Effect of Ketamine on Reward Processing in Depressive Disorders: A Systematic Review of Neuroimaging Studies

Ketamine rapidly alters brain reward circuitry in people with major depressive disorder, particularly in fronto-striatal and limbic networks. In a synthesis of 13 neuroimaging studies involving 623 participants (482 with depression, 141 controls), intravenous ketamine (typically 0.5 mg/kg over 40 minutes) changed resting-state connectivity in ventral striatal-prefrontal and default mode, salience, and executive networks within 2 to 48 hours, with some effects lasting up to 10 days. Task-based imaging showed altered ventral striatal responses during reward anticipation and feedback, and changes in medial prefrontal activity during emotion processing. PET scans indicated increased prefrontal-cingulate metabolism and region-specific serotonin receptor binding changes. Few studies directly measured anhedonia, suggesting the findings reflect broader antidepressant mechanisms.

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Abstract

Background: Anhedonia and reward-processing deficits are core features of major depressive disorder (MDD) that respond poorly to traditional antidepressants.Ketamine has rapid antidepressant effects, yet its neurofunctional actions within reward circuits remain unclear.We synthesized human neuroimaging evidence on ketamine-related modulation of reward circuitry and implications for anhedonia.Methods: Following PRISMA guidelines, we searched Ovid Embase/MEDLINE/PsycINFO, Cochrane Library, Scopus, Web of Science, and Google Scholar (February-September 2025).Eligible studies included adults with MDD receiving ketamine or esketamine and undergoing fMRI, PET, or related imaging during rest or reward/emotion tasks.Thirteen studies met inclusion criteria (N = 623; 482 MDD/TRD, 141 controls), mostly randomized, double-blind, and placebocontrolled; no eligible esketamine neuroimaging studies were identified.Results: Intravenous ketamine (typically 0.5 mg/kg over 40 min) was associated with short-term modulation of fronto-striatal and limbic networks.Resting-state fMRI commonly showed altered ventral striatal-prefrontal/ACC connectivity and broader DMN/salience/executive network reorganization across acute-to-subacute windows (2-48 h), with some effects changing at later follow-up (10 days).Task-based fMRI showed altered ventral striatal/putaminal responses during reward anticipation/feedback and modulation of medial prefrontal/cingulate activity during emotion processing.PET findings suggested increased prefrontal-cingulate metabolism and region-specific 5-HTB binding/availability changes, with baseline ventral striatal 5-HTB measures associated with symptom profiles and symptom change.Conclusions: Ketamine is associated with rapid reconfiguration of reward-related circuitry (ventral striatum-ACC-mPFC), but few studies directly measured anhedonia; findings likely reflect broader reward-processing and antidepressant-associated mechanisms.Larger longitudinal multimodal studies are needed to validate biomarkers and durability.