Differential expression of haptoglobin in individuals at clinical high risk of psychosis and its association with global functioning and clinical symptoms.

BACKGROUND: Immune dysregulation has been observed in patients with schizophrenia or first-episode psychosis, but few have examined dysregulation in those at clinical high-risk (CHR) for psychosis. The aim of this study was to examine whether the peripheral blood-based proteome was dysregulated in those with CHR. Secondly, we examined whether baseline dysregulation was related to current and future functioning and clinical symptoms. METHODS: We used data from participants of the North American Prodromal Longitudinal Studies (NAPLS) 2 and 3 (n = 715) who provided blood samples (Unaffected Comparison subjects (UC) n = 223 and CHR n = 483). Baseline proteomic data was quantified from plasma samples using mass spectrometry. Differential expression was examined between CHR and UC using logistic regression. Psychosocial functioning was measured using the Global Assessment of Functioning scale (GAF). Symptoms were measured using the subscale scores from the Scale of Psychosis-risk Symptoms; positive, negative, general, and disorganised. Three measures of each outcome were included: baseline, longest available follow-up (last follow-up) and most severe follow-up (MSF). Associations between the proteomic data, GAF and symptoms were assessed using ordinal regression. RESULTS: Of the 99 proteins quantified, six were differentially expressed between UC and CHR. However, only haptoglobin (HP) survived FDR-correction (OR:1.45, 95 %CI:1.23-1.69, padj = <0.001). HP was cross-sectionally and longitudinally associated with functioning and symptoms such that higher HP values were associated with poorer functioning and more severe symptoms. Results were evident after stringent adjustment and poorer functioning was observed in both NAPLS cohort separately. CONCLUSION: We demonstrate that elevated HP is robustly observed in those at CHR for psychosis, irrespective of transition to psychosis. HP is longitudinally associated with poorer functioning and greater symptom severity. These results agree with previous reports of increased HP gene expression in individuals at-risk for psychosis and with the dysfunction of the acute phase inflammatory response seen in psychotic disorders.

Plasma complement and coagulation proteins as prognostic factors of negative symptoms: An analysis of the NAPLS 2 and 3 studies.

INTRODUCTION: Negative symptoms impact the quality of life of individuals with psychosis and current treatment options for negative symptoms have limited effectiveness. Previous studies have demonstrated that complement and coagulation pathway protein levels are related to later psychotic experiences, psychotic disorder, and functioning. However, the prognostic relationship between complement and coagulation proteins and negative symptoms is poorly characterised. METHODS: In the North American Prodrome Longitudinal Studies 2 and 3, negative symptoms in 431 individuals at clinical high-risk for psychosis (mean age: 18.2, SD 3.6; 42.5 % female) were measured at multiple visits over 2 years using the Scale of Psychosis-Risk Symptoms. Plasma proteins were quantified at baseline using mass spectrometry. Four factors were derived to represent levels of proteins involved in the activation or regulation of the complement or coagulation systems. The relationships between standardised protein group factors and serial measurements of negative symptoms over time were modelled using generalised least squares regression. Analyses were adjusted for baseline candidate prognostic factors: negative symptoms, positive symptoms, functioning, depressive symptoms, suicidal ideation, cannabis use, tobacco use, antipsychotic use, antidepressant use, age, and sex. RESULTS: Clinical and demographic prognostic factors of follow-up negative symptoms included negative, positive, and depressive symptoms, functioning, and age. Adjusting for all candidate prognostic factors, the complement regulators group and the coagulation regulators group were identified as prognostic factors of follow-up negative symptoms (ß: 0.501, 95 % CI: 0.160, 0.842; ß: 0.430, 95 % CI: 0.080, 0.780 respectively. The relationship between complement regulator levels and negative symptoms was also observed in NAPLS2 alone (ß: 0.501, 95 % CI: -0.037, 1.039) and NAPLS3 alone, additionally adjusting for BMI (ß: 0.442, 95 % CI: 0.127, 0.757). CONCLUSION: The results indicate that plasma complement and coagulation regulator levels are prognostic factors of negative symptoms, independent of clinical and demographic prognostic factors. These results suggest complement and coagulation regulator levels could have potential utility in informing treatment decisions for negative symptoms in individuals at risk.

Visual contrast sensitivity in clinical high risk and first episode psychosis.

BACKGROUND: Individuals at Clinical High Risk (CHR) for psychosis or in their First Episode (FE) of psychosis are in a pivotal time in adolescence or young adulthood when illness can greatly impact their functioning. Finding relevant biomarkers for psychosis in the early stages of illness can contribute to early diagnosis, therapeutic management and prediction of outcome. One such biomarker that has been studied in schizophrenia (SZ) is visual contrast sensitivity (VCS). VCS can be used to differentiate visual information processing function in the magnocellular versus parvocellular visual pathways. Few studies have assessed VCS in early psychosis. METHODS: Participants included CHR (n = 68), FE psychosis (n = 34) and Healthy Comparison (HC) (n = 63). All were clinically assessed and completed a VCS paradigm that involved near threshold luminance and chromatic stimuli. RESULTS: CHR and FE participants had lower VCS in the luminance condition (F[2166] = 3.42, p < 0.05) compared to HC. There was also a significant sex X group interaction (F[5163] = 4.3, p < 0.001) in the luminance condition (F[5163] = 4.3, p < 0.001) as FE males (p < 0.01) and CHR females (p < 0.01) had the greatest deficits compared to male and female HC participants respectively. VCS deficits in the luminance condition were associated with more thought disorder, slower processing speed, worse executive functioning and poor global functioning (r's 0.25-0.50, p < 0.05). CONCLUSION: This study supports the hypothesis that there are deficits in visual information processing, particularly in tasks that emphasize the magnocellular pathway, in patients experiencing early psychosis. VCS therefore has the potential to be used as a biomarker in this population.

Novel N100 area reliably captures aberrant sensory processing and is associated with neurocognition in early psychosis.

BACKGROUND: Despite findings from translational and genetic studies in the event-related potential (ERP) literature, the validity and reliability of P50 suppression as a schizophrenia spectrum endophenotype has been questioned. Here, we aimed to examine sensory registration and gating measures derived from P50 and N100 amplitude, as well as N100 area-a novel approach proposed herein-in early psychosis versus health. METHODS: Individuals at clinical high risk for psychosis (CHR; n = 77), first-episode psychosis (FE; n = 52), and healthy controls (HC; n = 65) were assessed in a paired-click auditory ERP paradigm. Eight CHR converted to psychosis (CHRC) and 39 did not (CHR-NC) by 24 months, while 30 CHR were lost to follow-. Group differences, test-retest reliability, and associations with neurocognitive function were assessed in nine ERP measures. RESULTS: Significant differences were observed in N100 S1 amplitude, S1 area, and area difference between HC and FE, as well as in N100 S1 area between HC and CHR, among the total population. Furthermore, significant differences were found in N100 S1 area between HC and CHR-NC (Cliff's delta, Δ = 0.32), as well as in N100 area difference between HC and CHR-C (Δ = 0.55). Both N100 S1 area and area difference demonstrated moderate to acceptable reliability (intraclass correlation coefficients: 0.61-0.78). Processing speed negatively correlated with both N100 S1 area and area difference, while executive function negatively correlated with N100 S1 area alone in CHR and FE. CONCLUSION: Among the ERP measures studied, N100 area measures may serve as a reliable biomarker of aberrant sensory processing and neurocognition in early psychosis.

Negative self-reference as a component of subthreshold psychotic symptoms in clinical high-risk youth.

AIM: Schizophrenia is a leading cause of disability worldwide; early detection and intervention are critical. Early in their illness, individuals at clinical high-risk (CHR) for psychosis have subthreshold psychotic symptoms that are often derogatory and self-directed. We hypothesized that CHR participants with negative self-reference (NSR) as a component of subthreshold psychosis would also have higher levels of social anxiety and depression, lower self-esteem and lower social/role/global functioning as compared with CHR participants without NSR. METHODS: One hundred and sixty-eight participants from the National Institute of Mental Health (NIMH) funded Regroup Cognitive Behavioural Social Skills Training (CBSST) study were included. Clinical vignettes that included the Scale of Psychosis-Risk Symptoms were coded categorically to indicate whether NSR was present. t-tests were used to determine the association between NSR, symptom, and functional measures. RESULTS: Participants with NSR demonstrated significantly more social interaction anxiety (p < .001), negative beliefs about the self (p ≤ .001), defeatist beliefs (p < .05), depressive symptoms (p < .05) and positive symptoms (p < .005). There were no significant differences in social self-efficacy, positive or negative beliefs about others, positive beliefs about the self or psychosocial functioning between the two groups. CONCLUSIONS: Clinically significant differences were found between CHR participants with and without NSR, suggesting that this may be a useful factor to identify and address. Follow-up studies are needed to determine whether NSR responds to CBSST and whether or not its resolution would be associated with improvement in other symptom domains.

