About the Study

Predictors and Mechanisms of Conversion to Psychosis

NAPLS-3 is the third project of the NAPLS consortium studying predictors and mechanisms of conversion to psychosis of youth at clinical high risk (CHR) of psychosis. NAPLS-3 is funded under the collaborative UO1 mechanism of NIMH. It is a longitudinal study with nine NAPLS sites (Calgary, UCLA, UCSD, UNC, UCSF, Yale, Harvard, Emory and Zucker Hillside Hospital in New York) with a potential sample of 774 participants at CHR of psychosis and 100 healthy controls generating one of the largest prodromal sample and highest number of converted subjects within the field, and will provide statistical power and scientific scope that cannot be duplicated by any single study. This is five-year study with participants remaining in the study for two years. Participants will be assessed every two months over the first eight months. These assessments will include both clinical (symptoms, functioning, neurocognition) and biomarker assessments (MRI, EEG, cortisol and blood draws). Only clinical assessments will be conducted in the second year of the study. Each site contributes an area of uniqueness to the overall study by leading a "task force" in a domain of assessment: clinical (J. Addington, Calgary), functional assessment (B. Cornblatt, ZHH), neurocognition (L. Seidman, Harvard), neuroimaging (T. Cannon, Yale), stress hormones (E. Walker, Emory), electrophysiology (K. Cadenhead, UCSD; D. Mathalon, UCSF), treatment (S. Woods Yale) and genomics (D. Perkins, UNC; M. Tsuang, UCSD). The Clinical Assessment Core forms the foundation on which the Biomarkers Assessment Core will interpret their findings since currently our definitions of schizophrenia are clinically determined. The Biomarkers Core will examine potential biological mechanisms of illness onset/progression in the neuroanatomical, electrophysiological, neurohormonal, and neurocognitive domains.

The major aim of the Clinical Assessment Core is to refine preliminary algorithms so that we can predict psychosis using clinical measures. Based on findings from previously enrolled NAPLS cases, the primary hypothesis is that the presence of each of four factors: genetic vulnerability to schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion-paranoia, greater social impairment at baseline, will independently predict a higher risk for conversion to psychosis, and that combining all of these indicators will substantially reduce false positive psychosis predictions over two years of follow-up. Since the pre-onset or 'prodromal' period provides a window of opportunity for preventive intervention, secondary aims of the clinical assessment core include identifying clinical variables (e.g. comorbid diagnoses, depression, anxiety, stress, social cognitive deficits) that are potential targets for treatment and identifying social risk factors that may contribute to the prediction algorithm or modify predictors in the algorithm. Targeting these variables with treatment could potentially contribute to reducing the risk of developing a full blown psychotic illness as well as alleviating presenting concerns.

The aim of the Biomarker Assessment Core is to determine whether neuroanatomical, neurophysiological, neurocognitive, and neurohormonal abnormalities that precede psychosis represent stable vulnerability markers or markers of progression during the prodromal phase. This will help determine whether biological and neurocognitive abnormalities can be combined with clinical measures to enhance predictive utility. This study also holds great promise for elucidating the course of change in neurobiological indicators of vulnerability to schizophrenia in relation to the onset and course of psychosis. This study will enable us to determine whether prodromal patients who convert to psychosis show a steeper rate of change in neurobiological risk indicators compared to non-converters and healthy controls and to isolate the brain systems involved (e.g., dorsolateral prefrontal cortex, superior temporal gyrus, hippocampus) across multiple levels of analysis (anatomical, physiological, behavioral).