Clinical High Risk Sample Research Articles

Motivational deficits in individuals at-risk for psychosis and across the course of schizophrenia

Motivational impairment is a critical factor that contributes to functional disability in schizophrenia and undermines an individual's ability to engage in and adhere to effective treatment. However, little is known about the developmental trajectory of deficits in motivation and whether these deficits are present prior to the onset of psychosis. We assessed several components of motivation including anticipatory versus consummatory pleasure (using the Temporal Experience of Pleasure Scale (TEPS)), and behavioral drive, behavioral inhibition, and reward responsivity (using the Behavioral Inhibition Scale/Behavioral Activation Scale (BIS/BAS)). A total of 234 participants completed study measures, including 60 clinical high risk (CHR) participants, 60 recent-onset schizophrenia participants (RO), 78 chronic schizophrenia participants (SZ) and 29 healthy controls (HC) age matched to the CHR group. CHR participants endorsed greater deficits in anticipatory pleasure and reward responsivity, relative to HC comparison participants and individuals diagnosed with schizophrenia. Motivational deficits were not more pronounced over the course of illness. Depressed mood was uniquely associated with impairments in motivation in the CHR sample, but not the schizophrenia participants. The results suggest that CHR individuals experience multiple contributors to impaired motivation, and thus multiple leverage points for treatment.

Impact of substance use on conversion to psychosis in youth at clinical high risk of psychosis

Elevated rates of substance use (alcohol, tobacco, cannabis) have been reported in people at clinical high risk (CHR) of developing psychosis and there is some evidence that substance use may be higher in those who convert to a psychosis compared to non-converters. However little is known about the predictive value of substance use on risk of conversion to psychosis in those at CHR of psychosis. In the current study, 170 people at CHR of psychosis were assessed at baseline on severity of alcohol, tobacco and cannabis using the Alcohol and Drug Use Scale. Participants were recruited across three sites over a four year period as part of the Enhancing the Prospective Prediction of Psychosis (PREDICT) study. Predictors of conversion to psychosis were examined using Cox proportional hazards models. Results revealed that low use of alcohol, but neither cannabis use nor tobacco use at baseline, contributed to the prediction of psychosis in the CHR sample. Prediction algorithms incorporating combinations of additional baseline variables known to be associated with psychotic conversion may result in increased predictive power compared with substance use alone.

Can quantitative EEG measures predict clinical outcome in subjects at Clinical High Risk for psychosis? A prospective multicenter study

BackgroundPrediction studies in subjects at Clinical High Risk (CHR) for psychosis are hampered by a high proportion of uncertain outcomes. We therefore investigated whether quantitative EEG (QEEG) parameters can contribute to an improved identification of CHR subjects with a later conversion to psychosis. MethodsThis investigation was a project within the European Prediction of Psychosis Study (EPOS), a prospective multicenter, naturalistic field study with an 18-month follow-up period. QEEG spectral power and alpha peak frequencies (APF) were determined in 113 CHR subjects. The primary outcome measure was conversion to psychosis. ResultsCox regression yielded a model including frontal theta (HR=1.82; [95% CI 1.00–3.32]) and delta (HR=2.60; [95% CI 1.30–5.20]) power, and occipital–parietal APF (HR=.52; [95% CI .35–.80]) as predictors of conversion to psychosis. The resulting equation enabled the development of a prognostic index with three risk classes (hazard rate 0.057 to 0.81). ConclusionsPower in theta and delta ranges and APF contribute to the short-term prediction of psychosis and enable a further stratification of risk in CHR samples. Combined with (other) clinical ratings, EEG parameters may therefore be a useful tool for individualized risk estimation and, consequently, targeted prevention.

