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Pleiotropy occurs when a genetic variant influences more than one trait. This is a key property of the genomic architecture of psychiatric disorders and has been observed for rare and common genomic variants. It is reasonable to hypothesize that the microscale genetic overlap (pleiotropy) across psychiatric conditions and cognitive traits may lead to similar overlaps at the macroscale brain level such as large-scale brain functional networks. We took advantage of brain connectivity, measured by resting-state functional MRI to measure the effects of pleiotropy on large-scale brain networks, a putative step from genes to behaviour. We processed nine resting-state functional MRI datasets including 32 726 individuals and computed connectome-wide profiles of seven neuropsychiatric copy-number-variants, five polygenic scores, neuroticism and fluid intelligence as well as four idiopathic psychiatric conditions. Nine out of 19 pairs of conditions and traits showed significant functional connectivity correlations (rFunctional connectivity), which could be explained by previously published levels of genomic (rGenetic) and transcriptomic (rTranscriptomic) correlations with moderate to high concordance: rGenetic—rFunctional connectivity = 0.71 [0.40–0.87] and rTranscriptomic—rFunctional connectivity = 0.83 [0.52; 0.94]. Extending this analysis to functional connectivity profiles associated with rare and common genetic risk showed that 30 out of 136 pairs of connectivity profiles were correlated above chance. These similarities between genetic risks and psychiatric disorders at the connectivity level were mainly driven by the overconnectivity of the thalamus and the somatomotor networks. Our findings suggest a substantial genetic component for shared connectivity profiles across conditions and traits, opening avenues to delineate general mechanisms—amenable to intervention—across psychiatric conditions and genetic risks.

Reductions in hippocampal volume (HV) have been associated with both prolonged exposure to stress and psychotic illness. This study sought to determine whether higher levels of neighborhood poverty would be associated with reduced HV among individuals at clinical high-risk for psychosis (CHR-P), and whether social engagement would moderate this association. This cross-sectional study included a sample of participants (N = 174, age-range = 12–33 years, 35.1% female) recruited for the second phase of the North American Prodrome Longitudinal Study. Generalized linear mixed models tested the association between neighborhood poverty and bilateral HV, as well as the moderating role of social engagement on this association. Higher levels of neighborhood poverty were associated with reduced left (β = −0.180, P = .016) and right HV (β = −0.185, P = .016). Social engagement significantly moderated the relation between neighborhood poverty and bilateral HV. In participants with lower levels of social engagement (n = 77), neighborhood poverty was associated with reduced left (β = −0.266, P = .006) and right HV (β = −0.316, P = .002). Among participants with higher levels of social engagement (n = 97), neighborhood poverty was not significantly associated with left (β = −0.010, P = .932) or right HV (β = 0.087, P = .473). In this study, social engagement moderated the inverse relation between neighborhood poverty and HV. These findings demonstrate the importance of including broader environmental influences and indices of social engagement when conceptualizing adversity and potential interventions for individuals at CHR-P.

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.

22q11.2 deletion syndrome (22q11DS) results from a hemizygous deletion that typically spans 46 protein-coding genes and is associated with widespread alterations in brain morphology. The specific genetic mechanisms underlying these alterations remain unclear. In the 22q11.2 ENIGMA Working Group, we characterized cortical alterations in individuals with 22q11DS (n = 232) versus healthy individuals (n = 290) and conducted spatial convergence analyses using gene expression data from the Allen Human Brain Atlas to prioritize individual genes that may contribute to altered surface area (SA) and cortical thickness (CT) in 22q11DS. Total SA was reduced in 22q11DS (Z-score deviance = −1.04), with prominent reductions in midline posterior and lateral association regions. Mean CT was thicker in 22q11DS (Z-score deviance = +0.64), with focal thinning in a subset of regions. Regional expression of DGCR8 was robustly associated with regional severity of SA deviance in 22q11DS; AIFM3 was also associated with SA deviance. Conversely, P2RX6 was associated with CT deviance. Exploratory analysis of gene targets of microRNAs previously identified as down-regulated due to DGCR8 deficiency suggested that DGCR8 haploinsufficiency may contribute to altered corticogenesis in 22q11DS by disrupting cell cycle modulation. These findings demonstrate the utility of combining neuroanatomic and transcriptomic datasets to derive molecular insights into complex, multigene copy number variants.

