Barbara A. Cornblatt

Prediction of Psychosis in Youth at High Clinical Risk: A Multisite Longitudinal Study in North America

CONTEXT Early detection and prospective evaluation of individuals who will develop schizophrenia or other psychotic disorders are critical to efforts to isolate mechanisms underlying psychosis onset and to the testing of preventive interventions, but existing risk prediction approaches have achieved only modest predictive accuracy. OBJECTIVES To determine the risk of conversion to psychosis and to evaluate a set of prediction algorithms maximizing positive predictive power in a clinical high-risk sample. DESIGN, SETTING, AND PARTICIPANTS Longitudinal study with a 2 1/2-year follow-up of 291 prospectively identified treatment-seeking patients meeting Structured Interview for Prodromal Syndromes criteria. The patients were recruited and underwent evaluation across 8 clinical research centers as part of the North American Prodrome Longitudinal Study. MAIN OUTCOME MEASURE Time to conversion to a fully psychotic form of mental illness. RESULTS The risk of conversion to psychosis was 35%, with a decelerating rate of transition during the 2 1/2-year follow-up. Five features assessed at baseline contributed uniquely to the prediction of psychosis: a genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Prediction algorithms combining 2 or 3 of these variables resulted in dramatic increases in positive predictive power (ie, 68%-80%) compared with the prodromal criteria alone. CONCLUSIONS 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.

The Psychosis High-Risk State A Comprehensive State-of-the-Art Review

CONTEXT During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. OBJECTIVE To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. DATA SOURCES Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. STUDY SELECTION AND DATA EXTRACTION Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. DATA SYNTHESIS Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. CONCLUSIONS The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

The continuous performance test, identical pairs version (CPT-IP): I. new findings about sustained attention in normal families

Thirty families, consisting of two parents and two adolescent children, were tested on a high-processing load Continuous Performance Test, the CPT-IP, which required identification of identical stimulus pairs within a continuously presented series of stimuli. The purpose of this study was to provide normative data for research concerned with the role of attention in psychopathology, especially schizophrenia and major affective disorder. Retest data collected from 23 of the 30 families showed the CPT-IP to be a reliable measure of attention. A major developmental effect was found in capacity to sustain attention to spatial vs. verbal stimuli, which suggested that spatial skills are most developed during childhood and adolescence, while verbal attentional skills tend to peak in adulthood. Factor analysis and family transmission patterns further suggested that the two types of attention (spatial and verbal) were independent and that each was heritable to some degree. Experimental distraction did not disrupt performance in any of the subjects and, in fact, tended to improve it in the adolescents, especially for spatial stimuli. We conclude that the CPT-IP is appropriate for use with families containing members differing widely in age and processing skills.

The continuous performance test, identical pairs version: II. Contrasting attentional profiles in schizophrenic and depressed patients

The Continuous Performance Test-Identical Pairs version was administered to 14 schizophrenic patients, 17 depressed patients, and 28 normal controls. The task was divided into verbal and spatial stimuli, as well as no-distraction and distraction (verbal and auditory) conditions. Both patient groups displayed attentional impairments compared to normal subjects, but they differed from each other in specific profiles. Schizophrenic patients were characterized by a global impairment and a particular inability to focus on the critical stimuli, whether verbal or spatial. They also made an excess of random responses throughout the task but showed no evidence that attention declined from its initial level over time. Depressed patients did not display a global attentional deficit but did show a specific inability to attend to spatial as compared to verbal stimuli and, in particular, a confusion when the spatial stimuli were only slightly different. Performance on a secondary task in response to a change in expectation improved dramatically for depressed but not schizophrenic patients, suggesting a more efficient allocation strategy, a greater reserve of processing capacity, or more dependence on motivational factors in depressed patients. Schizophrenic and depressed patients were alike in extent of distractibility. Whereas normal controls improved with the onset of external distraction, schizophrenic and depressed patients deteriorated to an equal extent. Distractibility was thus concluded to be a correlate of acute psychiatric illness and not specific for schizophrenia.

Generalized and specific neurocognitive deficits in prodromal schizophrenia.

BACKGROUND Neurocognitive deficits are considered to be central to the pathophysiology of schizophrenia, and the neurodevelopmental model suggests that such deficits precede full-blown psychosis. The present study examined performance on a broad neuropsychological battery of young subjects considered to be at clinical high risk for schizophrenia, who were subsequently followed to determine clinical outcome. METHODS Subjects were 38 clinical high-risk patients (58% male patients; mean age = 16.5) and 39 sex- and age-matched healthy control subjects. At baseline, all high-risk patients had attenuated (subpsychotic) schizophrenialike positive symptoms. Clinical follow-up data of at least 6 months duration was available on 33 patients, of whom 12 developed nonaffective psychotic disorders. RESULTS At baseline, clinical high-risk patients had significantly impaired global cognitive performance relative to control subjects and to estimates of their own prior intellectual functioning. Measures of verbal memory and executive functioning/working memory showed significantly greater impairments; visuospatial functioning was relatively spared. Prodromal patients who later developed psychosis had significantly lower verbal memory scores at baseline compared with patients who remained nonpsychotic. CONCLUSIONS Verbal memory deficits may be an important risk marker for the development of schizophrenia-spectrum psychotic disorders, possibly indicating the presence of a prefrontal-hippocampal neurodevelopmental abnormality. Generalized neurocognitive impairment may be a nonspecific vulnerability marker.

