Abstract

Background

A dysregulated immune system is implicated in the development of psychotic disorders. Persons with schizophrenia have altered levels of circulating immune cell signaling molecules (cytokines), and elevation of specific cytokines predict conversion to psychosis in persons at clinical high risk. Whether these peripheral signals are a causal or a secondary phenomenon is unclear. But, subpopulations of circulating immune cells do regulate the brain from meningeal and perivascular locations influencing cognition, mood, and behavior, and thus may be relevant to schizophrenia vulnerability. Hematopoietic stem cells in the bone marrow differentiate into cascading subtypes depending on signals from other organs, especially the brain. For example, a monocyte subpopulation emerges with repeated social defeat that establish the persistence of anxiety-like behaviors; blocking their release or inhibiting their attachment to brain vascular endothelium prevents the emergence of anxiety-like behaviors. In humans, a similar monocyte subpopulation is associated with social isolation and other adversities including low SES, chronic stress, and bereavement.

Methods

The North American Prodrome Longitudinal Study (NAPLS2) is an eight-site observational study of predictors and mechanisms of conversion to psychosis The full cohort includes 763 at clinical high risk (CHR) based on the Criteria of Prodromal State (COPS) and 279 demographically similar unaffected comparison (UC) subjects. Methylation of whole blood DNA collected in PAXgene tubes at baseline was analyzed with the Illumina 450k array in a subgroup of 59 subjects who converted to psychosis (CHR-C), 84 CHR subjects followed for 2 years who did not develop psychosis (CHR-NC) and 67 unaffected subjects (UC). Our analyses focused on methylation of promoter regions of genes, associated with gene expression. Classifier construction used Coarse Approximation Linear Function (CALF) with bootstrapping of 1000 random 80% subsets with replacement to determine statistical likelihood.

Results

We found highly overlapping sets of differentially methylated promoter regions in CHR-C subjects compared to CHR-NC and to UC subjects. A set of 10 markers correctly classified CHR-C and CHR-NC subjects with high accuracy (AUC=0.94, 95% CI 0.89–0.98). Included was SIRT1, a gene that is upregulated with HSV reactivation.

Discussion

Circulating immune cells excerpt powerful influences on mood, cognition and behavior. An obvious example is the experience of most human with “sickness syndrome”, characterized by apathy, avolition, and withdrawal, and triggered by immune-cell-released cytokines producing an adaptive, resource conserving, behavioral response. While at an early stage, our findings further implicate immune system dysregulation as a mechanism in the development of psychosis.

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 vast majority of studies of neuropsychological (NP) functioning in Clinical High Risk (CHR) cohorts have examined group averages, possibly concealing a range of subgroups ranging from very impaired to high functioning. Our objective was to assess NP profiles and to explore associations with conversion to psychosis, functional and diagnostic outcome.

Methods

Data were acquired from 324 participants (mean age 18.4) in the first phase of the North American Prodrome Longitudinal Study (NAPLS-1), a multi-site consortium following individuals for up to 2½ years. We applied Ward’s method for hierarchical clustering data to 8 baseline neurocognitive measures, in 166 CHR individuals, 49 non-CHR youth with a family history of psychosis, and 109 healthy controls. We tested whether cluster membership was associated with conversion to psychosis, social and role functioning, and follow-up diagnosis. Analyses were repeated after data were clustered based on independently developed clinical decision rules.

Results

Four neurocognitive clusters were identified: Significantly Impaired (n=33); Mildly Impaired (n=82); Normal (n=145) and High (n=64). The Significantly Impaired subgroup demonstrated the largest deviations on processing speed and memory tasks and had a conversion rate of 58%, a 40% chance of developing a schizophrenia spectrum diagnosis (compared to 24.4% in the Mildly Impaired, and 10.3% in the other two groups combined), and significantly worse functioning at baseline and 12-months. Data clustered using clinical decision rules yielded similar results, pointing to high convergent validity.

Discussion

Despite extensive neuropsychological investigations within CHR cohorts, this is one of the first studies to investigate NP clustering profiles as a contributor to heterogeneity in outcome. Our results indicate that the four NP profiles vary substantially in their outcome, underscoring the relevance of cognitive functioning in the prediction of illness progression. Our findings tentatively suggest that individualized cognitive profiling should be explored in clinical settings.

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.

The National Institutes of Health has established the PhenX Toolkit as a web-based resource containing consensus measures freely available to the research community. The National Institute of Mental Health (NIMH) has introduced the Mental Health Research Core Collection as part of the PhenX Toolkit and recently convened the PhenX Early Psychosis Working Group to generate the PhenX Early Psychosis Specialty Collection. The Working Group consisted of two complementary panels for clinical and translational research. We review the process, deliberations, and products of the translational research panel. The Early Psychosis Specialty Collection rationale for measure selection as well as additional information and protocols for obtaining each measure are available on the PhenX website (https://www.phenxtoolkit.org). The NIMH strongly encourages investigators to use instruments from the PhenX Mental Health Research Collections in NIMH-funded studies and discourages use of alternative measures to collect similar data without justification. We also discuss some of the potential advances that can be achieved by collecting common data elements across large-scale longitudinal studies of early psychosis.

