Search

This cross-sectional study examined the associations between neighborhood-level socioeconomic-status (NSES), and psychosocial functioning and personality pathology among 335 adults drawn from the Collaborative Longitudinal Personality Disorders Study. Participants belonged to four personality disorder (PD) diagnostic groups: Avoidant, Borderline, Schizotypal, and Obsessive Compulsive. Global functioning, social adjustment, and PD symptoms were assessed following a minimum two-year period of residential stability. Residence in higherrisk neighborhoods was associated with more PD symptoms and lower levels of functioning and social adjustment. These relationships were consistent after controlling for individual-level socioeconomic-status and ethnicity; however, the positive association between neighborhood-level socio-economic risk and PD symptoms was evident only at higher levels of individual-level socio-economic risk. Our findings identify NSES as a candidate for explaining some of the variability in symptoms and functioning among PD individuals.

Background and hypothesisNegative symptom trajectory in clinical high risk (CHR) for psychosis is ill defined. This study aimed to better characterize longitudinal patterns of change in negative symptoms, moderators of change, and differences in trajectories according to clinical subgroups. We hypothesized that negative symptom course will be nonlinear in CHR. Clinical subgroups known to be more severe variants of psychotic illness-deficit syndrome (DS), persistent negative syndrome (PNS), and acute psychosis onset-were expected to show more severe baseline symptoms, slower rates of change, and less stable rates of symptom resolution.Study designLinear, curvilinear, and stepwise growth curve models, with and without moderators, were fitted to negative symptom ratings from the NAPLS-3 CHR dataset (N = 699) and within clinical subgroups.Study resultsNegative symptoms followed a downward curvilinear trend, with marked improvement 0-6 months that subsequently stabilized (6-24 months), particularly among those with lower IQ and functioning. Clinical subgroups had higher baseline ratings, but distinct symptom courses; DS vs non-DS: more rapid initial improvement, similar stability of improvements; PNS vs non-PNS: similar rates of initial improvement and stability; transition vs no transition: slower rate of initial improvement, with greater stability of this rate.ConclusionsContinuous, frequent monitoring of negative symptoms in CHR is justified by 2 important study implications: (1) The initial 6 months of CHR program enrollment may be a key window for improving negative symptoms as less improvement is likely afterwards, (2) Early identification of clinical subgroups may inform distinct negative symptom trajectories and treatment needs.

The North American Prodrome Longitudinal Study (NAPLS) is a consortium of nine programs focusing on youth at clinical high risk (CHR) for psychosis. Funded by the National Institute of Mental Health (NIMH), the sites are located at Emory University, Harvard University, University of Calgary, University of California at Los Angeles, at San Diego, and at San Francisco, University of North Carolina Chapel Hill, Yale University, and Zucker Hillside Hospital. There have been two previous endeavors completed by this consortium, known as NAPLS-1 and NAPLS-2. This paper first offers an overview of the methodology of the third phase of the NAPLS consortium, the second five-year prospective study NAPLS-3, which aims to determine mechanisms of the development of psychosis. In addition, we report on the ascertainment and demographics of the 710 CHR participants in NAPLS-3.

The clinical high-risk period before a first episode of psychosis (CHR-P) has been widely studied with the goal of understanding the development of psychosis; however, less attention has been paid to the 75%-80% of CHR-P individuals who do not transition to psychosis. It is an open question whether multivariable models could be developed to predict remission outcomes at the same level of performance and generalizability as those that predict conversion to psychosis. Participants were drawn from the North American Prodrome Longitudinal Study (NAPLS3). An empirically derived set of clinical and demographic predictor variables were selected with elastic net regularization and were included in a gradient boosting machine algorithm to predict prodromal symptom remission. The predictive model was tested in a comparably sized independent sample (NAPLS2). The classification algorithm developed in NAPLS3 achieved an area under the curve of 0.66 (0.60-0.72) with a sensitivity of 0.68 and specificity of 0.53 when tested in an independent external sample (NAPLS2). Overall, future remitters had lower baseline prodromal symptoms than nonremitters. This study is the first to use a data-driven machine-learning approach to assess clinical and demographic predictors of symptomatic remission in individuals who do not convert to psychosis. The predictive power of the models in this study suggest that remission represents a unique clinical phenomenon. Further study is warranted to best understand factors contributing to resilience and recovery from the CHR-P state.

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FAT) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FAT in adolescence, and 4% lower FAT by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p

BackgroundAdolescence/early adulthood coincides with accelerated pruning of cortical synapses and the onset of schizophrenia. Cortical gray matter reduction and dysconnectivity in schizophrenia are hypothesized to result from impaired synaptic plasticity mechanisms, including long-term potentiation (LTP), since deficient LTP may result in too many weak synapses that are then subject to over-pruning. Deficient plasticity has already been observed in schizophrenia. Here, we assessed whether such deficits are present in the psychosis risk syndrome (PRS), particularly those who subsequently convert to full psychosis.MethodsAn interim analysis was performed on a sub-sample from the NAPLS-3 study, including 46 healthy controls (HC) and 246 PRS participants. All participants performed an LTP-like visual cortical plasticity paradigm involving assessment of visual evoked potentials (VEPs) elicited by vertical and horizontal line gratings before and after high frequency ("tetanizing") visual stimulation with one of the gratings to induce "input-specific" neuroplasticity (i.e., VEP changes specific to the tetanized stimulus). Non-parametric, cluster-based permutation testing was used to identify electrodes and timepoints that demonstrated input-specific plasticity effects.ResultsInput-specific pre-post VEP changes (i.e., increased negative voltage) were found in a single spatio-temporal cluster covering multiple occipital electrodes in a 126-223 ms time window. This plasticity effect was deficient in PRS individuals who subsequently converted to psychosis, relative to PRS non-converters and HC.ConclusionsInput-specific LTP-like visual plasticity can be measured from VEPs in adolescents and young adults. Interim analyses suggest that deficient visual cortical plasticity is evident in those PRS individuals at greatest risk for transition to psychosis.

Psychotic symptoms are not only an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multiethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7225, 20% PS). Using an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects. The multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is driven by subjects of European ancestry (OR = 1.23 (1.14, 1.34), P = 4.15 × 10-7) but is not observed in African American subjects (P = 0.65). We find a significant interaction of ADHD PGS with age (P = 0.01), with a stronger association in younger children. The association is independent of phenotypic overlap between ADHD and PS, not indirectly driven by substance use or childhood trauma, and appears to be specific to PS rather than reflecting general psychopathology in youth. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P = 0.02). Our findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.

