Schizophrenia’s substantial heterogeneity poses a major challenge for understanding its neurobiological mechanisms and predicting treatment response. Moving toward precision psychiatry, we identified clinically meaningful subtypes and characterised their neural and pharmacological profiles. Clustering of multidimensional clinical feature space revealed two distinct patient subtypes, primarily differentiated by degree of illness insight. In parallel, three symptom-severity groups defined by positive and negative psychopathology dimensions provided a complementary stratification framework. Resting-state fMRI analyses revealed that higher-insight patients exhibited greater dynamic reconfiguration of regional functional connectivity, emerging as the primary neuroimaging feature differentiating subtypes. Multivariate classification and feature importance analysis confirmed the discriminative value of neuroimaging metrics. Across both subtyping approaches, regional flexibility was spatially associated with cortical receptor density maps in a subtype-specific manner, particularly for D2 and 5-HT2A when accounting for estimated antipsychotic receptor occupancies. Additionally, pharmacological–clinical associations were stronger and more spatially widespread in specific subtypes, indicating subtype-dependent pharmacodynamic relationships. Furthermore, structural equation modelling demonstrated that neuroimaging measures mediate receptor pharmacology’s influence on clinical outcomes. These findings together show that integrating clinical, neuroimaging, and pharmacological data can uncover biologically grounded schizophrenia subtypes, identify functional biomarkers, and inform personalised therapeutic strategies.

The authors have declared no competing interest.

This work was supported by the A*MIDEX foundation (Aix-Marseille University Initiative of Excellence) through the 2021 Interdisciplinarity Call for Projects, under the project "REPORTS" (bRain modEling and PharmacOclinical Response To Schizophrenia). This project was carried out within Aix-Marseille University and its affiliated institutions, including the Institut de Neurosciences des Systemes (Inserm UMR 1106), the Centre for Magnetic Resonance in Biology and Medicine (CRMBM UMR 7339), and the Academic Department of Psychiatry at AP-HM (Schizophrenia Expert Center, FondaMental Foundation). In addition this research has received funding from the European Union's Horizon Europe Programme under the Specific Grant Agreement No. 101147319 (EBRAINS 2.0 Project) and No. 101137289 (Virtual Brain Twin Project). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors report no biomedical financial interests or potential conflicts of interest.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committee of Aix-Marseille University gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors