C3 and C4 levels correlate with schizophrenia outcomes in a small cohort study

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Frontiers in Medicine Published April 14, 2026 Medically reviewed April 25, 2026 DOI ↗ By Dr. Ji-eun Park, MD · Brain, Mind & Pain

Key Takeaway

Interpret C3/C4 correlations in schizophrenia as exploratory, non-causal associations needing larger studies.

This cohort study included 39 patients with schizophrenia, with peripheral complement C3 and C4 levels measured as the exposure. Over a 12-week follow-up, baseline C3 levels correlated positively with duration of untreated psychosis (r=0.407, p=0.010), length of hospitalization (r=0.353, p=0.028), PANSS-P1 scores (r=0.325, p=0.043), and PANSS-G1 scores (r=0.330, p=0.040). Baseline C4 levels also correlated with PANSS-G1 scores (r=0.322, p=0.045). Anxiety measures (STAI-T1, STAI-S1, STAI-T2, STAI-S2) showed positive associations with C3 and C4 levels, with effect sizes ranging from r=0.338 to r=0.419 and p-values from 0.009 to 0.038. Cognitive performance (MoCA1) correlated negatively with C3 (r=-0.339, p=0.034). Associations with multiple PANSS domains after 12 weeks and CTQ subscales were reported but without specific effect sizes or p-values. Safety and tolerability data were not reported. Key limitations include the exploratory nature of analyses, small sample size of 39, and that none of the associations survived Benjamini–Hochberg false discovery rate correction (all q>0.05), indicating potential false positives. The findings are within-cohort and require replication in larger, controlled longitudinal studies. Practice relevance is not reported, but clinicians should interpret these results cautiously as preliminary evidence from an observational study without causal implications.

Study Details

Study typeCohort

EvidenceLevel 3

PublishedMar 2026

View Original Abstract ↓

AimSchizophrenia is a severe psychiatric disorder with heterogeneous outcomes; factors such as anxiety, childhood trauma, and duration of untreated psychosis (DUP) may influence symptom severity and disease progression. Growing evidence highlights immune dysregulation—particularly alterations in complement components C3 and C4—in the pathophysiology of schizophrenia; however, findings regarding peripheral complement levels and their clinical associations remain inconsistent.MethodThirty-nine patients with schizophrenia underwent clinical assessment using the Childhood Trauma Questionnaire (CTQ), the Positive and Negative Syndrome Scale (PANSS), the State–Trait Anxiety Inventory (STAI), and the Montreal Cognitive Assessment (MoCA). Serum concentrations of C3 and C4 were measured at admission.ResultsIn exploratory analyses (nominal p-values), baseline C3 correlated with DUP (r=0.407, p=0.010) and length of hospitalization (r=0.353, p=0.028). Higher C3 was associated with greater symptom severity on PANSS-P1 (r=0.325, p=0.043) and PANSS-G1 (r=0.330, p=0.040), while C4 correlated with PANSS-G1 (r=0.322, p=0.045) and multiple PANSS domains after 12 weeks. C3 was associated with anxiety at baseline and after 3 months (STAI-T1: r=0.376, p=0.018; STAI-S1: r=0.372, p=0.020; STAI-T2: r=0.376, p=0.018; STAI-S2: r=0.419, p=0.009), whereas C4 correlated with STAI-T1 (r=0.361, p=0.024), STAI-S1 (r=0.342, p=0.033), and STAI-S2 (r=0.338, p=0.038). Higher C3 and C4 levels were associated with CTQ subscales. C3 correlated negatively with cognitive performance (MoCA1: r=–0.339, p=0.034). However, none of the associations survived Benjamini–Hochberg false discovery rate (BH-FDR) correction (all q>0.05).ConclusionThese exploratory, within-cohort findings suggest that peripheral complement markers relate to variation in clinical severity and illness-course indicators in schizophrenia. Replication in larger, controlled longitudinal studies is warranted.