BACKGROUND: The clinical high-risk (CHR) period offers a temporal window into neurobiological deviations preceding psychosis onset, but little attention has been given to regions outside the cerebrum in large-scale studies of CHR. Recently, the North American Prodrome Longitudinal Study (NAPLS)-2 revealed altered functional connectivity of the cerebello-thalamo-cortical circuitry among individuals at CHR; however, cerebellar morphology remains underinvestigated in this at-risk population, despite growing evidence of its involvement in psychosis. STUDY DESIGN: In this multisite study, we analyzed T1-weighted magnetic resonance imaging scans obtained from N = 469 CHR individuals (61% male, ages = 12-36 years) and N = 212 healthy controls (52% male, ages = 12-34 years) from NAPLS-2, with a focus on cerebellar cortex and white matter volumes separately. Symptoms were rated by the Structured Interview for Psychosis-Risk Syndromes (SIPS). The outcome by two-year follow-up was categorized as in-remission, symptomatic, prodromal-progression, or psychotic. General linear models were used for case-control comparisons and tests for volumetric associations with baseline SIPS ratings and clinical outcomes. STUDY RESULTS: Cerebellar cortex and white matter volumes differed between the CHR and healthy control groups at baseline, with sex moderating the difference in cortical volumes, and both sex and age moderating the difference in white matter volumes. Baseline ratings for major psychosis-risk dimensions as well as a clinical outcome at follow-up had tissue-specific associations with cerebellar volumes. CONCLUSIONS: These findings point to clinically relevant deviations in cerebellar cortex and white matter structures among CHR individuals and highlight the importance of considering the complex interplay between sex and age when studying the neuromaturational substrates of psychosis risk.

Abstract

Background

The clinical high-risk period before a first episode of psychosis (CHR-P) has been widely studied in the past 30 years with the goal of understanding the development of psychosis. Despite the progress in understanding what factors are associated with conversion to psychosis from the CHR-P state, less attention has been paid to the individuals who do not transition to psychosis. It is estimated that approximately 75–80% of individuals do not go on to convert to psychosis from the CHR-P state and this group should not simply be characterized as the inverse of conversion. To date, only a handful of studies have examined the characteristics and predictors of those who do not convert to psychosis and ultimately either remit or continue to meet symptom-based CHR-P criteria. The present study took an exploratory empirical approach to determining potential factors that predict remission in non-converters.

Methods

Participants were drawn from the North American Prodrome Longitudinal Study (NAPLS2). Univariate Kaplan Meier survival analyses were performed on a pool of available demographic and clinical variables. Variables that were significant (p < 0.05) in the univariate analyses were then included in a multivariate Cox proportional hazard regression to predict remission. Remission was defined as all SOPS positive symptom subscale items rated as a 2 or lower at any given follow-up visit.

Results

A total of 359 participants from the NAPLS2 study who did not convert to psychosis and had data for at least the baseline and first follow-up visit and were included in this study. Of these participants, 174 met criteria for symptomatic remission. A total of 57 clinical variables were tested in univariate analyses and 14 of these variables met criteria for inclusion in the multivariate model. The variables included in the multivariate model were demographic variables (ethnicity, stressful life events), items from the Scale of Prodromal Symptoms (SOPS) (avolition, dysphoric mood), subtest scores from the MATRICS Cognitive Battery (speed of processing, verbal learning, verbal and non-verbal working memory, reasoning and problem solving, visual learning), one item from the Calgary Depression Scale for Schizophrenia (CDSS) (pathological guilt) and measures of functioning (GAF decline in past year, lowest GAF score in the past year). Overall, the multivariate model achieved a C-index of 0.64 (SE = 0.02) and p-value of 0.001 in predicting remission. In the multivariate model, significant covariates included stressful life events (HR = .95, p = .006), Hispanic ethnicity (HR = 1.45, p = .045), and avolition (HR = .89, p = .04). Covariates approaching significance included visual learning (HR = 1.02, p = .07), and GAF decline in the past year (HR = 1.01, p = .09).

Discussion

This study is the first to use a data-driven approach to systematically assess clinical and demographic predictors of symptomatic remission in individuals who do not convert to psychosis. The identified set of significant clinical variables is novel, suggesting that remission represents a unique clinical phenomenon and suggesting that further study is warranted to best understand factors contributing to resilience and recovery from the CHR-P period.

Abstract

Background

The development of the clinical high-risk (CHR) prodromal criteria has facilitated advancement in understanding conversion to psychosis and has provided opportunities for early intervention and treatment for these individuals. However, the majority of CHR cases do not meet full criteria for conversion, yet continue to experience clinically significant symptoms and impairment in daily functioning. It is likely that many of these individuals would also benefit from additional intervention and treatment, but the outcomes and needs of these “non-converters” are not well characterized. Identifying common longitudinal patterns of symptoms and functioning of non-converters would support the identification of individuals who continue to require treatment and tailoring of services to their specific needs.

Methods

We used group-based trajectory modeling to identify common longitudinal symptom and functioning trajectories among CHR cases (N=561) in the second phase of the North American Prodrome Longitudinal Study (NAPLS2). Covariant trajectories of symptoms (including positive, negative, disorganized, and general) and functioning (including role and social) were examined. Models were tested for replicability in an independent sample of CHR cases (N=291) from the first phase of NAPLS (NAPLS1).

Results

We identified a subgroup of individuals who exhibited symptom remission and functioning within the normal range, as well as at least two additional subgroups that exhibited different patterns of ongoing, clinically significant symptoms and functional deficits.

Discussion

We are currently investigating the validity of these subgroups by assessing their association with a variety of risk factors and biomarkers.

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.