Kynurenine pathway profiles as markers of ketamine response in treatment-resistant depression.
Bruno Pedraz-Petrozzi, Marta Marszalek-grabska, Emilia Fornal, Alicja Wielgosz, Anna Stachniuk, Paulina Marzec, Elena Neumann, Elena Riedinger, Maria Gilles, Gerhard Gründer, Lena Vera Danyeli, Zümrüt Duygu Sen, Martin Walter, Alexander Sartorius, Moritz Spangemacher, Jonathan R Reinwald
Brain, behavior, and immunity July 5, 2026 Peer reviewed DOI: 10.1016/j.bbi.2026.106889 via PubMed
Summary
Higher baseline levels of kynurenic acid (KYNA) in adults with treatment-resistant depression (TRD) were linked to greater improvement in depression symptoms after ketamine treatment. In a study involving 30 participants who received six ketamine infusions, KYNA was found to be stable over time and appeared to act as a trait-like marker rather than reflecting immediate changes in symptoms. Early shifts towards neurotoxic metabolites were associated with reduced hopelessness at an early stage, suggesting potential insights into ketamine's effects.
Study at a glance
| Design | observational cohort |
|---|---|
| Sample size | 30 |
| Population | adults with treatment-resistant depression |
| Key finding | Higher baseline kynurenic acid levels were associated with greater symptom improvement after ketamine treatment. |
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.