Abstract Background: Longitudinal studies examining youth at clinical high risk (CHR) of psychosis have predominantly focused on positive symptoms. However, youth at CHR often demonstrate persistent and significant negative symptoms, which have been reported to be predictive of conversion to psychosis. The goal of this study was to examine negative symptoms over time in youth at CHR of psychosis and compare baseline negative symptoms in those who convert to psychosis with those who did not convert. Methods: Youth at CHR (N = 764) 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. Difference in prevalence of negative symptoms was assessed using Z test and change in negative symptom severity over time was assessed using repeated measures analysis of variance ANOVA. Wilcoxon rank sum test and 2-sample t test were utilized to compare baseline negative symptoms in converters vs nonconverters. Results: The mean total negative symptom score at baseline was 11.90 (SD = 9.80). A majority of participants (84.57%) had at least one negative symptom rated ≥3 at baseline. Negative symptom severity significantly decreased over time compared to baseline measures. Eighty-six participants converted in total. In participants with at least one negative symptom of moderate severity or above (N ≥ 3), nonconverters had lower severity ratings on expression of emotion (M = 1.49, SD = 1.47 vs M = 1.94, SD = 1.64, P = .02) and ideational richness (M = 1.23, SD = 1.37 vs M = 1.60, SD = 1.35, P = .04) compared to converters at baseline. In participants who completed 24 months of assessment and had negative symptom severity of moderate severity or above (N ≥ 3), nonconverters had significantly better expression of emotion (M = 1.40, SD = 1.51) compared to converters (M = 1.79, SD = 1.63, P = .03). Conclusion: First, this study demonstrated that the majority of youth at CHR have moderate to severe negative symptoms at baseline. Second, both decreased expression of emotion and decreased ideational richness was significantly more severe in participants who converted and may be indicative of later conversion to psychosis. Thus, early and persistent higher negative symptom scores may represent subsequent risk of conversion to psychosis.

Abstract Background: Omega-3 Fatty Acids (FAs), EPA (eicosapentaenoic acid) and DHA (Docosahexaenoic acid), are essential for normal brain development and may also have neuroprotective properties. Dietary supplementation of EPA and DHA has beneficial effects in medical illnesses as well as depression, bipolar disorder, and dementia. Abnormal FA metabolism may play a role in the etiology of psychiatric illness. Studies of erythrocytes and skin fibroblasts have shown reduced levels of FAs and phospholipids in schizophrenia. Studies of Omega-3FA supplementation in schizophrenia have been mixed. Amminger et al performed a randomized, double-blind, placebo-controlled trial in 81 subjects with prodromal symptoms of psychosis. The treatment consisted of 1.2g/day of Omega-3FAs (700 mg EPA, 480 mg DHA). After 12 weeks, 2 (4.9%) of 41 individuals in the Omega-3FA group and 11 of 40 (27.5%) in the placebo group converted to a psychotic disorder. Omega-3FAs also significantly reduced symptoms and improved functioning. The Aims of the current study were to replicate the Amminger study in Clinical High Risk (CHR) subjects from the NAPLS consortium. Methods: This was a 24-week, randomized, double-blind, placebo, fixed dose-controlled study of Omega-3FA versus placebo in 127 CHR subjects. The Omega-3FA compound contained a 2:1 proportion of EPA to DHA. The total dose was 740 mg of EPA and 400 mg of DHA. Baseline diet characterization was assessed using a systematic checklist that includes Omega-3FA foods. In addition, fasting erythrocyte FA composition was assessed. Results: Of the 127 CHR subjects recruited into the trial, 118 completed baseline assessment, and 70 (59%) completed the 6-month trial. Seven (10% Kaplan-Meier) subjects converted to psychosis during the 24 months. The rate of psychotic conversion did not differ in the Omega-3FA (13%) versus Placebo (8%) samples. Conversion to psychosis was predicted by low Omega-3FA rich foods in the diet (Wald Statistic = 4.96, P < .05). Although there were significant improvements in symptom and functioning over time in Mixed Model analyses, there were no significant group or Group × Time interaction effects. Conclusion: The rate of conversion to psychosis in the present sample was lower than is typically observed in an at-risk population. Given the study attrition and low rate of conversion to psychosis, the trial was underpowered to replicate the conversion effect in the Amminger et al.’s study. Despite the overall improvement in symptoms and functioning over time in all subjects, there was no clear evidence of a differential effect in the sample on Omega-3FA vs Placebo. Further work is needed to better tease out the role of diet and Omega-3FA in mental illness. The finding of a significant association between baseline diet low in Omega-3FA rich foods and later conversion to psychosis raises the question of whether it is possible to influence both physical and mental health with lifestyle choices including diet.

