Effects of inflammation modulation on tryptophan and kynurenine pathway regulation in treatment resistant bipolar depression

Abstract

BackgroundAdjunctive immune-modulation can be safe and effective for treatment-resistant bipolar depression (TRBDD), but molecular work is needed to further characterize the safety and efficacy involved in treatment response and the reversal of treatment resistance. Here we profiled the kynurenine pathway (KP) for biomarkers associated with TRBDD and treatment response to celecoxib (CBX)-augmentation. Methods47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg twice daily) + CBX (200 mg twice daily), or ESC (10 mg twice daily) + placebo (PBO) (twice daily). Plasma kynurenine pathway (KP) metabolite levels were measured at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once. ResultsPatients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT=3, and 15.300 greater odds of remitting (p < 0.001) with NNT=2, compared with ESC + PBO patients. Study patients exhibited elevated baseline tryptophan (p < 0.001), low kynurenine/tryptophan (p < 0.001), elevated 3-hydryoxykynurenine/kynurenine (adj-p*<0.001), low kynurenic acid/3-hydroxykynurenine, and low picolinic acid/quinolinic acid (p < 0.001) compared to healthy controls. Treatment responders exhibited tryptophan depletion (p = 0.020) without a concomitant change in kynurenine/tryptophan ratio by week 8 (p = 0.163). ConclusionClinical response to CBX augmentation is not associated with altered neurotoxic or neuroprotective indices within the time frame of this study. TRBDD revealed alterations in neuroprotective and neurotoxic indices, in the context of low kynurenine/tryptophan and high tryptophan. Treatment responders revealed a depletion in tryptophan by week 8, without concomitant kynurenine pathway (KP) activation.