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Accelerating Treatment Development Research in Clinical High Risk for Psychosis


Robert K. Heinssen, Ph.D., ABPP
Division of Services and Intervention Research


This concept proposes to establish a network of academic and community sites that can rapidly recruit well-characterized cohorts of help-seeking individuals who meet criteria for “clinical high risk” (CHR) for psychosis. The multi-site network would conduct collaborative studies to test and validate biological measures and prediction algorithms to support experimental medicine trials involving CHR participants.


At any given time, over one million adolescents and young adults in the U.S. experience problems in perception, thinking, and functioning suggestive of a pre-psychosis risk state. Given the highly disruptive and disabling nature of psychotic disorders, early intervention is recommended to prevent or delay psychosis onset among at-risk individuals, as well as to lessen associated difficulties such as comorbid mood disorders and impaired social and role performance. Currently, there are no approved pharmacological treatments for attenuated psychosis or mood symptoms in CHR individuals.

Building upon existing approaches to screening, diagnosis, and harmonized assessment in CHR studies, this concept would support new research to deeply phenotype CHR individuals using measures such as genetic risk, cognitive performance, brain structure and function, physiology, and exploratory measures such as inflammatory markers or speech and language samples. Well-characterized cohorts would be followed longitudinally using structured clinical interviews, laboratory measures, and digital technologies to track illness trajectories and behavioral functioning over time. Large datasets would be combined across CHR projects; computational methods would be used to discern CHR subgroups, predict time points for therapeutic intervention, and suggest novel targets for pharmacologic treatment.

Anticipated outcomes from this program of research include, but are not limited to:

  • A network of academic research centers and linked community clinics that can rapidly recruit large numbers of at-risk individuals for observational or experimental medicine studies of CHR biomarkers, course of illness, or early testing of pharmacologic interventions that target outcomes such as reduction of cognitive deficits, negative symptoms, and/or psychosis onset;  
  • A multivariate biomarker approach for CHR risk stratification that improves prediction by combining data from standardized clinical assessments, neuroscience-based cognitive measures, structural and functional brain imaging, and polygenic risk scores;
  • Proof-of-concept clinical trials that can rapidly test the validity of multivariate individual risk prediction algorithms, putative biomarkers of risk and treatment response, and novel targets for CHR treatment and prevention trials.

This concept encourages new collaborations among academic research centers already engaged in translational research studies of psychosis risk, as well partnerships between academic centers and community-based treatment programs for CHR, such as those recently established by the Substance Abuse and Mental Health Services Administration (see SM-18-012 ).