Background Persistent negative symptoms (PNS) are defined as enduring moderate negative symptoms while controlling for principal sources of secondary negative symptoms. PNS symptoms have been associated with poor functional outcomes in schizophrenia. Furthermore, in schizophrenia negative symptoms and poor functioning have been reportedly associated with defeatist beliefs (e.g., “I always fail”). Youth at clinical high risk (CHR) for developing psychosis often demonstrate negative symptoms, poor functioning, and defeatist beliefs. The goal of this study was to determine if negative symptoms were associated with poor functioning and defeatist beliefs in a CHR longitudinal cohort. Methods CHR (N=764) participants were recruited for the North American Prodrome Longitudinal Study (NAPLS 2) at 8-sites across North America. Negative symptoms were rated on the Scale of Prodromal Symptoms (SOPS) at baseline, 6, 12, 18, and 24 months. For this study negative symptoms were restricted to social anhedonia (N1), avolition (N2), and expression of emotion (N3) based on recommendations from the NIMH-MATRICS consensus statement on negative symptoms. PNS were defined as having one of these three negative symptoms scored ≥4 (i.e., moderately severe to extreme) for a period of one year. Depressive symptoms were assessed with the Calgary Depression Scale for Schizophrenia (CDSS). To assess defeatist beliefs the Brief Core Schema Scale (BCSS) was utilized as a proxy to evaluate negative self-beliefs (e.g., “I am worthless”) and positive self-beliefs (e.g., “I am valuable”). Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups to accommodate for missing data and account for intra-participant correlations. Results Sixty-seven CHR individuals had PNS. Mixed-effect models demonstrated that the PNS group had significant global, social, and role functioning deficits at baseline, 6, 12, 18, and 24 months compared to CHR individuals without PNS (n=673). Moreover, functioning did not improve in the PNS group while functioning in the group without PNS significantly improved over time. There were no significant differences between the groups on depressive symptoms with the CDSS. The PNS group had significantly higher BCSS self-negative beliefs at 12 and 24 months compared to the group without PNS. Individuals without PNS had significantly higher positive self-beliefs (e.g., “I am valuable”) at baseline, 6 months, 12 months and 24 months compared to the PNS group. Discussion The results indicate that in the NAPLS cohort 10% of CHR individuals have PNS. Moreover, the PNS group demonstrated significant and persistent global, social, and role functioning deficits compared to those without PNS. The group without PNS had higher levels of positive beliefs (e.g., “I am successful”), which may indicate a protective factor against developing PNS.

Background Although the clinical high risk (CHR) for psychosis paradigm has become well-established over the past two decades, one key component has received surprisingly little direct investigative attention: the validity of the conversion to psychosis or transition criteria. This lack of evidence is surprising because many CHR treatment and prediction studies rely on the conversion measure as an outcome. In the absence of such evidence, some observers have raised the possibility that conversions from CHR may be trivial. The aim of this study is to evaluate the predictive validity of the transition to psychosis as measured by the Structured Interview for Psychosis-Risk Syndromes (SIPS) in CHR individuals. To our knowledge, this is the first study to examine the CHR conversion to psychosis at one-year follow-up. It is hypothesized that CHR participants whose conversion to frank psychosis was ascertained by SIPS (SIPS CV) will show similar diagnostic stability and severity of illness compared to the FEP sample and will differ significantly from SIPS Non-Converters (NCV) on clinical severity. Methods Participants included 33 SIPS Converters (CV) (met criteria for conversion to frank psychosis (COPS) on SIPS) and 399 CHR NCV 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 Coordinated Specialty Care (CSC) program in New Haven, CT. Comparisons using Chi-square and ANOVA were made at baseline and one-year follow-up on variables from demographic, diagnostic stability (SCID) and available measurement domains relating to severity of illness (psychotropic medication and resource utilization). Results The principal findings of the present study are: 1) large majority of cases in both SIPS CV (n=27/33, 81.8%) and FEP (n=57/67, 85.1%) samples continued to have current psychosis diagnoses at one year follow up, 2) exposure to antipsychotic medication was higher in SIPS CVs (n=17/32, 53.1%) compared to SIPS NCVs (n=81/397, 20.4%), and similar as compared to FEP cases (n=39/65, 60%), 3) at follow up, SIPS CV had higher rates of resource utilization (any psychiatric hospitalizations, day hospital admissions, and ER visits) than SIPS-NCV and were similar to FEP in most categories. Discussion The results suggest that the SIPS definition of psychosis onset carries substantial validity in that those with SIPS-defined psychosis demonstrate similar diagnostic stability and severity of illness at one-year follow as a first episode sample and greater severity of illness as compared to a SIPS-defined CHR con-converting sample. Limitations include the lack of functional assessments at follow-up in the SIPS-CV. Additional studies are needed to further validate the CHR vs transition to psychosis distinction. Since many patients who come to baseline evaluation for CHR are discovered to have previously unrecognized frank psychosis, future studies should aim to obtain additional evidence by following this important group.

Background Schizophrenia is a psychiatric disorder characterized by a deficit in reality testing, most often manifest in the form of delusions and hallucinations. Because differentiating real from imagined experiences is critically dependent on episodic and associative memory, deficits in mnemonic processes could be involved in the genesis of impaired reality testing. Prior work has shown that individuals with psychosis exhibit impairment in metamemory, or, awareness and knowledge of one’s own memory and memory processes, and that these impairments may be relevant to the emergence and/or maintenance of psychotic symptoms. Methods In the present study, we used a verbal associative memory paradigm incorporating subject confidence ratings to examine differences in metamemory processes in three separate samples: patients with chronic schizophrenia (CHR; n = 34), patients with recent-onset (first-episode) psychosis (n = 49), and individuals at clinical high risk for psychosis (n = 29) compared to control groups (n = 24, n = 26, and n = 22, respectively). We used an analysis of variance design to examine group differences in confidence gap and knowledge corruption between patients and controls. We further assessed the association of both of these metrics to symptom severity in each patient sample. Results We found that both chronic and first-episode patients displayed significantly decreased confidence gap compared to healthy controls, with patients being more confident in incorrect memory retrievals and less confident in correct memory retrievals as compared to healthy controls. Additionally, compared to healthy controls, chronic patients and first-episode patients showed significantly increased knowledge corruption (the proportion of confident incorrect memory retrievals compared to all confident retrievals). While there were no group differences in confidence gap and knowledge corruption between CHR subjects and healthy controls, decreased confidence gap was significantly correlated with positive symptom severity in CHR subjects, as well as in first-episode subjects. Discussion These findings suggest that underlying deficits in metamemory processes may possibly reflect mechanisms involved in the development and/or maintenance of disrupted reality testing in those with and at risk for psychosis.

Background Studies in individuals at clinical high risk (CHR) for psychosis provide a powerful means to predict outcomes and inform putative mechanisms underlying conversion to psychosis. In previous work, we applied advanced diffusion imaging methods to reveal that white matter pathology in a CHR population is characterized by cellular-specific changes in white matter, suggesting a preexisting neurodevelopmental anomaly. However, it remains unknown whether these deficits relate to clinical symptoms and/or conversion to frank psychosis. To address this gap, we examined cross-sectional and longitudinal white matter maturation in the largest imaging population of CHR individuals to date, obtained from the North American Prodrome Longitudinal Study (NAPLS-3). Methods Multi-shell diffusion magnetic resonance imaging (MRI) data were collected across multiple timepoints (1–6 at ~2 month intervals) in 286 subjects (age range=12–32 years). These were 230 unmedicated CHR subjects, including 11% (n=25) who transitioned to psychosis (CHR-converters), as well as 56 age and sex-matched healthy controls. Raw diffusion signals were harmonized to remove scanner/site-induced effects, yielding a unified imaging dataset. Fractional anisotropy of cellular tissue (FAt) and the volume fraction of extracellular free-water (FW) were assessed in 12 major tracts from the IIT Human Brain Atlas (v.5.0). Linear mixed effects (LME) models were fitted to infer developmental trajectories of FAt and FW across age for CHR-converters, CHR-nonconverters and control groups, while accounting for the repeated measurements on each individual. Results The rate at which FAt changed with age significantly differed between the three groups across commissural and association tracts (5 in total; p Discussion Our results revealed that clinical high-risk for psychosis is associated with cellular-specific alterations in white matter, regardless of conversion status. Only converters showed excess extracellular free-water, which involved tracts connecting occipital, posterior temporal, and orbito-frontal areas. We also demonstrate a direct impact of free-water on positive symptomatology, collectively, suggesting that excess free-water may signal acute psychosis and its onset. This marker may be useful for patient selection for clinical trials and assessment of individuals with prodromal psychosis.

Background: The presence and severity of attenuated-psychosis symptoms define a clinical high risk (CHR) population at elevated risk for psychotic disorders. The NAPLS project is a prospective study of mechanisms contributing to psychosis vulnerability in persons at CHR. Here we investigated a hypothesized role for the highly-integrated immune and redox systems in the development of psychosis. Methods: We examined expression of 143 plasma analytes from a subgroup of the NAPLS2 cohort, including 32 CHR with subsequent psychosis conversion, 40 CHR followed for 2years without psychosis, and 35 unaffected subjects. We used a Luminex platform with analytes chosen to reflect immune, redox, hormonal, and metabolic system status, including many analytes previously associated with schizophrenia and psychosis risk. We applied correlation network analysis to discover potentially co-regulated networks associated with later development of psychosis. Results: Several robust (r > .75) and highly significant (P < .0001 after correction for multiple testing) correlation networks were found in all groups, including a network involving IL3, IL5, IL7, and IL13, and a network involving CCL5, BDNF, TSH, and PDGF. There were significantly fewer nodes in CHR-converters compared with CHR-nonconverters and unaffected subjects. In unaffected subjects, plasminogen activator inhibitor-1 (PAI-1) was highly correlated with matrix metallopeptidases (MMP) 7, 9 and 10 and CD40LG, this network was absent in CHR subjects, and in CHR-converters PAI-1 was robustly and significantly correlated with TIMP1, CCL13, and TIMP1. Conclusion: Apattern of robust and highly significant correlation networks in plasma analytes suggests shared regulatory mechanisms for the inter-correlated analytes. The lower number of correlated analytes in CHR subjects who converted to psychosis suggest a shift in regulation, as does the change in the correlation network involving PAI-1. PAI-1 is of interest given studies linking schizophrenia with reduced tissue plasminogen activator (tPA) and increases in negative regulators of tPA, including activation of both PAI-1and TIMP1 with oxidative stress. In addition, a recent study links toxoplasmosis infection and schizophrenia risk to a pathway involving PAI-1 and TIMP1. Patricio O’Donnell, Pfizer Inc.

Background: Recent 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 accomplishment (ie, achievement), rather than on the skills required to carry-out a particular real-world function (ie, capacity). From this perspective capacity provides the foundation for what can actually be achieved. This is comparable to the comparison between IQ (capacity) vs grades at school (achievement). In one of the first reports of its kind, we introduced the Map task, a laboratory-based measure specifically designed to assess a young person’s basic capacity to carry-out age-appropriate skills that lead to independent community living (McLaughlin et al., 2016). Poor performance on the Map task was found to be predictive of conversion to psychosis, suggesting that functional capacity in the prodrome may represent a basic biologically-based vulnerability factor. Given that diminished functional capacity is often a key barrier to good functional outcomes in patients with schizophrenia, the current study sought to next evaluate whether deficits in capacity can also predict social and role (ie, academic) functioning in the prodrome.

