Neurochemical Correlates and Heterogeneous Clinical Response to Olanzapine in Schizophrenia: A Multidimensional Analysis of Central and Peripheral Biomarkers

This study aimed to identify neurochemical and clinical phenotypes among olanzapine-treated schizophrenia patients to inform biomarker-guided personalized therapy. We conducted a cross-sectional observational study of 51 adults with schizophrenia receiving chronic olanzapine treatment (mean duration = 5.6 years), integrating clinical assessments with peripheral neurochemical profiling and magnetic resonance spectroscopy (MRS) of the anterior and posterior cingulate cortices. Partial correlations controlling for age, sex, and treatment duration revealed significant associations: higher serum serotonin correlated with more severe negative symptoms (ρ = 0.32, p  = 0.029), and increased cingulate Glx ratios were linked to greater depressive burden (ρ = 0.31, p  = 0.031). Elevated serum glutamic acid was associated with overall psychopathology, whereas lower serum and cingulate glutamine levels were related to more severe symptoms and higher olanzapine exposure. Hierarchical clustering on principal components (HCPC) identified three phenotypic subgroups: (1) low-symptom, dose-efficient responders; (2) high-symptom, dose-resistant patients with cingulate hypoglutamatergia; and (3) younger individuals with elevated Glx ratios and moderate exposure, suggestive of a hyperglutamatergic, neurodevelopmental profile. These findings highlight the heterogeneity of olanzapine response in schizophrenia, shaped by neurochemical and demographic factors. Stratification based on glutamatergic markers and symptom profiles may advance precision psychiatry. This is the first study to integrate central and peripheral biomarkers with multivariate phenotyping in a naturalistic olanzapine-treated cohort.