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

Reed and colleagues place this study in the context of an urgent need for faster-acting, more effective treatments for major depressive disorder (MDD). Previous neuroimaging work has documented differences between people with MDD and healthy controls (HCs) during emotional processing, including altered anterior cingulate cortex (ACC) and prefrontal activation and a bias toward negative stimuli. Traditional antidepressants tend to ‘‘normalise’’ under- or overactivation in some regions, but ketamine, a glutamatergic modulator with rapid antidepressant effects, has been less well characterised in emotional processing tasks; prior studies of ketamine either lacked placebo controls or did not include both clinical and healthy samples. This study set out to examine how ketamine affects blood oxygen level-dependent (BOLD) activity during an emotional face-processing task in both treatment-resistant MDD participants and HCs using a double-blind, placebo-controlled crossover design. The investigators hypothesised that ketamine would differentially alter BOLD activity in MDD versus HCs, tending to decrease activation in MDD and shift their activity patterns toward those of HCs after placebo (a ‘‘normalisation’’), with task condition (explicit versus implicit processing) modulating these effects.

Participants comprised 33 individuals with treatment-resistant MDD (13 male, 20 female; mean age 35.9 ± 9.8 years) and 24 healthy controls (9 male, 15 female; mean age 34.4 ± 10.7 years). Diagnoses were established with the Structured Clinical Interview for DSM-IV-TR. Participants were admitted as inpatients; those with MDD tapered off psychotropic medications and completed a drug-free period of at least 2 weeks. The extracted text notes that inclusion/exclusion criteria are provided in the Supplement but does not reproduce those criteria. The trial used a randomised, double-blind, placebo-controlled crossover design. After a baseline fMRI, subjects were randomised to receive an intravenous infusion of ketamine (0.5 mg/kg over 40 minutes) or placebo (saline), then crossed over 2 weeks later to the other condition. Functional scans were performed at baseline and 1–3 days after each infusion (95% of post-infusion scans occurred at the 2-day time point). Depressive symptoms were measured repeatedly with the Montgomery–Åsberg Depression Rating Scale (MADRS), and MADRS changes were analysed in a mixed model with group, time and drug as factors. During fMRI, participants completed an emotional face-processing task that included explicit and implicit conditions and positive versus negative expressions. Faces (sad, angry, happy or neutral) were shown right-side-up or upside-down to vary difficulty; in the explicit block subjects judged emotion (negative versus positive), and in the implicit block they judged gender. Each face appeared for 750 ms with a 2500-ms interstimulus interval; two runs of the task were completed. Behavioural data (accuracy and reaction time) were analysed with mixed models (same factors as imaging); sessions with <50% accuracy were excluded, and reaction times <200 ms were discarded. Imaging was done on a 3T GE scanner using gradient-echo echo-planar imaging. Preprocessing used AFNI and first-level models included regressors for every combination of emotion (negative/positive), face orientation (right-side-up/upside-down) and condition (emotion/gender), with instruction screens and fixation as baseline. Group-level statistics used a linear mixed-effects model including emotion, face direction, condition, session (baseline, post-ketamine, post-placebo) and diagnostic group. Cluster-level familywise error correction was applied (initial voxel threshold p < .001, cluster extent threshold determined by 3dClustSim) to achieve FWE p < .05 (cluster size ≥ 11 voxels). When interactions were significant, percentage BOLD signal change was extracted and graphed to clarify directionality. The extracted text reports usable scan counts by session: baseline (33 MDD, 20 HC), post-ketamine (28 MDD, 15 HC), post-placebo (26 MDD, 15 HC).

