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Background: The COVID-19 pandemic is expected to increase stress and mental health symptoms. We present the case of a young man at risk for psychosis who has paradoxically shown symptomatic and functional improvement as a result of circumstances produced by COVID-19. These changes were unexpected given the client’s persistent mental health struggles in the year leading up to the COVID-19 outbreak in the United States and the expectation of an exacerbation of psychotic-like symptoms. Methods: This report is based on clinical assessments and the client’s first-person account during the height of the pandemic when stay at home orders were in place. Results: During the pandemic, the client demonstrated increased agency by taking on more responsibility at home and obtaining part-time employment. He showed improvement in his mood and relationships with others, had less symptom-related distress, and significantly reduced his cannabis use. The client interpreted these improvements in terms of changing his mindset toward more adaptive thoughts and engaging in healthy coping skills such as praying, reading, and healthy eating. Conclusions: This case highlights the importance of fostering agency in clients during a time of crisis and ensuring that clinicians be aware of potential biases about mental health symptom exacerbation. [ABSTRACT FROM AUTHOR] Copyright of Psychosis is the property of Routledge and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

To date, no measures are available that permit differentiation of discrete, clinically distinct subtypes of schizophrenia (SZ) with potential differential underlying pathophysiologies. Over recent years, there has been increasing recognition that SZ is heterogeneously associated with deficits in early auditory processing (EAP), as demonstrated using clinically applicable tasks such as tone-matching task (TMT). Here, we pooled TMT performances across 310 SZ individuals and 219 healthy controls (HC), along with clinical, cognitive, and resting-state functional-connectivity MRI (rsFC-MRI) measures. In addition, TMT was measured in a group of 24 patients at symptomatic clinical high risk (CHR) for SZ and 24 age-matched HC (age range 7–27 years). We provide the first demonstration that the EAP deficits are bimodally distributed across SZ subjects (P d = 2.1) and SZ-EAP+ patients (d = 3.4). The SZ-EAP− group predominated among samples drawn from inpatient sites, showed higher levels of cognitive symptoms (PANSS), worse social cognition and a differential deficit in neurocognition (MATRICS battery), and reduced functional capacity. rsFC-MRI analyses showed significant reduction in SZ-EAP− relative to controls between subcortical and cortical auditory regions. As opposed to SZ, CHR patients showed intact EAP function. In HC age-matched to CHR, EAP ability was shown to increase across the age range of vulnerability preceding SZ onset. These results indicate that EAP measure segregates between discrete SZ subgroups. As TMT can be readily implemented within routine clinical settings, its use may be critical to account for the heterogeneity of clinical outcomes currently observed across SZ patients, as well as for pre-clinical detection and efficacious treatment selection.

BACKGROUND: Identifying young people as at clinical high-risk (CHR) for psychosis affords opportunities for intervention to possibly prevent psychosis onset. Yet such CHR identification could plausibly increase stigma. We do not know whether these youth already perceive themselves to be at psychosis-risk (PR) or how their being told they are at PR might impact how they think about themselves. METHODS: 148 CHR youth were asked about labels they had been given by others (labeling by others) or with which they personally identified (self-labeling). They were then asked which had the greatest impact on how they thought about themselves. We evaluated whether being told vs. thinking they were at PR had stronger effects. FINDINGS: The majority identified nonpsychotic disorders rather than PR labels as having the greatest impact on sense of self (67.6% vs. 27.7%). However, participants who identified themselves as at PR had an 8.8 (95% CI=2.0-39.1) increase in the odds of the PR label having the greatest impact (p

The ability to perceive the motion of biological objects, such as faces, is a critical component of daily function and correlates with the ability to successfully navigate social situations (social cognition). Deficits in motion perception in schizophrenia were first demonstrated about 20 years ago but remain understudied, especially in the early, potentially prodromal, stages of the illness. The authors examined the neural bases of visual sensory processing impairments, including motion, in patients with schizophrenia (N=63) and attenuated psychosis (clinical high risk) (N=32) compared with age-matched healthy control subjects (N=67).Electrophysiological recordings during stimulus and motion processing were analyzed using oscillatory (time frequency) approaches that differentiated motion-onset-evoked activity from stimulus-onset sensory-evoked responses. These were compared with functional MRI (fMRI) measures of motion processing.Significant deficits in motion processing were observed across the two patient groups, and these deficits predicted impairments in both face-emotion recognition and cognitive function. In contrast to motion processing, sensory-evoked stimulus-onset responses were intact in patients with attenuated psychosis, and, further, the relative deficit in motion-onset responses compared with stimulus-onset responses predicted transition to schizophrenia. In patients with schizophrenia, motion detection deficits mapped to impaired activation in motion-sensitive visual cortex during fMRI. Additional visual impairments in patients with schizophrenia, not present in patients with attenuated psychosis, implicated other visual regions, including the middle occipital gyrus and pulvinar thalamic nucleus.The study findings emphasize the importance of sensory-level visual dysfunction in the etiology of schizophrenia and in the personal experience of individuals with the disorder and demonstrate that motion-processing deficits may predate illness onset and contribute to impaired function even in patients with attenuated psychosis.

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types.

ImportanceThe ENIGMA clinical high risk for psychosis (CHR) initiative, the largest pooled CHR-neuroimaging sample to date, aims to discover robust neurobiological markers of psychosis risk in a sample with known heterogeneous outcomes.ObjectiveWe investigated baseline structural neuroimaging differences between CHR subjects and healthy controls (HC), and between CHR participants who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). We assessed associations with age by group and conversion status, and similarities between the patterns of effect size maps for psychosis conversion and those found in other large-scale psychosis studies.Design, Setting, and ParticipantsBaseline T1-weighted MRI data were pooled from 31 international sites participating in the ENIGMA CHR Working Group. MRI scans were processed using harmonized protocols and analyzed within a mega- and meta-analysis framework from January-October 2020.Main Outcome(s) and Measure(s)Measures of regional cortical thickness (CT), surface area (SA), and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR, HC) and conversion status (CHR-PS+, CHR-PS-, HC).ResultsThe final dataset consisted of 3,169 participants (CHR=1,792, HC=1,377, age range: 9.5 to 39.8 years, 45% female). Using longitudinal clinical information, we identified CHR-PS+ (N=253) and CHR-PS- (N=1,234). CHR exhibited widespread thinner cortex compared to HC (average d=-0.125, range: -0.09 to -0.17), but not SA or subcortical volume. Thinner cortex in the fusiform, superior temporal, and paracentral regions was associated with psychosis conversion (average d=-0.22). Age showed a stronger negative association with left fusiform and left paracentral CT in HC, compared to CHR-PS+. Regional CT psychosis conversion effect sizes resembled patterns of CT alterations observed in other ENIGMA studies of psychosis.Conclusions and RelevanceWe provide evidence for widespread subtle CT reductions in CHR. The pattern of regions displaying greater CT alterations in CHR-PS+ were similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread CT disruptions coupled with abnormal age associations in CHR may point to disruptions in postnatal brain developmental processes.Key PointsQuestionHow do baseline brain morphometric features relate to later psychosis conversion in individuals at clinical high risk (CHR)?FindingsIn the largest coordinated international analysis to date, reduced baseline cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in CHR, in a manner highly consistent with thinner cortex in established psychosis. Regions that displayed greater cortical thinning in future psychosis converters additionally displayed abnormal associations with age.MeaningCHR status and later transition to psychosis is robustly associated with reduced cortical thickness. Abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in CHR, including pruning and myelination.

The diagnosis and treatment of psychiatric disorders depends on the analysis of behavior through language by a clinical specialist. This analysis is subjective in nature and could benefit from automated, objective acoustic and linguistic processing methods. This integrated approach would convey a richer representation of patient speech, particularly for expression of emotion. In this work, we explore the potential of acoustic and prosodic metrics to infer clinical variables and predict psychosis, a condition which produces measurable derailment and tangentiality in patient language. To that purpose, we analyzed the recordings of 32 young patients at high risk of developing clinical psychosis. The subjects were evaluated using the Structured Interview for Prodromal Syndromes/Scale of Prodromal Symptoms (SIPS/SOPS) criteria. To analyze the recordings, we examined the variation of different acoustic and prosodic metrics across time. This preliminary analysis shows that these features can infer negative symptom severity ratings (i.e., SIPS-Btotal), obtaining a Pearson correlation of 0.77 for all the subjects after cross-validated evaluation. In addition, these features can predict development of psychosis with high accuracy above 90%, outperforming classification using clinical variables only. This improved predictive power ultimately can help provide early treatment and improve quality of life for those at risk for developing psychosis.

Background: Malhi et al. in this issue critique the clinical high risk (CHR) syndrome for psychosis. Method: Response to points of critique. Results: We 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. Discussion: Malhi 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.

Introduction: In the past two decades, there have been a number of studies that test preventive intervention strategies for young people at imminent and elevated clinical risk for psychosis. We review these studies, integrate their findings, and lay out a framework for future clinical trials.

Sensory processing deficits are core features of schizophrenia, reflected in impaired generation of event-related potential (ERP) measures such as auditory mismatch negativity (MMN) and visual P1. To understand the potential time course of development of deficits in schizophrenia, we obtained MMN to unattended duration, intensity and frequency deviants, and visual P1 to attended LSF stimuli, in 43 healthy individuals ages 6 to 25 years (mean 17), and compared results to data from 30 adult schizophrenia patients (mean age 38). We analyzed “time-domain” measures of amplitude and latency, and event-related spectral perturbation (ERSP, “time-frequency”) to evaluate underlying neurophysiological mechanisms. Duration and intensity MMN amplitudes increased from childhood to late adolescence, while frequency MMN reached maximum amplitude during early development. As reported previously, in ERSP analyses, MMN activity corresponded primarily to theta-band (4–7 Hz) activity, while responses to standards occurred primarily in alpha (8–12 Hz) across age groups. Both deviant-induced theta and standard-induced alpha activity declined significantly with age for all deviant types. Likewise, visual P1 also showed an amplitude decline over development, reflecting a reduction in both evoked power and ITC. While MMN “difference” waveform ERP data suggest failure of maturation in schizophrenia, MMN ERSP analyses instead support a neurodegenerative process, as these isolate responses to deviants and standards, showing large low-frequency evoked power for both in children. Neurodegenerative processes are also supported by large visual P1 amplitudes and large low-frequency evoked power in children, in contrast with adult schizophrenia. Sensory processing deficits in schizophrenia may be related to accelerated synaptic pruning.

Aim We sought to examine attenuated first-rank symptoms (FRS) and subcomponents of the Unusual Thought Content (P.1.) section of the Structured Interview for Psychosis-Risk Syndromes (SIPS) to investigate the robust relationship between total P.1. and conversion. We hypothesized that attenuated FRS would drive the association and, additionally, be most predictive of a schizophrenia diagnosis. Method We assessed 189 clinical high-risk participants. Two independent raters separately scored attenuated FRS and each subcomponent of P.1. as if each were the only symptom reported. Total P.1. was also scored. Participants were evaluated for conversion up to 2 years. Results While total P.1. score significantly predicted conversion in the 54 converters, attenuated FRS, which were relatively uncommon in this sample, nor any subcomponent of P.1., was independently predictive. FRS did not predict conversion to schizophrenia among 35 subjects. Conclusion Although attenuated FRS, and subcomponents of P.1. of the SIPS, did not significantly predict transition to psychosis, our results support previous research affirming the value of total P.1. score as a tool for predicting conversion to psychosis.

BACKGROUND: Face processing deficits characterize schizophrenia, including in prodromal stages. Baseline face processing deficits predict psychosis onset in clinical high-risk (CHR) youths, specifically in fear/anger processing (Corcoran, 2015). Here, we evaluate the predictive value for psychosis onset, specifically of speed of face processing in CHR youths. METHODS: In a cohort of 49 CHR patients (of whom 7 later transitioned to psychosis), and 31 healthy controls, we examined reaction times for face processing using the UPenn battery, including the Emotion Recognition (ER-40; Kohler 2005), Emotion Discrimination (EMODIFF), Emotional Acuity (PEAT), Facial Identification, as well as motor praxis. RESULTS: CHR converters had significantly slower reaction time for face emotion recognition (FER) (p=.008), but not discrimination, acuity or facial identification. They also had slower motor praxis and greater baseline prodromal symptom severity (p

Aim Early detection and intervention (EDI) is a main challenge in psychosis research. The Chilean schizophrenia (SZ) national program has universal support and treatment by law for all SZ patients, but this does not yet extend to earlier stages of illness. Therefore, we have piloted an ultra-high risk (UHR) program to demonstrate the utility and feasibility of this public health approach in Chile. Methods We introduce "The University of Chile High-risk Intervention Program," which is the first national EDI program for UHR youths. Longitudinal follow-up included clinical and cognitive assessments, and monitoring of physiological sensory and cognitive indices, through electroencephalographic techniques. Results We recruited 27 UHR youths over 2 years. About 92.6% met criteria for attenuated psychosis syndrome (APS). Mean Scale of Psychosis-Risk Symptoms (SOPS) ratings in the cohort were 6.9 (SD 4.6) for positive, 9.1 (SD 8.3) for negative, 5.4 (SD 5.3) for disorganized and 6.3 (SD 4.1) for general symptoms. About 14.8% met criteria for comorbid anxiety disorders and 44.4% for mood disorders. Most participants received cognitive behavioural therapy (62.9%) and were prescribed low dose antipsychotics (85.2%). The transition rate to psychosis was 22% within 2 years. Conclusions We describe our experience in establishing the first EDI program for UHR subjects in Chile. Our cohort is similar in profile and risk to those identified in higher-income countries. We will extend our work to further optimize psychosocial and preventive interventions, to promote its inclusion in the Chilean SZ national program and to establish a South American collaboration network for SZ research.

The past two decades have marked an increase in research on the prodromal stages of schizophrenia that precede a first episode of psychosis. Criteria for a clinical high risk (CHR) state for psychosis have been validated and included in the DSM-5 as the attenuated psychosis syndrome and as requiring further study. This was hotly debated, given the concern of stigmatizing young people who would receive this psychosis risk label. In this article, I review ethical issues related to the psychosis risk label, including the potential harm of stigma and paternalism if risk labels are withheld in the context of the observed low predictive power of the psychosis risk designation. I review data that supports that the psychosis risk label need not be harmful, and could even confer benefit, and set out strategies for reducing stigma through individualized risk assessment and public health education.

Marijuana use is associated with psychosis, but its effects are understudied in individuals with preexisting risk for psychotic disorders. This preliminary study examined the acute psychological and physiological effects of smoked marijuana (0.0% or 5.5% Δ9-THC) in marijuana users at clinical high-risk (CHR; n = 6) to develop a psychotic disorder, and those not at risk (n = 6), under controlled laboratory conditions. CHR marijuana users exhibited temporary increases in psychotic-like states and decreases in neurocognitive performance during marijuana intoxication but control marijuana smokers did not. These findings, if replicated, may support a psychotogenic role for marijuana in CHR individuals.

The Structured Interview for Psychosis-Risk Syndromes (SIPS) contains criteria for the Attenuated Positive Symptom Syndrome (APSS), a period of subthreshold positive symptoms that predates full-blown psychosis. Motor abnormalities are often associated with these symptoms but have not been adequately studied. We assessed a diverse sample of 192 APSS participants (27.1% female; 47.9% white; mean age = 20.03 years) for motor dysfunction (SIPS G.3. score) at baseline and conversion to psychosis every 3 months for up to 2 years. Fifty-nine (30.7%) participants converted to psychosis. Baseline G.3. score was significantly higher among converters than nonconverters (mean difference = 0.66; t[95.929] = 2.579, p < 0.05). No significant differences in baseline G.3. were found between demographic groups or those with differential medication use. These results point to the use of G.3. as a potential predictor of psychosis among APSS individuals and potentially implicate the shared biological underpinnings of motor dysfunction in the APSS and full-blown psychotic illnesses.

Language and speech are the primary source of data for psychiatrists to diagnose and treat mental disorders. In psychosis, the very structure of language can be disturbed, including semantic coherence (e.g., derailment and tangentiality) and syntactic complexity (e.g., concreteness). Subtle disturbances in language are evident in schizophrenia even prior to first psychosis onset, during prodromal stages. Using computer-based natural language processing analyses, we previously showed that, among English-speaking clinical (e.g., ultra) high-risk youths, baseline reduction in semantic coherence (the flow of meaning in speech) and in syntactic complexity could predict subsequent psychosis onset with high accuracy. Herein, we aimed to cross-validate these automated linguistic analytic methods in a second larger risk cohort, also English-speaking, and to discriminate speech in psychosis from normal speech. We identified an automated machine-learning speech classifier – comprising decreased semantic coherence, greater variance in that coherence, and reduced usage of possessive pronouns – that had an 83% accuracy in predicting psychosis onset (intra-protocol), a cross-validated accuracy of 79% of psychosis onset prediction in the original risk cohort (cross-protocol), and a 72% accuracy in discriminating the speech of recent-onset psychosis patients from that of healthy individuals. The classifier was highly correlated with previously identified manual linguistic predictors. Our findings support the utility and validity of automated natural language processing methods to characterize disturbances in semantics and syntax across stages of psychotic disorder. The next steps will be to apply these methods in larger risk cohorts to further test reproducibility, also in languages other than English, and identify sources of variability. This technology has the potential to improve prediction of psychosis outcome among at-risk youths and identify linguistic targets for remediation and preventive intervention. More broadly, automated linguistic analysis can be a powerful tool for diagnosis and treatment across neuropsychiatry. Fil: Corcoran, Cheryl M.. Icahn School of Medicine at Mount Sinai; Estados Unidos. New York State Psychiatric Institute; Estados Unidos Fil: Carrillo, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigación en Ciencias de la Computación. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Investigación en Ciencias de la Computación; Argentina Fil: Fernandez Slezak, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigación en Ciencias de la Computación. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Investigación en Ciencias de la Computación; Argentina Fil: Bedi, Gillinder. University of Melbourne; Australia. New York State Psychiatric Institute; Estados Unidos. Columbia University; Estados Unidos Fil: Klim, Casimir. New York State Psychiatric Institute; Estados Unidos. Columbia University; Estados Unidos Fil: Javitt, Daniel C.. Columbia University; Estados Unidos. New York State Psychiatric Institute; Estados Unidos Fil: Bearden, Carrie E.. University of California at Los Angeles; Estados Unidos Fil: Cecchi, Guillermo Alberto. IBM T.J. Watson Research Center; Estados Unidos

