The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response

Bashkim Kadriu, Cristan A Farmer, Peixiong Yuan, Lawrence T Park, Zhi-De Deng, Ruin Moaddel, Ioline D Henter, Bridget Shovestul, Elizabeth D Ballard, Cristoph Kraus, Philip W Gold, Rodrigo Machado-Vieira, Carlos A Zarate Jr, Bashkim Kadriu, Cristan A Farmer, Peixiong Yuan, Lawrence T Park, Zhi-De Deng, Ruin Moaddel, Ioline D Henter, Bridget Shovestul, Elizabeth D Ballard, Cristoph Kraus, Philip W Gold, Rodrigo Machado-Vieira, Carlos A Zarate Jr

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00088699.

Conflict of interest statement

Conflict of Interest

Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. Drs. Zarate and Moaddel 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 post-traumatic stress disorders. They have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise.

© 2019. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Figures

Figure 1.
Figure 1.
The impact of depression on the kynurenine (KYN) pathway in brain and periphery. The figure depicts KYN metabolites and their related effects on neuronal cells (inside boxes) and the enzymes that metabolize them (arrows). The impact of inflammation or stress-related conditions on key rate-limiting enzymes such as indoleamine 2,3-dioxygenase (IDO) shifts KYN metabolism towards microglial byproducts such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QA). This metabolic change is associated with elevated oxidative stress (3-HK and QA) and glutamate excitotoxicity (QA) that could contribute to depressive symptoms (right panel). Conversely, during homeostasis, substantial amounts of KYN are converted to kynurenic acid (KynA), a process mediated by kynurenine aminotransferase II (KAT II) in astrocytes (left panel). At physiologic levels, KynA is an N-methyl-D-aspartate receptor (NMDAR) antagonist and contributes to the clearance of glutamate spillover in the brain. Abbreviations: TNF-α: tumor necrosis factor alpha; IFN-gamma: interferon gamma; IL-6: interleukin-6; α7nAChR: alpha-7-nicotinic acetylcholine receptor.
Figure 2.
Figure 2.
Results of mixed models: post-ketamine change in the kynurenine (KYN) pathway. Least square mean estimated scores (with standard error) are plotted by time point. Significance refers to change from baseline (−60 minutes). IDO: indoleamine 2,3-dioxygenase; KYN: kynurenine; KynA: kynurenic acid; QA: quinolinic acid. Results of the full analysis can be found in Supplementary Table S2.
Figure 3.
Figure 3.
Baseline inflammatory cytokine component scores as moderators of change in the kynurenine (KYN) pathway (Panel A), and baseline KYN levels as moderators of change in depressive symptom ratings (Panel B). Panel A: Results of a mixed model with component scores of pro-inflammatory (top) or anti-inflammatory (bottom) cytokines entered as moderators of change in KYN pathway analytes (Y-axis) at three time points post-ketamine infusion (X-axis). T-values (all df=24) for the simple slope of the moderator for change at each time point are plotted; positive values indicate that higher cytokine component scores were associated with increases in respective KYN pathway analytes, and negative values indicate that higher cytokine component scores were associated with decreases in respective KYN pathway analytes. Panel B: Results of a mixed model with baseline KYN pathway member entered as a moderator of change in depressive symptom ratings (Y-axis) post-ketamine infusion. T-values (all df=33) for the simple slope of the moderator for change at each time point are plotted; positive values indicate that higher baseline KYN pathway concentrations were associated with less improvement in depressive symptoms, and negative values indicate that higher baseline KYN pathway concentrations were associated with more improvement in depressive symptoms. In both models, age, body mass index (BMI), and type of mood stabilizer were included as covariates. Results of the full analysis can be found in Supplementary Table S5 and Supplementary Table S6. IDO: indoleamine 2,3-dioxygenase; KYN: kynurenine; KynA: kynurenic acid; QA: quinolinic acid.

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