This preregistration outlines a systematic review and meta-analysis investigating the role of high-sensitivity C-reactive protein (hs-CRP) as a transdiagnostic biomarker of treatment resistance across internalizing psychiatric disorders, including Major Depressive Disorder (MDD), anxiety disorders, and Post-Traumatic Stress Disorder (PTSD). Treatment resistance remains a major clinical challenge, affecting approximately 30–50% of patients within the internalizing spectrum. Traditional diagnostic frameworks treat these disorders as distinct entities; however, increasing evidence supports shared underlying biological mechanisms, particularly involving chronic low-grade inflammation. This study adopts a transdiagnostic perspective, focusing on hs-CRP as a clinically accessible and standardized marker of systemic inflammation. The primary objective is to determine whether baseline hs-CRP levels are significantly higher in treatment-resistant or non-responder populations compared to responders. Secondary objectives include assessing the consistency of this association across diagnostic categories, identifying potential moderating factors (e.g., body mass index, age, smoking status), and exploring clinically meaningful hs-CRP thresholds associated with increased risk of treatment failure. Eligible studies will include adult populations diagnosed with internalizing disorders using standardized diagnostic criteria (DSM or ICD), with baseline hs-CRP or CRP measurements obtained prior to treatment. Outcomes will include response to pharmacological, psychotherapeutic, or neuromodulatory interventions. Both continuous (e.g., standardized mean differences) and categorical (e.g., odds ratios) effect sizes will be synthesized using random-effects meta-analysis. By integrating evidence across diagnostic categories and treatment modalities, this study aims to evaluate hs-CRP as a practical risk stratification tool rather than a diagnostic marker. The findings are expected to inform precision psychiatry approaches by identifying an “immunometabolic” subgroup of patients at increased risk of poor treatment outcomes, potentially guiding early treatment intensification and adjunctive anti-inflammatory strategies.
Fedyk et al. (2026) studied this question.