Plasma kynurenine pathway metabolite levels increase in depressed patients after antidepressant treatment

The kynurenine (KYN) pathway helps regulate physiological systems implicated in major depressive disorder (MDD). We showed that plasma levels of KYN, kynurenic acid (KA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (3-HAA), and picolinic acid (PA) are lower in depressed individuals. However, whether these levels are restored following treatment with antidepressant drugs (AD) and if this restoration is associated with clinical improvement remains unclear. Fasting plasma levels of tryptophan (TRP) and these metabolites, as well as the KYN/TRP ratio, were investigated in 173 depressed patients of the METADAP cohort and 214 healthy controls of VARIETE. Measures were obtained at baseline and 3 and 6 months after beginning AD treatment. Post-treatment changes in metabolites and their associations with changes in the 17-item Hamilton Depression Rating Scale (HDRS) score were analyzed using linear mixed-effects models. Plasma metabolite levels increased following AD treatment, with significant increases in KA (P_FDR = 0.00014), 3-HAA (P_FDR = 0.034), and PA (P_FDR = 0.0097). The KYN/TRP ratio and KA failed to return to healthy control levels. Increases in the KYN/TRP ratio (coef = -1.08, 95 %CI [-1.92–-0.23], P_FDR = 0.045) and KYN levels (coef = -2.37, 95 %CI [-3.83–-0.91], P_FDR = 0.0011) were significantly associated with HDRS score reductions, indicating depressive symptom improvement. Altogether, we observed increases in plasma KYN pathway metabolite levels in depressed patients following 6 months of AD treatment that, for some, was significantly associated with clinical improvement. Our findings suggest increases in these metabolites may be relevant to treating depression.