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

IntroductionArea-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with reduced gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC). We hypothesize that greater ARI will be associated with reduced right CMFG and rACC GMVs.MethodsData were collected at baseline as part of the North American Prodrome Longitudinal Study Phase 2. Counties where participants resided during childhood were geographically coded using the US Census to area-level factors. ARI was defined as the percentage of residents living in a different house 5 years ago. Generalized linear mixed models tested associations between ARI and GMVs.ResultsThis study included 29 healthy controls (HC)s and 64 clinical high risk for psychosis (CHR-P) individuals who were aged 12 to 24 years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG (adjusted β = -0.258; 95% CI = -0.502 to -0.015) and right rACC volumes (adjusted β = -0.318; 95% CI = -0.612 to -0.023). The interaction term (ARI-by-diagnostic group) in the prediction of both brain regions was not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs.ConclusionsARI may adversely impact similar brain regions as urban upbringing. Further investigation into the potential mechanisms of the relationship between ARI and neurobiology, including social stress, is needed.

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.

IntroductionDisturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time.MethodsData were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations.ResultsDisturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar.DiscussionThe critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state.

OBJECTIVE: Accumulating evidence supports an association between residential instability and increased risk for psychosis, but the association between residential instability and conversion to psychosis among adolescents at clinical high risk (CHR) is unclear. In this study, we determined whether individual-level and area-level residential instability and their interaction are associated with conversion to psychosis within two years. METHODS: Data were collected as part of the North American Prodrome Longitudinal Study Phase 2. Individual-level residential instability, defined as having ever moved during lifetime, was derived from the Life Events Scale. Area-level residential instability, defined as the percentage of people who were not living in the same house five years ago, was derived from the U.S. Decennial Censuses. RESULTS: This study included 285 adolescents at CHR (including 36 subjects who later converted to full psychosis). We found that individual-level residential instability was associated with conversion (adjusted OR = 2.769; 95% CI = 1.037-7.393). The interaction between individual-level and area-level residential instability was significant (p = 0.030). In a subgroup of CHR participants who have never moved (n = 91), area-level residential instability during childhood was associated with conversion (adjusted OR = 1.231; 95% CI = 1.029-1.473). Conversely, in a subgroup of CHR participants who resided in residentially stable areas during childhood (n = 142), the association between individual-level residential instability and conversion remained significant (adjusted OR = 15.171; 95% CI = 1.753-131.305). CONCLUSIONS: These findings suggest that individual-level and area-level residential instability may be associated with conversion to psychosis.

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

Elevations in peripheral inflammatory markers have been reported in patients with psychosis. Whether this represents an inflammatory process defined by individual or subgroups of markers is unclear. Further, relationships between peripheral inflammatory marker elevations and brain structure, cognition, and clinical features of psychosis remain unclear. We hypothesized that a pattern of plasma inflammatory markers, and an inflammatory subtype established from this pattern, would be elevated across the psychosis spectrum and associated with cognition and brain structural alterations. Clinically stable psychosis probands (Schizophrenia spectrum, n = 79; Psychotic Bipolar disorder, n = 61) and matched healthy controls (HC, n = 60) were assessed for 15 peripheral inflammatory markers, cortical thickness, subcortical volume, cognition, and symptoms. A combination of unsupervised exploratory factor analysis and hierarchical clustering was used to identify inflammation subtypes. Levels of IL6, TNFα, VEGF, and CRP were significantly higher in psychosis probands compared to HCs, and there were marker-specific differences when comparing diagnostic groups. Individual and/or inflammatory marker patterns were associated with neuroimaging, cognition, and symptom measures. A higher inflammation subgroup was defined by elevations in a group of 7 markers in 36% of Probands and 20% of HCs. Probands in the elevated inflammatory marker group performed significantly worse on cognitive measures of visuo-spatial working memory and response inhibition, displayed elevated hippocampal, amygdala, putamen and thalamus volumes, and evidence of gray matter thickening compared to the proband group with low inflammatory marker levels. These findings specify the nature of peripheral inflammatory marker alterations in psychotic disorders and establish clinical, neurocognitive and neuroanatomic associations with increased inflammatory activation in psychosis. The identification of a specific subgroup of patients with inflammatory alteration provides a potential means for targeting treatment with anti-inflammatory medications.

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

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

Abstract 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

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