Kynurenine pathway profiles as markers of ketamine response in treatment-resistant depression

Treatment-resistant depression (TRD) remains a major clinical challenge, with highly variable responses to ketamine. Immune activation characterizes a subset of patients with TRD. The kynurenine pathway (KP), which integrates immunometabolic signals with glutamatergic neurotransmission, may provide candidate biomarkers to inform personalized treatment. We investigated whether KP metabolites and ratios are associated with ketamine response and clinical outcomes over time. Thirty adults with TRD received six intravenous ketamine infusions over three weeks. At baseline (D1), after the first infusion (D3), and before the final infusion (D18), we quantified serum tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), and assessed depression severity using the Montgomery-Åsberg Depression Rating Scale (MADRS). Higher baseline KYNA was associated with greater symptom improvement at D18 (β = -21.80, β_std = -0.54, p = 0.002, p_FDR = 0.022). Other markers, including TRP, KYNA/KYN, and KYNA/3-HK, showed concordant nominal associations not surviving multiple-comparisons correction. KYNA remained stable over time, and symptom changes did not track with KYNA changes, suggesting KYNA as a trait-like rather than state-dependent marker. Finally, early shifts toward the putatively neurotoxic KP branch (KYN and 3-HK) were associated with reductions in MADRS hopelessness/suicidality scores at D3. QUIN showed a nominal correlation with hopelessness not surviving multiple-comparisons correction. These exploratory findings may point to a role of KP dynamics in ketamine's rapid anti-suicidal effects, but require validation in larger samples. Overall, our findings suggest that a KP profile biased toward neuroprotective metabolites may inform future biomarker studies of response to ketamine treatment.