Assessing depression in youth at clinical high risk for psychosis: A comparison of three measures

Depressive symptoms are prevalent among individuals at clinical high-risk (CHR) for psychosis. Prior studies have used the Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS), and the “dysphoric mood” item of the Scale of Prodromal Symptoms (SOPS) to assess depressive symptoms in CHR samples. We compared the psychometric properties of these instruments in a CHR cohort, to support the selection of appropriate depressive symptoms measures in future studies and in clinical settings. Internal consistency was assessed using Cronbach's alpha. Construct validity was assessed through correlations with SOPS items that were expected or not expected to be related to depressive symptoms. Criterion validity was assessed by comparing scores between patients with and without a major depressive disorder diagnosis. We hypothesized based on the schizophrenia literature that the BDI would have superior internal consistency and discriminant validity compared to the HDRS, and that all three measures would show convergent validity and criterion validity. The BDI demonstrated superior internal consistency and construct validity in this at-risk sample. The BDI and HDRS differentiated patients with major depressive disorder, but SOPS dysphoria did not. This has implications for the choice of depression measures in future CHR studies and for the interpretation of past findings.

Premorbid functional development and conversion to psychosis in clinical high-risk youths

Deterioration in premorbid functioning is a common feature of schizophrenia, but sensitivity to psychosis conversion among clinical high-risk samples has not been examined. This study evaluates premorbid functioning as a predictor of psychosis conversion among a clinical high-risk sample, controlling for effects of prior developmental periods. Participants were 270 clinical high-risk individuals in the North American Prodrome Longitudinal Study-I, 78 of whom converted to psychosis over the next 2.5 years. Social, academic, and total maladjustment in childhood, early adolescence, and late adolescence were rated using the Cannon-Spoor Premorbid Adjustment Scale. Early adolescent social dysfunction significantly predicted conversion to psychosis (hazard ratio = 1.30, p = .014), independently of childhood social maladjustment and independently of severity of most baseline positive and negative prodromal symptoms. Baseline prodromal symptoms of disorganized communication, social anhedonia, suspiciousness, and diminished ideational richness mediated this association. Early adolescent social maladjustment and baseline suspiciousness together demonstrated moderate positive predictive power (59%) and high specificity (92.1%) in predicting conversion. Deterioration of academic and total functioning, although observed, did not predict conversion to psychosis. Results indicate early adolescent social dysfunction to be an important early predictor of conversion. As such, it may be a good candidate for inclusion in prediction algorithms and could represent an advantageous target for early intervention.

Prediction of Functional Outcome in Individuals at Clinical High Risk for Psychosis

A major public health concern associated with schizophrenia and psychotic disorders is the long-term disability that involves impaired cognition, lack of social support, and an inability to function independently in the community. A critical goal of early detection and intervention studies in psychosis is therefore to understand the factors leading to this often profound impairment. To develop a predictive model of functional (social and role) outcome in a clinical high-risk sample for psychosis. Prospective, naturalistic, longitudinal 3- to 5-year follow-up study. The Recognition and Prevention Program in New York, a research clinic located in the Zucker Hillside Hospital in New York. One hundred one treatment-seeking patients at clinical high risk for psychosis. Ninety-two (91%) were followed up prospectively for a mean (SD) of 3 (1.6) years. Neurocognitive and clinical assessment. The primary outcome variables were social and role functioning at the last follow-up visit. Poor social outcome was predicted by reduced processing speed (odds ratio [OR], 1.38; 95% CI, 1.050-1.823; P = .02), impaired social functioning at baseline (OR, 1.85; 95% CI, 1.258-2.732; P = .002), and total disorganized symptoms (OR, 5.06; 95% CI, 1.548-16.527; P = .007). Reduced performance on tests for verbal memory (OR, 1.74; 95% CI, 1.169-2.594; P = .006), role functioning at baseline (OR, 1.34; 95% CI, 1.053-1.711; P = .02), and motor disturbances (OR, 1.77; 95% CI, 1.060-2.969; P = .03) predicted role outcome. The areas under the curve for the social and role prediction models were 0.824 (95% CI, 0.736-0.913; P < .001) and 0.77 (95% CI, 0.68-0.87; P < .001), respectively, demonstrating a high discriminative ability. In addition, poor functional outcomes were not entirely dependent on the development of psychosis, because 40.3% and 45.5% of nonconverters at clinical high risk had poor social and role outcomes, respectively. Results from this study support the increasing emphasis on functional decline as a critically important outcome that parallels conversion to psychosis and suggest that both psychosis and long-term functional disability are equally important targets for prevention. Reduced neurocognitive performance, functional impairments, and nonpositive attenuated symptoms at baseline were associated with an increased risk of poor functional outcomes in our sample. Poor functional outcomes were not entirely dependent on positive symptoms and the development of psychosis, further highlighting the need for intervention at this early stage of development for those who do and do not convert to a full-blown psychotic disorder.

