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Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression.

Yanling Zhou, Wei Zheng, Weijian Liu, Chengyu Wang, Yanni Zhan, Hanqiu Li, Lijian Chen, Mingding Li, Yuping Ning

Brain, Behavior, and Immunity November 2018 DOI: 10.1016/j.bbi.2018.09.007 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Observational cohort study Peer reviewed
Sample size 84
Population Patients with unipolar and bipolar treatment-resistant depression; 60 healthy controls for comparison
Intervention Ketamine
Dose 0.5 mg/kg
Duration Six infusions over a 12-day period; assessments at baseline, 24 hours after the first infusion, and 24 hours and 14 days after the sixth infusion (24 hours, 13 days, and 26 days)
Measures Montgomery-Asberg Scale (MADRS)
Topics Depression Ketamine Esketamine
Keywords Kynurenine Predictor
Key findings Six ketamine infusions produced a response in 50 of 84 patients (59.5%) at day 13. Responders had higher serum kynurenic acid (KYNA) levels and KYNA/kynurenine ratios than nonresponders at 24 hours and 13 days, and early increases in KYNA and the KYNA/KYN ratio at 24 hours were associated with greater reductions in MADRS scores at 24 hours, 13 days, and 26 days. The authors propose that the kynurenine pathway may contribute to ketamine's rapid antidepressant effect and that early KYNA changes could serve as predictors of response.

Abstract

Ketamine has rapid antidepressant effects on treatment-resistant depression, but the biological mechanism underpinning this effect is less clear. Our aims were to examine whether kynurenine pathway metabolites were altered by six infusions of ketamine and whether these biological factors could act as potential biomarkers to predict ketamine's antidepressant effects. Six intravenous infusions of ketamine (0.5 mg/kg) were administered to 84 patients with unipolar and bipolar depression over a 12-d period. Symptom severity and response were assessed using the Montgomery-Asberg Scale (MADRS), and blood samples were collected at baseline and 24 h following the first infusion and at 24 h and 14 d after the sixth infusion (24 h, 13 d and 26 d). Blood samples from sixty healthy controls were collected for comparison with samples from the patients. Serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by the liquid chromatography-tandem mass spectrometry method. At baseline, serum levels of TRP and KYNA and the KYNA/KYN ratio were lower and the KYN/TRP ratio was greater in depressed patients than in healthy controls. Overall, fifty (59.5%) patients responded to ketamine at 13 d. Ketamine responders had a greater KYNA level and KYNA/KYN ratio than nonresponders at 24 h and 13 d (all P < 0.05). Elevations in the KYNA levels and KYNA/KYN ratio at 24 h were significantly associated with reductions in MADRS scores at 24 h, 13 d and 26 d in the linear regression analysis (all P < 0.05). Our results showed a possible involvement of the kynurenine pathway in the rapid antidepressant effect of ketamine. Early changes in serum KYNA levels and the KYNA/KYN ratio could be potential predictors of antidepressanteffects of repeated ketamine administration.

Comparable studies

Other observational and cohort studies on ketamine for depression, most cited first.

Study Year Design Participants
Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder 2012 Observational cohort n = 30
Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome Healthy controls and actively depressed patients with treatment-resistant depression... 2017 Observational cohort n = 59
Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression Treatment-resistant inpatients with DSM-IV-TR-diagnosed major depressive disorder or... 2014 Post hoc analysis of pooled data from four studies n = 108
An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression Drug-free patients with major depressive disorder 2011 Observational cohort n = 14
Efficacy of ketamine therapy in the treatment of depression Drug-free/naïve men with severe depression, no history of psychotic disorder, head... 2019 Observational cohort n = 25

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