Participant groups did not differ significantly in age or gender. MADRS scores showed a significant group-by-time-by-drug interaction (p = .002). In the MDD group, scores decreased from a pre-infusion mean of 33.8 to a post-ketamine mean of 24.0 (60 minutes pre-infusion to scan-day), whereas no comparable change occurred after placebo (pre 32.5, post 30.7). Imaging main effects indicated significant effects of session and condition but not of group, emotion or face direction when examined across all factors. The drug contrast (post-ketamine vs post-placebo) revealed widespread decreases in activation after ketamine (p FWE < .001), notably in bilateral middle/medial frontal gyri, anterior and posterior cingulate, and parietal and occipital cortices. The condition main effect (explicit emotion > implicit gender) produced extensive clusters of greater activation for the explicit condition (p FWE < .001), though some regions (e.g. bilateral medial frontal gyri, precuneus/posterior cingulate) showed the opposite pattern. When the drug effect was examined within groups, participants with MDD showed large regions of reduced activation post-ketamine versus post-placebo (bilateral frontal, temporal, precuneus and posterior cingulate; p FWE < .001), with no regions showing increased activation. Healthy controls displayed a mixed pattern: reduced activation in some cingulate areas but increased activation in a large frontal cluster (p FWE < .001). A significant group-by-drug interaction (p FWE < .001) included a right frontal cluster extending into the ACC and insula, bilateral posterior cingulate (extending into right occipital cortex and left parahippocampal gyri), and other regions. Graphical interrogation showed that post-placebo the MDD group exhibited greater activation than HCs in these regions, whereas post-ketamine the pattern reversed—activation decreased in MDD and increased in HCs—so that MDD post-ketamine resembled HC post-placebo. A group-by-drug-by-condition interaction (p FWE < .001) was also found in bilateral medial/superior frontal gyri, temporal gyri, and precuneus/posterior cingulate. Region-specific patterns varied, but the left temporal gyri and precuneus clusters illustrated that HCs showed a larger explicit-versus-implicit difference post-placebo than MDD; after ketamine this relationship reversed, with greater differentiation in the MDD group. This was interpreted as another instance where MDD post-ketamine more closely resembled HC post-placebo. Behaviourally, there was a main effect of group on accuracy (p = .014), with higher accuracy in MDD participants; no group effect was seen for reaction time (p = .700). Task factors (condition, emotion, direction) produced expected main effects on both accuracy and reaction time (all p < .005): better and faster performance for gender versus emotion blocks, positive versus negative faces, and right-side-up versus upside-down faces. There were trends for session effects on accuracy (p = .075) and a group-by-session interaction at trend level (p = .055), with group differences at baseline (trend) and post-placebo (p = .001) but not post-ketamine. Overall, behavioural findings diverged from imaging effects, with performance measures less sensitive to the drug-related neural changes.

The study found that ketamine produced differential effects on BOLD activity during emotional processing in participants with MDD versus healthy controls. Broadly, ketamine was associated with decreased activation across many regions when contrasted with placebo, a pattern that was pronounced and widespread in the MDD group and more heterogeneous in HCs (some frontal increases, cingulate decreases). In several regions implicated in emotion processing—most notably the insula and ACC—participants with MDD showed greater activation than HCs after placebo but exhibited reduced activation after ketamine, such that MDD post-ketamine resembled HC post-placebo. The investigators interpret these patterns as evidence that ketamine may ‘‘normalize’’ emotion-related brain activation in MDD. The authors note that many of the deactivated regions in MDD after ketamine are part of the default mode network (DMN), including medial prefrontal cortex, posterior cingulate and precuneus. They suggest two nonexclusive interpretations: decreased DMN activity may reflect increased efficiency of task-related processing post-ketamine, or greater disengagement of the DMN during the task might support improved engagement with externally directed emotional processing. The mixed frontal increases in HCs are discussed as potentially representing aberrant overactivation, consistent with prior observations of ketamine effects in healthy samples. Key limitations acknowledged by the investigators include reduced usable data for some sessions (fewer than the full sample of 57 for some scans), a complex analytic model with many factors that makes interpretation of higher-order interactions challenging, and the absence of a more active placebo control given ketamine’s dissociative effects (saline may not ensure blinding). They also cite task design limitations: collapsing happy and neutral faces into one response category and a limited number of trials per specific emotion may have reduced sensitivity to valence effects, and the study lacked baseline conditions specific to each infusion arm. Behavioural and imaging findings diverged, and the authors concede that participants with MDD were not consistently more attuned to emotional stimuli as hypothesised. Finally, the authors situate these results within prior work from their group—using attentional bias tasks, resting-state fMRI and magnetoencephalography—which likewise reported normalising effects of ketamine in MDD. They conclude that ketamine affects BOLD activity widely during emotional processing and that, in MDD, these effects tend toward normalising disorder-related abnormalities while producing different alterations in healthy individuals, thereby advancing understanding of ketamine’s neural actions in depression.