Background: Previous work has established a relationship between metabolic abnormalities and poorer health outcomes in individuals with schizophrenia spectrum disorders. It is likely that metabolic abnormalities, inflammation, and oxidative stress observed in individuals with schizophrenia actually begin to occur prior to the onset of psychosis and may potentially serve as a risk factor in populations at clinical high risk for developing psychosis. Further, in the general population, it has been established that Latino individuals have a higher incidence of metabolic abnormalities than non-Latinos, making CHR Latinos especially vulnerable to the compounded effects of pre-existing metabolic disturbances with added risk of further metabolic disturbance associated with the development of psychosis. In a Clinical Trial of Omega 3 Fatty Acid versus Placebo, baseline cardiometabolic and oxidative stress indices were investigated in a group at Clinical High Risk (CHR) for psychosis from the North American Prodromal Longitudinal Studies (NAPLS). The goal of the present report was to compare cardiometabolic indices in Latino versus non-Latino CHR subjects.

Background: In a recent prospective longitudinal neuroimaging study, clinical high-risk (CHR) individuals who later developed full-blown psychosis showed an accelerated rate of gray matter thinning in superior and medial prefrontal cortex (PFC) and expansion of the ventricular system after applying a stringent correction for multiple comparisons. Although cortical and subcortical volume loss and enlarged ventricles are well characterized structural brain abnormalities among patients with schizophrenia, no prior study has evaluated whether these progressive changes of neuroanatomical indicators are linked in time prior to onset of psychosis. Therefore, we investigated the relationship between the changes in cortical gray matter thickness and ventricular volume using the longitudinal neuroimaging data from the North American Prodrome Longitudinal Study (NAPLS) at the whole-brain level. Methods: MRI structural data were acquired at baseline and 12-month follow-up, and follow-up scans for those who developed fully psychotic symptoms were assessed at the point of conversion. In total, 37 CHR cases who converted to psychosis, 230 CHR cases who did not convert (nonconverters), and 132 healthy comparison subjects had usable baseline and second time point scans. Imaging measures were first transformed to annualized rates of percent change (ARCH) in each cortical vertex. Interval is the time between BL and FU scans in years. Relationships between ARCH of total ventricle volume and ARCH of cortical gray matter values were tested vertex-wise using the general linear model. Among the subjects with BL and 12-FU data available, 125 CHR cases and 66 controls were followed to an additional third time point for a 24-month MRI assessment. For the purpose of testing the replicability of our main hypotheses, neuroanatomical ARCH measures between the 12 and 24month follow-ups were also computed with a parallel set of statistical tests as described earlier. Results: The results showed that ventricular expansion is linked in time to progressive reduction of gray matter, rather than to structural changes in proximal subcortical regions, in a broadly distributed set of cortical regions among CHR youth, including superior, medial, lateral, and inferior PFC, superior temporal gyrus, and parietal cortices. In contrast, the healthy controls did not show the same pattern of associations. The main findings were further replicated using a third assessment wave of MRI scans in a subset of study participants who were followed for an additional year. Conclusion: In summary, expansion of the ventricular spaces is linked in time with an accelerated rate of widespread cortical thinning prior to psychosis onset. The cortical regions experiencing altered maturation during the psychosis prodrome may be more widespread than the regionally specific clusters that have been identified in previous case–control studies

Background: The purpose of this study was to evaluate the role of tobacco use in the development of psychosis in individuals at clinical high risk. Methods: The North American Prodrome Longitudinal Study is a 2-year multisite prospective case–control study of persons at clinical high risk that aims to better understand predictors and mechanisms for the development of psychosis. The cohort consisted of 764 clinical high risk and 279 healthy comparison subjects. Clinical assessments included tobacco and substance use and several risk factors associated with smoking. Results: Clinical high risk subjects were more likely to smoke cigarettes than unaffected subjects (Light Smoking OR=3.0, 95%CI=1.9–5; Heavy Smoking OR=4.8, 95%CI=1.7–13.7). In both groups, smoking was associated with substance use, stressful life events, and perceived discrimination and in clinical high risk subjects with childhood emotional neglect and adaption to school. Clinical high risk subjects reported higher rates of several factors previously associated with smoking. After controlling for these factors, the relationship between clinical high risk state and smoking became non-significant (Light Smoking OR=1.9, 95%CI=0.7–5.2; Heavy Smoking OR=0.9, 95%CI=0.1–7.2). Moreover, baseline smoking status (HR=1.16, 95%CI=0.82–1.65) and categorization as ever smoked (HR=1.3, 95%CI=0.8–2.1) did not predict time to conversion. Conclusion: Persons at high risk for psychosis are more likely to smoke compared to unaffected persons. Factors associated with smoking in both groups were more common in the clinical high risk cohort, and smoking status in clinical high risk subjects did not predict conversion risk. These findings did not support a causal relationship between smoking and psychosis. Funding: This study was supported by the National Institute of Mental Health (NIMH) [grant U01 MH081984 to J.A.; grants U01 MH081928; P50 MH080272; Commonwealth of Massachusetts SCDMH82101008006 to L.J.S.; grants R01 MH60720, U01 MH082022 and K24 MH76191 to K.S.C.; grant U01 MH081902 to T.D.C.; P50 MH066286 (Prodromal Core) to C.E.B.; grant U01 MH082004 to D.O.P.; grant U01 MH081988 to E.F.W.; grant U01 MH082022 to S.W.W.; and U01 MH081857-05 grant to B.A.C.] and the National Institute of Environmental Health Sciences (NIEHS) grant T32ES007018 to M.T.W. The NIMH and NIEHS had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Background: The presence of altered white matter microstructure in disorders involving psychosis is well established, but the nature and developmental course of these changes are not well understood (Peters & Karlsgodt, 2015). It is not clear whether the presence of attenuated frontal white matter anisotropy at any phase of illness indexes a pathophysiological change that occurs only within the prodromal and/or first episode phases, or whether early white matter changes are part of a lifespan trajectory of accelerated white matter degeneration in patients (Schwehm et al., 2016; Wright et al., 2014). It also remains to be determined whether schizophrenia-linked anisotropy changes are the result of axon damage or if they also reflect organizational changes.

