This open-label between-subjects fMRI study (n=38) investigated the antidepressant effects of ketamine (35mg/70kg) with regard to changes in the neural correlates of emotional processing, 24 hours after infusion, in patients with major depression (n=18) compared to baseline measures from healthy volunteers (n=20). They found that ketamine rapidly increases brain responses to positive emotion, which correlated with increased connectivity of the right caudate during and improvement in depression severity.
Abstract
“Introduction: 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.
Methods: 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.
Results: 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.
Discussion: 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.”
Authors: J. W. Murrough, K. A. Collins, J. Fields, K. E. de Wilde, M. L. Phillips, S. J. Mathew, E. Wong, C. Y. Tang, D. S. Charney & D. V. Iosifescu
Summary
INTRODUCTION
Ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, is rapidly and robustly antidepressant, even in patients with treatment-resistant depression. Human in vivo neuroimaging research provides a unique opportunity to examine the neurocircuit functions regulated by ketamine.
MDD is characterized by dysfunctional processing of social, emotional and reward-related information, leading to pervasive depressed mood, anhedonia (i.e., reduced capacity to experience pleasure) and a negative cognitive bias.
Functional neuroimaging studies in MDD demonstrate increased responses to negative stimuli and reduced responses to positive stimuli, with hypo-responsiveness to positive self-referential, social or reward-related information observed in the striatum and related PFC regions. Antidepressant treatment improves clinical symptoms by normalizing dysfunctional circuit activation.
Ketamine treatment in patients with MDD and bipolar depression results in an antidepressant response within one day of a single intravenous infusion, but few studies have investigated changes in neurocircuitry following ketamine administration.
In the current study, antidepressant-free patients with TRD showed reduced neural responses to positive faces and increased neural responses to negative faces during positive and negative emotion perception tasks. These abnormalities were rapidly reversed following treatment with ketamine.
Male and female individuals with MDD were eligible to participate in the current neuroimaging study if they were enrolled in a concurrent ketamine clinical trial and met the following additional requirements: being at least 21 years of age, being free of concurrent antidepressant medication, and having moderate depressive symptoms.
Eligible individuals with TRD underwent MRI at two time points: baseline and 24 h following a single intravenous infusion of ketamine. Depression severity was assessed using the Montgomery – sberg Depression Rating Scale.
Ketamine treatment
After an overnight fast, patients were given Ketamine hydrochloride via an infusion pump over 40 min and underwent a second fMRI session 24 h after the treatment.
Facial emotion perception task
Participants underwent event-related fMRI during two separate emotion perception tasks. They were presented with stimuli consisting of high emotion, low emotion or neutral facial expressions and were instructed to rate the emotional valence expressed in each stimulus by making a response using a fiber optic button system.
Neuroimaging data acquisition
Participants were scanned using a Philips Achieva 3.0 T X-series MRI with an eight-channel birdcage headcoil for radio frequency transmission and reception. High-resolution T1-weighted anatomical images were collected using a three-dimensional turbo field echo sequence.
Neuroimaging data analysis
Preprocessing included slice scan time correction, voxel-wise linear de-trending, intensity normalization, high-pass filtering, motion correction, co-registration, and three-dimensional smoothing.
fMRI modeling of brain activity was conducted using Neuroelf version 9c to identify brain regions specifically engaged by emotion perception. Difference maps were computed for healthy volunteers and TRD participants and paired sample t-tests were used to identify voxels displaying significant changes in blood oxygen level-dependent contrast.
We examined potential associations between functional connectivity and depressive symptom severity using significant clusters as functionally defined regions of interest and linear correlation analysis.
We constructed general linear models using three stimuli-type and six nuisance motion regressors, and inserted each subject’s MADRS score percent change into the model. The models showed significant correlations between MADRS score percent change and seed-functional connectivity values.
Participant characteristics and clinical outcomes
Twenty people with TRD underwent fMRI at baseline and 24 h following ketamine, and 20 healthy volunteers underwent a single fMRI session.
Neuroimaging results
Baseline comparisons between TRD and healthy groups showed that the TRD group demonstrated hypoactivation for the emotion 4 neutral contrast compared with the healthy group, whereas the responses to neutral stimuli were similar.
Effects of ketamine treatment in TRD
A significant interaction between emotion and time was found in the right caudate for the positive emotion task, and in the left middle frontal gyrus for the negative emotion task.
No correlation was found between brain activity and depressive symptoms in the positive emotion task or in a follow-up whole-brain analysis. However, there was a significant correlation between right caudate connectivity and clinical improvement following ketamine treatment.
Brain responses during positive emotion task at baseline and following treatment with ketamine are shown in Table 2.
DISCUSSION
Ketamine increased neural responses to positive emotion in the right caudate in unmedicated patients with TRD, and increased caudate connectivity during positive emotion perception was positively correlated with improvement in depression severity following ketamine.
Our study found that depressed patients had reduced brain responses to positive emotion within the caudate and putamen, which is consistent with prior studies showing reduced striatal activation in response to positive social and nonsocial stimuli in MDD and in the context of reward processing.
Our findings are partially consistent with prior reports that the insula is reduced in MDD to positive emotion, although there is considerable variability in the published literature.
We did not observe robust differences in brain responses to negative emotion between the TRD and healthy control groups. This may be because we used an explicit facial emotion perception task, which may have rendered the task less robust in probing limbic activation in response to negative emotion.
Ketamine reversed the blunted response to positive emotion within the caudate in patients with TRD, and potentiated glutamate signaling in cortical and subcortical circuits, and facilitated dopaminergic responses within the striatum. Ketamine may be involved in alleviating depressive symptoms at least in part by reversing impaired glutamate signaling within PFC-striatal pathways.
Ketamine was observed to alter brain responses to negative emotion within the left middle frontal gyrus, extending into the orbitofrontal cortex. The meaning of these findings is not entirely clear, however.
The current findings do not address the specificity of the observed effect of ketamine on neurocircuit activation, and future studies comparing ketamine to conventional antidepressants or to other putative rapidly acting agents will be required to further elucidate these issues.
Our study has several limitations, including the lack of a placebo treatment condition and the 24-h time point for imaging. It cannot address important issues related to durability of antidepressant response, or nonspecific practice effects.
Ketamine increased brain responses to positive emotion within the caudate in patients with TRD, and this effect was consistent with normalization of a blunted response to positive emotion at baseline.
CONFLICT OF INTEREST
JWM has served on advisory boards for Janssen Research and Development and Genentech, and has received research support from Janssen and Avanir Pharmaceuticals. DVI has consulted for Avanir, CNS Response, INSYS Therapeutics, Lundbeck, Otsuka, Servier, Sunovion. DSC and Icahn School of Medicine at Mount Sinai have been named on a patent for the use of ketamine for the treatment of depression, and have received funding from the U.S. Department of Defense, NIH, NIMH, NARSAD, USAMRAA, and Bristol-Myers Squibb.
ACKNOWLEDGMENTS
Research reported in this publication was supported by the National Institute of Mental Health and several other organizations. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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