These findings demonstrate that prospective ascertainment of individuals at risk for psychosis is feasible, with a level of predictive accuracy comparable to that in other areas of preventive medicine. They provide a benchmark for the rate and shape of the psychosis risk function against which standardized preventive intervention programs can be compared.

Background Individuals at clinical high-risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with those without symptomatic progression and with healthy controls. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown. Methods In this multisite study, 274 CHR cases, including 35 who converted to psychosis, and 135 healthy comparison subjects were scanned with MRI at baseline, 12-month follow-up, and/or the point of conversion for those who developed fully psychotic symptoms. Results In a traveling subjects sub-study, we observed excellent reliability for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR converters showed a steeper rate of gray matter loss in right superior frontal, middle frontal, and medial orbitofrontal cortical regions, as well as a greater rate of expansion of the third ventricle, compared with CHR non-converters and healthy controls. Differential tissue loss was present among cases who had not received antipsychotic medications during the inter-scan interval and was predicted by baseline levels of an aggregate measure of pro-inflammatory cytokines in plasma. Conclusions These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs, but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced among cases with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

Objective About 20–35% of individuals aged 12–30 years who meet criteria for a prodromal risk syndrome convert to psychosis within two years. However, this estimate ignores the fact that clinical high-risk (CHR) cases vary considerably in risk. Here we sought to create a risk calculator that can ascertain the probability of conversion to psychosis in individual patients based on profiles of risk indicators. The high risk category predicted by this calculator can inform research criteria going forward. Method Subjects were 596 CHR participants from the second phase of the North American Prodrome Longitudinal Study (NAPLS 2) who were followed up to the time of conversion to psychosis or last contact (up to 2 years). Our scope was limited to predictors supported by prior studies and readily obtainable in general clinical settings. Time-to-event regression was used to build a multivariate model predicting conversion, with internal validation using 1000 bootstrap resamples. Results The 2-year probability of conversion to psychosis in this sample was 16%. Higher levels of unusual thought content and suspiciousness, greater decline in social functioning, lower verbal learning and memory performance, slower speed of processing, and younger age at baseline each contributed to individual risk for psychosis, while stressful life events, traumas, and family history of schizophrenia were not significant predictors. The multivariate model achieved a Concordance index of 0.71, and was validated in an independent external dataset. The results are instantiated in a web-based risk prediction tool envisioned to be most useful in research protocols involving the psychosis prodrome. Conclusions A risk calculator comparable in accuracy to those for cardiovascular disease and cancer is available to predict individualized conversion risks in newly ascertained CHR cases. Given that the risk calculator can only be validly applied for patients who screen positive on the Structured Clinical Interview for Psychosis Risk Syndromes, which requires training to administer, it's most immediate uses will be in research on psychosis risk factors and in research driven clinical (prevention) trials.

Treatment and prevention studies over the past decade have enrolled patients believed to be at risk for future psychosis. These patients were considered at risk for psychosis by virtue of meeting research criteria derived from retrospective accounts of the psychosis prodrome. This study evaluated the diagnostic validity of the prospective "prodromal risk syndrome" construct. Patients assessed by the Structured Interview for Prodromal Syndromes as meeting criteria of prodromal syndromes (n = 377) from the North American Prodrome Longitudinal Study were compared with normal comparison (NC, n = 196), help-seeking comparison (HSC, n = 198), familial high-risk (FHR, n = 40), and schizotypal personality disorder (SPD, n = 49) groups. Comparisons were made on variables from cross-sectional demographic, symptom, functional, comorbid diagnostic, and family history domains of assessment as well as on follow-up outcome. Prodromal risk syndrome patients as a group were robustly distinguished from NC subjects across all domains and distinguished from HSC subjects and from FHR subjects on most measures in many of these domains. Adolescent and young adult SPD patients, while distinct from prodromal patients on definitional grounds, were similar to prodromals on multiple measures, consistent with SPD in young patients possibly being an independent risk syndrome for psychosis. The strong evidence of diagnostic validity for the prodromal risk syndrome for first psychosis raises the question of its evaluation for inclusion in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition).

Despite a lack of recent progress in the treatment of schizophrenia, our understanding of its genetic and environmental causes has considerably improved, and their relationship to aberrant patterns of neurodevelopment has become clearer. This raises the possibility that 'disease-modifying' strategies could alter the course to - and of - this debilitating disorder, rather than simply alleviating symptoms. A promising window for course-altering intervention is around the time of the first episode of psychosis, especially in young people at risk of transition to schizophrenia. Indeed, studies performed in both individuals at risk of developing schizophrenia and rodent models for schizophrenia suggest that pre-diagnostic pharmacotherapy and psychosocial or cognitive-behavioural interventions can delay or moderate the emergence of psychosis. Of particular interest are 'hybrid' strategies that both relieve presenting symptoms and reduce the risk of transition to schizophrenia or another psychiatric disorder. This Review aims to provide a broad-based consideration of the challenges and opportunities inherent in efforts to alter the course of schizophrenia.