Investigation Of Ketamine’s Clinical Antidepressant Effects And Related Inflammatory Mechanisms

Objective:Recently more and more abroad clinical studies have suggested that ketamine, a nonselective N-methyl-D-aspartate (NMDA) receptor antagonist, possesses rapid and robust antidepressant effects. However, there is no domestic research in this field. The underlying mechanisms are not totally understood. Activated inflammatory responses play an important role in the pathogenesis of depression. Numerous studies have suggested that major depression is accompanied by activation of the inflammatory response system has been demonstrated by increased production of pro-inflammatory cytokines in plasma and cerebrospinal fluid, which was abolished by traditional antidepressant treatment. Several reports have shown that ketamine can limit and even prevent inflammation. In this study, (1) we observed the clinical antidepressant effects of ketamine the role of pro-inflammatory in ketamine’s antidepressant actions; (2) we discuss the role of ketamine’s down-regulation of pro-inflammatory cytokines in it’s antidepressant actions.Methods:The first part:16 patients which were satisfied the inclusion criteria received a single dose of 0.5 mg/kg ketamine through intravenous infusion during the course of 40 minutes. Montgomery-Asberg Depression Scale (MADRS),17-item Hamilton Depression Scale (HDRS) and Scale for Suicide Ideation (SSI) were evaluated and blood samples were obtained in depressed patients receiving intravenous infusion ketamine at 60 min pre-infusion and 110 min,230 min,1 d,3 d, and 7 d after infusion. Blood samples of 21 healthy controls were also obtained. Levels of IL-1β,IL-6 were measured by radioimmunoassay (RIA); kynurenine (KYN) and tryptophan (TRP) were measured by high performance liquid chromatography (HPLC).The second part:in animals, forty-eight rats were equally randomized into a control group receiving saline and five chronic unpredictable mild stress (CUMS) groups receiving saline (saline group) or 10 mg/kg ketamine (ketamine 0.5 h group, ketamine 1 h group, ketamine 2 h group and ketamine 4 h group, respectively). The forced swimming test (FST) was performed and then the hippocampus was harvested. Levels of IL-1β, IL-6 were measured by RIA; kynurenine and tryptophan were measured by HPLC; indoleamine 2,3-dioxygenase (IDO) were measured by enzyme-linked immunosorbent assay (ELISA).Results:The first part:MARDS and HDRS of the patients from 230 min to 7 d post-infusion decreased significantly (all P< 0.001). Ketamine significantly decreased SSI scores of the patients’from 110 min to 7 d post-infusion decreased significantly (P<0.01). Depressed patients showed higher baseline serum levels of IL-1J3, IL-6, and KYN/TRP than healthy controls (respectively P<0.001; P<0.01; P<0.05). Pre-infusion serum levels of IL-ip, IL-6 and KYN/TRP ratio in responders to ketamine treatment significantly higher than non-responders to ketamine treatment (all P<0.05). IL-1β decreased in the responders at 230 min and 1 d after infusion (P<0.01); IL-6 levels decreased in the responders at 230 min,1 d and 3 d after infusion (P<0.05). Post-infusion KYN/TRP ratio has no significantly changes in the responders (P>0.05), as well as the IL-1β, IL-6, and KYN/TRP ratio in non-responders. The MADRS, HDRS, and SSI scores at baseline and 1 d after infusion have no significantly correlation with the IL-1β, IL-6, and KYN/TRP ratio in serum of the responders (all P>0.05).The second part:CUMS exposure induced depression-like behaviors and up-regulated hippocampal IL-1β, IL-6, IDO, and KYN/TRP in rats which was partially antagonized by ketamine.Conclusions:Ketamine can improve depressive symptoms rapidly and robustly; the patients with higher level of IL-1β, IL-6, and KYN/TRP at 60 min pre-infusion more sensitive to ketamine’s antidepressive therapy. Down-regulation of pro-inflammatory cytokines contributes to the antidepressant effects of ketamine, probably via inhibiting IDO and its downstream signaling pathways.