Immunoinflammatory Features and Cognitive Function in Treatment-Resistant Schizophrenia: Unraveling Distinct Patterns in Clozapine-Resistant Patients

Patients with treatment-resistant schizophrenia (TRS), particularly those resistant to clozapine (CTRS), pose a clinical challenge due to limited response to standard antipsychotic treatments. Inflammatory factors like tumor necrosis factor-alpha (TNF-α), interleukin 2 (IL-2), and interleukin 6 (IL-6) are implicated in schizophrenia's pathophysiology. Our study examines cognitive function, psychopathological symptoms and inflammatory factors in TRS patients, focusing on differences between CTRS and non-CTRS individuals, as well as healthy controls. A cohort of 115 TRS patients were recruited, assessing IL-2, IL-6 and TNF-α. The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathological symptoms, while the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to assess cognitive functioning. CTRS patients showed lower visuospatial constructional score ( p  = 0.015), higher PANSS scores, higher levels of IL-2 and reduced TNF-α than non-CTRS patients ( p  < 0.05). Notably, IL-2 was independently associated with psychopathology symptoms in CTRS patients (Beta = 0.268, t  = 2.075, p  = 0.042), while IL-6 was associated with psychopathology symptoms in non-CTRS patients (Beta = -0.327, t = -2.109, p  = 0.042). Sex-specific analysis in CTRS patients revealed IL-2 associations with PANSS total and positive symptoms in females, and TNF-α associations with PANSS positive symptoms in males. Furthermore, IL-2, IL-6, and TNF-α displayed potential diagnostic value in TRS patients and CTRS patients ( p  < 0.05). Clozapine‑resistant symptoms represent an independent endophenotype in schizophrenia with distinctive immunoinflammatory characteristics, potentially influenced by sex.