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

Summary

Ketamine, a rapid-acting antidepressant for treatment-resistant depression, appears to reduce inflammation in at least some depressed patients. A systematic review of 9 human studies and 22 rodent studies found strong evidence in rodents that ketamine lowers pro-inflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α, and also affects tryptophan metabolism by decreasing the enzyme indoleamine 2,3-dioxygenase. Human studies showed less consistent results but most reported decreases in peripheral inflammation including the same cytokines. Preliminary evidence also suggested reduced activation of the neurotoxic arm of the kynurenine pathway. Future research should investigate markers in the central nervous system and the clinical relevance of these inflammatory changes.

Study at a glance

Abstract

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.