2026 ECNP Congress

PS01-1043

Longitudinal trajectory of c-reactive protein and its association with troponin levels during clozapine titration in treatment-resistant schizophrenia

Bedirhan Senol — R. Govind, M.A. Nettis, J. MacCabe · Ankara Bilkent City Hospital, Psychiatry, Ankara, Türkiye

2026 ECNP Congress

Introduction

Treatment-resistant schizophrenia (TRS) has been increasingly associated with dysregulated inflammatory processes[1]. Clozapine remains the gold-standard treatment for TRS, however, its initiation is frequently associated with a systemic inflammatory response, which in rare cases progresses to myocarditis[2]. While cross-sectional elevations in the inflammatory marker C-reactive protein(CRP) are well-documented, longitudinal evidence regarding the specific trajectory of CRP in clozapine users remains limited[3]. Moreover, while CRP and troponin are usually interpreted together in myocarditis monitoring, the real-time relationship between their changes in clozapine-treated patients without myocarditis is unclear[4].

Aims

This study aimed to 1)characterise the 6-month trajectory of CRP following clozapine initiation, accounting for socio-demographic and clinical covariates; 2)determine the relationship between CRP and troponin changes in a sample of patients without clozapine-induced myocarditis.

Methods

This retrospective cohort study was conducted using de-identified electronic health records via the Clinical Record Interactive Search(CRIS) platform. We identified all patients with TRS initiated on clozapine with at least 6 months of continuous treatment and no reported myocarditis(N=439). From these patients, all CRP and troponin test results within the first 6 months of clozapine treatment were obtained:a total of 1,908 CRP and 1,143 troponin observations were identified. Baseline(Week 0) was defined as the most recent measurement within one month before clozapine initiation. The 24-week follow-up period comprised nine time-windows: Weeks 1(days 1–7;n=139), 2(8–14;n=182), 3(15–21;n=157), 4(22–28;n=139), 8(n=322), 12(n=172), 16(n=153), 20(n=95), and 24(n=110). CRP values were log-transformed to address the significant right-skewness inherent in inflammatory marker distributions. The analysis used Linear Mixed-Effects (LME) models, adjusted for age, gender, ethnicity, BMI, smoking, illicit substance use, and multimorbidity, accounting for repeated measures.

Results

The cohort (N=439;61.7% male; median age 38[IQR 29–49]) was predominantly Black(48.2%) and White(37.0%), with high rates of smoking(80.2%) and illicit substance use(67.2%). The median BMI was 28.5[IQR 23.9–34.0] and the median multimorbidity score was 4[IQR 3–6]. CRP levels increased significantly following clozapine initiation, following a “spike and recovery” trajectory (Wald chi2=12.72, p=0.0017). CRP levels rose from a baseline median of 2.0 mg/L[IQR:1.0–6.0], and peaked (median:4.0; IQR:1.0–8.9) at 10.2 weeks before entering a stable phase (median:3.4; IQR:1.7–8.0). Troponin did not follow a quadratic trajectory over the 24 weeks (both linear and quadratic p>0.05), remaining statistically stable at the population level across the 24-week period. However, throughout the 6-month period, multivariable analysis identified CRP as a significant independent predictor of synchronous troponin levels (B=1.45, p=0.020). Observations where CRP exceeded 50 mg/L were associated with significantly higher troponin levels (Mean=14.97, SD=12.4 ng/L) compared to those <50 mg/L (Mean=7.2, SD=6.1 ng/L;Mann-Whitney U=2204, p=0.0029). Baseline CRP was significantly higher in females (Median=2.6 mg/L,IQR=1.0–7.0) than in males (Median=2.0 mg/L,IQR=1.0–5.0;p=0.037), but subsequent CRP 6-month trajectory and the CRP/troponin correlation were independent of gender and ethnicity.

Conclusions

Over 6 months of treatment, clozapine initiation was associated with a significant CRP elevation that peaked within the first three months of treatment, before stabilising. The association between CRP and troponin may reflect a subclinical inflammatory-cardiac biomarker coupling. It also supports existing monitoring recommendations[4] in which CRP >50 mg/L may warrant closer biochemical surveillance, while higher thresholds and clinical features remain necessary to suspect clozapine-associated myocarditis[4].

References

  1. Fond, G., Lançon, C., Korchia, T., et al., 2021. Immune Signatures of Treatment-Resistant Schizophrenia: A FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) Study. Front. Psychiatry 12, 704177.
  2. Laks, J., Tan, S.N., et al., 2024. A systematic review of clozapine-associated inflammation and related monitoring. Schizophr. Res. 263, 10-18.
  3. Lôo, H., et al., 2010. Clozapine therapy raises serum concentrations of high sensitive C-reactive protein in schizophrenic patients. Int. Clin. Psychopharmacol. 25 (2), 114-118.
  4. Ronaldson, K.J., Fitzgerald, P.B., Taylor, A.J., 2011. A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls. Aust. N. Z. J. Psychiatry 45 (6), 458-465