Dysfunction in a wide array of systems—including the immune, monoaminergic, and glutamatergic systems—is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23 F, ages 18–65) received a single ketamine infusion (0.5 mg/kg) over 40 min. KYN pathway analytes—including plasma concentrations of indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)—were assessed at baseline (pre-infusion), 230 min, day 1, and day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the residuals with an unstructured matrix. After controlling for age, sex, and body mass index (BMI), post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.
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Funding for this work was supported by the Intramural Research Program at the National Institute of Mental Health, National Institutes of Health (IRP-NIMH-NIH) (ZIA-MH002857; NCT00088699; 04-M-0222); by a NARSAD Independent Investigator to CAZ; by a Brain & Behavior Mood Disorders Research Award to CAZ; and by the Intramural Research Program at the National Institute of Aging (RM). The authors thank the 7SE research unit and staff for their support.
Conflict of interest
CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ and RM are listed as co-inventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as co-inventors 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 posttraumatic stress disorders. They have assigned their patent rights to the US government but will share a percentage of any royalties that may be received by the government. The remaining authors declare that they have no conflict of interest.
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Kadriu, B., Farmer, C.A., Yuan, P. et al. The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0589-8