Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review

• Published in: Journal of psychopharmacology (Oxford) Vol. 35; no. 8; pp. 934 - 945
• Main Authors: Kopra, Emma, Mondelli, Valeria, Pariante, Carmine, Nikkheslat, Naghmeh
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.08.2021
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Antidepressive Agents - pharmacology; Bipolar Disorder - drug therapy; Cytokines - metabolism; Depressive Disorder, Major - drug therapy; Depressive Disorder, Major - physiopathology; Humans; Inflammation - drug therapy; Inflammation - pathology; Ketamine - pharmacology; Kynurenine - metabolism; Tryptophan - metabolism; cytokine; kynurenine; Ketamine; depression; inflammation
• ISSN: 0269-8811; 1461-7285
• DOI: 10.1177/02698811211026426

Background: Ketamine is a novel rapid-acting antidepressant with high efficacy in treatment-resistant patients. Its exact therapeutic mechanisms of action are unclear; however, in recent years its anti-inflammatory properties and subsequent downstream effects on tryptophan (TRP) metabolism have sparked research interest. Aim: This systematic review examined the effect of ketamine on inflammatory markers and TRP–kynurenine (KYN) pathway metabolites in patients with unipolar and bipolar depression and in animal models of depression. Methods: MEDLINE, Embase, and PsycINFO databases were searched on October 2020 (1806 to 2020). Results: Out of 807 initial results, nine human studies and 22 animal studies on rodents met the inclusion criteria. Rodent studies provided strong support for ketamine-induced decreases in pro-inflammatory cytokines, namely in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α and indicated anti-inflammatory effects on TRP metabolism, including decreases in the enzyme indoleamine 2,3-dioxygenase (IDO). Clinical evidence was less robust with high heterogeneity between sample characteristics, but most experiments demonstrated decreases in peripheral inflammation including in IL-1β, IL-6, and TNF-α. Preliminary support was also found for reduced activation of the neurotoxic arm of the KYN pathway. Conclusion: Ketamine appears to induce anti-inflammatory effects in at least a proportion of depressed patients. Suggestions for future research include investigation of markers in the central nervous system and examination of clinical relevance of inflammatory changes.