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

In adults with treatment-resistant depression receiving six intravenous ketamine infusions over three weeks, higher baseline levels of the neuroprotective metabolite kynurenic acid (KYNA) in the kynurenine pathway were associated with greater symptom improvement by day 18. KYNA remained stable over time and did not track with symptom changes, suggesting it acts as a trait-like marker rather than a state-dependent one. Early shifts toward the neurotoxic branch of the pathway (kynurenine and 3-hydroxykynurenine) were linked to reductions in hopelessness and suicidality scores after the first infusion. These exploratory findings indicate that a kynurenine pathway profile biased toward neuroprotective metabolites may inform future biomarker studies of ketamine response, but require validation in larger samples.

Study at a glance

Abstract

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, βstd = -0.54, p = 0.002, pFDR = 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.