Background: Treatment guidelines for the clinical high risk (CHR) syndrome for psychosis currently recommend psychotherapies such as cognitive behavior therapy and focused family therapy as first line treatment. Antipsychotic medications are generally discouraged for routine use, partly because of concern for adverse effects and partly due to a paucity of efficacy data, although some guidelines recommend them for more severe cases. The current study evaluated the safety and efficacy of ziprasidone in delaying or preventing conversion to psychosis among individuals meeting CHR syndrome criteria. Methods: Eligible subjects were treatment-seeking individuals 16 to 40 years old who met diagnostic criteria for CHR according to the Structured Interview for Psychosis-risk Syndromes. Exclusions were (1) use of antipsychotic medication in the previous 3 months, (2) initiation or increase in dosage of an antidepressant within 6 weeks, or (3) medical contraindications to taking ziprasidone (QTcF≥450 msec at screening or baseline, history of arrhythmia or QTc prolongation or syncope, family history of QTc prolongation, current receipt of medication known to prolong QTc, or K+, Mg++, or Ca++ below the normal range). Randomized subjects received ziprasidone 20–160 mg/d vs matching placebo for 24 weeks in two divided doses with meals. In addition, each subject was offered a Supportive Interpersonal Therapy session at each visit. Target enrollment was 80. Analyses were conducted in SPSS 21. Results: Six sites randomized 51 subjects, 27 to placebo, and 24 to ziprasidone. One ziprasidone case was never dispensed medication and was removed from analysis. Two conversions were identified in the placebo group and one in the active group; Cox regression showed no significant effect. Mixed regression on the SOPS positive symptom subscale with slope and intercept each modeled as random effects revealed a significant difference favoring ziprasidone (F = 6.64, df = 1.21, P = .017, slope difference −0.19 points per week, 95% CI −0.35 to −0.04). Two patients met QTcF criteria for safety withdrawal; both were assigned to placebo. Maximum QTcF across follow-up (placebo mean 407 msec, ziprasidone mean 403 msec) did not differ significantly. Mixed regression on weight measurements revealed no significant treatment effect (F = 0.22, df = 1.37, P = 0.645, slope difference −0.05 pounds per week, 95% CI −0.29 to 0.18). Conclusion: The primary outcome was not met, in part because the study did not meet its enrollment target and was consequently underpowered. The significant drug effect on attenuated positive symptoms provides some evidence for efficacy of ziprasidone in CHR syndrome. Together with the lack of QTc prolongation or significant weight gain in this study, the current evidence of efficacy supports consideration of ziprasidone when an antipsychotic is selected for clinical use in CHR syndrome.

Background: Contrary to popular belief the majority of patients with schizophrenia will never commit an act of severe violence. Highest risk for violent offending appears to be during the first episode of psychosis (FEP), a meta-analysis by Large and Nielssen (2010) reporting that about a third of patients in the FEP exhibited some violent behavior before initial treatment. However, most acts involve minor violence and fewer than 1 in 100 patients committed assaults resulting in serious injury. Risk of violence in clinical high risk populations, those with attenuated psychosis symptoms (APS) remains unexplored although recent findings by Marshall and colleagues (2016) suggest that a significant amount of APS involve violent content although most is self-directed violence. The aim of the current study was to explore risk of violence in individuals with attenuated psychosis symptom syndrome (APSS). We were also interested to investigate whether risk of violence as assessed was associated with symptomology. Methods: The Structured Assessment of Violence Risk in Youth (SAVRY) was completed for 285 individuals who met criteria for APSS as well as 44 Healthy Controls. The SAVRY is a clinician rated assessment tool and provides a clinical risk rating for each individual by assessing multiple domains including Historical Risk Factors, Social/Contextual Risk Factors, and Individual/Clinical Factors. Results: Violence risk was significantly different between the two groups with healthy controls assessed to be at a lower risk than individuals in the attenuated psychosis symptoms group, χ2(2)=13.03, P < .001. Only 2 of the APSS group and none of the healthy controls were rated to be at high level of risk for violence. Violence risk was not different between men and women, χ2(2)=4.58, P=1.01. Abetween-group ANOVA conducted to compare severity of attenuated psychotic symptoms and risk of violence within the APSS group showed that symptom severity was significantly different across levels of violence risk, F(2, 235)=6.32; P < .002. This was largely driven by negative symptoms severity. Individuals with low risk for violence as compared to moderate level of violence risk had lower negative symptoms, F(2, 235)=13.42; P < .000. Severity of positive, disorganized, or general symptoms independently did not differ across levels of violence risk. This relationship remained unchanged when income level was adjusted. Level of income, age, ethnicity, or parental education was not associated with level of risk. Conclusion: To our knowledge this is the first study to assess violence risk in individuals with APSS. While, the APSS group was assessed to be at a higher risk for violence as compared to healthy controls, the majority were judged to be at a moderate risk and high risk ratings were rare. In the APSS group higher risk was associated with symptoms. Specifically, results suggest that negative symptoms uniquely contribute to risk of violence.