Abstract 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 2 years 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: A pattern 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.

Abstract Background: Longitudinal studies examining youth at clinical high risk (CHR) of psychosis have predominantly focused on positive symptoms. However, youth at CHR often demonstrate persistent and significant negative symptoms, which have been reported to be predictive of conversion to psychosis. The goal of this study was to examine negative symptoms over time in youth at CHR of psychosis and compare baseline negative symptoms in those who convert to psychosis with those who did not convert. Methods: Youth at CHR (N = 764) 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. Difference in prevalence of negative symptoms was assessed using Z test and change in negative symptom severity over time was assessed using repeated measures analysis of variance ANOVA. Wilcoxon rank sum test and 2-sample t test were utilized to compare baseline negative symptoms in converters vs nonconverters. Results: The mean total negative symptom score at baseline was 11.90 (SD = 9.80). A majority of participants (84.57%) had at least one negative symptom rated ≥3 at baseline. Negative symptom severity significantly decreased over time compared to baseline measures. Eighty-six participants converted in total. In participants with at least one negative symptom of moderate severity or above (N ≥ 3), nonconverters had lower severity ratings on expression of emotion (M = 1.49, SD = 1.47 vs M = 1.94, SD = 1.64, P = .02) and ideational richness (M = 1.23, SD = 1.37 vs M = 1.60, SD = 1.35, P = .04) compared to converters at baseline. In participants who completed 24 months of assessment and had negative symptom severity of moderate severity or above (N ≥ 3), nonconverters had significantly better expression of emotion (M = 1.40, SD = 1.51) compared to converters (M = 1.79, SD = 1.63, P = .03). Conclusion: First, this study demonstrated that the majority of youth at CHR have moderate to severe negative symptoms at baseline. Second, both decreased expression of emotion and decreased ideational richness was significantly more severe in participants who converted and may be indicative of later conversion to psychosis. Thus, early and persistent higher negative symptom scores may represent subsequent risk of conversion to psychosis.

Abstract Background: Social skills develop along with metacognitive abilities from early childhood through young adulthood. Impairment in metacognitive and other social cognitive abilities may contribute to poorer social function in clinical high risk for psychosis (CHR) adolescents. However, it is unclear whether social cognitive impairment represents developmental delay in skill acquisition or, rather, a consequence of emerging symptoms. Furthermore, it is unknown how early pharmacotherapy could influence this developmental trajectory. This study examined the hypotheses that (1) age-related trajectories of social cognition differ between CHR and normally developing youth and (2) age-related trajectories are partially explained by history of symptoms and psychotropic medication. Methods: Emotion perception, social perception, and theory of mind abilities were assessed in 675 CHR and 264 age-matched healthy comparison (HC) participants aged 12–35 (average = 19.0 ± 4.5 years). Linear and nonlinear curves were fit to relationships between social cognitive variables and age. Differences in age effects between CHR and HC were modeled as interaction terms. Duration of a prodromal syndrome prior to baseline and medication history were tested for interactions with age effects. Results: Emotion perception and social perception age trajectories did not differ by group. Theory of mind age trajectory, particularly for sarcasm items, had a lower slope for CHR than HC. CHR diverged from HC from mid-adolescence onward (starting to differ between approximately ages 15 and 17.5), with a minimum observation window of 4 years required to detect correlations with age. Age trajectory for theory of mind was unrelated to the presence or duration of a prior prodromal syndrome but did interact with medication history, wherein participants with an antipsychotic or antidepressant medication history did not differ from HCs. Only antipsychotic- and antidepressant-naive CHR participants showed a smaller slope for theory of mind, with differences from HC increasing with advanced age. Conclusion: In the current study, all social cognitive abilities increased during adolescence, but development of theory of mind appeared blunted for CHR participants starting in mid-adolescence. This difference, however, was only true for participants without an antipsychotic or antidepressant medication history, which could suggest benefits of early treatment or subgroups within CHR for whom social cognition is affected differently. These cross-sectional results require longitudinal replication and further inquiry into the relationships between treatment history and social cognitive development. Current results suggest that factors related to risk for psychosis may moderate adolescent social development, and that interventions targeting social cognition may be particularly helpful at this stage.

