Open Access Tryptophan catabolites and depression in the general population: results from the Gutenberg Health Study

Depression has been linked to alterations in tryptophan metabolism, a precursor of serotonin and melatonin. The kynurenine pathway, particularly the indoleamine-2,3-dioxygenase (IDO1)–mediated catabolism of tryptophan into kynurenine, kynurenic acid (neuroprotective), and quinolinic acid (neurotoxic), has been implicated in the etiology of depression and is responsive to proinflammatory cytokines. Because tryptophan metabolism is also associated with various inflammatory and medical conditions that commonly co-occur with depression, prior findings may be confounded and have limited generalizability due to small clinical samples. Previous studies and meta-analyses have suggested decreased kynurenine and kynurenic acid and increased quinolinic acid in depression, with some proposing tryptophan catabolites as diagnostic markers or treatment targets. However, heterogeneity across studies remains high. Recognizing that depression is multidimensional, with distinct somatic and cognitive-affective symptom clusters measured by the PHQ-9, this study aimed to assess: (1) whether circulating tryptophan catabolites differ by current depression status in a large population sample; (2) the diagnostic potential of these metabolites; and (3) linear associations of tryptophan catabolites with depression severity and its somatic versus cognitive-affective dimensions.

Prior clinical and meta-analytic evidence indicates alterations in kynurenine pathway metabolites in depression: reductions in kynurenine and kynurenic acid and elevations in quinolinic acid have been reported. Some studies have suggested that blood levels of kynurenic acid and related ratios differentiate depressed patients from controls with moderate accuracy, and that kynurenic acid may predict antidepressant response (e.g., post-ketamine changes) or relate to cognitive deficits in late-life depression. Conversely, community-based studies (e.g., Netherlands Study of Depression and Anxiety) have observed no differences in plasma tryptophan catabolites between depressed individuals and controls. Meta-analyses have proposed tryptophan and kynurenic acid as consistently downregulated markers with potential for distinguishing depressive states and treatment response, though study heterogeneity and small sample sizes limit certainty. Given tryptophan metabolism’s involvement in many inflammatory diseases, specificity for depression is questionable. The multidimensional structure of depression suggests potential differential links of metabolites to cognitive-affective versus somatic symptoms, warranting symptom-level analyses.

Design and cohort: Analysis of the first 5,000 participants from the population-based Gutenberg Health Study (GHS), a prospective observational single-center cohort in western Mid-Germany (age 35–74 years), stratified by sex, residence, and age decades. Exclusions for this analysis: fasting time < 8 h (n=1,298), current infection (CRP ≥ 10 mg/L; n=154), missing depression score or other variables (n=114), yielding n=3,389. Ethics approvals obtained; written informed consent provided. Assessments: Baseline and 5-year follow-up in-center visits with questionnaires, interviews, and medical/lab exams. Depression: PHQ-9; depression defined as PHQ-9 ≥ 10; somatic (sleep, energy, appetite, psychomotor) and cognitive-affective (interest, mood, self-worth, concentration, suicidality) subscales analyzed. Anxiety: GAD-2 (cutoff ≥3). Socioeconomic status (SES): Lampert & Kroll index (3–21). Medical history: self-report of physician-diagnosed depression/anxiety; lifetime suicide attempts assessed at 5-year follow-up. Lifestyle/clinical covariates: smoking (current vs non), obesity (BMI ≥30), alcohol at-risk use (≥24 g/day men; ≥12 g/day women), physical activity (SQUASH; METs), BP, heart rate, CAD, lipids, CRP, fasting glucose/insulin, HOMA-IR. Medication: on-site barcode scanning; antidepressant classes per ATC (N06AA, N06AB, N06AX). Biospecimens: Fasting blood; routine assays for lipids and CRP; other measures stored at −80 °C and analyzed in batch, blinded. Tryptophan catabolites: Plasma tryptophan, kynurenine, kynurenic acid, quinolinic acid quantified by validated LC-MS/MS at Nuvisan (Neu-Ulm, Germany). Extraction with internal standards ([D5]kynurenic acid, [D4]kynurenine, [D5]tryptophan, [D3]quinolinic acid), protein precipitation, UPLC on Force C18 (3 μm, 50×3.0 mm), AB Sciex API 5000, Waters Acquity LC; LOQs: tryptophan 2000 nmol/L, kynurenine 100 nmol/L, kynurenic acid 5 nmol/L, quinolinic acid 50 nmol/L; in-study precision CVs: tryptophan 3.9–6.1%, kynurenine 3.7–5.1%, kynurenic acid 5.2–8.4%, quinolinic acid 4.3–5.9%. Grouping for analyses: (a) Depressed: PHQ-9 ≥10; (b) Controls: PHQ-9 <5 and no prior depression/anxiety diagnosis and no psychiatric medication; (c) Intermediate: PHQ-9 5–9 or prior depression/anxiety or any psychiatric drug intake. Statistics: Descriptive summaries. Unadjusted t-tests comparing metabolite levels in depressed vs controls. Logistic regressions predicting depression (PHQ-9 ≥10 vs control) from each metabolite with progressive adjustments: Model 1 (sex, age); Model 2 (sex, age, SES); Model 3 (sex, age, SES, smoking, obesity, alcohol abuse, physical activity, heart rate, systolic BP, CRP, HOMA-IR, lipids). ROC analyses to assess diagnostic performance (AUC) of metabolites. Spearman correlations between metabolites and PHQ-9 severity. Linear regressions for PHQ-9 total and subscales (somatic, cognitive-affective) on kynurenine and kynurenic acid with extensive covariate adjustment (sex, postmenopausal status, age, BP, CAD, heart rate, BMI, smoking, HDL, LDL, triglycerides, CRP, HOMA-IR, physical activity, alcohol). Prospective analysis: logistic regression of 5-year depression (PHQ-9 ≥10) on baseline log kynurenic acid, adjusting for baseline PHQ-9, age, sex.