Background Schizophrenia, a neurodevelopmental disorder, involves abnormalities in functional connectivity (FC) across distributed neural networks, which are thought to antedate the emergence of psychosis. In a cohort of adolescents and young adults at clinical high risk (CHR) for psychosis, we applied data-driven approaches to resting-state functional magnetic resonance imaging data in order to systematically characterize FC abnormalities during this period and to determine whether these abnormalities are associated with psychosis risk and severity of psychotic symptoms. Methods Our analyses included 51 CHR participants and 47 matched healthy control subjects. Of the CHR participants, 12 developed psychosis within 3.9 years. We estimated one multivariate measure of FC and studied its relationship to CHR status, conversion to psychosis, and positive symptom severity. Results Multivariate analyses revealed between-group differences in whole-brain connectivity patterns of bilateral temporal areas, mostly affecting their functional connections to the thalamus. Further, more severe positive symptoms were associated with greater connectivity abnormalities in the anterior cingulate and frontal cortex. Conclusions Our study demonstrates that the well-established FC abnormalities of the thalamus and temporal areas observed in schizophrenia are also present in the CHR period, with aberrant connectivity of the temporal cortex most associated with psychosis risk.

Summary Background Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals. Methods We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13–35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT00826202. Findings We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2). Interpretation This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia. Funding National Institutes of Health.

BackgroundDSM-5 proposes an Attenuated Psychosis Syndrome (APS) for further investigation, based upon the Attenuated Positive Symptom Syndrome (APSS) in the Structured Interview for Psychosis-Risk Syndromes (SIPS). SIPS Unusual Thought Content, Disorganized Communication and Total Disorganization scores predicted progression to psychosis in a 2015 NAPLS-2 Consortium report. We sought to independently replicate this in a large single-site high-risk cohort, and identify baseline demographic and clinical predictors beyond current APS/APSS criteria.MethodWe prospectively studied 200 participants meeting criteria for both the SIPS APSS and DSM-5 APS. SIPS scores, demographics, family history of psychosis, DSM Axis-I diagnoses, schizotypy, and social and role functioning were assessed at baseline, with follow-up every 3 months for 2 years.ResultsThe conversion rate was 30% (n = 60), or 37.7% excluding participants who were followed under 2 years. This rate was stable across time. Conversion time averaged 7.97 months for 60% who developed schizophrenia and 15.68 for other psychoses. Mean conversion age was 20.3 for males and 23.5 for females. Attenuated odd ideas and thought disorder appear to be the positive symptoms which best predict psychosis in a logistic regression. Total negative symptom score, Asian/Pacific Islander and Black/African-American race were also predictive. As no Axis-I diagnosis or schizotypy predicted conversion, the APS is supported as a distinct syndrome. In addition, cannabis use disorder did not increase risk of conversion to psychosis.ConclusionsNAPLS SIPS findings were replicated while controlling for clinical and demographic factors, strongly supporting the validity of the SIPS APSS and DSM-5 APS diagnosis.

Prior studies have implicated baseline positive and negative symptoms as predictors of psychosis onset among individuals at clinical high risk (CHR), but none have evaluated latent trajectories of symptoms over time. This study evaluated the dynamic evolution of symptoms leading to psychosis onset in a CHR cohort.100 CHR participants were assessed quarterly for up to 2.5 years. Latent trajectory analysis was used to identify patterns of symptom change. Logistic and proportional hazards models were employed to evaluate the predictive value for psychosis onset of baseline symptoms and symptom trajectories.Transition rate to psychosis was 26%. Disorganized communication (i.e., subthreshold thought disorder) presented an increased hazard for psychosis onset, both at baseline (Hazard Ratio (95% CI)=1.4 (1.1-1.9)) and as a trajectory of high persistent disorganized communication (Hazard Ratio (95% CI)=2.2 (1.0-4.9)). Interval clinical data did not improve the predictive value of baseline symptoms for psychosis onset.High baseline disorganized communication evident at ascertainment tended to persist and lead to psychosis onset, consistent with prior behavioral and speech analysis studies in similar cohorts. Remediation of language dysfunction therefore may be a candidate strategy for preventive intervention.

Literature suggests that social maladjustment is predictive of psychosis. We assessed 70 clinical high risk (CHR) patients for social maladjustment. There were no significant differences between patients with a positive or negative family history, suggesting that the relationship between social maladjustment and psychosis found in the recent literature may not translate to a relationship between social maladjustment and family history of psychosis in a CHR population.

Aim Social cognition impairment is a hallmark of schizophrenia and contains multiple domains. The domain of social inference has been relatively understudied in schizophrenia and its risk states. Methods Social inference was assessed in 60 clinical high-risk (CHR) patients and 28 healthy control subjects, using the video social inference task. We hypothesized a deficit in social inference in CHR participants and examined predictive value for psychosis transition. Results Social inference was positively associated with increasing age. Social inference did not differ significantly between CHR patients and controls, or predict transition to psychosis. Conclusions Few studies have examined social inference of individuals at clinical high risk for psychosis, and findings have been inconclusive. Additional studies using a variety of measures of social inference in CHR participants are recommended.

The ability to read passages of information fluently and with comprehension is a basic component of socioeconomic success. Reading ability depends on the integrity of underlying visual and auditory (phonological) systems. This study investigated the integrity of reading ability in schizophrenia relative to the integrity of underlying visual and auditory function.The participants were 45 schizophrenia patients, 19 clinical high-risk patients, and 65 comparison subjects. Reading was assessed using tests sensitive to visual or phonological reading dysfunction. Sensory, neuropsychological, and functional outcome measures were also obtained.Schizophrenia patients displayed reading deficits that were far more severe (effect size2.0) than would be predicted based on general neurocognitive impairments (effect size 1.0-1.4). The deficits correlated highly with both visual and auditory sensory measures, including impaired mismatch negativity generation (r=0.62, N=51, p=0.0002). Patients with established schizophrenia displayed both visual and phonological impairments, whereas high-risk patients showed isolated visual impairments. More than 70% of schizophrenia patients met criteria for acquired dyslexia, with 50% reading below eighth grade level despite intact premorbid reading ability. Reading deficits also correlated significantly (rp=0.4, N=30, p=0.03) with failure to match parental socioeconomic achievement, over and above contributions of more general cognitive impairment.Patients with schizophrenia display severe deficits in reading ability that represent a potentially remediable cause of impaired socioeconomic function. Such deficits are not presently captured during routine clinical assessment. Deficits most likely develop during the years immediately surrounding illness onset and may contribute to the reduced educational and occupational achievement associated with schizophrenia.

