Risperidone reduces individualized morphometric similarity deviation in schizophrenia and associates with cortical transcriptomic patterns.

Schizophrenia has been linked to reduced cortical thickness and abnormal gene expression. While antipsychotic treatment has been found to affect cortical morphology and gene expression, its impact on subject-specific deviations in cortical morphometric similarity and the underlying genetic mechanisms remain unclear. To quantify risperidone-related changes in morphometric similarity at the individual level and test their spatial alignment with cortical transcriptomic patterns. Twenty-four drug-naive first-episode schizophrenia patients and 30 healthy controls underwent T1-weighted imaging scans. Patients were scanned before and after 12 weeks of treatment with risperidone; symptoms and cognitive function were assessed with PANSS and MCCB scale. For each scan, cortical morphometric similarity matrices were built from regional cortical thickness distributions using the Wasserstein distance. We defined Morphometric Similarity Deviation (MSD) as a subject-level, normative-referenced departure from the healthy morphometric similarity pattern, derived from node-wise fingerprint correlations with the healthy template. Partial least squares regression related treatment-induced MSD changes to cortical transcriptomic data obtained from the Allen Human Brain Atlas. Patients exhibited high MSD in the frontal, temporal, and temporoparietal regions. Greater baseline MSD across the whole brain and multiple networks were associated with more severe positive symptoms. After treatment, MSD decreased, and reductions within the salience/ventral attention network associated with improved Emotional Intelligence. Moreover, risperidone-induced changes in MSD were spatially correlated with the expression of specific genes enriched in neurotransmission, cell adhesion, immune function, and schizophrenia. Specific expression analyses revealed that these genes were specifically expressed in astrocytes and oligodendrocytes, and spanned almost all developmental stages. Risperidone reduces MSD, reflecting convergence toward a normative cortical morphometric similarity pattern. These changes were spatially aligned with gene expression patterns involved in neurotransmission and immune processes, suggesting a molecular basis for treatment-linked structural normalization and its cognitive benefits.