PROJECT SUMMARY It has now been two decades since the clinical high risk for psychosis (CHR) criteria were first formulated in service of the goal of preventing psychotic disorders, one of the most urgent unmet clinical needs in behavioral health if not in all of medicine. As with most psychiatric patients, CHR patients benefit from psychotherapies but are also often left with important treatment needs not fully addressed. Despite the critical public health need, drug development for CHR is viewed in many quarters as risky. The Foundation for the National Institutes of Health and the National Institute of Mental Health along with other public and private partners established the Psychosis Risk Outcomes Network (ProNET) and the Accelerating Medicines Partnership® Schizophrenia Observational Study (AMP® SCZ) in 2020 to develop tools to parse the heterogeneity of the CHR syndrome and de-risk the drug development that could lead to improvement of symptoms and functioning in CHR patients and ultimately to the prevention of schizophrenia. The current project, the Psychosis Risk Outcomes Compound Assessment Network (ProCAN), follows up on this successful previous initiative and will establish infrastructure to determine, in partnership with the Clinical Trials Data Processing Analysis and Coordination Center (CT-DPACC), whether the biological, digital, cognitive, and clinical outcome measures developed in AMP SCZ are viable as drug development tools (DDTs) for use in Phase 2 clinical trials in participants at clinical high risk for psychosis (CHR). One or two Phase 2-ready compounds will be studied, each selected by the AMP SCZ Compound Selection Committee. Aim 1 will evaluate the potential of selected compound(s) to detect a signal in CHR participants on one or more biological, digital, cognitive, or clinical outcome measures developed in the AMP SCZ Observational Study within a 16 week time frame. We propose two trials, each with 15 sites, each with three arms and 65 participants per arm (total per trial N=195), and each with the Network RFA specified maximum 16 week follow-up. Compound safety will also be evaluated. Aim 2 will determine whether biomarkers developed in the AMP SCZ Observational Study and/or novel biomarkers can act as pharmacodynamic readouts of drug response and/or provide insights into proposed mechanisms or pathways underlying CHR for psychosis. We propose biomarker timepoints at baseline and 8 and 16 weeks. If outcome or biomarker signals are detected, findings will pave the way for further development of phase-specific and safe new interventions to benefit CHR patients and their families and communities.

PROJECT NARRATIVE Although the clinical high risk for psychosis (CHR) criteria offer an important public health target and opportunity to prevent psychotic disorders, drug development tools (DDTs) need to be tested for use in Phase 2 clinical trials before new medications can enter clinical practice. The 15 US sites of the Psychosis Risk Outcomes Compound Assessment Network (ProCAN) will test DDTs from the Accelerating Medicines Partnership® Schizophrenia Observational Study in one or two 16-week proof-of-principle clinical trials. Study drug signal on outcome measures, biomarkers, and safety will also be evaluated; in addition, in partnership with the Clinical Trials Data Processing, Analysis, and Coordinating Center, ProCAN will deliver outcome and biomarker metrics that are analyzable to detect drug signal upon trial completion.