Effect of Ketamine on Reward Processing in Depressive Disorders: A Systematic Review of Neuroimaging Studies
Halima Faisal, Gia Han Le, Angela T H Kwan, Sabrina Wong, Will Cheung, Christine E. Dri, Bing Cao, Taeho Greg Rhee, Stavroula Bargiota, Heidi K.y. Lo, Bianca Shen, Hernán F Guillen-Burgos, Roger S McIntyre
CNS Spectrums March 10, 2026 DOI: 10.1017/s109285292610087x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Double-blind Longitudinal Peer reviewed |
|---|---|
| Sample size | 623 |
| Population | Adults with major depressive disorder or treatment-resistant depression, plus healthy controls |
| Intervention | Intravenous ketamine |
| Dose | 0.5 mg/kg over 40 min |
| Topics | Depression Ketamine Esketamine |
| Keywords | Depressive symptoms Depression economics Medline Functional neuroimaging |
| Key findings | Ketamine is associated with rapid reconfiguration of reward-related circuitry, particularly the ventral striatum, anterior cingulate cortex, and medial prefrontal cortex, though few studies directly measured anhedonia. |
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.
Comparable studies
Other systematic reviews and meta-analyses on ketamine for depression, most cited first.