Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces anti-inflammatory M2 macrophages by NMDAR and mTOR

Abstract

BackgroundDepression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses.MethodsOur goal was to characterize the pro-inflammatory profile of patients with MDD by measuring pro-inflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo.FindingOur results show that patients with MDD without other comorbidities (N = 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11b+CD16brightCD14neg) monocytes and increased activation state (CD40+CD86+) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Sub-anaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS.InterpretationOur results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases.FundingThis study was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-FONCYT).

Impact of COVID-19 in the Mental Health in Elderly: Psychological and Biological Updates

“…The reduction of mTOR activity can lead to MDD, while drugs that increase the activity, such as ketamine, are considered potent antidepressants [ 41 ]. Some studies show that ketamine induces an anti-inflammatory profile through mTOR in parallel to antidepressant effects in humans’ severe depression [ 42 ]. Notwithstanding, animal studies have shown that ketamine increased TNF-α in serum, and rapamycin did not reverse the effect of ketamine.…”

How Does COVID-19 Affect the Neurobiology of Suicide?

“…Microglial activation is also induced by peripheral inflammation first within the circumventricular organs, leptomeninges, and choroid plexus and then throughout the CNS [ 78 ]. Interestingly, the monocyte-to-lymphocyte ratio in peripheral blood samples has been associated with age at first suicide attempt [ 80 ], and activated monocytes are more likely to be detected in plasma from patients with depression [ 81 ]. Higher monocyte count and increased IL-6 level were observed in patients at risk for suicide [ 82 ].…”

“…Importantly, it has been proposed that the rapid action of ketamine (NMDA antagonist) significantly reduces depression and suicidal ideation through the decrease of pro-inflammatory cytokines [ 83 ]. Its antidepressant effect partially relies on modulation of the immune response: reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophages [ 81 ]. Finally, some anti-inflammatory agents (such as anti-IL6 antibodies) that are currently tested in COVID-19 have shown efficacy in individuals with mood disorders (Table 1 ).…”

Immunoregulation and antidepressant effect of ketamine

“…For example, ketamine has anti-inflammatory properties in the treatment of MDD, which can polarize macrophages to an M2-like phenotype [ 87 ]. Ketamine also decreases gene expressions of macrophage TNF-α, IL-6 [ 88 ], and IL-1β [ 89 ].…”