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

Major depressive disorder (MDD) causes substantial disability and current treatments are often inadequate, particularly for people with treatment-resistant depression (TRD). Recent research has shown that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine can produce rapid antidepressant effects within 24 h of a single administration, motivating investigation of glutamatergic mechanisms and the neurocircuitry that ketamine may regulate. Depression is associated with biased processing of social and emotional information, characterised by increased attention to negative stimuli and blunted responses to positive stimuli; neuroimaging studies have repeatedly implicated increased limbic responses to negative stimuli and reduced prefrontal–striatal responses to positive or reward-related stimuli in MDD. Murrough and colleagues set out to examine how a single ketamine infusion alters neural responses to positive and negative emotional facial expressions in unmedicated individuals with TRD. Using functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks (happy versus neutral faces; sad versus neutral faces), the study aimed to characterise baseline group differences between TRD patients and healthy volunteers and to test whether ketamine rapidly normalises dysfunctional neural activation. The investigators further tested whether neural activation or task-related functional connectivity related to clinical improvement, measured as percent change in depression severity 24 h after ketamine.

Design and participants: The study enrolled adults with MDD who had failed at least two prior antidepressant trials (TRD) and who were participating in concurrent ketamine clinical trials. Eligible participants were ≥21 years old, had a primary diagnosis of recurrent or chronic MDD by Structured Clinical Interview for DSM-IV, were free of antidepressant medication for at least 1 week before imaging, and had moderate or greater depressive severity (Inventory of Depressive Symptomatology–Clinician Rated score ≥32). Exclusion criteria included lifetime psychotic or bipolar disorder, current substance abuse, unstable medical illness and MRI contraindications. Twenty TRD participants underwent MRI at baseline and again ~24 h after a single ketamine infusion; adequate fMRI data were available for 18 participants for each task. A control group of 20 age- and sex-matched healthy volunteers underwent a single fMRI session for baseline comparison. Intervention and clinical outcome: Ketamine hydrochloride was administered intravenously at 0.5 mg kg^-1 over 40 min under anaesthesiologist supervision. Depression severity was assessed at baseline and ~24 h post-infusion using a version of the Montgomery–Åsberg Depression Rating Scale (MADRS) modified to cover the preceding 24 h. The primary clinical variable for brain–symptom analyses was percent change in MADRS score from baseline to 24 h. Emotion perception tasks: Each participant completed two event-related fMRI experiments (8 min each): a positive emotion task (happy versus neutral faces) and a negative emotion task (sad versus neutral faces). Stimuli included prototypical facial expressions at 100% (high emotion), 50% (mild emotion) and neutral, presented for 2 s with variable interstimulus intervals. Participants made explicit valence ratings on a 1–5 scale for each face. The order of the two tasks was randomised across participants. Neuroimaging acquisition and preprocessing: Scans were performed on a Philips Achieva 3.0 T scanner. Functional data used a T2*-weighted echo-planar imaging sequence (TR = 2000 ms; TE = 26.6 ms; voxel dimensions ~2.2 × 2.2 × 2.5 mm; 38 slices). High-resolution T1-weighted anatomical images were also collected. Preprocessing in SPM8 included slice timing correction, detrending, intensity normalisation, high-pass filtering, motion correction, co-registration, normalisation to MNI space and 6 mm full-width-at-half-maximum smoothing. Statistical analysis: Whole-brain voxel-wise general linear models were constructed separately for the two tasks. Models included three stimulus-type regressors (100% emotion, 50% emotion, neutral) and six motion regressors, convolved with a canonical haemodynamic response. Primary contrasts compared 100% emotion versus neutral (happy 100% > neutral; sad 100% > neutral). Between-group baseline differences used independent-sample t-tests comparing TRD and healthy controls. Within-TRD pre/post changes were tested with paired t-tests contrasting baseline (Time 1) and 24 h post-ketamine (Time 2). Cluster-size thresholds controlling the family-wise error (FWE) rate at P < 0.05 were determined using Alphasim. Percent signal change was extracted from significant clusters for correlation with baseline MADRS or percent MADRS change. Functional connectivity: Psychophysiological interaction (PPI) analyses assessed task-modulated connectivity of regions showing main effects of time. Models included the seed time course, the task regressor and their interaction; subject-level percent MADRS change was entered at the second level to identify regions whose task-specific connectivity with the seed correlated with clinical improvement.

