Serum neuregulin -1 (NRG-1) is a potential biomarker for early diagnosis and prediction in refractory schizophrenia

This study tends to identify serum biomarkers for early diagnosis of treatment-resistant schizophrenia (TRS) and prediction of clozapine treatment response, given the heterogeneity of schizophrenia and limitations of antipsychotic treatment. Participants of this prospective cohort study (recruited at Shanghai Mental Health Center; 2020–2023) included 42 TRS patients (TRRIP criteria), 42 first-line antipsychotic responders (age/sex-matched 1:1 to TRS), and 70 age/sex-matched healthy controls. TRS patients were stratified post-clozapine into responders (TRS-R, <i>n</i> = 26) and ultra-treatment-resistant (UTRS, <i>n</i> = 16) subgroups. Symptom severity was assessed using PANSS. Serum neuregulin-1 (NRG-1) levels were quantified via ELISA. Healthy controls showed significantly higher NRG-1 levels than schizophrenia patients (F = 39.76, <i>p</i> &lt; 0.001). TRS patients had lower NRG-1 than treatment responders (<i>p</i> &lt; 0.001). Clozapine responders (TRS-R) exhibited increased NRG-1 post-treatment (<i>t</i> = −3.32, <i>p</i> &lt; 0.001), unlike UTRS patients (<i>t</i> = −0.332, <i>p</i> = 0.745). NRG-1 negatively correlated with symptom severity in both TRS (<i>r</i> = −0.647, <i>p</i> &lt; 0.001) and responders (<i>r</i> = −0.596, <i>p</i> &lt; 0.001). NRG-1 demonstrated diagnostic utility for TRS (AUC = 0.827, 95% CI:0.741–0.914; specificity = 0.786, sensitivity = 0.786). Serum NRG-1 shows significant promise as a potential biomarker for diagnosing TRS and monitoring clozapine treatment response, suggesting involvement in TRS pathophysiology.