Theory of mind and social judgments in people at clinical high risk of psychosis

BackgroundSocial cognitive deficits are consistently reported in psychotic populations. Few studies have longitudinally investigated social cognition in clinical high-risk (CHR) populations. AimsLongitudinally examine theory of mind (ToM) and social judgments in a CHR sample to investigate the stability of performance over time and potential ability to predict conversion to psychosis. Method147 CHR individuals and 85 help seeking controls (HSC) were assessed for up to 2years; 28 participants developed psychosis across both groups. Generalized linear mixed models for repeated measures were used to examine change over time for ratings on the three social cognitive indices of ToM, trustworthiness, and approachability. Hierarchical regression was used to test whether social cognitive variables explain more variance in conversion than IQ. ResultsCHR individuals showed a positive bias in approachability judgments over time compared to HSC. Baseline ToM performance significantly (p<.05) predicted later conversion beyond IQ scores. These results were attenuated when controlling for baseline symptom level. ConclusionsAlthough ToM deficits might predate conversion to psychosis, one must consider initial symptoms as well. Social judgments were not associated with conversion to schizophrenia.

White Matter Microstructure in Individuals at Clinical High Risk of Psychosis: A Whole-Brain Diffusion Tensor Imaging Study

The study of individuals at clinical high risk (CHR) for psychosis provides an important opportunity for unraveling pathological mechanisms underlying schizophrenia and related disorders. A small number of diffusion tensor magnetic resonance imaging (DTI) studies in CHR samples have yielded anatomically inconsistent results. The present study is the first to apply tract-based spatial statistics (TBSS) to perform a whole-brain DTI analysis in CHR subjects. A total of 28 individuals meeting CHR criteria and 34 healthy controls underwent DTI. TBSS was used for a group comparison of fractional anisotropy (FA), as well as axial, radial, and mean diffusivity (AD, RD, and MD). Conversion to psychosis was monitored during a mean follow-up period of 12.3 months. The rate of conversion to psychosis was relatively low (4%). TBSS revealed increased MD in several clusters in the right hemisphere, most notably in the superior longitudinal fasciculus (SLF), posterior corona radiata, and corpus callosum (splenium and body). Increased RD was restricted to a smaller area in the posterior parietal lobe. We present further evidence that white matter microstructure is abnormal in CHR individuals, even in a sample in which the vast majority do not transition to psychosis over the following year. In accord with previous studies on CHR individuals and patients with early-onset schizophrenia, our findings suggest an important pathological role for the parietal lobe and especially the SLF. The latter is known to undergo particularly dynamic microstructural changes during adolescence and early adulthood, a critical phase for the development of psychotic illness.

Perceived discrimination in those at clinical high risk for psychosis

There is evidence to suggest that perceived discrimination may be associated with psychosis. Less is known about its potential impact on those at clinical high risk (CHR) for psychosis. The aim of this study was to determine the prevalence of perceived discrimination in a CHR sample and its possible relationship to attenuated positive symptoms and negative self-beliefs. Participants were 360 CHR individuals and 180 healthy controls. Assessments included a self-report measure of perceived discrimination, the Scale of Prodromal Symptoms and the Brief Core Schema Scale. CHR participants reported significantly more perceived discrimination. Perceived discrimination was significantly associated with negative schemas, but not with attenuated positive symptoms. These results suggest that individuals at CHR for psychosis endorse a higher level of perceived discrimination, which is associated with increased negative schemas, but not attenuated positive symptoms.

