Kristin S. Cadenhead

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.

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.

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.

Transient versus sustained visual channels in the visual backward masking deficits of schizophrenia patients

BACKGROUND Schizophrenia patients have information-processing deficits that can be quantified using visual backward masking. The visual information processing system is divided functionally and structurally into transient and sustained visual channels. When visual stimuli are presented to a subject, the transient pathway detects the presence and location of the stimulus while the sustained pathway is involved in fine discrimination and identification of the stimulus. While independent subcortically, the transient and sustained visual channels converge cortically into the dorsal and ventral processing streams that assess spatial relationships and object recognition respectively. METHODS To better understand the underlying mechanisms of the visual backward masking deficits, 16 schizophrenia patients and 17 comparison subjects were tested on two different visual backward masking paradigms that required either locating or identifying a target letter. RESULTS Schizophrenia patients had visual backward masking deficits in a task that involved locating a target letter while there were no deficits in the task that involved identification of a target letter. CONCLUSIONS The visual backward masking deficits of schizophrenia patients suggest impairment in the processing of spatial information. These deficits are discussed in the context of our current knowledge of visual information processing and the neuropathophysiology of schizophrenia.

Risk Factors for Psychosis: Impaired Social and Role Functioning

OBJECTIVES Risk for psychosis is currently defined primarily on the basis of attenuated positive symptoms (APS), with no inclusion of the functional deficits characteristic of schizophrenia. Impaired social and role functioning have been of interest for reflecting poor outcome but far less is known about the developmental impact of these deficits as vulnerability or risk factors. METHODS Age-appropriate social and role functioning were prospectively assessed in 100 individuals at clinical high risk (CHR) for psychosis included in the 8-site North American Prodromal Longitudinal Study database. A nested case-control design was used to compare changes in social and role functioning in 26 individuals converting to psychosis shortly after baseline assessment and 24 converting over a year later. Individuals in each converter subgroup were directly matched to a non-converter at the same site, controlling for time to conversion, age, gender, and severity of baseline symptoms. RESULTS At baseline, CHR subjects who later became psychotic were significantly more likely to be impaired socially than matched non-converters. Onset of psychosis did not further disrupt social difficulties. Role functioning showed some of the same trends, but the overall pattern was not as consistent as for the social domain. Controlling for neurocognition did not change the pattern of group differences. CONCLUSIONS Early impaired social functioning appears to be a risk factor for psychosis and, added to APS, could potentially contribute to accurate identification of CHR individuals and provide a new direction for early intervention to reduce long-term disability.

Course of neurocognitive deficits in the prodrome and first episode of schizophrenia.

Understanding the trajectory of cognitive changes in the development of schizophrenia may shed light on the neurodevelopmental processes in the beginning stage of illness. Subjects at risk for psychosis (AR, n = 48), patients in their first episode of schizophrenia (FE, n = 20), and normal comparison subjects (n = 29) were assessed on a neurocognitive battery at baseline and at a 6-month follow-up. There were significant group differences across all cognitive domains as well as a significant group by time interaction in the verbal learning domain. After statistically controlling for practice effects and regression to the mean, a high proportion of FE subjects showed an improvement in verbal learning, and a significant number of AR subjects improved in general intelligence. Moreover, a higher than expected percentage of FE subjects, as well as AR subjects who later converted to psychosis, showed a deterioration in working memory and processing speed. These inconsistent trajectories suggest that some domains may improve with stabilization in the early stages of psychosis, whereas others may decline with progression of the illness, indicating possible targets for cognitive remediation strategies and candidate vulnerability markers for future psychosis.

Negative symptoms in individuals at clinical high risk of psychosis.

