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

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.

Inflammation and serotonin deficiency in major depressive disorder: molecular docking of antidepressant and anti-inflammatory drugs to tryptophan and indoleamine 2,3-dioxygenases

“…Ketamine is the only antidepressant tested that failed to dock to TDO or IDO ( Tables 2 and 3 ; Supplementary Figure S6). The mechanism of the antidepressant action of this rapidly acting drug is currently under investigation [ 9 , 30 ]. Its failure to bind to TDO or IDO, and thus unlikely to inhibit either enzyme, suggests that it may not enhance serotonin synthesis.…”

“…Overproduction of these metabolites can be deleterious to neuronal function and immune activity. Thus, modulation of NMDA receptor function can influence the state of neuronal excitability, which appears to be determined by the balance between KA and QA [ 8 ], and it is of interest that altered NMDA receptor function through modulation of KP activity has been implicated in the rapid antidepressant action of ketamine [ 9 ]. On the other hand, elevation of 3-HK, 3-HAA and QA induces immunosuppression by undermining T-cell function [ 1 ].…”

“…Although the immune status in MDD has received much attention [ 17 ], it is not clearly understood or well-defined. Not all MDD patients have an activated immune system and, when present, inflammation is of a mild and/or transient nature and its reversal is not associated with clinical outcome [ 9 , 17 ]. These features, compounded by heterogeneity of the disorder, associated comorbidities and biological factors, such as hypothalamic–pituitary–adrenal (HPA) axis activity and the immune status, illustrate the need for further studies.…”

Role of BMI in the Relationship Between Dietary Inflammatory Index and Depression: An Intermediary Analysis

“…Inflammation plays a key role in the pathogenesis of depression. Obesity, hyperglycemia, insulin resistance, and overexpression of pro-inflammatory proteins, such as C-reactive protein and cytokines (IL-1β, IL-6, and TNF-α), can induce chronic inflammation of depression ( 7 ). The association between inflammation and mental illness is described as a two-way comorbidity, which means that increased inflammation of the body is associated with an increased risk of mental problems (such as depression), and depression itself is associated with increased behaviors that trigger inflammation, such as Unhealthy eating habits ( 8 ).…”

The Journal of Psychopharmacology: La Plus ça change. . .

“…Emma Kopra and colleagues conducted an interesting systematic review, investigating ketamine's therapeutic mechanisms. They report that its anti-inflammatory properties and subsequent downstream effects on tryptophan metabolism have sparked research interest (Kopra et al, 2021). They suggest future research including an investigation of markers in the central nervous system and examination of clinical relevance of inflammatory changes.…”