© The Author 2017. Nearly one-third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop a psychotic disorder during life, most of them by early adulthood. Importantly, a fullblown psychotic episode is usually preceded by subthreshold symptoms. In the current study, 760 participants (aged 6-55 years) with a confirmed hemizygous 22q11.2 microdeletion have been recruited through 10 medical sites worldwide, as part of an international research consortium. Of them, 692 were nonpsychotic and with complete measurement data. Subthreshold psychotic symptoms were assessed using the Structured Interview for Prodromal Syndromes (SIPS). Nearly one-third of participants met criteria for positive subthreshold psychotic symptoms (32.8%), less than 1% qualified for acute positive subthreshold symptoms, and almost a quarter met criteria for negative/disorganized subthreshold symptoms (21.7%). Adolescents and young adults (13-25 years) showed the highest rates of subthreshold psychotic symptoms. Additionally, higher rates of anxiety disorders and attention deficit/hyperactivity disorder (ADHD) were found among the study participants with subthreshold psychotic symptoms compared to those without. Full-scale IQ, verbal IQ, and global functioning (GAF) scores were negatively associated with participants' subthreshold psychotic symptoms. This study represents the most comprehensive analysis reported to date on subthreshold psychosis in 22q11.2DS. Novel findings include age-related changes in subthreshold psychotic symptoms and evidence that cognitive deficits are associated with subthreshold psychosis in this population. Future studies should longitudinally follow these symptoms to detect whether and how early identification and treatment of these manifestations can improve long-term outcomes in those that eventually develop a psychotic disorder.

Background Language offers a privileged view into the mind; it is the basis by which we infer others’ thoughts. Subtle language disturbance is evident in schizophrenia prior to psychosis onset, including decreases in coherence and complexity, as measured using clinical ratings in familial and clinical high-risk (CHR) cohorts. Bearden et al previously used manual linguistic analysis of baseline speech transcripts in CHR to show that illogical and referential thinking, and poverty of content, predict later psychosis onset. Then, Bedi et al used automated natural language processing (NLP) of CHR transcripts to show that decreased semantic coherence and reduction in syntactic complexity predicted psychosis onset. To determine validity and reproducibility, we have applied automated NLP methods, with machine learning, to Bearden’s original CHR transcripts to identify a language profile predictive of psychosis. Methods Participants in the Bearden UCLA cohort include 59 CHR, of whom 19 developed psychosis (CHR+) within 2 years, whereas 40 did not (CHR-), as well as 16 recent-onset psychosis and 21 healthy individuals, similar in demographics; speech was elicited using Caplan’s “Story Game. Participants in the Bedi NYC cohort include 34 CHR (29 CHR+), with speech elicited using open-ended interview. Speech was audiotaped, transcribed, de-identified and then subjected to latent semantic analysis to determine coherence and part-of-speech tagging to characterize syntactic structure and complexity. A machine-learning speech classifier of psychosis onset was derived from the UCLA CHR cohort, and then applied both to the NYC CHR cohort and to the UCLA psychosis/control comparison, with convex hull (three-dimension depiction of model) and receiver operating characteristics analyses. Correlational analyses with demographics, symptoms and manual linguistic features were also done. Results A four-factor model language classifier derived from the UCLA CHR cohort that comprised three semantic coherence variables and one syntax (usage of possessive pronouns) predicted psychosis t with accuracy of 83% (intra-protocol) for UCLA CHR, 79% (cross-protocol) for NYC CHR, and 72% for discriminating psychosis from normal speech (UCLA psychosis/control). Convex hulls were defined as the smallest space containing all datapoints within a set for CHR- or healthy controls: these convex hulls showed substantial overlap, with CHR+ and psychosis speech datapoints largely outside these convex hulls. Coherence was associated with age, but speech variables did not vary by gender, race, or socioeconomic status in this study. While automated text features were unrelated to prodromal symptom severity, they were highly correlated with manual text features (r = 0.7, p < .000001). Discussion In this small preliminary study, we identified and cross-validated a robust language classifier of psychosis risk that comprised measures of semantic coherence (flow of meaning in language) and syntactic usage (usage of possessive pronouns). This classifier had utility in discriminating speech in individuals with recent-onset psychosis from the norm. It demonstrated concurrent validity in that it was highly correlated with manual linguistic features previously identified by Bearden et al, important as automated methods are fast and inexpensive. Automated language features were unrelated to sex, ethnicity or social class in these small samples, and semantic coherence increased with age, consistent with prior studies of normal language development. Of interest, overlapping convex hulls could be defined for groups of individuals without psychosis (UCLA CHR-, NYC CHR- and UCLA healthy), suggesting a constrained hull of normal language in respect to syntax and semantics, from which pre-psychosis and psychosis speech deviates. The RDoC linguistic corpus-based variables of semantic coherence and syntactic structure hold promise as biomarkers of psychosis risk and expression, with initial validation and reproducibility. Next steps in biomarker development include larger multisite studies with standardization of protocols for speech elicitation, test-retest, and attention to traction/feasibility, acceptability, cost, and utility. Mechanistic studies can also yield neural and physiological correlates of abnormal semantic coherence and syntax.

