Investigation of the Gut Microbiome in Treatment-Resistant Schizophrenia Compared to Healthy Controls: A Cross-Sectional Pilot Study: Étude du microbiome intestinal chez les patients atteints de schizophrénie résistante au traitement par rapport aux

Background Schizophrenia (SCZ) is a debilitating disorder affecting approximately 1% of the Canadian population and remains a major contributor to disease burden and disability. Up to one-third of individuals with SCZ are affected by treatment-resistant SCZ (TRS). Clozapine remains the most effective treatment for TRS. However, its use is limited by serious metabolic and immune-related side effects. The gut microbiome may be a potential contributor to both SCZ pathology and antipsychotic-induced side effects, though studies examining this in the clozapine-treated TRS population remain limited. Methods This cross-sectional case-control study compared the gut microbiome composition of 25 TRS patients receiving long-term clozapine treatment to 25 healthy controls (HCs) matched for age, sex, body mass index, and smoking status. Participants provided fecal samples and completed assessments of psychiatric symptoms, eating behaviors, dietary intake, and metabolic measures. Fecal microbiome composition and predicted function were assessed using 16S rRNA gene sequencing (v3 region). Results Individuals with TRS being treated with clozapine presented with a distinct microbiome in comparison to HC, including reduced microbial diversity. Taxonomic analyses revealed reduced relative abundance of Firmicutes, while elevated relative abundance of Eggerthella spp., Mucispirillum spp., and unclassified species within the order SHA-98 (class Clostridia). Exploratory analyses also identified nominal associations between select microbial features and clinical measures, including Positive and Negative Syndrome Scale (PANSS) scores and gastrointestinal symptoms. Predicted functional pathway analysis suggested alterations in microbial metabolic potential consistent with a metabolically stressed, pro-inflammatory microbiome. Conclusions Individuals with clozapine-treated TRS demonstrate differences in gut microbiome composition compared to HC and are predicted to have some functional consequences relating to metabolic potential. These findings remain exploratory but contribute to a limited but growing body of literature in this clinically relevant population and provide a basis for longitudinal studies with appropriate comparator groups to better characterize these relationships and assess their clinical relevance.