Effect of Ketamine on Reward Processing in Depressive Disorders: A Systematic Review of Neuroimaging Studies
CNS Spectrums – March 10, 2026
Source: OpenAlex
Summary
Ketamine shows promise in rapidly reconfiguring reward circuitry in individuals with major depressive disorder (MDD). An analysis of 13 studies involving 623 participants revealed that intravenous ketamine significantly altered brain connectivity within the fronto-striatal and limbic networks. Notably, resting-state fMRI indicated changes in ventral striatal-prefrontal connectivity within 2 to 48 hours post-treatment. Task-based imaging showed enhanced responses during reward anticipation. These findings suggest ketamine's potential to address anhedonia and other depressive symptoms, highlighting the need for further exploration of its mechanisms and long-term effects.
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.