Kynurenine pathway metabolites are increased in inflammatory depression and decrease with omega-3 treatment

Activation of the kynurenine pathway (KP) with resulting accumulation of neuroactive metabolites may be a downstream pathophysiological mechanism in inflammatory depression. The aims of this study were to investigate KP metabolites in inflammatory depression compared to non-inflammatory depression and healthy controls, and whether these metabolites change with nutraceutical interventions with potential KP-modulating effects. We combined data from two antidepressant clinical trials: one with omega-3 polyunsaturated fatty acids (n-3 PUFAs) and one with a Limosilactobacillus reuteri probiotic supplement as the active intervention. Patients with Major Depressive Disorder (MDD) (n=170) were stratified at baseline according to high-sensitivity C-reactive protein (hs-CRP) levels into an inflammatory (hs-CRP ≥1 mg/L, n=127) and a non-inflammatory (hs-CRP <1 mg/L, n=43) group. We also included 80 non-depressed healthy controls (HC). We investigated between-group differences in KP metabolites at baseline, treatment-associated changes in these biomarkers and how they relate to clinical response. At baseline, the inflammatory depression group had significantly elevated levels of quinolinic acid (QUIN) (p<0.01), 3-hydroxykynurenine (3-HK) (p<0.05), and kynurenine (p<0.05) levels compared to both non-inflammatory depression and controls. N-3 PUFAs, but not probiotics or placebo, significantly decreased QUIN (p<0.05) and 3-HK (p<0.05). Higher baseline levels and a greater treatment-associated decrease of several KP metabolites were associated with a greater clinical response to n-3 PUFAs (p<0.05). In contrast, probiotic supplementation was not associated with significant changes in KP metabolites, and biomarker associations with treatment response were limited in this cohort. We found evidence of KP activation in MDD, but only in an inflammatory subgroup, suggesting that these biological alterations may be specific to a subset of patients with low-grade inflammation. These findings encourage further investigations into whether, and how, biomarkers of KP activation may predict antidepressant response. • MDD patients with low-grade inflammation had elevated kynurenine pathway metabolites. • N-3 PUFA supplementation reduced quinolinic acid, kynurenic acid and 3-hydroxykynurenine • Baseline activation of the kynurenine pathway was associated with n-3 PUFA treatment response • Decrease in kynurenine pathway metabolites was associated with n-3 PUFA treatment response