At Clinical High Risk for Psychosis: Outcome for Nonconverters

OBJECTIVE A major focus of early intervention research is determining the risk of conversion to psychosis and developing optimal algorithms of prediction. Although reported rates of nonconversion vary in the literature, the nonconversion rate always encompasses a majority (50%-85%) of the sample participants. Less is known about the outcome among this group, referred to as false positive individuals. METHOD A longitudinal study was conducted of more than 300 prospectively identified treatment-seeking individuals meeting criteria for a psychosis-risk syndrome. Participants were recruited and evaluated across eight clinical research centers as part of the North American Prodrome Longitudinal Study. Over a 2.5-year follow-up assessment period, 214 (71%) participants had not made the transition to psychosis. RESULTS The sample examined included 111 individuals who had at least 1 year of follow-up data available and did not transition to psychosis within the study duration. In year 1, there was significant improvement in ratings for attenuated positive and negative symptoms. However, at least one attenuated positive symptom was still present for 43% of the sample at 1 year and for 41% at 2 years. At the follow-up timepoints, social and role functioning were significantly poorer in the clinical sample relative to nonpsychiatric comparison subjects. CONCLUSIONS Help-seeking individuals who meet prodromal criteria appear to represent those who are truly at risk for psychosis and are showing the first signs of illness, those who remit in terms of the symptoms used to index clinical high-risk status, and those who continue to have attenuated positive symptoms.

Cognitive and behavioral precursors of schizophrenia

Attentional deficits are well-established characteristics of patients with schizophrenia and their at-risk offspring, suggesting a biological connection between attention and schizophrenia. The goal of this study is to clarify the developmental role of attention in the illness. Data has been collected from 87 subjects at high and low risk for schizophrenia who have participated in the New York High-Risk Project from 1977 to the present. Individuals are considered to be at high risk if either or both of their parents has schizophrenia. Analyses of attention and global behaviors, measured at intervals from about 12 to 26 years of age, indicate (a) attentional deficits can be reliably detected in high-risk children who will develop future schizophrenia-spectrum disorders (the prespectrum [PSP] group); (b) these deficits are stable, enduring over time, and appear to reflect a compromised attentional capacity; (c) attention is not affected by the onset of illness in the PSP group; (d) for all subjects, attention and global behaviors follow independent developmental pathways; and (e) behavioral difficulties, but not attention deficits, appear to be highly sensitive to environmental factors, especially rearing by a mentally ill parent. It is concluded that in PSP individuals impaired attention probably results from prenatal developmental abnormalities (possibly on the cellular level) and is likely to be a marker of a biological vulnerability to schizophrenia. In addition, attentional deficits, as opposed to early behavioral difficulties, are concluded to be a useful first step in screening for youngsters in need of early intervention.

Impaired attention as an endophenotype for molecular genetic studies of schizophrenia.

Attentional abnormalities have long been known to characterize patients with schizophrenia. The data discussed in this report suggest that impaired attention (at least as measured by a specific task, the Continuous Performance Test, Identical Pairs (CPT-IP) version) may also be an endophenotype of particular promise for use in molecular genetic studies of schizophrenia. This conclusion is based on findings indicating that the deficits in verbal and spatial attentional processing tapped by the CPT-IP are heritable, developmentally stable, independent of clinical state, and predict future spectrum disorders in the at-risk offspring of parents with schizophrenia.

Nonspecific and attenuated negative symptoms in patients at clinical high-risk for schizophrenia

BACKGROUND Retrospective studies have shown that nonspecific psychopathology and negative symptoms, including social isolation and academic dysfunction, tend to precede onset of psychosis. The present report describes the baseline psychopathology of subjects in the Hillside Recognition and Prevention (RAP) Program, and presents an operationalized classification algorithm for the prospective study of both positive and negative symptoms of clinical high-risk (CHR) for schizophrenia. METHODS Eighty-two adolescent and young adult patients were characterized using semi-structured interviews of both a parent informant and the patient. The Scale of Prodromal Symptoms (SOPS) was utilized to derive a three-part classification scheme: CHR- subjects (n=20) were defined as having at least one attenuated negative symptom with no positive symptoms; CHR+ subjects (n=42) were defined as having one or more attenuated positive symptoms without psychosis; schizophrenia-like psychosis (SLP) subjects (n=20) were defined as having a psychotic symptom, but without meeting criterion A, B, or C of DSM-IV schizophrenia. RESULTS Social isolation was the most common presenting symptom. The three RAP subgroups did not significantly differ in levels of attenuated negative and disorganized symptoms, despite the fact that these were not required for inclusion in the CHR+ and SLP groups. Common co-morbid diagnoses included major depression, attention deficit hyperactivity disorder, avoidant personality disorder, and Cluster A personality disorders. CONCLUSIONS Negative symptoms and other nonspecific behavioral abnormalities represent clinically important phenomena in prodromal patients, and may provide insight into pathophysiologic mechanisms in schizophrenia and possible preventive interventions.

Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk

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 individuals without symptomatic progression and with healthy control subjects. 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 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms. RESULTS In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the 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 subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory 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 in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.