Symptom dimensions and functional impairment in early psychosis: More to the story than just negative symptoms

Functional impairment is a defining feature of psychotic disorders and usually appears well before their onset. Negative symptoms play a prominent role in the impaired functioning of individuals with schizophrenia and those at clinical-high-risk (CHR) for psychosis. Despite high rates of depression and anxiety in early psychosis, few studies have examined the contribution of these symptoms to functioning in the putative ‘prodrome.’ In the current study, we tested the hypotheses that 1) worse negative and disorganized, but not positive, symptoms would be significantly related to impaired social and role functioning in two cohorts of CHR individuals (combined N=98) and a separate sample of individuals with recent-onset (RO) psychotic disorders (N=88); and 2) worse anxiety and depression would be significantly related to impaired functioning in both samples, above and beyond the contributions of negative and disorganized symptoms. Findings largely supported our hypotheses that more severe negative and disorganized symptoms were related to poorer social and role functioning in both samples. Anxiety and depression severity were significantly related to poorer functioning in both samples. In addition, depression, but not anxiety, predicted poorer global and social functioning above and beyond that explained by negative symptoms in the CHR sample. These results suggest the need for phase-specific treatment in early psychosis, with a focus on symptom dimensions to improve functional outcomes for CHR individuals.

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

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. 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. 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. 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.

P-1015 - Persistence of positive symptoms in patients at high risk of developing a psychosis

A considerable part of clinical high-risk samples does not convert to psychosis within the studies' limited observation periods. A part of these ‘non-converters’ shows a remission of symptoms (with unknown future course). Another part, however, maintains the risk state during follow-up. Persistence of indicators for an increased risk of psychosis. To investigate, if persistence of attenuated (APS) or brief limited intermittent psychotic symptoms (BLIPS), the core syndromes of ultra-high risk (UHR) criteria, can be predicted clinically. N = 129 participants of the European Prediction of Psychosis (EPOS) Study were included into the current analysis. Persistent Risk Symptoms (pRS) were defined as an at-least ‘moderate’ level (SIPS) of at least one positive symptom at all visits (symptom had to remain the same). Functional significance was defined by a GAF-M score ≤60 at 18-month follow-up (T2). 23.3% displayed persistent risk symptoms throughout follow-up. Most frequent pRS were ‘unusual thought contents’, ‘ideas of persecution’ and ‘perceptual disturbances’. In 90% of the pRS subjects, but only in 25.3% of the non-pRS subjects, GAF scores at T2 were below 60 points (p < 0.01). Logistic regression analysis revealed that the presence of the pRS syndrome at T2 was predictable by the early course of attenuated positive symptoms with maximum accuracy when the number of at least ‘moderate’ symptoms was considered. A considerable number of subjects at risk showed persistent attenuated positive symptoms associated with long-lasting functional impairments, irrespective of conversion within the foreseeable future.

Neuropsychological profiles in individuals at clinical high risk for psychosis: Relationship to psychosis and intelligence

Background Characterizing neuropsychological (NP) functioning of individuals at clinical high risk (CHR) for psychosis may be useful for prediction of psychosis and understanding functional outcome. The degree to which NP impairments are associated with general cognitive ability and/or later emergence of full psychosis in CHR samples requires study with well-matched controls. Methods We assessed NP functioning across eight cognitive domains in a sample of 73 CHR youth, 13 of whom developed psychotic-level symptoms after baseline assessment, and 34 healthy comparison (HC) subjects. Groups were matched on age, sex, ethnicity, handedness, subject and parent grade attainment, and median family income, and were comparable on WRAT-3 Reading, an estimate of premorbid IQ. Profile analysis was used to examine group differences and the role of IQ in profile shape. Results The CHR sample demonstrated a significant difference in overall magnitude of NP impairment but only a small and nearly significant difference in profile shape, primarily due to a large impairment in olfactory identification. Individuals who subsequently developed psychotic-level symptoms demonstrated large impairments in verbal IQ, verbal memory and olfactory identification comparable in magnitude to first episode samples. Conclusions CHR status may be associated with moderate generalized cognitive impairments marked by some degree of selective impairment in olfaction and verbal memory. Impairments were greatest in those who later developed psychotic symptoms. Future study of olfaction in CHR samples may enhance early detection and specification of neurodevelopmental mechanisms of risk.

