The Kynurenine Pathway as a Mediator Between Childhood Adversity and Suicidal Ideation in Adults with Major Depressive Disorder: A Proposed Clinical Study Protocol

Abstract

Introduction: Childhood adversity (CA) is widely recognized as a major risk factor for adult suicidal ideation (SI). Chronic inflammation is frequently proposed as a potential mechanism, although the precise biological pathway that may contribute to SI remains unclear. The kynurenine pathway (KP) becomes activated in response to inflammation, shifts tryptophan metabolism away from serotonin production toward the generation of neurotoxic metabolites such as quinolinic acid, thereby potentially bridging this explanatory gap. This study aims specifically to test whether KP activation is consistent with a mediating role in the relationship between CA and SI in adults diagnosed with Major Depressive Disorder (MDD), independent of overall depression severity. Methods: A cross-sectional case-control study will be conducted, recruiting a total of 120 participants (aged 25–55 years) into three distinct groups: MDD with SI (n=40), MDD without SI (n=40), and healthy controls (n=40). Comprehensive assessments will include the Childhood Trauma Questionnaire (CTQ), the Hamilton Depression Rating Scale (HAM-D-17), and the Beck Scale for Suicide Ideation (BSS). Fasting blood samples will be collected and analyzed for inflammatory markers (CRP, IL-6, TNF-α) and KP metabolites (Tryptophan, Kynurenine, Quinolinic Acid) to calculate the Kynurenine/Tryptophan (K/T) ratio. A simple mediation analysis (PROCESS Macro, Model 4) will then be employed to test the indirect effect of CA on SI via the K/T ratio, while controlling for HAM-D-17 scores. Results: This manuscript presents a research protocol; as such, results from the proposed study are not yet available. The study is currently in the planning stage, and participant recruitment is anticipated to begin following the receipt of ethics approval. Discussion: We hypothesize that the MDD+SI group will demonstrate the highest level of KP activation and that the KP will show a significant indirect effect in the CA-SI relationship, independent of depression severity. Such a finding would support the KP’s role as a key biological pathway linking early adversity to later suicidal thinking. Conclusion: Confirmation of this proposed model would offer a novel neurobiological explanation for SI, thereby suggesting the KP as a potential therapeutic target for suicide prevention that is distinct from treatments aimed solely at alleviating general depressive symptoms.