OBJECTIVE: Psychosis-like experiences may be clinically significant given their demonstrated associations with concurrent psychological distress and the later development of diagnosable psychotic disorders. Prior studies of treatment for psychosis-like experiences have yielded conflicting results. The aims of this study were to investigate help seeking and need for care among individuals with psychosis-like experiences in a large general population sample. METHODS: Data from the Collaborative Psychiatric Epidemiology Surveys (N=10,541) were used to examine help-seeking behaviors among survey respondents who reported psychosis-like symptoms over a 12-month period. Adjusted odds ratios were calculated for a variety of help-seeking variables, with control for demographic factors and co-occurring psychiatric conditions. RESULTS : Among the 10,541 respondents, 3.4% reported a psychosis-like experience in the past 12 months. Respondents who reported psychosis-like experiences were more than twice as likely as those who did not to seek treatment. Those who reported such experiences but who did not seek treatment were more likely to have felt the need for or to have been encouraged by others to seek treatment and less likely to have felt that they had no psychiatric problem. Associations with unmet need for care were largely attributable to co-occurring psychiatric disorders. CONCLUSIONS: Respondents with psychosis-like experiences had elevated rates of help seeking, as well as significant unmet clinical need among those not in treatment.

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.

There has been recent interest in understanding the role that sleep disturbance plays in patients at Clinical High Risk for psychosis (CHR). We assessed sleep disturbance in 194 CHR patients and 66 healthy control subjects and their relationship to symptoms (positive, negative and general functioning). Patients experienced significantly more sleep disturbance than healthy control subjects and their sleep disturbance was related to greater positive and negative symptoms and worse overall functioning. Targeting sleep disturbance in CHR individuals may provide alternative means of treating the CHR syndrome.

Aim Cannabis use is prevalent in schizophrenia and its risk states, despite its association with anxiety and positive symptoms. While schizophrenia patients report using cannabis for mood enhancement and social motives, it is not known what motivates clinical high risk (CHR) patients to use cannabis. Methods Among 102 CHR patients, 24 (23%) endorsed cannabis use, and were queried as to reasons for use, using a scale previously administered in schizophrenia patients. We hypothesized a primary motivation for mood enhancement related to anhedonia. We evaluated the ‘self-medication’ hypothesis by examining if motivation for symptom relief was associated with concurrent severity of symptoms. Results The rank order of reasons for use in CHR patients was similar to that previously reported by schizophrenia patients, with mood enhancement and social motives as primary reasons for use, and the motivation to use cannabis for symptom relief comparatively less common. Motivation for mood enhancement had a trend association with anhedonia. Motivation for symptom relief was entirely unrelated to concurrent severity of positive and anxiety symptoms. Conclusion As in schizophrenia, CHR patients primarily use cannabis for mood enhancement, especially in the context of decreased motivation to seek pleasure otherwise. Negative symptoms may drive cannabis use in schizophrenia and its risk states, which may exacerbate positive symptoms. By contrast, CHR patients do not report using cannabis to ‘self-medicate’ emergent positive symptoms. The understanding of motives for cannabis use among CHR patients may be informative for treatments aimed at reducing use, such as motivational interviewing.

Aim The public health benefits of utilizing an ‘at-risk for psychosis’ designation are tempered by concerns about stigma. It is therefore of interest to examine whether symptoms associated with this designation might spontaneously induce labels associated with a psychotic disorder, other non-psychotic disorders or non-psychiatric labels. This pilot study explored the labels associated with characteristics of ‘high risk for psychosis’ and the corresponding stigma level. Methods A vignette describing an identical character, followed by a series of questions about stigmatizing attitudes towards the vignette character, was administered in the present investigation. Results The results indicated that even though most young people (59%) did not spontaneously label the vignette character with psychotic-like diagnostic labels, the single most frequent label provided was ‘paranoid/a’. When such labelling, that is, strongly tied to psychosis, occurred, respondents exhibited stronger stigmatizing attributions of fear compared to those indicating non-psychiatric labels (e.g. ‘weird’). Conclusions These results suggest that the majority of respondents did not endorse diagnostic labels spontaneously, thus signaling that stigma in the majority of cases would not naturalistically be elicited. However, a segment of respondents evidenced stigma simply from behavioural changes manifested by individuals exhibiting signs of psychosis, independent of diagnosis. Implications for reducing any stigma associated with an ‘at-risk for psychosis’ designation are discussed.

Aim Reduced cognitive insight has been associated with psychotic symptoms, in particular with the presence of delusions; however, there is little information about whether such reductions are present in at-risk individuals prior to the onset of threshold psychotic symptoms. Method We conducted a cross-sectional comparison of cognitive insight (as indexed by the Beck Cognitive Insight Scale) in 62 help-seeking individuals at clinical high risk for psychosis, Fifty-nine individuals with schizophrenia-spectrum disorders and 37 healthy controls (HC). In patients, we evaluated associations of insight with positive symptoms, including later transition to psychosis in high-risk patients. Results Individuals with schizophrenia reported significantly higher self-certainty scores than the at-risk patients and HCs, with the at-risk patients scoring intermediate to the individuals with schizophrenia andcontrols. Similarly, individuals with schizophrenia scored significantly higher on self-reflectiveness, with no differences between the at-risk patients and controls. In individuals with schizophrenia, delusions were significantly correlated with self-certainty. In at-risk patients, cognitive insight was not associated with positive symptom severity and did not differentiate those at-risk patients who later developed psychosis from those who did not. However, post hoc analyses suggested that at-risk patients with marked unusual thought content (approaching threshold psychosis) had lower self-reflectiveness; whereas those with high suspiciousness had significantly higher self-certainty. Conclusions The findings are discussed in the context of normal developmental processes occurring during adolescence, their putative links to neurobiological functioning, and their implications for treatment and future research.

Impairment in social cognition, including emotion recognition, has been extensively studied in both Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the relative patterns of deficit between disorders have been studied to a lesser degree. Here, we applied a social cognition battery incorporating both auditory (AER) and visual (VER) emotion recognition measures to a group of 19 high-functioning individuals with ASD relative to 92 individuals with SZ, and 73 healthy control adult participants. We examined group differences and correlates of basic auditory processing and processing speed. Individuals with SZ were impaired in both AER and VER while ASD individuals were impaired in VER only. In contrast to SZ participants, those with ASD showed intact basic auditory function. Our finding of a dissociation between AER and VER deficits in ASD relative to Sz support modality-specific theories of emotion recognition dysfunction. Future studies should focus on visual system-specific contributions to social cognitive impairment in ASD.