BackgroundMalhi et al. in this issue critique the clinical high risk (CHR) syndrome for psychosis.MethodResponse to points of critique.ResultsWe agree that inconsistency in CHR nomenclature should be minimized. We respectfully disagree on other points. In our view: a) individuals with CHR and their families need help, using existing interventions, even though we do not yet fully understand disease mechanisms; b) substantial progress has been made in identification of biomarkers; c) symptoms used to identify CHR are specific to psychotic illnesses; d) CHR diagnosis is not "extremely difficult"; e) the pattern of progression, although heterogenous, is discernible; f) "psychosis-like symptoms" are common but are not used to identify CHR; and g) on the point described as 'the real risk,' CHR diagnosis does not frequently cause harmful stigma.DiscussionMalhi et al.'s arguments do not fairly characterize progress in the CHR field nor efforts to minimize stigma. That said, much work remains in areas of consistent nomenclature, mechanisms of disease, dissecting heterogeneity, and biomarkers. With regard to what the authors term the "real risk" of stigma associated with a CHR "label," however, our view is that avoiding words like "risk" and "psychosis" reinforces the stigma that both they and we mean to oppose. Moreover, patients and their families benefit from being given a term that describes what is happening to them.

BackgroundRisk calculators are useful tools that can help clinicians and researchers better understand an individual's risk of conversion to psychosis. The North American Prodrome Longitudinal Study (NAPLS2) Individualized Risk Calculator has good predictive accuracy but could be potentially improved by the inclusion of a biomarker. Baseline cortisol, a measure of hypothalamic-pituitary-adrenal (HPA) axis functioning that is impacted by biological vulnerability to stress and exposure to environmental stressors, has been shown to be higher among individuals at clinical high-risk for psychosis (CHRP) who eventually convert to psychosis than those who do not. We sought to determine whether the addition of baseline cortisol to the NAPLS2 risk calculator improved the performance of the risk calculator.MethodsParticipants were drawn from the NAPLS2 study. A subset of NAPLS2 participants provided salivary cortisol samples. A multivariate Cox proportional hazards regression evaluated the likelihood of an individual's eventual conversion to psychosis based on demographic and clinical variables in addition to baseline cortisol levels.ResultsA total of 417 NAPLS2 participants provided salivary cortisol and were included in the analysis. Higher levels of cortisol were predictive of conversion to psychosis in a univariate model (C-index = 0.59, HR = 21.5, p-value = 0.004). The inclusion of cortisol in the risk calculator model resulted in a statistically significant improvement in performance from the original risk calculator model (C-index = 0.78, SE = 0.028).ConclusionsSalivary cortisol is an inexpensive and non-invasive biomarker that could improve individual predictions about conversion to psychosis and treatment decisions for CHR-P individuals.

Comorbid diagnoses are common in youth who are at clinical high-risk (CHR) for developing psychosis, with depression being the most common. The aim of this paper is to examine depression over two years in a large sample of CHR youth who do not make the transition to psychosis, considering both categorical and dimensional ratings of depression severity. The sample consisted of 267 CHR youth who were followed for two years. Based on DSM-IV diagnoses over this time period, 100 CHR individuals never received a diagnosis of depression, 64 individuals continuously met criteria for depression, 92 individuals received a diagnosis of depression at one or more timepoints, and 11 participants had a diagnosis of depression only at 24-months. These groupings were supported by six-monthly ratings on the Calgary Depression Scale. The majority of this sample experienced a major depressive episode on more than one occasion, suggesting that depression and depressive symptoms identify a domain of substantial unmet clinical need. Recommendations are that depression in CHR youth and young adults should be monitored more frequently and that there is a need for clinical trials to address depression systematically in this vulnerable population.

ObjectivesWhile co-morbid depression is associated with poor functional outcome among patients with schizophrenia, whether depression similarly predicts poorer outcomes in individuals at clinical high-risk for psychosis (CHR-P) is not clear. The present study aimed to examine depressive symptoms in relation to long-term global functional outcomes in the North American Prodrome Longitudinal Study cohort (NAPLS2).MethodsCHR individuals were evaluated clinically at baseline and at 12- and 24-month follow-ups for depressive and prodromal symptom severity as well as general functioning. Regression models were built to investigate whether baseline positive and depressive symptom scores predicted longitudinal improvement in global functioning.ResultsA total of 406 CHR individuals completed the 12-month follow-up assessment and 259 CHR individuals completed the 24-month assessment. Baseline depressive symptoms in the CHR-P population were found to predict better global functional outcomes at 2 years. Furthermore, the degree of recovery of depressive symptoms in the first year following baseline completely mediated the association between depressive symptoms at baseline and functional improvement at 2 years.ConclusionsPresence of affective symptoms within the CHR-P population has different implications for prognosis compared with patients with schizophrenia. The present findings support the view that among those at risk for psychosis, depressive symptoms at baseline predict a more favorable course of functional recovery, and highlight the potential importance of treating co-occurring depressive symptoms at an early stage of psychosis risk.

Individuals face discrimination based on characteristics including race/ethnicity, gender, age, and disability. Discriminatory experiences (DE) are associated with poor psychological health in the general population and with worse outcomes among individuals at clinical high risk for psychosis (CHR). Though the brain is sensitive to stress, and brain structural change is a well-documented precursor to psychosis, potential relationships between DE and brain structure among CHR or healthy individuals are not known. This report assessed whether lifetime DE are associated with cortical thinning and clinical outcomes across time, after controlling for discrimination-related demographic factors among CHR individuals who ultimately do (N = 57) and do not convert to psychosis (N = 451), and healthy comparison (N = 208) participants in the North American Prodrome Longitudinal Study 2. Results indicate that DE are associated with thinner cortex across time in several cortical areas. Thickness in several right hemisphere regions partially mediates associations between DE and subsequent anxiety symptoms, but not attenuated positive symptoms of psychosis. This report provides the first evidence to date of an association between DE and brain structure in both CHR and healthy comparison individuals. Results also suggest that thinner cortex across time in areas linked with DE may partially explain associations between DE and cross-diagnostic indicators of psychological distress.

Mounting evidence has shown disrupted brain network architecture across the psychosis spectrum. However, whether these changes relate to the development of psychosis is unclear. Here, we used graph theoretical analysis to investigate longitudinal changes in resting-state brain networks in samples of 72 subjects at clinical high risk (including 8 cases who converted to full psychosis) and 48 healthy controls drawn from the North American Prodrome Longitudinal Study (NAPLS) consortium. We observed progressive reduction in global efficiency (P = 0.006) and increase in network diversity (P = 0.001) in converters compared with non-converters and controls. More refined analysis separating nodes into nine key brain networks demonstrated that these alterations were primarily driven by progressively diminished local efficiency in the default-mode network (P = 0.004) and progressively enhanced node diversity across all networks (P

The mismatch negativity (MMN) event-related potential (ERP) component is increasingly viewed as a prediction error signal elicited when a deviant sound violates the prediction that a frequent "standard" sound will repeat. Support for this predictive coding framework emerged with the identification of the repetition positivity (RP), a standard stimulus ERP component that increases with standard repetition and is thought to reflect strengthening of the standard's memory trace and associated predictive code. Using electroencephalographic recordings, we examined the RP elicited by repeating standard tones presented during a traditional "constant standard" MMN paradigm in individuals with the psychosis risk syndrome (PRS; n = 579) and healthy controls (HC; n = 241). Clinical follow-up assessments identified PRS participants who converted to a psychotic disorder (n = 77) and PRS nonconverters who were followed for the entire 24-month clinical follow-up period and either remained symptomatic (n = 144) or remitted from the PRS (n = 94). In HC, RP linearly increased from early- to late-appearing standards within local trains of repeating standards (p < .0001), consistent with auditory predictive code/memory trace strengthening. Relative to HC, PRS participants showed a reduced RP across standards (p = .0056). PRS converters showed a relatively small RP deficit for early appearing standards relative to HC (p = .0.0107) and a more prominent deficit for late-appearing standards (p = .0006) relative to both HC and PRS-remitted groups. Moreover, greater RP deficits predicted shorter time to conversion in a subsample of unmedicated PRS individuals (p = .02). Thus, auditory predictive coding/memory trace deficits precede psychosis onset and predict future psychosis risk in PRS individuals. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Whilst elevations in basal cortisol levels have been reported among individuals at-risk for psychosis, the extent to which this represents hyperresponsivity of the hypothalamic-pituitary-adrenal (HPA) axis to psychosocial stressors encountered in the natural environment is currently unclear. We aimed to examine stressor-cortisol concordance among youth at clinical high-risk (CHR) for psychosis in the North American Prodrome Longitudinal Study 2 (NAPLS 2) and the relationship with clinical outcome. At baseline, CHR (N = 457) and healthy (N = 205) individuals provided salivary cortisol samples and completed daily stressor, life event, and childhood trauma measures. CHR youth were categorised as remitted, symptomatic, progression of positive symptoms, or psychosis conversion at the two-year follow-up. Within-group regression models tested associations between psychosocial stressors and cortisol; standardised beta coefficients (Stβ) were subsequently derived to enable within-group pooling of effect sizes across stressor types. After adjustment for potential confounders, all CHR subgroups reported greater exposure to life events and daily stressors, and more distress in relation to these events, relative to controls. All CHR groups were also more likely to experience childhood trauma; only CHR converters, however, were characterised by elevated basal cortisol. Daily stressor distress was significantly associated with cortisol in controls (β = 0.60, 95% CI: 0.12-1.08) and CHR youth who converted to psychosis (β = 0.91, 95% CI: 0.05-1.78). In controls only, life event exposure was associated with cortisol (β = 0.45, 95% CI: 0.08-0.83). When pooled across stressors, stressor-cortisol concordance was substantially higher among CHR converters (Stβ = 0.26, 95% CI: 0.07 to 0.44) relative to CHR progressed (Stβ = 0.02, 95% CI: -0.11 to 0.15), symptomatic (Stβ = 0.01, 95% CI: -0.11 to 0.12), and remitted groups (Stβ = 0.00, 95% CI: -0.13 to 0.13); however, unexpectedly, healthy controls showed intermediate levels of concordance (Stβ = 0.15, 95% CI: 0.05 to 0.26). In conclusion, whilst all CHR subgroups showed increased psychosocial stress exposure and distress relative to controls, only those who later converted to psychosis were characterised by significantly elevated basal cortisol levels. Moreover, only CHR converters showed a higher magnitude of stressor-cortisol concordance compared to controls, although confidence intervals overlapped considerably between these two groups. These findings do not support the notion that all individuals at CHR for psychosis show HPA hyperresponsiveness to psychosocial stressors. Instead, CHR individuals vary in their response to stressor exposure/distress, perhaps driven by genetic or other vulnerability factors.

ObjectiveThe 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%-25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator.MethodsPersons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis.ResultsFor Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory.ConclusionsThe PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

Although the clinical high risk for psychosis (CHR) paradigm has become well-established over the past two decades, one key component has received surprisingly little investigative attention: the predictive validity of the criteria for conversion or transition to frank psychosis. The current study evaluates the predictive validity of the transition to psychosis as measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR individuals. Participants included 33 SIPS converters and 399 CHR non-converters both from the North American Prodromal Longitudinal Study (NAPLS-2), as well as a sample of 67 separately ascertained first-episode psychosis (FEP) patients from the STEP program. Comparisons were made at baseline and one-year follow-up on demographic, diagnostic stability (SCID), and available measurement domains relating to severity of illness (psychotropic medication, psychosocial treatment, and resource utilization). Principal findings are: 1) a large majority of cases in both SIPS converters (n = 27/33, 81.8%) and FEP (n = 57/67, 85.1%) samples met criteria for continued psychosis at one-year follow-up; 2) follow-up prescription rates for current antipsychotic medication were higher in SIPS converters (n = 17/32, 53.1%) compared to SIPS non-converters (n = 81/397, 20.4%), and similar as compared to FEP cases (n = 39/65, 60%); and 3) at follow-up, SIPS converters had higher rates of resource utilization (psychiatric hospitalizations, day hospital admissions, and ER visits) than SIPS non-converters and were similar to FEP in most categories. The results suggest that the SIPS definition of psychosis onset carries substantial predictive validity. Limitations and future directions are discussed.

The recognition of a prodromal period preceding the onset of frank psychosis dates back to its first descriptions. Despite insights gained from a prospective approach to the study of the Clinical High Risk syndrome for psychosis (CHR-P), a prospectively-based understanding of the duration of the psychosis prodrome and the factors that may influence is not well-established. Here we analyze data from the second North American Prodrome Longitudinal Study (NAPLS-2) to characterize prodrome duration in those who converted to psychosis. Of the 764 participants identified as being at CHR-P, 94 converted to psychosis and 92 of these had recorded estimates of prodrome onset. Estimates of prodrome duration were derived from CHR-P syndrome onset and conversion dates from the Structured Interview for Psychosis-risk Syndromes. Results identified a mean prodrome duration of 21.6 months. Neither CHR-P sub-syndrome nor medication exposure was found to significantly influence prodrome duration in this sample. These results provide the most precise estimate of prodrome duration to date, although results are limited to prodromes identified by ascertainment as being at CHR-P. Our findings also suggest a rule of thirds with regard to prodrome duration in those followed for two years: one third of CHR-P patients who convert will do so by 1 year after CHR-P syndrome onset, another third 1-2 years after onset, and the final third more than 2 years after onset.

AbstractBiomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals.MethodsStartle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35.ResultsAt 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR>NC) and non-users (NC>CHR).DiscussionThis is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants.

There has been growing interest on the effect of sleep problems on psychotic and prodromal symptoms. The current study investigated cross-sectional relations between sleep problems and attenuated psychotic symptoms in a large sample of 740 youth at Clinical High Risk (CHR) for psychosis in an attempt to replicate previous findings and assess whether findings from general population samples and psychotic samples extend to this CHR sample. Sleep problems were found to be significantly positively associated with attenuated psychotic symptom severity. Sleep problems were also found to be more closely associated with certain specific prodromal symptoms (e.g., suspiciousness and perceptual abnormalities) than other attenuated psychotic symptoms. Further, we found that depression mediated the cross-sectional association between sleep problems and paranoid symptoms only. This adds to a growing body of evidence suggesting the mediation role of depression is more pronounced for paranoid-type psychotic symptoms as compared to other psychotic symptoms (e.g., hallucinations).

Identification of neurophysiological abnormalities associated with schizophrenia that predate and predict psychosis onset may improve clinical prediction in the psychosis risk syndrome (PRS) and help elucidate the pathogenesis of schizophrenia. Amplitude reduction of the P300 event-related potential component reflects attention-mediated processing deficits and is among the most replicated biological findings in schizophrenia, making it a candidate biomarker of psychosis risk. The relative extent to which deficits in P300 amplitudes elicited by auditory and visual oddball stimuli precede psychosis onset during the PRS and predict transition to psychosis, however, remains unclear. Forty-three individuals meeting PRS criteria, 19 schizophrenia patients, and 43 healthy control (HC) participants completed baseline electroencephalography recording during separate auditory and visual oddball tasks. Two subcomponents of P300 were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. Auditory and visual target P3b and novel P3a amplitudes were reduced in PRS and schizophrenia participants relative to HC participants. In addition, baseline auditory and visual target P3b, but not novel P3a, amplitudes were reduced in 15 PRS participants who later converted to psychosis, relative to 18 PRS non-converters who were followed for at least 22 months. Furthermore, target P3b amplitudes predicted time to psychosis onset among PRS participants. These results suggest that P300 amplitude deficits across auditory and visual modalities emerge early in the schizophrenia illness course and precede onset of full psychosis. Moreover, target P3b may represent an important neurophysiological vulnerability marker of the imminence of risk for psychosis.

Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether the neural dysfunction underlying these deficits is present before the onset of illness and potentially predicts conversion to psychosis is unclear. In this study, we investigated brain functional alterations during memory processing in a sample of 155 individuals at clinical high risk (including 18 subjects who later converted to full psychosis) and 108 healthy controls drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). All participants underwent functional magnetic resonance imaging with a paired-associate memory paradigm at the point of recruitment and were clinically followed up for approximately 2 years. We found that at baseline, subjects at high risk showed significantly higher activation during memory retrieval in the prefrontal, parietal, and bilateral temporal cortices (PFWE < .035). This effect was more pronounced in converters than nonconverters and was particularly manifested in unmedicated subjects (P < .001). The hyperactivation was significantly correlated with retrieval reaction time during scan in converters (P = .009) but not in nonconverters and controls, suggesting an exaggerated retrieval effort. These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis, and such measures have potential as biomarkers for psychosis prediction.

ObjectiveTraditional measures for assessing functioning with adult patients with schizophrenia have been shown to be insufficient for assessing the issues that occur in adolescents and young adults at clinical high risk (CHR) for psychosis. The current study provides an expanded validation of the Global Functioning: Social (GF:Social) and Role (GF:Role) scales developed specifically for use with CHR individuals and explores the reliability and accuracy of the ratings, the validity of the scores in comparison to other established clinical measures, stability of functioning over a 2-year period, and psychosis predictive ability.MethodsSeven hundred fifty-five CHR individuals and 277 healthy control (HC) participants completed the GF:Social and Role scales at baseline as part of the North American Prodrome Longitudinal Study (NAPLS2).ResultsInter-rater reliability and accuracy were high for both scales. Correlations between the GF scores and other established clinical measures demonstrated acceptable convergent and discriminant validity. In addition, GF:Social and Role scores were unrelated to positive symptoms. CHR participants showed large impairments in social and role functioning over 2-years, relative to the HCs, even after adjusting for age, IQ, and attenuated positive symptoms. Finally, social decline prior to baseline was more pronounced in CHR converters, relative to non-converters.ConclusionsThe GF scales can be administered in a large-scale multi-site study with excellent inter-rater reliability and accuracy. CHR individuals showed social and role functioning impairments over time that were not confounded by positive symptom severity levels. The results of this study demonstrate that social decline is a particularly effective predictor of conversion outcome.

ObjectiveThe overlap versus independence of autism spectrum disorder (ASD) and schizophrenia is a topic that has garnered the attention of generations of clinicians and scientists. Although high rates of psychotic symptoms have been identified in individuals with ASD, the nature, prevalence, and prognostic significance of subclinical psychotic experiences in ASD remain poorly understood.MethodThis study sought to compare baseline characteristics, clinical profiles, and conversion outcomes between young individuals at clinical high risk for psychosis (CHR) who presented with or without a prior ASD diagnosis during the second phase of the North American Prodrome Longitudinal Study (NAPLS, N = 764).ResultsPatients with CHR and ASD (CHR/ASD+, n = 26) tended to exhibit greater social and social cognitive difficulties, but expressed relatively levels of core psychosis symptoms similar to those of to patients with CHR but no ASD (CHR/ASD-). Risk for conversion to co-occurring psychosis (18.2% CHR/ASD+ versus 16.8% CHR/ASD-) was equivalent between CHR/ASD+ and CHR/ASD- groups, and the NAPLS2 Psychosis Risk Calculator predicted conversion to psychosis equally well across groups.ConclusionThese results suggest that baseline psychosis symptoms, predictors of risk for conversion, and ultimate conversion rates are similar in patients with CHR with and without ASD. They further suggest that ASD must not be considered a mutually exclusive diagnosis when such youth present in CHR settings. Future research is needed to better track trajectories in larger cohorts of individuals with CHR and comorbid ASD and to understand whether treatment recommendations effective in the broader CHR population are useful for this particular population as well.

AimThere is an interest in the transition to psychosis for those at clinical high risk of developing psychosis. This transition is typically determined by a change in severity of the attenuated symptoms as they reach a psychotic level. However, any concomitant change in the content of such symptoms has not been examined. The current study aimed to examine potential qualitative changes in the symptom content from a clinical high-risk state to a first episode of psychosis.MethodsSixty-seven individuals, who had been identified as meeting the attenuated psychotic syndrome based on the Structured Interview of Psychosis-Risk Syndromes and who later developed a full-blown psychosis were included in the study. Comprehensive clinical vignettes were written and raters were trained using the Content of Attenuated Psychotic Symptoms codebook to code for the presence of specific symptom content found within the attenuated psychotic symptoms of unusual thought content, suspicious ideas, grandiose ideas and perceptual abnormalities.ResultsTwo main changes in symptom content from baseline to conversion were observed. First, content that was vague and lacked intensity progressed to being more specific, concrete and severe. Second, new symptoms appeared whose onset occurred for the first time at conversion.ConclusionA change in symptom content should be monitored by clinicians, as changes in content may be indications of a possible transition to psychosis.

BackgroundMost studies of neurocognitive functioning in Clinical High Risk (CHR) cohorts have examined group averages, likely concealing heterogeneous subgroups. We aimed to identify neurocognitive subgroups and to explore associated outcomes.MethodsData were acquired from 324 participants (mean age 18.4) in the first phase of the North American Prodrome Longitudinal Study (NAPLS-1), a multi-site consortium following individuals for up to 2 1/2 years. We applied Ward's method for hierarchical clustering data to 8 baseline neurocognitive measures, in 166 CHR individuals, 49 non-CHR youth with a family history of psychosis, and 109 healthy controls. We tested whether cluster membership was associated with conversion to psychosis, social and role functioning, and follow-up diagnosis. Analyses were repeated after data were clustered based on independently developed clinical decision rules.ResultsFour neurocognitive clusters were identified: Significantly Impaired (n = 33); Mildly Impaired (n = 82); Normal (n = 145) and High (n = 64). The Significantly Impaired subgroup demonstrated the largest deviations on processing speed and memory tasks and had a conversion rate of 58%, a 40% chance of developing a schizophrenia spectrum diagnosis (compared to 24.4% in the Mildly Impaired, and 10.3% in the other two groups combined), and significantly worse functioning at baseline and 12-months. Data clustered using clinical decision rules yielded similar results, pointing to high convergent validity.ConclusionNeurocognitive profiles vary substantially in their severity and are associated with diagnostic and functional outcome, underscoring neurocognition as a predictor of illness outcomes. These findings, if replicated, are a first step toward personalized treatment for individuals at-risk for psychosis.

ObjectivePatients with schizophrenia have a high prevalence of metabolic disorders and cardiovascular mortality. It is possible that a vulnerability to metabolic abnormalities is associated with risk for psychosis, symptoms and functionality. In this study, we evaluate demographic information, cardiometabolic indices, symptoms and functioning in an antipsychotic free cohort at Clinical High Risk (CHR) for psychosis from the NAPLS Omega 3 fatty acid clinical trial.MethodSubjects received physical exams and metabolic monitoring prior to randomization into the Omega 3 versus Placebo trial. Anthropometrical measures, vital signs, glucose, and lipids were assessed along with symptoms, functioning, dietary Omega 3 fatty acids, erythrocyte polyunsaturated fatty acid content and a measure of lipid peroxidation (TBARS, Thiobarbituric acid-reactive substances).ResultsThe sample included 113 CHR subjects (42.1% female; 17.5% Latino) ages 12-29. The mean BMI was 24.3 with a trend toward higher BMI and a higher incidence of metabolic syndrome in Latino subjects; 36% of the sample was obese/overweight; 37.6% met criteria for prehypertension/hypertension; 4.2% met criteria for prediabetes/diabetes; 9.6% showed evidence of insulin resistance and 44.7% had dyslipidemia. The TBARS was elevated at 9.8 μM ± 6.1 (normal 1.86-3.94 μM). Metabolic parameters and a diet low in Omega 3 rich foods were significantly associated with prodromal symptoms and poor functioning.ConclusionsCHR subjects show a high percentage of metabolic abnormalities prior to exposure to antipsychotic medication. These findings reinforce that early detection of metabolic disturbances and food insecurity is crucial since these factors are modifiable with the potential for significant gains in terms of quality of life, physical and mental health.

Response inhibition (RI) is a component of the cognitive control systems that support optimal cognition. Cognitive control deficits are well-described in schizophrenia, but are not well characterized in individuals at clinical high risk (CHR) for developing psychosis. Functional magnetic resonance imaging during Go/NoGo task performance was collected from 30 CHR youth, 23 early illness schizophrenia patients (ESZ), and 72 healthy adolescents and young adults (HC). Voxelwise main effects of group were examined (P < .005 height threshold, family-wise error-corrected cluster threshold, P < .05) for correct NoGo-Go contrast values and task-based functional connectivity. CHR and ESZ groups had slower and more variable reaction times (RT) on Go trials compared to HCs. Significant main effects of group in bilateral dorsal anterior cingulate (dACC) and right inferior frontal cortex stemmed from CHR and ESZ groups showing significantly less NoGo-Go activation, relative to HCs. Faster responding HCs had less functional coupling between dACC and medial prefrontal cortex, a default mode network (DMN) region during NoGo vs Go trials. This functional connectivity-performance relationship was not present in ESZ or CHR groups. The pattern of findings suggests CHR and ESZ groups were deficient in developing strong and consistent prepotent responding, based on their slow and variable motor responses and decreased engagement of dACC and right inferior frontal regions implicated in inhibitory control. Furthermore, only the control group showed a functional connectivity relationship consistent with greater response prepotency requiring more decoupling of inhibitory control regions from DMN regions during RI.

Atypical antipsychotics (AT) and stress are related to weight gain in individuals with severe mental illness. This cross-sectional study examines AT use, stressful life events, and baseline weight in a sample of youth at clinical high risk for psychosis. Results showed that dependent and desirable life events moderated the relationship between AT use and weight after controlling for demographic factors and selective serotonin reuptake inhibitor antidepressant (AD) use. The relation of AD and weight was explored as a secondary analysis and showed no relation between AD use and weight. Further, stress did not moderate the relationship between AD medication and weight after controlling for antipsychotic use. Results suggest that stress exposure may exacerbate the relationship between ATs and increased weight in clinical high-risk populations. Findings have implications for the development of interventions to address psychosocial factors that worsen or buffer the adverse effects of antipsychotic medication on weight.

BackgroundClinical high risk (CHR) status is characterized by impairments in social cognition, but questions remain concerning their stability over development. In cross-sectional analysis of a large naturalistic sample, the current study examined whether those at CHR status show deviant trajectories for age-related change in social cognitive ability, and whether these trajectories are influenced by treatment history.MethodEmotion perception (EP) and theory of mind (ToM) were assessed in 675 CHR and 263 healthy comparison (HC) participants aged 12-35. Age effects in CHR were modeled against HC age-expected performance. Prior medication status was tested for interactions with age.ResultsCHR exhibited normal age trajectory for EP, but significantly lower slopes for ToM from age 17 onward. This effect was specific to stimuli exhibiting sarcasm and not to detection of lies. When treatment history was included in the model, age-trajectory appeared normal in CHR subjects previously prescribed both antipsychotics and antidepressant medication, although the blunted trajectory still characterized 80% of the sample.DiscussionCross-sectional analyses suggested that blunting of ToM in CHR develops in adolescence, while EP abilities were diminished evenly across the age range. Exploratory analyses of treatment history suggested that ToM was not affected, however, in CHRs with lifetime histories of both antipsychotic and antidepressant medications. Reduction in age-expected ToM ability may impair the ability of individuals at CHR to meet social developmental challenges in adolescence. Medication effects on social cognition deserve further study.

Understanding the fundamental alterations in brain functioning that lead to psychotic disorders remains a major challenge in clinical neuroscience. In particular, it is unknown whether any state-independent biomarkers can potentially predict the onset of psychosis and distinguish patients from healthy controls, regardless of paradigm. Here, using multi-paradigm fMRI data from the North American Prodrome Longitudinal Study consortium, we show that individuals at clinical high risk for psychosis display an intrinsic "trait-like" abnormality in brain architecture characterized as increased connectivity in the cerebello-thalamo-cortical circuitry, a pattern that is significantly more pronounced among converters compared with non-converters. This alteration is significantly correlated with disorganization symptoms and predictive of time to conversion to psychosis. Moreover, using an independent clinical sample, we demonstrate that this hyperconnectivity pattern is reliably detected and specifically present in patients with schizophrenia. These findings implicate cerebello-thalamo-cortical hyperconnectivity as a robust state-independent neural signature for psychosis prediction and characterization.

The clinical-high-risk for psychosis (CHR-P) syndrome is heterogeneous in terms of clinical presentation and outcomes. Identifying more homogenous subtypes of the syndrome may help clarify its etiology and improve the prediction of psychotic illness. This study applied latent class cluster analysis (LCCA) to symptom ratings from the North American Prodrome Longitudinal Studies 1 and 2 (NAPLS 1 and 2). These analyses produced evidence for three to five subgroups within the CHR-P syndrome. Differences in negative and disorganized symptoms distinguished among the subgroups. Subgroup membership was found to predict conversion to psychosis. The authors contrast the methods employed within this study with previous attempts to identify more homogenous subgroups of CHR-P individuals and discuss how these results could be tested in future samples of CHR-P individuals.

Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets.

More than 20 years after the clinical high risk syndrome for psychosis (CHR) was first articulated, it remains controversial whether the CHR syndrome predicts onset of psychosis with diagnostic specificity or predicts pluripotential diagnostic outcomes. Recently, analyses of observational studies, however, have suggested that the CHR syndrome is not pluripotential for emergent diagnostic outcomes. The present report conducted additional analyses in previously reported samples to determine (1) whether comorbid disorders were more likely to persist in CHR patients compared to a comparison group of patients who responded to CHR recruitment efforts but did not meet criteria, termed help-seeking comparison subjects (HSC); and (2) whether clinically defined pluripotential CHR subgroups could be identified. All data were derived from 2 multisite studies in which DSM-IV structured diagnostic interviews were conducted at baseline and at 6-month intervals. Across samples we observed persistence of any nonpsychotic disorder in 80/147 CHR cases (54.4%) and in 48/84 HSC cases (57.1%, n.s.). Findings with persistence of anxiety, depressive, and bipolar disorders considered separately were similar. Efforts to discover pluripotential CHR subgroups were unsuccessful. These findings add additional support to the view that the CHR syndrome is not pluripotential for predicting various diagnostic outcomes but rather is specific for predicting emergent psychosis.

The developmental course of daily functioning prior to first psychosis-onset remains poorly understood. This study explored age-related periods of change in social and role functioning. The longitudinal study included youth (aged 12-23, mean follow-up years = 1.19) at clinical high risk (CHR) for psychosis (converters [CHR-C], n = 83; nonconverters [CHR-NC], n = 275) and a healthy control group (n = 164). Mixed-model analyses were performed to determine age-related differences in social and role functioning. We limited our analyses to functioning before psychosis conversion; thus, data of CHR-C participants gathered after psychosis onset were excluded. In controls, social and role functioning improved over time. From at least age 12, functioning in CHR was poorer than in controls, and this lag persisted over time. Between ages 15 and 18, social functioning in CHR-C stagnated and diverged from that of CHR-NC, who continued to improve (p = .001). Subsequently, CHR-C lagged behind in improvement between ages 21 and 23, further distinguishing them from CHR-NC (p < .001). A similar period of stagnation was apparent for role functioning, but to a lesser extent (p = .007). The results remained consistent when we accounted for the time to conversion. Our findings suggest that CHR-C start lagging behind CHR-NC in social and role functioning in adolescence, followed by a period of further stagnation in adulthood.

Depressed mood appears to be highly prevalent in clinical high risk (CHR) samples. However, many prior CHR studies utilize modest size samples and do not report on the specific impact of depression on CHR symptoms. The aim of the current paper is to investigate the prevalence of depressive disorders and the impact of lifetime depression on baseline clinical presentation and longitudinal outcomes in a large cohort of individuals meeting CHR criteria in the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). Depression was assessed both categorically (via DSM-IV-TR diagnoses) and symptomatically (using a clinician-rated scale of depressive symptoms) within a sample of 764 individuals at CHR and 279 controls. Current and lifetime depressive disorders were highly prevalent (60%) in this sample. Depression diagnoses were associated with more pronounced negative and general symptoms; individuals with remitted depression had significantly less severe negative, disorganized, and general symptoms and better social and role functioning relative to those with current depression. Current mood disturbance, as measured by scores on a clinician-rated symptom scale, contributed beyond the impact of positive and negative symptoms to impairments in social functioning. Both symptomatic and diagnostic baseline depression was significantly associated with decreased likelihood of remission from CHR status; however depression did not differentially distinguish persistent CHR status from transition to psychosis at follow-up. These findings suggest that depressed mood may function as a marker of poor prognosis in CHR, yet effective treatment of depression within this population can yield improvements in symptoms and functioning.

Early intervention for psychotic disorders, a growing international priority, typically targets help-seeking populations with emerging psychotic ("positive") symptoms. We assessed the nature of and degree to which treatment of individuals at high risk for psychosis preceded or followed the onset of positive symptoms. The North American Prodrome Longitudinal Study-2 collected psychosocial treatment histories for 745 (98%) of 764 high-risk participants (M age = 18.9, 57% male, 57.5% Caucasian, 19.1% Hispanic) recruited from 8 North American communities. Similar to prior findings, 82% of participants reported psychosocial treatment prior to baseline assessment, albeit with significant variability across sites (71%-96%). Participants first received treatment a median of 1.7 years prior to the onset of a recognizable psychosis-risk syndrome. Only one fourth sought initial treatment in the year following syndrome onset. Although mean sample age differed significantly by site, age at initial treatment (M = 14.1, SD = 5.0) did not. High rates of early treatment prior to syndrome onset make sense in light of known developmental precursors to psychotic disorders but are inconsistent with the low rates of treatment retrospectively reported by first-episode psychosis samples. Findings suggest that psychosis risk studies and clinics may need to more actively recruit and engage symptomatic but non-help-seeking individuals and that community clinicians be better trained to recognize both positive and nonspecific indicators of emerging psychosis. Improved treatments for nonspecific symptoms, as well as the characteristic attenuated positive symptoms, are needed.

Several studies have demonstrated that youth at clinical high risk (CHR) of developing psychosis have a high prevalence of comorbid psychiatric disorders. Less is known about the impact of comorbid diagnoses on later conversion to psychosis and the change over time. The aim of this study was to determine the frequency and distribution of psychiatric diagnoses at baseline and over time in the North American Prodrome Longitudinal Study (NAPLS 2) and the role of comorbid diagnoses in conversion to psychosis. The NAPLS 2 sample consisted of 744 CHR youth and 276 healthy controls. Only 21% of the CHR group did not have a comorbid diagnosis with many have 2-3 DSM-IV comorbid diagnoses. The most common diagnoses were anxiety and depressive disorders, which did improve over time. The only diagnosis at baseline that differentiated the converters from the non-converters was cannabis misuse. Comorbidity, except for cannabis use, was essentially independent of clinical outcome. It is possible that those with comorbid diagnoses are preferentially the help-seeking individuals that present for help in our clinics and research projects and that those who are at risk but do not have a comorbid diagnosis may not be seeking help in the prodromal phase.

Recent research suggests that perceptual abnormalities are a group of diverse experiences, which have been associated with trauma, cannabis use, and anxiety. Of the attenuated psychotic symptoms that are present in youth at clinical high risk (CHR) of psychosis, perceptual abnormalities tend to be one of the most frequently endorsed symptoms. However, very few studies have explored perceptual abnormalities and their relationships with the above environmental and affective factors in a CHR sample. Four hundred and forty-one CHR individuals who met criteria for attenuated psychotic symptom syndrome (APSS) determined by the Structured Interview for Psychosis-risk Syndromes (SIPS) were assessed on the content of their perceptual abnormalities, early traumatic experience, cannabis use and self-reported anxiety. Logistic regression analyses suggested that both simple auditory and simple visual perceptual abnormalities were more likely to be reported by CHR who had early traumatic experiences, who are current cannabis users, and who have higher levels of anxiety. Multiple regression analysis revealed that only trauma and anxiety were independent predictors of both simple auditory and simple visual perceptual abnormalities. It is possible that examining subtypes of perceptual abnormalities in CHR leads to an improved understanding of the prevalence of such symptoms.

AimHigh rates of anxiety have been observed in youth at clinical high risk (CHR) of developing psychosis. In CHR, anxiety often co-occurs with depression, and there is inconsistent evidence on anxiety in relation to transition to psychosis. The aim of this study was to examine: (i) the prevalence of anxiety disorders in individuals at CHR; (ii) clinical differences between those with and without anxiety; and (iii) the association of baseline anxiety with later transition to psychosis.MethodsThe sample consisted of 765 CHR individuals and 280 healthy controls. CHR status was determined with the Structured Interview of Prodromal Syndromes, mood and anxiety diagnoses with the Structured Clinical Interview for DSM-IV Disorders, and severity of anxiety with the Social Interaction Anxiety Scale and Self-Rating Anxiety Scale.ResultsIn the CHR sample, 51% met criteria for an anxiety disorder. CHR participants had significantly more anxiety diagnoses and severity than healthy controls. Anxiety was correlated to attenuated psychotic and negative symptoms in CHR and those with an anxiety disorder demonstrated more suspiciousness. CHR participants with obsessive-compulsive disorder (OCD) exhibited more severe symptomatology than those without OCD. An initial presentation of anxiety did not differ between those who did or did not transition to psychosis.ConclusionsIn this large sample of individuals at CHR, anxiety is common and associated with more severe attenuated psychotic symptoms. Treatment not only to prevent or delay transition to psychosis but also to address presenting concerns, such as anxiety, is warranted.

In a recent report of the North American Prodrome Longitudinal Study (NAPLS), clinical high-risk individuals who converted to psychosis showed a steeper rate of cortical gray matter reduction compared with non-converters and healthy controls, and the rate of cortical thinning was correlated with levels of proinflammatory cytokines at baseline. These findings suggest a critical role for microglia, the resident macrophages in the brain, in perturbations of cortical maturation processes associated with onset of psychosis. Elucidating gene expression pathways promoting microglial action prior to disease onset would inform potential preventative intervention targets. Here we used a forward stepwise regression algorithm to build a classifier of baseline microRNA expression in peripheral leukocytes associated with annualized rate of cortical thinning in a subsample of the NAPLS cohort (N=74). Our cortical thinning classifier included nine microRNAs, p=3.63 × 10-08, R2=0.358, permutation-based p=0.039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (p

ImportanceNeurocognition is a central characteristic of schizophrenia and other psychotic disorders. Identifying the pattern and severity of neurocognitive functioning during the "near-psychotic," clinical high-risk (CHR) state of psychosis is necessary to develop accurate risk factors for psychosis and more effective and potentially preventive treatments.ObjectivesTo identify core neurocognitive dysfunctions associated with the CHR phase, measure the ability of neurocognitive tests to predict transition to psychosis, and determine if neurocognitive deficits are robust or explained by potential confounders.Design, setting, and participantsIn this case-control study across 8 sites, baseline neurocognitive data were collected from January 2009 to April 2013 in the second phase of the North American Prodrome Longitudinal Study (NAPLS 2). The dates of analysis were August 2015 to August 2016. The setting was a consortium of 8 university-based, outpatient programs studying the psychosis prodrome in North America. Participants were 264 healthy controls (HCs) and 689 CHR individuals, aged 12 to 35 years.Main outcomes and measuresNeurocognitive associations with transition to psychosis and effects of medication on neurocognition. Nineteen neuropsychological tests and 4 factors derived from factor analysis were used: executive and visuospatial abilities, verbal abilities, attention and working memory abilities, and declarative memory abilities.ResultsThis study included 264 HCs (137 male and 127 female) and 689 CHR participants (398 male and 291 female). In the HCs, 145 (54.9%) were white and 119 (45.1%) were not, whereas 397 CHR participants (57.6%) were white and 291 (42.3%) were not. In the HCs, 45 (17%) were of Hispanic origin, whereas 127 CHR participants (18.4%) were of Hispanic origin. The CHR individuals were significantly impaired compared with HCs on attention and working memory abilities and declarative memory abilities. The CHR converters had large deficits in attention and working memory abilities and declarative memory abilities (Cohen d, approximately 0.80) compared with controls and performed significantly worse on these dimensions than nonconverters (Cohen d, 0.28 and 0.48, respectively). These results were not accounted for by general cognitive ability or medications. In Cox proportional hazards regression, time to conversion in those who transitioned to psychosis was significantly predicted by high verbal (premorbid) abilities (β = 0.40; hazard ratio [HR], 1.48; 95% CI, 1.08-2.04; P = .02), impaired declarative memory abilities (β = -0.87; HR, 0.42; 95% CI, 0.31-0.56; P

ObjectiveApproximately 20%-35% of individuals 12-35 years old who meet criteria for a prodromal risk syndrome convert to psychosis within 2 years. However, this estimate ignores the fact that clinical high-risk cases vary considerably in risk. The authors sought to create a risk calculator, based on profiles of risk indicators, that can ascertain the probability of conversion to psychosis in individual patients.MethodThe study subjects were 596 clinical high-risk participants from the second phase of the North American Prodrome Longitudinal Study who were followed up to the time of conversion to psychosis or last contact (up to 2 years). The predictors examined were limited to those that are supported by previous studies and are readily obtainable in general clinical settings. Time-to-event regression was used to build a multivariate model predicting conversion, with internal validation using 1,000 bootstrap resamples.ResultsThe 2-year probability of conversion to psychosis 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. Stressful life events, trauma, and family history of schizophrenia were not significant predictors. The multivariate model achieved a concordance index of 0.71 and, as reported in an article by Carrión et al., published concurrently with this one, was validated in an independent external data set. The results are instantiated in a web-based risk prediction tool envisioned to be most useful in research protocols involving the psychosis prodrome.ConclusionsA risk calculator comparable in accuracy to those for cardiovascular disease and cancer is available to predict individualized conversion risks in newly ascertained clinical high-risk cases. Given that the risk calculator can be validly applied only for patients who screen positive on the Structured Clinical Interview for Psychosis Risk Syndromes, which requires training to administer, its most immediate uses will be in research on psychosis risk factors and in research-driven clinical (prevention) trials.

ObjectivesRecent studies have recognized that signs of functional disability in schizophrenia are evident in early phases of the disorder, and, as a result, can potentially serve as vulnerability markers of future illness. However, functional measures in the psychosis prodrome have focused exclusively on real-world achievements, rather than on the skills required to carry-out a particular real-world function (ie, capacity). Despite growing evidence that diminished capacity is critical to the etiology of the established disorder, virtually no attention has been directed towards assessing functional capacity in the pre-illness stages. In the present study, we introduce the Map task, a measure to assess functional capacity in adolescent and young-adult high-risk populations.MethodsThe Map task was administered to 609 subjects at Clinical High-Risk (CHR) for psychosis and 242 Healthy Controls (HCs) participating in the North American Prodrome Longitudinal Study (NAPLS2). Subjects were required to efficiently complete a set of specified errands in a fictional town.ResultsCHR participants showed large impairments across major indices of the Map task, relative to the HCs. Most importantly, poor performance on the Map task significantly predicted conversion to psychosis, even after adjusting for age, IQ, clinical state, and other potential confounders.ConclusionsTo the best of our knowledge, the Map task is one of the first laboratory-based measures to assess functional capacity in high-risk populations. Functional capacity deficits prior to the onset of psychosis may reflect a basic mechanism that underlies risk for psychosis. Early intervention targeting this domain may help to offset risk and independently improve long-term outcome.

Among people at genetic risk of schizophrenia, those who use cannabis show smaller thalamic and hippocampal volumes. We evaluated this relationship in people at clinical high risk (CHR) of psychosis. The Alcohol and Drug Use Scale was used to identify 132 CHR cannabis users, the majority of whom were non-dependent cannabis users, 387 CHR non-users, and 204 healthy control non-users, and all participants completed magnetic resonance imaging scans. Volumes of the thalamus, hippocampus and amygdala were extracted with FreeSurfer, and compared across groups. Comparing all CHR participants with healthy control participants revealed no significant differences in volumes of any ROI. However, when comparing CHR users to CHR non-users, a significant ROI×Cannabis group effect emerged: CHR users showed significantly smaller amygdala compared to CHR non-users. However, when limiting analysis to CHR subjects who reported using alcohol at a 'use without impairment' severity level, the amygdala effect was non-significant; rather, smaller hippocampal volumes were seen in CHR cannabis users compared to non-users. Controlling statistically for effects of alcohol and tobacco use rendered all results non-significant. These results highlight the importance of controlling for residual confounding effects of other substance use when examining the relationship between cannabis use and neural structure.

The relationship between psychosis and violence has typically focused on factors likely to predict who will commit violent acts. One unexplored area is violence in the content of subthreshold positive symptoms. The current aim was to conduct an exploratory analysis of violent content in the attenuated psychotic symptoms (APS) of those at clinical high risk of psychosis (CHR) who met criteria for attenuated psychotic symptom syndrome (APSS). The APS of 442 CHR individuals, determined by the Structured Interview for Prodromal Syndromes, were described in comprehensive vignettes. The content of these symptoms were coded using the Content of Attenuated Positive Symptoms Codebook. Other measures included clinical symptoms, functioning, beliefs and trauma. Individuals with violent content had significantly higher APS, greater negative beliefs about the self and others, and increased bullying. The same findings and higher ratings on anxiety symptoms were present when participants with self-directed violence were compared to participants with no violent content. Individuals reporting violent content differ in their clinical presentation compared to those who do not experience violent content. Adverse life events, like bullying, may impact the presence of violent content in APS symptoms. Future studies should explore violent content in relation to actual behavior.

BackgroundRecent research suggests that a traumatic brain injury (TBI) can significantly increase the risk of later development of psychosis. However, it is unknown whether people at clinical high risk (CHR) of psychosis have experienced TBI at higher rates, compared to otherwise healthy individuals. This study evaluated the prevalence of mild TBI, whether it was related to past trauma and the relationship of mild TBI to later transition to psychosis.MethodsSeven-hundred forty-seven CHR and 278 healthy controls (HC) were assessed on past history of mild TBI, age at first and last injury, severity of worst injury and number of injuries using the Traumatic Brain Injury Interview. Attenuated psychotic symptoms were assessed with the Scale of Psychosis-risk Symptoms. IQ was estimated using the Wechsler Abbreviated Scale of Intelligence and past trauma and bullying were recorded using the Childhood Trauma and Abuse Scale.ResultsCHR participants experienced a mild TBI more often than the HC group. CHR participants who had experienced a mild TBI reported greater total trauma and bullying scores than those who had not, and those who experienced a mild TBI and later made the transition to psychosis were significantly younger at the age at first and most recent injury than those who did not.ConclusionA history of mild TBI is more frequently observed in CHR individuals than in HC. Inclusion or study of CHR youth with more severe TBI may provide additional insights on the relationship between TBI and later transition to psychosis in CHR individuals.

PurposeThere is evidence to suggest that both early traumatic experiences and perceived discrimination are associated with later onset of psychosis. Less is known about the impact these two factors may have on conversion to psychosis in those who are at clinical high risk (CHR) of developing psychosis. The purpose of this study was to determine if trauma and perceived discrimination were predictors of conversion to psychosis.MethodsThe sample consisted of 764 individuals who were at CHR of developing psychosis and 280 healthy controls. All participants were assessed on past trauma, bullying and perceived discrimination.ResultsIndividuals at CHR reported significantly more trauma, bullying and perceived discrimination than healthy controls. Only perceived discrimination was a predictor of later conversion to psychosis.ConclusionsGiven that CHR individuals are reporting increased rates of trauma and perceived discrimination, these should be routinely assessed, with the possibility of offering interventions aimed at ameliorating the impact of past traumas as well as improving self-esteem and coping strategies in an attempt to reduce perceived discrimination.