Abstract Background: In a recent report of the North American Prodrome Longitudinal Study (NAPLS), clinical high-risk individuals who converted to psychosis showed a steeper rate of cortical gray matter reduction compared with nonconverters and healthy controls, and the rate of cortical thinning was correlated with levels of proinflammatory cytokines at baseline. These findings suggest a critical role for microglia, the resident macrophages in the brain, in perturbations of cortical maturation processes associated with onset of psychosis. Elucidating gene expression pathways promoting microglial action prior to disease onset would inform potential preventative intervention targets. Methods: We used a forward stepwise regression algorithm to build a classifier of baseline microRNA expression in peripheral leukocytes associated with annualized rate of cortical thinning in a subsample of the NAPLS cohort (N = 74). Results: Our cortical thinning classifier included 9 microRNAs, P = 3.63 × 108, R2 = 0.358, permutation-based P = .039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (P < .05, Benjamini-Hochberg corrected). The classifier was also related to proinflammatory cytokine levels in serum (P = .038). Furthermore, miRNAs that predicted conversion status were found to do so in a manner partially mediated by rate of cortical thinning (point estimate = 0.078 [95% CIs: 0.003, 0.168], P = .03). Conclusion: Many of the miRNAs identified here have been previously implicated in brain development, synaptic plasticity, immune function, and/or schizophrenia, showing some convergence across studies and methodologies. Altered intracellular signaling within the immune system may interact with cortical maturation in individuals at high risk for schizophrenia promoting disease onset.

Introduction

Persistent negative symptoms (PNS) are described as continuing moderate negative symptoms. More severe negative symptoms have been associated with poor premorbid functioning in both chronic schizophrenia and first episode psychosis patients. Furthermore, youth at clinical high risk (CHR) for developing psychosis may also present with negative symptoms and poor premorbid functioning. The aim of this current study was to: (1) define the relationship between PNS and premorbid functioning, life events, trauma and bullying, previous cannabis use, and resource utilization, and (2) to examine what explanatory variables best predicted PNS.

Method

CHR participants (N = 709) were recruited from the North American Prodrome Longitudinal Study (NAPLS 2). Participants were divided into two groups: those with PNS (n = 67) versus those without PNS (n = 673). A K-means cluster analysis was conducted to distinguish patterns of premorbid functioning across the different developmental stages. The relationships between premorbid adjustment and other variables were examined using independent samples t-tests or chi square for categorical variables.

Results

There was significantly more males in the PNS group. Participants with PNS had significantly lower levels of premorbid adjustment in childhood, early adolescence, and late adolescence, compared to CHR participants without PNS. There were no differences between the groups in terms of trauma, bullying, and resource utilization. The non-PNS group had more cannabis use and more desirable and non-desirable life events.

Conclusion

In terms of better understanding relationships between early factors and PNS, a prominent factor associated with PNS was premorbid functioning, in particular poor premorbid functioning in later adolescence.