IMPORTANCE Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra-high-risk (UHR) inclusion criteria (brief limited intermittent psychotic symptoms [BLIPS] and/or attenuated psychotic symptoms [APS] and/or genetic risk and deterioration syndrome [GRD]) and/or basic symptoms [BS]. Themeta-analytical risk of psychosis of these different subgroups is still unknown. OBJECTIVE To compare the risk of psychosis in CHR individuals who met at least one of the major inclusion criteria and in individuals not at CHR for psychosis (CHR-). DATA SOURCES Electronic databases (Web of Science, MEDLINE, Scopus) were searched until June 18, 2015, along with investigation of citations of previous publications and a manual search of the reference lists of retrieved articles. STUDY SELECTION We included original follow-up studies of CHR individuals who reported the risk of psychosis classified according to the presence of any BLIPS, APS and GRD, APS alone, GRD alone, BS, and CHR-. DATA EXTRACTION AND SYNTHESIS Independent extraction by multiple observers and random-effects meta-analysis of proportions. Moderators were tested with meta-regression analyses (Bonferroni corrected). Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and the Egger test. MAIN OUTCOMES AND MEASURES The proportion of each subgroup with any psychotic disorder at 6, 12, 24, 36, and 48 or more months of follow-up. RESULTS Thirty-three independent studies comprising up to 4227 individualswere included. The meta-analytical proportion of individuals meeting each UHR subgroup at intakewas: 0.85 APS (95%CI, 0.79-0.90), 0.1 BLIPS (95%CI, 0.06-0.14), and 0.05 GRD (95%CI, 0.03-0.07). There were no significant differences in psychosis risk at any time point between the APS and GRD and the APS-alone subgroups. Therewas a higher risk of psychosis in the any BLIPS greater than APS greater than GRD-alone subgroups at 24, 36, and 48 or more months of follow-up. Therewas no evidence that the GRD subgroup has a higher risk of psychosis than the CHR- subgroup. There were too fewBS or BS and UHR studies to allowrobust conclusions. CONCLUSIONS AND RELEVANCE There is meta-analytical evidence that BLIPS represents separate risk subgroup compared with the APS. The GRD subgroup is infrequent and not associated with an increased risk of psychosis. Future studies are advised to stratify their findings across these different subgroups. The CHR guidelines should be updated to reflect these differences.

article i nfo Obsessive-compulsive symptoms, particularly aggressive obsessions, are prevalent in schizophrenia patients and associatedwith othersymptomseverity,suicidal ideationand functionalimpairment.In a psychosis-risk co- hort, obsessive-compulsive diagnosis and symptoms were assessed in terms of prevalence and content, and for associations with clinical measures. Obsessive-compulsive symptoms were prevalent in the CHR cohort, as was suicidal ideation. The presence and severity of aggressive obsessions were associated with depression, suicidal ideation and social impairment. The high prevalence of aggressive obsessions and associated suicidal ideation in a clinical high risk cohort, and their relationship to depression, is relevant for risk assessment and treatment strategies.

BackgroundIncreased sensitivity and exposure to stress are associated with psychotic symptoms in schizophrenia and its risk states, but little is known about the co-evolution of stress sensitivity and exposure with positive and other symptoms in a clinical high-risk (CHR) cohort.MethodA combined cross-sectional and longitudinal design was used to examine the associations over time of stress sensitivity and exposure (i.e. life events) with ‘prodromal’ symptoms in a cohort of 65 CHR patients assessed quarterly for up to 4 years, and at baseline in 24 healthy controls similar in age and gender.ResultsImpaired stress tolerance was greater in patients, in whom it was associated over time with positive and negative symptoms, in addition to depression, anxiety and poor function. By contrast, life events were comparable in patients and controls, and bore no association with symptoms. In this treated cohort, there was a trajectory of improvement in stress tolerance, symptoms and function over time.ConclusionsImpaired stress tolerance was associated with a wide range of ‘prodromal’ symptoms, consistent with it being a core feature of the psychosis risk state. Self-reported life events were not relevant as a correlate of clinical status. As in other treated CHR cohorts, most patients improved over time across symptom domains.

While increasing evidence suggests that cannabis use may play a role in the development of schizophrenia in some young people, less is known about the strength and specificity of its relationship to latent schizophrenia liability, i.e., schizotypal personality disorder traits.Determine the predictive value of cannabis use during childhood and early adolescence on schizotypal personality disorder (SPD) symptoms projecting into adulthood, using a community-based longitudinal cohort from upstate New York.Prospective data from 804 participants was used to determine associations between early cannabis use and later schizotypal symptoms, accounting for important potential confounds (e.g., adolescent schizotypal symptoms).Cannabis use with onset prior to age 14 strongly predicted SPD symptoms in adulthood, independent of early adolescent SPD symptoms, major depression, anxiety disorder, other drug use, and cigarette use. There was no interaction effect of early cannabis use and early adolescent SPD symptoms on SPD symptoms into adulthood.Our data provide further support for a strong association of early cannabis use with the development of symptoms characteristic of schizophrenia spectrum disorders. As with studies in schizophrenia, early SPD symptoms could not fully explain the association of early cannabis use with later schizotypal symptoms. The mechanisms that underlie the association of cannabis use and schizotypal symptoms in a developmental context deserve further exploration.

Aim: A biased attributional style, in which negative events are attributed to external and personal causes, is associated with paranoid delusions in schizophrenia. It is not known whether this biased attributional style also characterizes individuals at clinical risk for psychosis or if it is associated with their emergent paranoia. Methods: Thirty-three clinical high-risk patients and 15 age- and gender-similar controls were assessed with the Internal, Personal, and Situational Attributions Questionnaire for externalizing and personalizing attributional biases and for potential correlates with suspiciousness and other symptoms. Results: Both patients and controls had a similar external-personalizing attributional style that was unrelated to symptoms, including suspiciousness. Conclusions: Consistent with other studies, a biased attributional style was not associated with subthreshold paranoia. Therefore, a biased attributional style is likely not a trait that contributes to emergent paranoid delusions but is instead a state-dependent correlate of paranoid delusions.