Negative symptoms are present in the psychosis prodrome. However, the extent to which these symptoms are present prior to the onset of the first episode of psychosis remains under-researched. The goal of this study is to examine negative symptoms in a sample of individuals at clinical high risk (CHR) for psychosis and to determine if they are predictive of conversion to psychosis. Participants (n=138) were all participants in the North American Prodrome Longitudinal Study (NAPLS 1) project. Negative symptoms were assessed longitudinally using the Scale of Prodromal Symptoms. The mean total negative symptom score at baseline was 11.0, with 82.0% of the sample scoring at moderate severity or above on at least one negative symptom. Over the course of 12 months, the symptoms remained in the above moderate severity range for 54.0% of participants. Associations between individual symptoms were moderate, and a factor analysis confirmed that all negative symptoms loaded heavily on one factor. Negative symptoms were more severe and persistent overtime in those who converted to psychosis, significantly predicting the likelihood of conversion. Thus, early and persistent negative symptoms may represent a vulnerability for risk of developing psychosis.

Cortisol Levels and Risk for Psychosis: Initial Findings from the North American Prodrome Longitudinal Study

BACKGROUND Studies of biomarkers of hypothalamic-pituitary-adrenal activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy control subjects and individuals who met clinical high-risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be 1) elevated in the CHR group relative to control subjects, 2) positively correlated with symptom severity, and 3) most elevated in CHR patients who transition to psychotic level severity. METHODS Baseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study. The present CHR sample included 256 individuals meeting the Scale for Prodromal Symptoms criteria and 141 control subjects, all of whom underwent baseline assessment and measurement of salivary cortisol. RESULTS Consistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and analysis of covariance revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared with healthy control subjects and CHR subjects who remitted. CONCLUSIONS The present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of hypothalamic-pituitary-adrenal activity in prediction of conversion to psychosis and its relation with other biomarkers of risk should receive attention in future research.

Cognitive functions in schizotypal personality disorder

OBJECTIVE Schizophrenia spectrum subjects have cognitive deficits in a variety of domains. Schizotypal personality disordered (SPD) subjects do not have many of the confounds seen in schizophrenic patients, but may have the same pattern of cognitive deficits in attention and executive functioning. HYPOTHESIS We hypothesized that SPD subjects would have impairments on measures of attention, abstract reasoning, cognitive inhibition, working memory and verbal recognition memory when compared to normal subjects, and that these deficits would be intermediate to those observed in schizophrenic patients. METHOD SPD subjects (N=20) were compared to age-, gender- and education-matched schizophrenic patients (N=20) and normal comparison subjects (N=20) on a battery of cognitive measures. RESULTS The data were analyzed using standard statistical methods, including effect sizes. Using a conservative alpha level of 0.01, schizophrenic patients had deficits on many of these measures compared to normal subjects. Although the SPD subjects did not significantly differ from normal comparison subjects at the p < 0.01 level, there were trends (p < 0.019-0.028) toward impairment on measures of working memory and general intellectual functioning. On further effect size analyses, SPD subjects performed intermediate to normals and schizophrenic patients on measures of attention, abstract reasoning, cognitive inhibition, verbal working memory, recognition memory, and general intellectual functioning, with moderate to large effect sizes separating groups. CONCLUSIONS These results suggest that SPD subjects have possible widespread cognitive deficits that are of lesser magnitude than those observed in schizophrenic patients.

Information processing deficits of schizophrenia patients: relationship to clinical ratings, gender and medication status

Information processing deficits were explored in a large cohort of schizophrenia patients (N = 125) and non-psychiatric subjects (N = 52). Gender, medication status and symptom factors were assessed relative to measures of performance in critical stimulus duration (CSD), visual backward masking (VBM) and auditory reaction time (RT) paradigms. Schizophrenia patients exhibited significant impairments in measures of CSD, VBM and both RT speed and RT set. Females in both groups had inflated CSDs relative to males. Female schizophrenia patients showed slower RTs and elevated RT set scores, but comparable VBM performance, when compared to males. This gender difference was not observed in the non-psychiatric subjects. To test the hypothesis that impaired performance in the VBM and RT paradigms would be related to negative symptoms and thought disorder, regression analyses were performed using factor scores derived from a factor analysis of SANS and SAPS items that generated three symptom factors: negative, disorganized, and reality distortion. Significant variance in performance on VBM and RT measures was accounted for only by the negative symptom factor. We conclude that VBM and RT assess information processing deficits in schizophrenia patients that are more related to the negative versus positive or disorganized symptoms of schizophrenia. It is possible that VBM and RT share overlapping or interacting neural substrates.