Working memory neural correlates after ketamine in treatment-resistant depression: a randomized placebo-controlled functional magnetic resonance imaging study

Ketamine exerts rapid antidepressant effects in treatment-resistant depression (TRD), but its impact on working memory and neural circuitry remains unclear. This secondary analysis investigated behavioral and neural changes during a working memory task post-ketamine infusion in TRD participants versus healthy volunteers (HVs). Data were previously collected from a randomized, double-blind, placebo-controlled, crossover trial of 22 unmedicated TRD participants (14F/8 M) and 19 matched HVs (12F/7 M). Participants received ketamine (0.5mg/kg) and placebo two weeks apart. 3T fMRI was acquired during an N-back task at baseline and two days post-ketamine. Accuracy, reaction time, and differential neural activation during 3-back versus 1-back contrasts were analyzed. Ketamine significantly reduced Montgomery-Asberg Depression Rating Scale scores compared to placebo (p < 0.01). N-back task performance did not significantly differ between drug conditions. In region of interest (ROI) analyses, TRD participants showed reduced activation in the superior temporal gyrus versus HVs (p < 0.01) after both infusions, and both groups demonstrated decreased parieto-occipital junction activation post-ketamine versus post-placebo (p = 0.01). Baseline dorsolateral prefrontal cortex activity significantly predicted post-infusion activity (p < 0.01). Ketamine's antidepressant effects occurred without significant changes in working memory performance, though region-specific task-related brain changes were observed. Interpretation is limited by modest sample size and the exploratory nature of the ROI analyses. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT00088699.