Biomarkers of ketamine efficacy: role of the kynurenine pathway
B. Pedraz Petrozzi1, M. Marszalek-Grabska2, E. Fornal3, E. Neumann4, L.V. Danyeli5, Z.D. Sen5, M. Walter5, G. Gründer1, M. Gilles1, A. Sartorius1, M. Spangemacher1, J. Reinwald1
1Central Institute of Mental Health, Department of Psychiatry, Mannheim, Germany, 2Institute of Rural Health, Department of Neurotoxicology, Lublin, Poland, 3Medical University of Lublin, Poland, Department of Bioanalytics, Lublin, Poland, 4Campus Kerckhoff of the Justus-Liebig University, Internal Medicine and Rheumatology, Bad Nauheim, Germany, 5Jena University Hospital, Department of Psychiatry and Psychotherapy, Jena, Germany
Background: Understanding the interplay between inflammation, the kynurenine pathway, and clinical response to ketamine may offer insights into predictive biomarkers and individualized treatment strategies for treatment-resistant depression (TRD).
Aims & Objectives: We assessed whether pre-treatment levels of kynurenine metabolites predict ketamine response and explored their temporal dynamics concerning clinical outcomes.
Method: Thirty-six adults with TRD received six intravenous ketamine infusions (0.5 mg/kg) over three weeks. Biological assessments included kynurenine pathway metabolites (tryptophan, kynurenine, kynurenic acid [KYNA], 3-hydroxykynurenine [3-HK], and quinolinic acid [QUIN]). Depression severity (MADRS) and biomarkers were assessed at baseline (D1), after the first infusion (D3), and before the final infusion (D18). Absolute monocyte count (AMC) was assessed only at baseline.
Results: Higher baseline KYNA predicted greater symptom improvement at D18, as did AMC at D3 and D18, along with BMI. Including KYNA in a GLM with AMC, sex, age, and BMI increased the explained variance in treatment response, indicating independent and additive predictive value. While higher BMI was associated with greater improvement, this effect was fully mediated by KYNA. Early changes in QUIN and 3-HK at D3 were linked to reductions in MADRS hopelessness scores, suggesting a role in ketamine’s rapid effects on pessimism and suicidality. In contrast, longitudinal changes in KYNA were not associated with overall treatment response.
Discussion & Conclusions: Baseline KYNA predicts antidepressant response to ketamine and mediates BMI-related effects. A stable KYNA-tilted “trait” coupled with a downstream state shift (TRP→KYN dial-down; bigger KYN drop in responders) may explain who benefits. Early shifts in kynurenine metabolites may underlie improvements in hopelessness.
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