Background In spite of evidence for the premorbid and prodromal onset of cognitive deficits in schizophrenia and related psychotic disorders, there is some limited evidence to suggest that deficits may progress with psychosis onset. Cognitive remediation in youth at risk for psychosis is being touted as an opportunity not only to remediate deficits but to potentially prevent this progression. Yet trajectories of cognitive functioning over time remain poorly understood in youth at risk, including the degree to which age at assessment or illness onset, sociodemographic factors, or symptom progression influence these trajectories. Methods The North American Prodrome Longitudinal Study (NAPLS) -2 collected data on an extensive battery of neuropsychological (NP) tests at baseline, one year, two years, and post-conversion in a sample of clinical high risk (CHR) youth and healthy comparison (HC) subjects ages 12–35 (N= 960, 92% of the full sample) followed clinically for up to 2 years. NP data were available for 694 at CHR and 265 HC. Linear mixed effects analyses were used to test the effects of group, age, gender, age of onset, maternal education, and clinical outcome on cognitive trajectories. Results Those who transitioned to a psychotic disorder over the course of follow-up performed significantly below those who did not and well below healthy comparisons. Tasks reliant on attention, visual and auditory working memory, visuospatial and verbal memory, and processing speed best differentiated those who transitioned from those who did not at one year (Cohen’s d from -0.33 to -0.54). Discrepancies from normal functioning on these tests were generally large (Cohen’s d from -0.67 to -1.02) consistent with findings for first episode samples. Although clinical outcome was not associated with a significantly different trajectory over time on any cognitive domain, these are likely due to high rates of conversion in this sample within the first year. Predictors of different trajectories will be presented. Discussion These data from one of the largest CHR studies to date suggest that much of the neuropsychological dysfunction in major psychotic disorders is present early in the course of illness and prior to its full expression. However, trajectories are highly heterogeneous. More frequent assessment prior to and during the onset of illness are needed to fully understand the cognitive correlates of psychosis onset and the implications for early intervention.

Background Individuals with autism spectrum disorders (ASD) have symptoms, including social and sensory deficits, and neurobiological alterations that overlap with schizophrenia. Though there is evidence of high rates of psychosis symptoms in ASD, little is known about psychosis prodrome in ASD, or about predictors of psychosis conversion in this population. In this study, we leverage data from clinical high risk (CHR) patients from the NAPLS2 consortium to examine: a) baseline differences in psychosis symptoms and social functioning, b) relative risk of conversion, and c) whether neural response to sensory stimuli yields differential predictors of conversion in CHR individuals with and without ASD (CHR/ASD+; CHR/ASD-). Methods Clinical, electrophysiological, and 24-month follow-up data were available for 305 individuals (14 CHR/ASD+; 291 CHR/ASD-). We examined baseline differences on the SOPS, GFS, and TASIT. Conversion risk was computed with the Cannon conversion calculator, and conversion was defined as SOPS>6 at 2-year outcome. P300 event-related potentials (ERP) were extracted from ongoing EEG collected at baseline in response to Target and Novel auditory and visual stimuli, each presented on 10% of trials within streams of 80% standard stimuli in the same modality. Results In line with our expectations, CHR/ASD+ had worse functioning than CHR/ASD- on the GF-Social scale (t=-4.2, p

Background Accumulated evidence from non-human animal studies suggests that the prominent deficits in memory and executive function that characterise individuals with psychosis may, at least in part, be due to the effects of stress on the brain regions that support these functions. However, studies of patients with established psychosis have yielded inconsistent findings with regards to the relationship between stress and cognition, and research in high-risk populations is notably lacking. Utilising data from the North American Prodrome Longitudinal Study 2 (NAPLS 2), we aimed to further elucidate the relationship between stress (daily stressors, life events, and childhood trauma) and cognitive function in clinical high-risk (CHR) individuals and healthy controls (HC). We additionally explored the role of potential mediators [hypothalamic-pituitary-adrenal (HPA) axis function] and moderators (group status, sex, family history of illness). Methods The sample comprised 885 participants (CHR=646; HC=239) who completed measures of stress and cognitive function at the NAPLS 2 baseline assessment. Stress measures included the Daily Stress Inventory and a modified version of the Psychiatric Epidemiology Research Interview Life Events Scale, both of which provided continuous measures of stress exposure (number of events) and distress (subjective feelings of distress). Participants were also interviewed using the Childhood Trauma and Abuse Scale to determine any exposure to childhood trauma (abuse, neglect, and bullying occurring prior to age 16 years). Basal HPA axis activity was determined via salivary cortisol samples obtained at the baseline assessment and standardised scores from selected subtests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) were used to derive two cognitive domain scores (memory and executive function). To examine relationships between stress and cognitive domain scores, linear regression analyses were performed on standardised variables. Results Daily stressor exposure, daily stressor distress, and life event exposure exhibited negative quadratic (i.e., inverted U-shaped) associations with both memory and executive function (P < 0.01 for all). In contrast, the reverse pattern (i.e., a negative linear relationship and a positive quadratic relationship) was shown in the model for life event distress and memory domain scores (P < 0.01) whilst trauma history showed only a trend-level association with poorer memory performance (P = 0.084). These relationships, which did not differ across CHR and healthy control groups, were largely unchanged after adjusting for demographic factors and salivary cortisol. Exploratory analyses suggested that trauma exposure and a family history of psychosis may moderate the relationship between daily stressors/life events and cognitive function. Discussion In this large sample of predominately CHR individuals, we observed that the association between stress and cognition is complex and differs across stressor types. The negative quadratic associations that we observed for daily stressor exposure, daily stressor distress, and life event exposure imply that whist lower levels of stress may facilitate memory and executive function, there may be a negative impact on cognition when these stressors become more frequent and distressing. Interventions aiming to minimise stress exposure and promote effective coping strategies might feasibly improve cognition in CHR individuals.

