224. Biomarkers of ketamine efficacy: role of the kynurenine pathway
B. P. Petrozzi, Marta Marszalek-Grabska, Emilia Fornal, Elena Neumann, Lena Danyeli, Z. Sen, M. Walter, Gerhard Gründer, M. Gilles, Alexander Sartorius, Moritz Spangemacher, Jonathan R Reinwald
The International Journal of Neuropsychopharmacology September 1, 2026 DOI: 10.1093/ijnp/pyag040.203 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Prospective observational cohort (biomarker sub-study of an open-label ketamine trial) Longitudinal Peer reviewed |
|---|---|
| Sample size | 36 |
| Population | Adults with treatment-resistant depression |
| Intervention | Ketamine |
| Dose | 0.5 mg/kg |
| Duration | Six infusions over three weeks; assessments at baseline (D1), after first infusion (D3), and before final infusion (D18) |
| Measures | MADRS, absolute monocyte count (AMC) |
| Topics | Esketamine Ketamine |
| Key findings | Higher pre-treatment kynurenic acid predicted greater antidepressant response to ketamine at day 18 and mediated the association between higher BMI and improvement; absolute monocyte count and BMI also predicted improvement. Early decreases in quinolinic acid and 3-hydroxykynurenine at day 3 were associated with reduced hopelessness scores, while longitudinal kynurenic acid changes were not associated with overall response. |
Abstract
Abstract 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.
Comparable studies
Other non-randomized and open-label trials on ketamine, most cited first.