Polygenic liability to C-reactive protein defines immunometabolic depression phenotypes and influences antidepressant therapeutic outcomes

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Inflammation has been implicated in the pathophysiology of major depressive disorder (MDD), with elevated serum C-reactive protein (CRP) and CRP polygenic scores (PGSs) previously associated with atypical symptoms and treatment outcomes. However, few studies have examined genetic CRP liability in relation to both depressive symptom profiles and pharmacological response within the same patient cohort. We investigated 1059 Caucasian patients with MDD from the European Group for the Study of Resistant Depression (GSRD) who received ≥ 4 weeks of antidepressant treatment. Depression severity was measured using Montgomery–Åsberg Depression Rating Scale (MADRS), with patients categorized as responders, nonresponders, or treatment-resistant cases. CRP-PGS were computed from individual-level genotypes using L1-penalized regression weights (snpnet) based on UK Biobank Genome‐wide association studies (GWAS) training data (n = 223,327), and scores were standardized. Associations were tested through univariable and multivariable models controlling for population stratification and established prognostic variables. Higher CRP-PGS correlated with greater body mass index, lower employment status, and less weight and appetite loss following treatment. Notably, CRP-PGS demonstrated significant differences between treatment outcome groups (F = 3.52, p = 0.03), with highest values observed in treatment-resistant patients yet also elevated among responders compared to nonresponders, indicating a nonlinear relationship. When controlling for age, episode frequency, suicidal ideation, anxiety comorbidity, employment status, functional disability scores, antipsychotic comedication, illness duration, and previous antidepressant trials, CRP-PGS retained an independent and stronger association with treatment outcome (F = 7.69, p < 0.001), with CRP-PGS accounting for an additional 1.9% of outcome variance. CRP-related genetic liability may delineate an immunometabolic subtype of MDD characterized by metabolic dysregulation, which may modestly influence therapeutic efficacy. CRP-PGS captures independent prognostic information beyond conventional staging approaches and may facilitate inflammation-guided treatment selection.

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