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 DOI: 10.1016/j.bbi.2026.106889 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Sample size | 30 |
| Population | Adults with treatment-resistant depression |
| Intervention | Ketamine |
| Dose | six intravenous ketamine infusions |
| Duration | Three weeks |
| Topics | Depression Ketamine Esketamine |
| Keywords | Immunometabolic depression Kynurenic acid Kynurenine pathway |
| Key findings | Higher baseline kynurenic acid was associated with greater symptom improvement after six ketamine infusions, and early shifts toward the neurotoxic kynurenine pathway branch were associated with reductions in hopelessness and suicidality scores. |
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.
Comparable studies
Other observational and cohort studies on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
| Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome Healthy controls and actively depressed patients with treatment-resistant depression... | 2017 | Observational cohort | n = 59 |
| Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression Treatment-resistant inpatients with DSM-IV-TR-diagnosed major depressive disorder or... | 2014 | Post hoc analysis of pooled data from four studies | n = 108 |
| An investigation of amino-acid neurotransmitters as potential predictors of clinical improvement to ketamine in depression Drug-free patients with major depressive disorder | 2011 | Observational cohort | n = 14 |
| Efficacy of ketamine therapy in the treatment of depression Drug-free/naïve men with severe depression, no history of psychotic disorder, head... | 2019 | Observational cohort | n = 25 |