include each participant’s usable scans.

2.3. Experimental task

To examine the brain correlates underlying attentional bias, a dot probe task was administered during fMRI scanning using E-Prime presentation software. The task used a mixed block/event-related design and consisted of two faces, one with an angry, happy, or neutral expression, and the other always neutral. Trials were grouped into blocks, and each run included one angry block and one happy block. Ketamine and placebo arms were counterbalanced in each scanning session.

2.4. Imaging acquisition and analysis

Participants were scanned using a 3 Tesla General Electric HDx scanner to measure blood oxygen-level-dependent (BOLD) signal. Data were preprocessed using standard steps in AFNI, including despiking, slice timing correction, realignment to the third volume, aligning the anatomical images to the echo-planar images, and motion regressing and censoring. In a mixed block/event-related design task, individual subject regressors were created to model emotion blocks, stimulus events, and instruction screens. The group analysis model only analyzed event-related effects pertaining to individual trial types.

We performed a linear mixed-effects model with emotion, congruency, scan session (all five sessions), and diagnostic group as factors, and thresholded images at voxel- and cluster-level using FWE-corrected p .05 for significant clusters at the whole-brain level.

In a follow-up analysis, we explored the association between brain activity post-ketamine and change in MADRS score in MDD participants using a linear mixed-effects model.

2.5. Behavioral data analysis

Accuracy on the dot probe task was analyzed using IBM SPSS, Version 23.0 (Armonk, NY). Reaction times were between 200 and 1500 ms, and attentional bias scores were calculated for each emotion as the difference in reaction time between incongruent and congruent trials.

3.1. Participants

No significant difference in age or gender was observed between the participant groups. MADRS scores differed between groups at all time points, with lower scores in MDD participants post-ketamine infusion than post-placebo infusion.

3.2.1. Main effects: Group, emotion, congruency, and session

No significant main effect of group was observed across sessions and task conditions. However, a significant main effect of emotion was observed across groups and sessions, with participants showing greater activation to the presentation of angry stimuli than happy stimuli.

3.2.2. Two-way interaction effects

A significant diagnosis by emotion interaction was observed in both the HC and MDD groups. A significant session by emotion interaction was also observed across both groups, most notably in the bilateral orbital cortex and ACC.

A significant group by session interaction was observed, with MDD participants exhibiting less activation in clusters including bilateral thalamus and caudate and right middle/inferior temporal gyri. No significant emotion by congruency, group by congruency, or session by congruency interactions were observed.

3.2.3. Three- and four-way interaction effects

A significant three-way session by emotion by group interaction was observed. The post-ketamine session showed a large medial prefrontal and anterior cingulate cluster activation during angry trials and deactivation during happy trials.

3.2.4. Association with MADRS in MDD participants

MADRS score was significantly associated with activation in several brain regions, including the left parahippocampal gyrus and amygdala. A decreased MADRS score was associated with less activation to angry trials and greater activation to happy trials.

3.3.1. Reaction times

The mean reaction time across trials was 516.56 ms (SD = 82.06), and there was a significant main effect of emotion and session. There was no significant effect of group nor any interaction effects.

Discussion

This study used a dot probe task to investigate how the glutamatergic modulator ketamine affected brain activation during emotionally valenced attentional processing in treatment-resistant MDD participants and healthy controls across multiple time points.

In the drug session by group interaction, MDD participants showed greater general task activation post-ketamine compared to post-placebo, but HCs showed the opposite pattern. This is consistent with published findings of regions associated with emotion regulation in depression, specifically related to automatic attentional control.

A cluster within the ACC was found to be activated in response to angry versus happy trials post-placebo and post-ketamine. The pattern of activation in MDD participants post-ketamine was similar to the pattern of activation in HC participants post-placebo.

A recent magnetoencephalography study found that HCs had similar activation patterns to MDD participants post-ketamine, suggesting that homeostatic dysregulation in MDD may be improved by ketamine.

The present study used the dot probe task to investigate emotional processing post-ketamine in healthy controls. The results echo previous studies conducted in healthy controls and MDD participants, but differ from the results obtained in MDD participants.

The follow-up analysis of activation associated with percent change in MADRS score showed that ketamine reduced activation in the left parahippocampal gyrus and amygdala during angry trials and increased activation during happy trials.

The present study has several strengths, such as including both MDD and HC participants, using multiple time points, and using placebo infusions as a control condition. However, the study is also associated with several limitations, such as the lack of behavioral bias towards angry faces.

Although the study included 59 participants, not all had usable data for the post-ketamine and post-placebo scans, reducing the sample sizes for these sessions.

4.1. Conclusions

This study found that ketamine had different effects on brain activity in different brain regions and that the effects in MDD participants were often opposite to those seen in HCs.

Declaration of interest

Dr. Zarate is listed as a co-inventor on several patents for the use of ketamine, and Dr. Furey is listed as a co-inventor on several patents for the use of scopolamine. All other authors have no conflict of interest to disclose.

Acknowledgements and role of funding source

This work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health, a NARSAD Independent Investigator Award, and a Brain and Behavior Mood Disorders Research Award.