Central and peripheral glutamatergic biomarkers delineate heterogeneous clinical phenotypes in olanzapine-treated schizophrenia

This study aimed to identify central and peripheral glutamatergic biomarkers underlying heterogeneous clinical phenotypes in olanzapine-treated patients with schizophrenia, with the goal of informing 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 demonstrate that central and peripheral glutamatergic markers delineate distinct clinical phenotypes of olanzapine response in schizophrenia, shaped by both neurochemical and demographic factors. Stratification based on glutamatergic profiles and symptom patterns may contribute to the development of precision psychiatry approaches. To our knowledge, this is the first study to integrate central and peripheral glutamatergic biomarkers with multivariate phenotyping in a naturalistic olanzapine-treated cohort, identifying (i) a low-symptom, low-exposure phenotype, (ii) a high-symptom, high-exposure phenotype characterised by reduced cingulate Glx, and (iii) a younger phenotype with elevated cingulate Glx ratios, consistent with, though not confirmatory of, a neurodevelopmental trajectory. These findings are exploratory and warrant prospective validation to determine their potential utility for biomarker-guided treatment stratification in schizophrenia.