Longitudinal Trajectories of Premorbid Social and Academic Adjustment in Youth at Clinical High Risk for Psychosis: Implications for Conversion.

BACKGROUND AND HYPOTHESIS: Social and academic adjustment deteriorate in the years preceding a psychotic disorder diagnosis. Analyses of premorbid adjustment have recently been extended into the clinical high risk for psychosis (CHR) syndrome to identify risk factors and developmental pathways toward psychotic disorders. Work so far has been at the between-person level, which has constrained analyses of premorbid adjustment, clinical covariates, and conversion to psychosis. STUDY DESIGN: Growth-curve models examined longitudinal trajectories in retrospective reports of premorbid social and academic adjustment from youth at CHR (n = 498). Interaction models tested whether known covariates of premorbid adjustment problems (attenuated negative symptoms, cognition, and childhood trauma) were associated with different premorbid adjustment trajectories in converters vs non-converters (ie, participants who did/did not develop psychotic disorders within 2-year follow-up). STUDY RESULTS: Converters reported poorer social adjustment throughout the premorbid period. Converters who developed psychosis with an affective component reported poorer academic adjustment throughout the premorbid period than those who developed non-affective psychosis. Tentatively, baseline attenuated negative symptoms may have been associated with worsening social adjustment in the premorbid period for non-converters only. Childhood trauma impact was associated with fewer academic functioning problems among converters. Cognition effects did not differ based on conversion status. CONCLUSIONS: Premorbid social function is an important factor in risk for conversion to psychosis. Negative symptoms and childhood trauma had different relationships to premorbid functioning in converters vs non-converters. Mechanisms linking symptoms and trauma to functional impairment may be different in converters vs non-converters, suggesting possible new avenues for risk assessment.

The Complex Latent Structure of Attenuated Psychotic Symptoms: Hierarchical and Bifactor Models of SIPS Symptoms Replicated in Two Large Samples at Clinical High Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: The Structured Interview for Psychosis-Risk Syndromes (SIPS) and other assessments of psychosis risk define clinical high risk for psychosis (CHR) by the presence of attenuated psychotic symptoms. Despite extensive research on attenuated psychotic symptoms, substantial questions remain about their internal psychometric structure and relationships to comorbid non-psychotic symptoms. STUDY DESIGN: Hierarchical and bifactor models were developed for the SIPS in a large CHR sample (NAPLS-3, N = 787) and confirmed through preregistered replication in an independent sample (NAPLS-2, N = 1043). Criterion validity was tested through relationships with CHR status, comorbid symptoms/diagnoses, functional impairment, demographics, neurocognition, and conversion to psychotic disorders. STUDY RESULTS: Most variance in SIPS items (75%-77%) was attributable to a general factor. Hierarchical and bifactor models included a general factor and five specific/lower-order factors (positive symptoms, eccentricity, avolition, lack of emotion, and deteriorated thought process). CHR participants were elevated on the general factor and the positive symptoms factor. The general factor was associated with depressive symptoms; functional impairment; and mood, anxiety, and schizotypal personality diagnoses. The general factor was the best predictor of psychotic disorders (d ≥ 0.50). Positive symptoms and eccentricity had specific effects on conversion outcomes. The deteriorated thought process was least meaningful/replicable. CONCLUSIONS: Attenuated psychotic symptoms, measured by the SIPS, have a complex hierarchical structure with a strong general factor. The general factor relates to internalizing symptoms and functional impairment, emphasizing the roles of general psychopathological distress/impairment in psychosis risk. Shared symptom variance complicates the interpretation of raw symptom scores. Broad transdiagnostic assessment is warranted to model psychosis risk accurately.