Stress sensitivity and HPA axis activity may be relevant to the development and expression of psychotic disorders. Cortisol secretion has been associated with positive symptoms both in patients with psychotic disorders and in young people at clinical risk for psychosis. Herein, we aimed to replicate these findings, to determine which positive symptoms may be associated with cortisol levels, and to explore any associations with affective symptoms and impaired stress tolerance.Thirty-one clinical high risk patients were evaluated in cross-section for associations between salivary cortisol levels upon clinic entry at 11 am, demographic variables, and clinical symptoms.Salivary cortisol levels were unrelated to medication exposure or demographics, except for higher levels in the ten females studied. Salivary cortisol bore no relationship to overall positive symptom severity but was associated with anxiety, as well as with suspiciousness and impaired stress tolerance, which were themselves highly intercorrelated.Cortisol secretion in the context of a putative novel social situation (i.e. clinic entry) may be a biological correlate of suspiciousness, impaired stress tolerance and affective symptoms in individuals vulnerable to developing psychosis. These associations are consistent with findings from experience sampling studies in individuals at risk for psychosis as well as basic studies of animal models of schizophrenia.

Objectives The negative symptoms of schizophrenia are difficult to treat and are predictors of poor outcome. New somatic treatments are needed to reverse these symptoms and improve function. One promising approach is repetitive transcranial magnetic stimulation (rTMS), although results to date have been mixed. This pilot study assessed higher doses of rTMS and assessed particular demographic factors that may influence treatment response. Methods Five patients with schizophrenia or schizoaffective disorder enrolled to receive 20 sessions of rTMS administered with a Magstim Super Rapid device (The Magstim Company Ltd, Wales, UK). Treatment was administered at 20 Hz for 2 seconds, intertrain interval of 28 seconds, and at 100% motor threshold to the left dorsolateral prefrontal cortex in an open-label pilot study. Positive and Negative Syndrome Scale symptom assessments occurred at 2-week intervals during treatment and twice at 4-week intervals after termination. Results Treatments were well tolerated with no adverse events. One patient withdrew from the study in the setting of medication noncompliance. Of the patients who completed treatment, 2 had reductions in positive symptoms by 9% and 26%, maintained at 1 month. A third patient had a 14% reduction in negative symptoms at week 4, and a fourth patient had a 55% reduction at week 4. Negative symptom improvement was not related to depressive or extrapyramidal symptoms, which were unchanged with treatment. Conclusions This pilot study of rTMS treatment for the negative symptoms of schizophrenia is promising with respect to safety and feasibility. The promising preliminary evidence for improvements in this open-label setting should be followed up with a randomized clinical trial to establish efficacy. Further work may explore the potential utility of rTMS for the otherwise largely untreatable negative symptoms, which account for so much of the morbidity of schizophrenia.

Aim: Coping by families of patients with schizophrenia include ‘approach’ strategies considered to be adaptive (e.g. reinterpretation) and potentially maladaptive ‘avoidant’ strategies (denial/disengagement, use of alcohol and drugs). Little is known about coping strategies used by families of individuals with incipient or emergent psychosis. Methods: Self-reported coping styles were assessed in family members of 11 ultra high risk and 12 recent-onset psychosis patients, using a modified version of Carver's Coping Orientations to Problems Experienced questionnaire. Results: Families reported moderate use of ‘approach’ coping (e.g. planning, seeking social support, positive reinterpretation, acceptance and turning to religion) and rare use of ‘avoidant’ coping strategies (denial/disengagement and use of alcohol and drugs). Conclusions: The greater endorsement of ‘approach’ coping by these families is consistent with findings for families of first episode psychosis patients, and it is in contrast to more prevalent ‘avoidant’ coping by families of patients with more chronic psychotic illness. Early intervention could plausibly help families maintain the use of potentially more adaptive ‘approach’ coping strategies over time.

Schizophrenia is a common disorder, affecting approximately 1 out of every 100 people, with a typical onset during adolescence and early adulthood. The personal and societal costs of schizophrenia are extremely high. Prevention of schizophrenia, would offer substantial benefits to patients, their family members, and the community at large. The prodromal phase of schizophrenia has been recognized since the 19th century. At-risk individuals for psychosis and schizophrenia are the subjects who can provide information for intervention prior to development of frank psychosis. This approach is currently being investigated. The question remains, however, whether it can be a diagnostic category by itself. The proposal for including the risk syndrome is one of the recommendations by the working group on schizophrenia and psychotic disorders for the forthcoming DSM-V. There are differing views in academia regarding this proposal. Prior to becoming fully psychotic, a consistent literature demonstrates that patients generally had suffered from accelerating attenuated symptoms and distress. It is important that the prodromal phase be accurately recognized in order to accomplish the goal of prevention. We can then purposefully engage in early intervention aiming toward prevention. A recent strong resurgent interest in this area stems largely from two developments: First, the identification of the neurobiological deficit processes associated with the severity and chronicity of schizophrenia, and second, the development of reliable criteria for diagnosis. Although the general at-risk construct appears to offer great potential to advance both the treatment and research dealing with psychotic illnesses, it seems premature to many researchers to include the syndrome as an established entity in the text of the new DSM-V. It would be far more appropriate to include this proposed syndrome in the appendix and evaluate the many contemporary issues in future studies. The main issues involved in this discussion are the clinical validity of the syndrome, concern about stigma and unnecessary treatment, and need for responding to patients' distress in addition to the ethical dilemma. In this review we examine the issue of inclusion of the risk syndrome as a diagnosis.

BackgroundSocial dysfunction is a hallmark symptom of schizophrenia which commonly precedes the onset of psychosis. It is unclear if social symptoms in clinical high-risk patients reflect depressive symptoms or are a manifestation of negative symptoms.MethodWe compared social function scores on the Social Adjustment Scale-Self Report between 56 young people (aged 13–27 years) at clinical high risk for psychosis and 22 healthy controls. The cases were also assessed for depressive and ‘prodromal’ symptoms (subthreshold positive, negative, disorganized and general symptoms).ResultsPoor social function was related to both depressive and negative symptoms, as well as to disorganized and general symptoms. The symptoms were highly intercorrelated but linear regression analysis demonstrated that poor social function was primarily explained by negative symptoms within this cohort, particularly in ethnic minority patients.ConclusionsAlthough this study demonstrated a relationship between social dysfunction and depressive symptoms in clinical high-risk cases, this association was primarily explained by the relationship of each of these to negative symptoms. In individuals at heightened risk for psychosis, affective changes may be related to a progressive decrease in social interaction and loss of reinforcement of social behaviors. These findings have relevance for potential treatment strategies for social dysfunction in schizophrenia and its risk states and predict that antidepressant drugs, cognitive behavioral therapy and/or social skills training may be effective.

Background Profound FER deficits exist in Sz, causing social disability, though can be partly remediated with computer-based training. Neurostimulation might augment remediation if critical nodes were identified. We aimed to 1) briefly recapitulate FER deficits of Sz in HV using rTMS to rpSTS, 2) identify connectivity patterns of rpSTS regressed by FER, and 3) apply TMS to rpSTS with fMRI as readout. Methods 1) Nine healthy volunteers had rTMS (10 Hz; 500 msec; 110% RMT) to rpSTS or rOFA (counterbalanced; 10/10 system overlay with standard MRI) concurrent (1/3 trials) with stimuli (http://faces.mpdl.mpg.de/) for emotion or gender identification (button press). 14 Sz patients completed these tasks without TMS. 2) Whole-brain resting-connectivity analyses, seeded by rpSTS, was applied in 27 Sz and 35 HV who also completed the UPenn FER task. 3) BOLD fMRI was obtained in 4 HV pre- and post-TMS to rpSTS (1 Hz; 20 minutes). Results 1) In HV, rTMS to rpSTS only (not OFA) significantly slowed reaction time for FER only (not gender identification): overall F test for logRT (p=.001) with post-hoc rpSTS vs.OFA (p=.005) and rpSTS vs. non-stim trials (p=.004). rpSTS recapitulated slowed RT ad lower FER accuracy of Sz. 2) In both HV and Sz, rpSTS had significant resting connectivity with V1 (p= .00013), positively modulated by FER accuracy. 3) Analyses are ongoing. Discussion rpSTS is a critical node in the FER circuit with connectivity to primary visual cortex modulated by FER, whose disruption recapitulates FER deficits, making it a candidate target for remediatory neurostimulation.

Background Psychosis has significant effects on language, to the extent that its disturbance is one of the principal components of diagnosis and prognosis. In particular, two features of language seem to be prominently affected: discourse coherence, observed in patients as derailment (or tangentiality), and discourse richness, observed as poverty of speech. Using automated linguistic analysis on baseline interviews, we have shown in a previous study that it is possible to predict with high accuracy of conversion to psychosis (100%) among a cohort of clinical high-risk youth, by quantifying the subjects’ semantic coherence and syntactic complexity as proxies for derailment and poverty of speech, respectively.1 In the present study, we seek to explore to what extent the prodromal prediction model can discriminate recent-onset schizophrenia patients from matching controls, with the intent of understanding how the prodromal-onset transition is reflected in language. Methods Eighteen recent-onset schizophrenic patients and twelve matching controls had baseline interviews, using an open-ended protocol previously introduced.2 Using automated analysis, transcripts of interviews were evaluated for semantic and syntactic features predicting psychosis onset in an independent cohort. These features were then used to discriminate between patients and controls, applying the same classifier that predicted conversion to psychosis, namely converts laying outside the convex hull of non-converts. Additionally, we compared the discrimination power of this approach against alternative models including alternative linguistic features (e.g. metaphoricity3) and protocols (e.g. short prompts4). Results The convex hull of the controls subjects misclassifies only one of the patient samples, a result that amounts to 95% true positive rate. Surrogating by label randomization and accounting for false and positive negative rates results in a balanced accuracy of 80%, which is comparable to those obtained with alternative automated models, which range from 70% to 85%. Moreover, the present cohort is clearly separable from both converts and non-converts in the CHR cohort when projected in the feature space. Discussion The automated features optimized for prediction of psychotic onset convey highly significant information regarding the discrimination between recent-episode patients and controls. The directionality of effects, however, is not obviously derived from that observed in the prodromal-onset transition. This preliminary study provides the basis for a larger study to better understand language disturbances across these cohorts. References 1.Bedi, G., et al. npj Schizophrenia 1 (2015): 15030. 2. Ben-David, S., et al. Psychiatric Services 65.12 (2014): 1499–1501. 3. Gutiérrez, E.D., et al. Proceedings of the 2017 Conference on Empirical Methods in Natural Language Processing. 2017. 4. Mota, N.B., et al. PloS one 7.4 (2012): e34928.

Background The clinical high-risk state for psychosis syndrome (CHR) offers substantial potential benefits in terms of early identification and treatment for at-risk youth. Early treatment might lead to decreased symptoms, thus leading to reduced symptom-related stigma. However, stigma of the clinical high-risk state for psychosis designation might also initiate further stigma through the label of risk for psychosis. Identifying the effects of these sources of stigma is critical in order to best minimize stigma associated with CHR identification and to facilitate recovery. Methods Baseline stigma assessments were conducted with 170 clinical high risk state for psychosis individuals in a major, NIH-funded longitudinal study at Columbia University Medical Center, Harvard University Medical Center, and Maine Medical Center from 2012 to 2017. Labeling-related measures of stigma (e.g., “shame of being identified as at psychosis-risk”) adapted to the CHR group, and a parallel measure of symptom-related stigma (e.g., “shame of the symptoms associated with CHR”) were administered. These measures were examined in relation to outcomes of: a) self-esteem, b) quality of life, and c) social functioning, adjusting for sociodemographics and core CHR symptoms (e.g. attenuated psychotic symptoms). Results Results indicated that stigma related to symptoms was more strongly associated with all outcomes when compared with shame related to the risk-label. Stigma related to symptoms remained a significant predictor of self-esteem and quality of life even after accounting for stigma related to the risk-label and the effects of sociodemographics and CHR symptoms. Conversely, stigma related to the risk-label was no longer a significant predictor for outcomes after accounting for stigma related to symptoms. Discussion Overall, symptom-related stigma was a more salient correlate and was independently linked with self-esteem and quality of life even after accounting for the effects of stigma related to the risk-label. These results indicate that treating of symptoms through early identification and treatment may provide major benefit for CHR youth by also alleviating symptom-related stigma. These findings also indicate that CHR services should address stigma associated with symptoms immediately at first identification, as these have substantial effects on psychological and functional outcomes. These findings have implications for guiding implementation of specialized CHR services both in the United States and worldwide.