Sample and data availability: Twenty TRD participants completed baseline and 24 h scans, with adequate imaging data available for 18 participants on each emotion task. Twenty healthy volunteers were scanned once for baseline comparison. Behavioural task results are reported in Supplementary Information (not reproduced here). Baseline group differences: For the positive emotion task (happy 100% > neutral), both groups showed main effects of emotion, and a significant group × emotion interaction emerged in the left insula and right caudate. In these regions, participants with TRD exhibited hypoactivation for the emotion versus neutral contrast relative to healthy volunteers. In the right caudate specifically, responses to positive faces were reduced in TRD while responses to neutral faces were similar between groups. No significant baseline group differences survived correction for the 50% happy versus neutral contrast. For the negative emotion task (sad 100% > neutral), no main effects of emotion or group × emotion interactions survived correction. Effects of ketamine: Following ketamine, the positive emotion task revealed a significant emotion × time interaction, with a large cluster centred in the right caudate (peak coordinates 12, 21, 3; cluster size k = 4589; FWE P < 0.05). Percent signal data indicated that neural responses to positive emotion increased after ketamine, whereas responses to neutral stimuli remained approximately unchanged. There were no significant effects for the happy 50% > neutral contrast. For the negative emotion task, a time × emotion interaction was observed in the left middle frontal gyrus (extending into orbitofrontal cortex); post-ketamine changes reflected reduced deactivation to sad faces and greater deactivation to neutral faces. Brain–symptom relationships: No significant correlations were found between magnitude of regional activation (for example, in insula or caudate) during the happy 100% > neutral contrast and baseline depressive severity or percent MADRS change, either within functionally defined regions of interest or in whole-brain follow-up analyses. However, PPI connectivity analyses revealed a significant positive correlation between right caudate connectivity during positive emotion following ketamine and clinical improvement (cluster k = 4451; FWE P < 0.05). This association remained when using an anatomically defined right caudate seed. At baseline, caudate connectivity did not correlate with depression severity or subsequent improvement.

Murrough and colleagues interpret their findings as showing that ketamine rapidly modulates neural responses to positive emotional stimuli in TRD, specifically by enhancing activity in the right caudate and increasing task-related caudate connectivity in association with clinical improvement. The baseline observation of reduced caudate and insula responses to positive faces in TRD aligns with prior literature reporting striatal hypo-responsiveness to positive and reward-related information in depression; the right-sided localisation is consistent with meta-analytic evidence but the authors note that lateralisation of emotional processing remains incompletely understood. The investigators suggest mechanistic links whereby subanesthetic ketamine potentiates glutamatergic and downstream dopaminergic signalling in cortical–striatal circuits, and by enhancing AMPA receptor-mediated synaptic function may reverse impaired PFC–striatal communication implicated in anhedonia and motivational deficits. The observed post-ketamine change in orbitofrontal/middle frontal activation during the sad versus neutral task was acknowledged but its meaning is uncertain because no baseline group difference for negative emotion was detected; the authors note explicit versus implicit task differences and unmeasured factors such as childhood trauma may influence negative-emotion findings. Several key limitations are acknowledged. The study lacked a placebo control, so nonspecific effects of time or repeated measurement cannot be excluded. Healthy controls were not given ketamine and were scanned only once, preventing determination of whether ketamine's neural effects are specific to depression and limiting evaluation of practice or scan–rescan effects. Imaging was performed only ~24 h after infusion, so durability of neural changes beyond this rapid window remains unknown. The sample size was modest and some behavioural and clinical subgroup data (for example, trauma history) were not systematically available. Finally, because the study did not include conventional antidepressant or other rapidly acting treatment comparators, specificity of the caudate effect to ketamine versus other treatments cannot be concluded. Overall, the authors conclude that a single ketamine infusion rapidly increases caudate responses to positive emotional cues in TRD, in a manner that appears to normalise baseline blunted activation, and that enhanced caudate connectivity during positive emotion perception is associated with clinical improvement. They propose that further studies should test the specificity, temporal durability and relationship to reward circuitry of these effects to clarify the striatum's role in ketamine's antidepressant mechanism.