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Review
. 2023 Apr;28(4):103518.
doi: 10.1016/j.drudis.2023.103518. Epub 2023 Feb 8.

Inflammation, stress and depression: An exploration of ketamine's therapeutic profile

Jenessa N Johnston  1 , Maximillian S Greenwald  2 , Ioline D Henter  2 , Christoph Kraus  2 , Anahit Mkrtchian  2 , Neil G Clark  3 , Lawrence T Park  2 , Philip Gold  2 , Carlos A Zarate Jr  2 , Bashkim Kadriu  2
Affiliations
Review

Inflammation, stress and depression: An exploration of ketamine's therapeutic profile

Jenessa N Johnston et al. Drug Discov Today. 2023 Apr.

Abstract

Well-established animal models of depression have described a proximal relationship between stress and central nervous system (CNS) inflammation - a relationship mirrored in the peripheral inflammatory biomarkers of individuals with depression. Evidence also suggests that stress-induced proinflammatory states can contribute to the neurobiology of treatment-resistant depression. Interestingly, ketamine, a rapid-acting antidepressant, can partially exert its therapeutic effects via anti-inflammatory actions on the hypothalamic-pituitary adrenal (HPA) axis, the kynurenine pathway or by cytokine suppression. Further investigations into the relationship between ketamine, inflammation and stress could provide insight into ketamine's unique therapeutic mechanisms and stimulate efforts to develop rapid-acting, anti-inflammatory-based antidepressants.

Keywords: Ketamine; anhedonia; depression; inflammation; stress; treatment-resistant depression.

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Conflict of interest statement

Conflicts of interest

Dr Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation and post-traumatic stress disorders. He has assigned his patent rights to the US Government but will share a percentage of any royalties that might be received by the government. All other authors have no conflicts of interest to disclose, financial or otherwise.

Figures

Figure 1.
Figure 1.
The hypothesized impact of ketamine on stress and inflammatory pathways. Chronic stress leads to overactivation of the hypothalamic-pituitary-adrenal (HPA) axis, which increases levels of corticotropin-releasing hormone (CRH) and cortisol while decreasing expression of glucocorticoid receptors (GRs). This decrease in GR expression prevents the shut-off of the HPA axis, leading to prolonged activation that can have negative consequences. Ketamine, an N-methyl-d-aspartate receptor (NMDAR) antagonist, appears to mediate this stress response by increasing the number of GRs. Studies examining ketamine’s effect on cortisol levels have yielded mixed results. Under chronic stress conditions, the kynurenine pathway, another potential mediator between stress and inflammation, demonstrates increased levels of indoleamine-2,3-dioxygenase (IDO), tryptophan-2,3-dioxygenase (TDO) and quinolinic acid, as well as decreased levels of kynurenic acid. Ketamine decreases IDO levels and the ratio of kynurenine:tryptophan through indirect mechanisms while blocking the action of quinolinic acid through direct NMDAR antagonism. Ketamine also decreases proinflammatory cytokine levels (increased by chronic stress) through the NLPR3-inflammasome pathway, decreasing microglial activation via TLR/p38 signaling, P2X7 receptors and signal transducer and activator of transcription 3 (STAT3) activation, as well as switching macrophages to the anti-inflammatory M2 phenotype. Figure created using Biorender.
See this image and copyright information in PMC

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