Ketamine for co-occurring chronic pain and depression: A scoping review highlighting the dual-outcome evidence gap and its treatment and research implications.
Simon Asnes, Julio C Nunes, Rebecca Suh, Gabriel P. A. Costa, Katherine Jones, Melissa C Funaro, Samuel T. Wilkinson, John H. Krystal, Joao P De Aquino
Journal of Pain November 9, 2026 DOI: 10.1016/j.jpain.2026.106491 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Scoping review Randomized Peer reviewed |
|---|---|
| Intervention | Ketamine |
| Topics | Depression Ketamine Esketamine |
| Keywords | Analgesia Nmda receptor antagonist Pain |
| Key findings | Across 12 studies, most reported concurrent improvement in pain and depressive symptoms after ketamine, but heterogeneity in population definitions, dosing, study design, and psychiatric comorbidity precludes concluding that depression modifies ketamine's analgesic effect. The authors argue that prospective randomized studies with standardized chronic pain and depression measures are needed. |
Abstract
Chronic pain and depression frequently co-occur, share clinical features, and involve shared neurobiological substrates. Ketamine, an NMDA-receptor antagonist, has established antidepressant efficacy, whereas its analgesic efficacy for chronic pain remains uncertain. Given the overlap between chronic pain and depression, ketamine may serve as a potential dual-action treatment. We conducted a scoping review of studies in which pain and depressive outcomes were both assessed longitudinally after ketamine treatment. Following PRISMA-ScR guidelines, we searched MEDLINE, Embase, Web of Science, and Scopus through August 2026. Experimental and observational studies reporting post-treatment pain and depression outcomes were included; acute, perioperative, perinatal, and cancer-related pain were excluded. Of 2187 records screened, 12 studies met inclusion criteria (2007-2025). Eight enrolled patients with consensus-based chronic pain (≥3 months); among these, only two used clinical diagnoses to characterize depression (one being retrospective chart review), whereas the remainder used symptom scales. Four depression-primary studies enrolled patients with major depressive disorder, treatment-resistant depression, or bipolar depression but did not rigorously establish chronic pain duration. Most studies reported concurrent improvement in pain and depressive symptoms, but heterogeneity in population definitions, ketamine administration regimens, study design, and psychiatric comorbidity precludes inference that depression modifies ketamine's analgesic effect. Prospective randomized studies using standardized chronic pain and depression measures are needed to clarify ketamine's efficacy and real-world applicability. REGISTRATION: This protocol was registered on the Open Science Framework (OSF) (registration: OSF.IO/3ER5W) PERSPECTIVE: This review maps studies that assessed pain and depressive symptoms longitudinally during ketamine treatment. Concurrent improvement was commonly reported, but inconsistent depression ascertainment, pain phenotyping, dosing, and study design prevent conclusions about depression-specific analgesic effects. Prospective trials with clinically defined comorbidity are needed.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cites 12
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Enhanced Medial Prefrontal-Default Mode Network Functional Connectivity in Chronic Pain and Its Association with Pain Rumination Journal of Neuroscience March 12, 2014
- Fast-acting antidepressant activity of ketamine: highlights on brain serotonin, glutamate, and GABA neurotransmission in preclinical studies. Pharmacology & Therapeutics July 1, 2019
- Ketamine for the acute treatment of severe suicidal ideation: double blind, randomised placebo controlled trial British medical journal February 2, 2022
- Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. The Lancet Psychiatry November 1, 2022
and 7 more in the library