Language network dysfunction as a predictor of outcome in youth at clinical high risk for psychosis

Objectives Language processing abnormalities are a hallmark feature of schizophrenia. Yet, no study to date has investigated underlying neural networks associated with discourse processing in adolescents at clinical high risk (CHR) for developing psychosis 1 1 Please note that our journal previously published the following paper with similar methodology in people at genetic high-risk for schizophrenia: Li, X., Branch, C.A., Bertisch, H.C., Brown, K., Szulc, K.U., Ardekani, B.A., DeLisi, L.E., 2007. An fMRI study of language processing in people at high genetics risk for schizophrenia. Schizophr. Res. 91: 62–72. Bhojraj, T.S., Francis, A.N., Rajarethinam, R., Eack, S., Kulkarni, S. Prasad, K.M., Montrose, D.M., Dworakowski, D., Diwadkar, V., Keshavan, M.S., 2009. Verbal fluency deficits and altered lateralization of language brain areas in individuals genetically predisposed to schizophrenia. Schizophr. Res. 115 (2009) 202–208. . Methods Forty CHR youth and 24 demographically comparable healthy controls underwent functional magnetic resonance imaging while performing a naturalistic discourse processing paradigm. We assessed differences in blood oxygenation level-dependent (BOLD) activity between task conditions (Topic Maintenance vs. Reasoning) and between groups. Furthermore, we examined the association of regional brain activity with symptom severity and social outcome at follow-up, 6 to 24 months after the scan. Results Relative to controls, CHR participants showed increased neural activity in a network of language-associated brain regions, including the medial prefrontal cortex bilaterally, left inferior frontal (LIFG; BA44/45, 47) and middle temporal gyri, and the anterior cingulate (BA24 and 32). Further, increased activity in the superior temporal gyrus (STG), caudate, and LIFG distinguished those who subsequently developed psychosis. Within the CHR sample, severity of positive formal thought disorder at follow-up was positively correlated with signal change in the LIFG, superior frontal gyrus, and inferior/middle temporal gyri, whereas social outcome was inversely correlated with signal change in the LIFG and anterior cingulate. Conclusions These findings are consistent with a neural inefficiency hypothesis in those at greatest risk for psychosis, and additionally suggest that baseline activation differences may predict symptomatic and functional outcome. These results highlight the need to further investigate the neural systems involved in conversion to psychosis, and how language disruption changes over time in at-risk adolescents.

Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention

Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth.

White Matter Integrity and Prediction of Social and Role Functioning in Subjects at Ultra-High Risk for Psychosis

White matter microstructural disruptions have been observed in patients with schizophrenia. However, whether changes exist prior to disease onset or in high-risk individuals is unclear. Here, we investigated white matter integrity, as assessed by diffusion tensor imaging (DTI), in individuals at ultra-high risk for psychosis (UHR) relative to healthy control subjects (HC) and the relationship between baseline DTI measures and functional outcome over time. Thirty-six UHR participants and 25 HCs completed baseline DTI scans. Subjects also completed clinical follow-up assessments approximately 6 months (26 subjects) and 15 months (13 subjects) later. We used a rigorous registration approach (Tract-Based Spatial Statistics [TBSS]) to examine fractional anisotropy (FA) in six major white matter tracts. Relative to the HC group, UHR subjects showed lower baseline FA in the superior longitudinal fasciculus, the major frontoparietal white matter connection. Cross-sectional analyses demonstrated that UHR youth failed to show the same age-associated increases in FA in the medial temporal lobe (MTL) and inferior longitudinal fasciculus as HCs. Finally, lower baseline FA in the MTL and inferior longitudinal fasciculus predicted deterioration in social and role functioning in UHR participants at 15-month follow-up. This is the first investigation of white matter microstructural alterations in a clinical high-risk sample. Our findings indicate that white matter development may be altered in youth at risk for psychosis, possibly due to disrupted developmental mechanisms, and further, that white matter integrity may be predictive of functional outcome.

Prediction of Psychosis in Youth at High Clinical Risk

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. 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. 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. Time to conversion to a fully psychotic form of mental illness. 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. 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.