Predictors and Moderators of Long-Term Outcome of Persons at Clinical High Risk for Psychosis

Description/Abstract
Schizophrenia and related psychotic illnesses are neurodevelopmental disorders with evidence of pathological
changes beginning in utero; neuromotor and neurocognitive abnormalities in the premorbid period;
subsyndromal psychotic symptoms in the prodromal period of illness (also called clinical high risk, CHR); and
full manifestation of a psychotic syndrome during late adolescence or early adulthood. CHR research over the
past 2+ decades, has provided (i) important insights into risk factors for later conversion to full psychotic
illness, (ii) the development of a “Psychosis Risk Calculator”, (iii) biomarkers linked to psychosis riskand (iv)
evidence of dynamic brain changes that are likely present before the onset of illness and continue to evolve
into the first episode psychosis (FEP), as well as into more chronic forms of psychosis. Despite these
advances in our understanding of the CHR state, the longer-term outcomes (5+ years), and the trajectory of
diagnoses, symptoms and psychosocial function have been seldom investigated in this population. Meta-
analyses show that 20-30% of identified CHR individuals develop psychosis within 2 years. Little is known
about what type of psychosis (affective versus non-affective) "declares itself" after evidence of the initial
conversion to psychosis, the rate of later psychotic conversion (i.e. post 2-3-year follow-up periods) or risk
factors that might predict a later onset of psychosis. The majority of individuals who meet CHR criteria do not
develop overt psychosis within 2 years but demonstrate outcomes ranging from complete remission to
continued symptoms and functional impairment, at least within this relatively short time frame. Longer-term
follow-up of CHR individuals provides a unique and rare opportunity to investigate the full trajectory of illness
from CHR -> First Episode -> Chronic Illness, in addition to longer-term outcomes in symptomatic individuals
who did not develop psychosis within 2 years after ascertainment. Substantial evidence already exists for
multiple biomarker abnormalities in CHR subjects. Specifically, CHR youth show deficits in neurocognition,
regional cortical gray matter, event related potential (ERP) amplitudes as well as higher polygenic risk scores
(PRS), inflammatory markers and cortisol relative to comparison subjects. Biomarkers also predict who will
convert to psychosis and functional outcomes at 2 years. However, it is not known whether these biomarkers
predict longer term conversion and outcomes. The Specific Aims are to 1) Perform long-term (5-20 year)
diagnostic, symptom and functional assessments of up to 2000 individuals who previously met CHR criteria,
some of whom converted to psychosis, across 9 academic centers. 2) Determine the 5+ year psychotic
conversion rate of CHR individuals and use baseline demographic, clinical, functional, neurocognitive and
biomarker data to predict longer term functional and diagnostic outcomes of individuals who convert to
psychosis and 3) Investigate the long-term diagnostic and functional outcomes of CHR individuals who do not
convert to psychosis and test whether outcomes are influenced by treatment and substance use.

Grant Number: 5R01MH123641-04
NIH Institute/Center: NIH
Principal Investigator: KRISTIN CADENHEAD