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Working Memory Neural Correlates After Ketamine in Treatment-Resistant Depression: A Randomized Placebo-Controlled Functional Magnetic Resonance Imaging Study

Adam Fijtman, Níall Lally, Jennifer W. Evans, Gregory H. Jones, Jonathan Paul Roiser, Carlos A. Zarate

Psychiatry Research Neuroimaging November 1, 2026 DOI: 10.1016/j.pscychresns.2026.112367 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Secondary analysis of a randomized, double-blind, placebo-controlled crossover trial Peer reviewed
Sample size 41
Population 22 unmedicated participants with treatment-resistant depression (14 female, 8 male) and 19 matched healthy volunteers (12 female, 7 male)
Interventions Ketamine Placebo
Dose 0.5mg/kg
Duration Two infusions two weeks apart; fMRI at baseline and two days post-ketamine
Measures Montgomery-Asberg Depression Rating Scale, N-back task (accuracy, reaction time), 3T fMRI
Topics Depression Esketamine Ketamine
Registration NCT00088699
Key findings Ketamine reduced Montgomery-Asberg Depression Rating Scale scores compared with placebo (p<0.01) without significant changes in N-back working memory performance. Depressed participants showed reduced superior temporal gyrus activation versus healthy volunteers after both infusions, and both groups showed decreased parieto-occipital junction activation after ketamine versus placebo (p=0.01). Baseline dorsolateral prefrontal cortex activity predicted post-infusion activity (p<0.01).

Abstract

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/8M) and 19 matched HVs (12F/7M). 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

Comparable studies

Other randomized controlled trials on ketamine for depression, most cited first.

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68

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