Sample: n=3,389 (fasting ≥8 h; CRP <10 mg/L). Groups: depressed PHQ-9 ≥10 n=248; mild symptoms n=1,101; no depression n=2,040. Baseline characteristics: Depressed participants were younger, more often female (notably postmenopausal), had lower SES, lower partnership rates, higher arthritis and COPD rates, higher obesity and smoking prevalence, higher CRP, and lower systolic BP; 44% had prior depression diagnosis, >12% reported suicide attempts; at 5 years, 52.9% still had PHQ-9 ≥10. Cross-sectional metabolite differences: • Kynurenine lower in depressed vs controls; fully adjusted logistic regression (Model 3) OR per SD (log) 0.861 (95% CI 0.753–0.984), p=0.028. • Kynurenic acid lower in depressed vs controls; Model 3 OR per SD (log) 0.834 (95% CI 0.731–0.951), p=0.0071. • Tryptophan: no significant difference (t-test diff p=0.091; OR ~1.0 across models). • Quinolinic acid: no significant difference (Model 3 OR 0.917, 95% CI 0.796–1.053, p=0.23). Diagnostic performance: ROC curves for tryptophan, kynurenine, kynurenic acid, and quinolinic acid were not significant; AUCs were near 0.5, indicating no diagnostic utility for depression (PHQ-9 ≥10). Correlations and linear associations: • Spearman correlations between metabolites and PHQ-9 severity were very small: rho from −0.042 (quinolinic acid, p=0.015) to −0.080 (kynurenic acid, p<0.0001). • In multivariable linear models, kynurenine and kynurenic acid were not associated with somatic symptom scores; both were inversely associated with cognitive-affective symptom severity and overall PHQ-9 severity. Reported p-values: overall severity—kynurenine p=0.013, kynurenic acid p=0.0051; cognitive symptoms—kynurenine p=0.00072, kynurenic acid p=0.00011; somatic symptoms—non-significant. Prospective findings: Baseline kynurenic acid did not predict 5-year depression status after adjusting for baseline PHQ-9, age, sex (estimate −0.0216; 95% CI −0.136 to 0.0923; p=0.71). Overall: The study replicated small inverse associations of kynurenine and kynurenic acid with current depression and with cognitive-affective symptoms, but effect sizes were small and not clinically discriminative.

Findings in this large population-based cohort align with meta-analytic evidence indicating lower kynurenine and kynurenic acid in depression. Unlike some prior clinical studies, tryptophan and quinolinic acid did not differ significantly by depression status. Importantly, associations were specific to cognitive-affective symptoms (e.g., low mood, anhedonia, concentration problems, suicidality), not somatic symptoms, supporting a differential symptom-domain link to kynurenine pathway metabolites. However, diagnostic ROC analyses showed no discriminatory ability, challenging the proposed role of these metabolites as screening biomarkers for depression in general populations. The lack of diagnostic utility may reflect the broad involvement of the kynurenine pathway in many inflammatory and medical conditions, reducing specificity, and the lower case-control contrast in community samples compared with clinical cohorts. Prospective analyses did not support kynurenic acid as a predictor of persistence or recurrence of depression over five years. Taken together, while biologically plausible and statistically significant, the associations are small and of limited clinical utility for diagnosis or monitoring at the population level.

This study confirms that circulating kynurenine and kynurenic acid are lower among individuals with current depression in a large, population-based sample, and that these metabolites are inversely associated with overall depression severity and specifically with cognitive-affective symptoms. However, effect sizes were small, ROC analyses showed no diagnostic capability, and baseline kynurenic acid did not predict depression at five-year follow-up. These findings highlight the complexity and low specificity of tryptophan catabolites for depression in the general population. Future research should focus on identifying subgroups (e.g., more severe depression, specific inflammatory profiles) in which kynurenine pathway alterations may be more pronounced and clinically informative, and on integrating metabolite measures with other biomarkers and symptom dimensions.

Depression status was assessed via the PHQ-9 rather than structured clinical interviews, which may introduce misclassification. Only peripheral metabolites were measured; central-peripheral differences may limit inferences about brain kynurenine pathway activity. A substantial number of participants were excluded due to fasting time <8 hours, potentially introducing selection bias. The kynurenine pathway is influenced by multiple inflammatory and medical conditions, which, despite extensive adjustments, may confound associations. Generalizability to clinical populations or severe psychiatric cases may be limited due to the community-based sample and exclusion criteria.