Plasma interleukin-6 levels and treatment responses to antipsychotics in schizophrenia: Focus on clozapine treatment.

Abstract

Neuroinflammation is a key pathophysiological mechanism underlying treatment-resistant schizophrenia (TRS). Interleukin (IL)-6 is a trait-related biomarker that exhibits consistently elevated levels in schizophrenia. However, studies focusing on TRS and examining the associations of clozapine treatment with inflammatory marker and clinical characteristics remain limited. Therefore, this multicenter cross-sectional study focused on patients with TRS and antipsychotic-responsive schizophrenia (ARS). Plasma IL-6 levels were measured in all participants, while plasma clozapine and N-desmethylclozapine concentrations were quantified in patients with TRS. Psychotic symptoms and cognitive function were assessed using the Positive and Negative Syndrome Scale (PANSS) and the Brief Assessment of Cognition in Schizophrenia-Short Form (BAC-SF), respectively. Multiple regression analysis was conducted to identify clinical factors associated with plasma IL-6 levels in the TRS group. In total, 37 patients with TRS and 22 with ARS were included in this study. Plasma IL-6 levels were significantly higher in the TRS group than in the ARS group (p < 0.001). In the TRS group, clozapine treatment duration was negatively associated with plasma IL-6 levels after adjustment for age, diabetes mellitus, and treatment setting (β = -0.398; p = 0.031). No significant associations were observed between plasma IL-6 levels and psychiatric symptom severity (PANSS total) or cognitive function (BAC-SF) in the TRS group. Overall, these findings suggest that TRS may differ from ARS in terms of peripheral inflammatory profiles and that longer-term clozapine treatment may be associated with lower plasma IL-6 levels in TRS.