842. Elevated systemic immune-inflammation index in DSM-5 Schizophrenia - A controlled case–control study

Abstract

Abstract Background Low-grade systemic inflammation has been increasingly implicated in the pathophysiology of schizophrenia. Peripheral immune activation (characterized by relative neutrophilia, lymphocyte reduction, and platelet activation) has been associated with cytokine-mediated pathways (e.g., IL-6, TNF-α) and immune–brain signaling mechanisms. The Systemic Immune-Inflammation Index (SII: platelets × neutrophils/lymphocytes) integrates these hematological components into a composite marker of systemic inflammatory burden. Prior studies generally report small-to-moderate inflammatory alterations in psychotic disorders. Aims & Objectives This study aimed to investigate whether DSM-5-confirmed patients with schizophrenia exhibit elevated systemic immune-inflammatory burden, as measured by the Systemic Immune-Inflammation Index, compared with healthy controls. Method This observational case–control study was conducted between March 2024 and January 2025. The schizophrenia group comprised 124 patients aged 18–65 years (mean 39.8 ± 10.7 years), including 87 males (70.16%) and 37 females (29.84%). All patients fulfilled DSM-5 diagnostic criteria for schizophrenia, including the requirement of at least 6 months of continuous disturbance. At the time of assessment, all patients were receiving atypical antipsychotic treatment (excluding clozapine), either as monotherapy or combination therapy. Each participant had undergone at least one adequate prior antipsychotic treatment trial. The control group included 128 healthy individuals (mean age 34.2 ± 9.5 years), consisting of 77 females (60.16%) and 51 males (39.84%), screened to exclude psychiatric and inflammatory conditions. Exclusion criteria for both groups included autoimmune disorders, chronic inflammatory or hematological diseases, recent infection (≤4 weeks), malignancy, substance use disorder, pregnancy/postpartum status, and immunomodulatory treatment. Between-group comparisons were conducted using independent t-tests. Categorical variables were analyzed using chi-square tests. ANCOVA was performed to adjust for age and sex. Effect size was calculated using Cohen’s d. ROC analysis evaluated discriminative performance. Results Sex distribution differed significantly between groups (χ2 = 23.4, df = 1, p < 0.001). Mean SII was higher in the schizophrenia group (610 ± 240) compared with controls (520 ± 220), with a statistically significant difference (t = 3.18, p = 0.002) and a small-to-moderate effect size (Cohen’s d = 0.39). The difference remained significant after adjustment for age and sex (ANCOVA F = 9.6, p = 0.002). ROC analysis demonstrated limited-to-moderate discriminative capacity (AUC = 0.66; 95% CI 0.59–0.73), consistent with existing literature indicating that inflammatory indices reflect biological vulnerability rather than diagnostic specificity. Discussion & Conclusions In this controlled sample of DSM-5-confirmed schizophrenia patients receiving non-clozapine atypical antipsychotic treatment, SII values were modestly but significantly elevated compared with healthy controls. The magnitude of difference is congruent with current literature describing small-to-moderate peripheral inflammatory alterations in psychotic disorders. Limitations include the cross-sectional design, significant sex distribution differences between groups, ongoing antipsychotic treatment exposure, and absence of metabolic covariates (e.g., BMI). SII should therefore be interpreted as a nonspecific marker of systemic inflammatory burden rather than a diagnostic biomarker. Longitudinal studies controlling for metabolic and treatment-related variables are warranted to clarify clinical relevance.