22q11.2 deletion syndrome (22q11DS) is associated with elevated levels of impulsivity, inattention, and distractibility, which may be related to underlying neurobiological dysfunction due to haploinsufficiency for genes involved in dopaminergic neurotransmission (i.e. catechol-O-methyltransferase). The Stop-signal task has been employed to probe the neural circuitry involved in response inhibition (RI); findings in healthy individuals indicate that a fronto-basal ganglia network underlies successful inhibition of a prepotent motor response. However, little is known about the neurobiological substrates of RI difficulties in 22q11DS. Here, we investigated this using functional magnetic resonance imaging while 45 adult participants (15 22q11DS patients, 30 matched controls) performed the Stop-signal task. Healthy controls showed significantly greater activation than 22q11DS patients within frontal cortical and basal ganglia regions during successful RI, whereas 22q11DS patients did not show increased neural activity relative to controls in any regions. Using the Barratt Impulsivity Scale, we also investigated whether neural dysfunction during RI was associated with cognitive impulsivity in 22q11DS patients. RI-related activity within left middle frontal gyrus and basal ganglia was associated with severity of self-reported cognitive impulsivity. These results suggest reduced engagement of RI-related brain regions in 22q11DS patients, which may be relevant to characteristic behavioral manifestations of the disorder.

22q11.2 deletion syndrome (22q11DS) is a genetic mutation associated with disorders of cortical connectivity and social dysfunction. However, little is known about the functional connectivity (FC) of the resting brain in 22q11DS and its relationship with social behavior. A seed-based analysis of resting-state functional magnetic resonance imaging data was used to investigate FC associated with the posterior cingulate cortex (PCC), in (26) youth with 22qDS and (51) demographically matched controls. Subsequently, the relationship between PCC connectivity and Social Responsiveness Scale (SRS) scores was examined in 22q11DS participants. Relative to 22q11DS participants, controls showed significantly stronger FC between the PCC and other default mode network (DMN) nodes, including the precuneus, precentral gyrus and left frontal pole. 22q11DS patients did not show age-associated FC changes observed in typically developing controls. Increased connectivity between PCC, medial prefrontal regions and the anterior cingulate cortex, was associated with lower SRS scores (i.e. improved social competence) in 22q11DS. DMN integrity may play a key role in social information processing. We observed disrupted DMN connectivity in 22q11DS, paralleling reports from idiopathic autism and schizophrenia. Increased strength of long-range DMN connectivity was associated with improved social functioning in 22q11DS. These findings support a ‘developmental-disconnection’ hypothesis of symptom development in this disorder.

Callosal volume reduction has been observed in patients with bipolar disorder, but whether these deficits reflect genetic vulnerability to the illness remains unresolved. Here, we used computational methods to map corpus callosum abnormalities in a population-based sample of twin pairs discordant for bipolar disorder. Twenty-one probands with bipolar I disorder (mean age 44.4 ± 7.5 years; 48% female), 19 of their non-bipolar co-twins, and 34 demographically matched control twin individuals underwent magnetic resonance imaging. Three-dimensional callosal surface models were created to visualize its morphologic variability and to localize group differences. Neurocognitive correlates of callosal area differences were additionally investigated in a subsample of study participants. Bipolar (BPI) probands, but not their co-twins, showed significant callosal thinning and area reduction, most pronounced in the genu and splenium, relative to healthy twins. Altered callosal curvature was additionally observed in BPI probands. In bipolar probands and co-twins, genu and splenium midsagittal areas were significantly correlated with verbal processing speed and response inhibition. These findings suggest that aberrant connections between cortical regions--possibly reflecting decreased myelination of white matter tracts--may be involved in bipolar pathophysiology. However, findings of callosal thinning appear to be disease related, rather than reflecting genetic vulnerability to bipolar illness.

Introduction: Research on prediction and prevention of schizophrenia has increasingly focused on prodromal (prepsychosis) social and role dysfunction as developmentally early, stable, and treatment-resistant illness components. In this report, 2 new measures, Global Functioning: Social and Global Functioning: Role, are presented, along with preliminary findings about psychometric properties and course of social and role (academic/work) functioning in the prodromal phase of psychosis. Methods: Subjects included 69 participants from the Recognition and Prevention program and 52 from the Center for the Assessment and Prevention of Prodromal States. Ages ranged from 12 to 29 years, and all met criteria for Attenuated Positive Symptom syndrome. Retrospective (past year) and baseline data are reported for all 121 prodromal subjects and for 44 normal controls (NCs). Prospective follow-up data are reported for a subsample of patients reevaluated at both 6 and 12 months (N = 44). Results: For both scales, inter-rater reliability was high, and preliminary data supported construct validity. Relative to NCs, prodromal individuals displayed impaired social and role functioning at baseline. Analyses of change over time indicated that role functioning declined over the year before ascertainment and improved over 12-month follow-up, presumably with treatment. Social impairment, by contrast, was constant across time and predicted later psychosis (P = .002). Discussion: Using 2 new global measures, social functioning was found to be a stable trait, unchanged by treatment, with considerable potential to be a marker of schizophrenia. Role functioning, by contrast, may be a more direct barometer of clinical change and may be responsive to treatment and environmental change.