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 most daunting obstacle may be the heterogeneity of CHR course.
In Aim 1 we will deeply pheno- type 1040 CHR patients across the ProNET network of 26 international sites with multi-modal biomarkers that span brain structure-function (MRI and EEG), psychopathology and cognition, genetics, body fluid analytes, natural speech/language, and passive/ecological momentary digital phenotyping, and map these biomarkers onto a core set of clinical outcome mea- sures and trajectories over a treatment-relevant time window at eight timepoints over 24 months. Biomarkers will be collected at two timepoints to map brain-behavior trajectories. Healthy volunteers (N=260) will complete a baseline assessment to quan- tify typical variation. We will also conduct exploratory studies to assess real-time behavioral data from smartphone sensors and symptom reports from surveys; novel repetition positivity and alpha-desynchronization measures derived from standard EEG paradigms; and pilot an evaluation of excitatory/inhibitory imbalance with MR spectroscopy for glutamate, glutamine, and GABA at 7 Tesla.
In Aim 2 we will partner with the NIMH-selected Data Processing, Analysis, and Coordinating Center for rapid data integration and NIMH Data Archive (NDA) uploads with the proposed informatics platform. We will implement ProNET-wide standardized and near real-time data integration with the DPACC architecture to facilitate on-site monitoring, unification of standard operating procedures, and rapid data aggregation across ProNET for seamless DPACC to NDA transfer.
In Aim 3 we will test the hypothesis that data-driven variation assessed by multivariate neural, genetic, and behavioral measures within the CHR syndrome predicts individualized clinical trajectories, expanding CHR stratification for broad clinical endpoints encompassing affect, anxiety, cognition, and APS with the goal of identifying behavioral and biomarker-driven patterns that can refine the CHR syndrome and promote personalized treatment decisions. These analy- ses will yield expanded outcome stratification calculators for the CHR syndrome that can predict actionable mental health trajectories in individual patients. The stratification calculators will allow future clinical trial designers to select optimal samples for determining whether a novel compound improves the particular CHR outcome of interest and pave the way for phase-specific and safe new interventions to benefit patients and their families and communities.

Public Health Relevance

Although the clinical high risk for psychosis (CHR) criteria offer an important public health target and opportunity to prevent psychotic disorders, substantial heterogeneity exists in CHR both at ascertainment and in outcome that limits treatment development. Our 26 international sites will recruit 1040 CHR and follow them with clinical and biomarker assessments over two years, along with 260 healthy controls assessed at baseline. In partnership with the Data Processing, Analysis, and Coordinating Center, we will contribute to analyses to dissect the heterogeneity of CHR and develop tools for outcome definition and patient stratification.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZMH1)
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Morris, Sarah E
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Yale University
Schools of Medicine
New Haven
United States
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