Sex differences in clinical presentation in youth at high risk for psychosis who transition to psychosis.

Sex differences have been observed in individuals with schizophrenia and for those at clinical high risk (CHR) for psychosis. However, specific differences in CHR individuals who transition to psychosis remain inconsistent and understudied. This study aimed to investigate sex differences in 156 CHR individuals who made the transition to psychosis. A wide range of demographics, positive and negative symptoms, depression, anxiety, social and role functioning, trauma, and substance use were assessed at baseline and symptoms and diagnoses at the time of transition. Fluctuations in positive and negative symptoms and different medications were also assessed. No sex differences were observed at baseline for those who later transitioned to psychosis. At transition, males were significantly more likely to be diagnosed as having schizophrenia or schizophreniform disorder and through the course of the study, males were more likely to be taking stimulants. Limitations in this study was the lack of longitudinal follow-up post transition. The study highlights the need for further research on sex differences in individuals who transition to psychosis. Understanding these differences can have implications for treatment and monitoring of CHR individuals.

Neurocognition in adolescents and young adults at clinical high risk for psychosis: Predictive stability for social and role functioning.

The prodromal phase of schizophrenia provides an optimal opportunity to mitigate the profound functional disability that is often associated with fully expressed psychosis. Considerable evidence supports the importance of neurocognition in the development of interpersonal (social) and academic (role) skills. Further findings from adolescents and young adults at clinical high risk for developing psychosis (CHRP) suggest that treatment for functioning might be most effective when targeting early and specific neurocognitive deficits. The current study addresses this critical intervention issue by examining the potential of neurocognitive deficits at intake for predicting social and role functioning over time in CHR-P youth. The study included 345 CHR-P participants from the second phase of the North American Prodrome Longitudinal Study (NAPLS2) with baseline neurocognition and 2-year follow-up data on social and role functioning. Slower baseline processing speed consistently predicted poor social functioning over time, while attention deficits predicted poor role functioning at baseline and follow-up. In addition, the impact of processing speed and attention impairments on social and role functioning, respectively, persisted even when adjusting the regression models for attenuated positive, negative, and disorganized symptoms, and transition status. The current study demonstrates for, arguably the first time, that processing speed and attention are strongly predictive of social and role functioning over time, respectively, above and beyond the impact of symptoms and those CHR-P individuals that develop psychosis over the course of the study. These findings imply that early neurocognition is a critical treatment target linked to the developmental trajectory of social and role functioning.

The hierarchical taxonomy of psychopathology in clinical high risk for psychosis: Validation and extension.

The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium's transdiagnostic dimensional model of psychopathology has considerable support; however, this model has been underresearched in individuals at clinical high risk for psychosis (CHR-P), a population that may advance the model. CHR-P individuals not only have attenuated psychotic symptoms that vary in severity, but also have many comorbid diagnoses and varied clinical outcomes, including disorders with uncertain relations to HiTOP (e.g., obsessive-compulsive disorder). The present study used self-report and interview data from North American Prodrome Longitudinal Study-3 (710 CHR, 96 controls) to replicate the HiTOP model and test specific hypotheses regarding disorders with uncertain relations to its dimensions. Additionally, the present study examined the HiTOP model in relation to childhood trauma, declines in social functioning, and development of full psychosis. Confirmatory factor analysis indicated that the HiTOP model's fit was nearly adequate (e.g., comparative fit index = .89), though several theory-relevant modifications were indicated. Additionally, specific tests were conducted to gain a more fine-grained perspective on how disorders with less clear prior evidence were related to the HiTOP model. Notable findings from these analyses include bipolar spectrum disorders relating to the psychosis super spectrum (i.e., .39 loading), and obsessive-compulsive disorder showing a complex pattern of loadings (e.g., internalizing and psychosis). The final model parsimoniously accounted for childhood trauma (e.g., super spectra rs = .22-.32), associations with current functioning, and predicted future conversion to a psychotic disorder (e.g., super spectra R² = .13). Overall, these results inform the HiTOP model and suggest its promise for CHR-P research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ): Rationale and Study Design of the Largest Global Prospective Cohort Study of Clinical High Risk for Psychosis.

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals.