Every year ~100,000 young people in the US develop a first episode of psychosis and more than one million have attenuated psychotic symptoms such as problems in perception, thinking and communication, which are suggestive of a clinical high risk (CHR) for psychosis. These symptoms appear during critical periods in brain development and have important ramifications for current and future function and morbidity. Of note, prior clinical trials have not been successful in preventing psychosis onset, or other non-psychosis outcomes. There are many reasons why. One is that clinical trials have been small, which is especially problematic given that attenuated symptoms are heterogeneous, and stratification into meaningful subgroups requires large samples. Another issue is that most clinical trials have not been mechanistic, due to a dearth of validated and robust biomarkers for psychosis risk, and for other clinically important outcomes, such as mood and substance disorders, suicidal ideation and behavior, persistent motivational/hedonic deficits and further functional decline. Prior investigations have also not included standardized data protocols across studies. In response to these challenges, in 2020, the NIMH launched the Accelerated Medicines Partnership® Schizophrenia (AMP® SCZ) project, a large, observational study designed to de-risk the drug development process through validation of drug development tools, including biomarkers related to cognition, brain structure and function, fluid biomarkers, genetic vulnerability and communication. Investigators in the current proposal led the Data Processing, Analysis and Coordination Center (DPACC) for the AMP SCZ project to manage and coordinate data from the clinical networks, overseeing all aspects of data flow, quality assurance, processing, and analysis. The current proposal is in response to RFA-MH-24-151, the next phase of the AMP SCZ project, to perform Proof of Principle (PoP) clinical trials utilizing Phase 2 ready compounds to target pathophysiologically relevant mechanisms that have the potential to produce a detectable signal (change) in biological, digital, cognitive, or clinical outcome measures within a 12-16 week period of study. We propose the Clinical Trial DPACC (CT-DPACC) to provide executive management, direction, and overall coordination, including data processing and analyses of data for the PoP trial(s). We will maintain the current research team and organizational structure and augment it with a strong regulatory team, including a contract research organization, to support investigational new drug submission(s) and perform regulatory and safety monitoring. Our specific goals are (1) offer study design and regulatory support, (2) manage, direct, monitor, and coordinate the multi-site clinical trials, and (3) develop data operation procedures, biostatistics, and data analysis. Successful completion of the CT-DPACC project, in conjunction with the supported PoP clinical trials network, is expected to yield clinically validated compounds for CHR.

NARRATIVE The “Clinical High Risk” (CHR) for psychosis syndrome in young people represents an opportune window for early intervention to prevent the onset of psychosis and other disorders, and to forestall disability; however, clinical heterogeneity and the paucity of biomarkers have hampered the development of effective intervention. To address these challenges, working with NIMH and key stakeholders, we will leverage our experience in the current observational study, the Accelerated Medicines Partnership® Schizophrenia (AMP® SCZ) Project, to validate potential drug development tools including biomarkers, digital measures, clinical outcome measures and predictive algorithms to refine and adapt these tools in the proposed clinical trial data processing, analysis, and coordination center (CT-DPACC), to support the Clinical Trial Network in a 12-16 week Proof of Principle trial(s) that will utilize a phase 2 ready compound.