Publications by authors named "Scott W Woods"

224 Publications

Prevalence of Individuals at Clinical High-Risk of Psychosis in the General Population and Clinical Samples: Systematic Review and Meta-Analysis.

Brain Sci 2021 Nov 20;11(11). Epub 2021 Nov 20.

Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AB, UK.

(1) The consistency and magnitude of the prevalence of Clinical High-Risk for Psychosis (CHR-P) individuals are undetermined, limiting efficient detection of cases. We aimed to evaluate the prevalence of CHR-P individuals systematically assessed in the general population or clinical samples. (2) PRISMA/MOOSE-compliant (PROSPERO: CRD42020168672) meta-analysis of multiple databases until 21/01/21: a random-effects model meta-analysis, heterogeneity analysis, publication bias and quality assessment, sensitivity analysis-according to the gold-standard CHR-P and pre-screening instruments-leave-one-study-out analyses, and meta-regressions were conducted. (3) 35 studies were included, with 37,135 individuals tested and 1554 CHR-P individuals identified (median age = 19.3 years, Interquartile range (IQR) = 15.8-22.1; 52.2% females, IQR = 38.7-64.4). In the general population (k = 13, = 26,835 individuals evaluated), the prevalence of the CHR-P state was 1.7% (95% Confidence Interval (CI) = 1.0-2.9%). In clinical samples (k = 22, = 10,300 individuals evaluated), the prevalence of the CHR-P state was 19.2% (95% CI = 12.9-27.7%). Using a pre-screening instrument was associated with false negatives (5.6%, 95% CI = 2.2-13.3%) and a lower CHR-P prevalence (11.5%, 95% CI = 6.2-20.5%) compared to using CHR-P instruments only (28.5%, 95% CI = 23.0-34.7%, = 0.003). (4) The prevalence of the CHR-P state is low in the general population and ten times higher in clinical samples. The prevalence of CHR-P may increase with a higher proportion of females in the general population and with a younger population in clinical samples. The CHR-P state may be unrecognized in routine clinical practice. These findings can refine detection and preventive strategies.
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http://dx.doi.org/10.3390/brainsci11111544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8615691PMC
November 2021

Association between residential instability at individual and area levels and future psychosis in adolescents at clinical high risk from the North American Prodrome Longitudinal Study (NAPLS) consortium.

Schizophr Res 2021 Dec 19;238:137-144. Epub 2021 Oct 19.

Department of Health Policy and Management, Rollins School of Public Health, Emory University, Atlanta, GA, United States.

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.
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http://dx.doi.org/10.1016/j.schres.2021.09.025DOI Listing
December 2021

Individualized Prediction of Prodromal Symptom Remission for Youth at Clinical High Risk for Psychosis.

Schizophr Bull 2021 Sep 28. Epub 2021 Sep 28.

Department of Psychology, Yale University, New Haven, CT, USA.

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.
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http://dx.doi.org/10.1093/schbul/sbab115DOI Listing
September 2021

Sleep Disturbance in Individuals at Clinical High Risk for Psychosis.

Schizophr Bull 2022 Jan;48(1):111-121

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.

Introduction: Disturbed 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.

Methods: Data 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.

Results: Disturbed 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.

Discussion: The 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.
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http://dx.doi.org/10.1093/schbul/sbab104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8781348PMC
January 2022

Toward Generalizable and Transdiagnostic Tools for Psychosis Prediction: An Independent Validation and Improvement of the NAPLS-2 Risk Calculator in the Multisite PRONIA Cohort.

Biol Psychiatry 2021 11 6;90(9):632-642. Epub 2021 Jul 6.

Institute of Mental Health, University of Birmingham, Birmingham, United Kingdom; School of Psychology, University of Birmingham, Birmingham, United Kingdom.

Background: Transition to psychosis is among the most adverse outcomes of clinical high-risk (CHR) syndromes encompassing ultra-high risk (UHR) and basic symptom states. Clinical risk calculators may facilitate an early and individualized interception of psychosis, but their real-world implementation requires thorough validation across diverse risk populations, including young patients with depressive syndromes.

Methods: We validated the previously described NAPLS-2 (North American Prodrome Longitudinal Study 2) calculator in 334 patients (26 with transition to psychosis) with CHR or recent-onset depression (ROD) drawn from the multisite European PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Patients were categorized into three risk enrichment levels, ranging from UHR, over CHR, to a broad-risk population comprising patients with CHR or ROD (CHR|ROD). We assessed how risk enrichment and different predictive algorithms influenced prognostic performance using reciprocal external validation.

Results: After calibration, the NAPLS-2 model predicted psychosis with a balanced accuracy (BAC) (sensitivity, specificity) of 68% (73%, 63%) in the PRONIA-UHR cohort, 67% (74%, 60%) in the CHR cohort, and 70% (73%, 66%) in patients with CHR|ROD. Multiple model derivation in PRONIA-CHR|ROD and validation in NAPLS-2-UHR patients confirmed that broader risk definitions produced more accurate risk calculators (CHR|ROD-based vs. UHR-based performance: 67% [68%, 66%] vs. 58% [61%, 56%]). Support vector machines were superior in CHR|ROD (BAC = 71%), while ridge logistic regression and support vector machines performed similarly in CHR (BAC = 67%) and UHR cohorts (BAC = 65%). Attenuated psychotic symptoms predicted psychosis across risk levels, while younger age and reduced processing speed became increasingly relevant for broader risk cohorts.

Conclusions: Clinical-neurocognitive machine learning models operating in young patients with affective and CHR syndromes facilitate a more precise and generalizable prediction of psychosis. Future studies should investigate their therapeutic utility in large-scale clinical trials.
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http://dx.doi.org/10.1016/j.biopsych.2021.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500930PMC
November 2021

Navigating the Benefits and Pitfalls of Online Psychiatric Data Collection.

JAMA Psychiatry 2021 11;78(11):1185-1186

Yale University, School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamapsychiatry.2021.2315DOI Listing
November 2021

Family-focused therapy for individuals at high clinical risk for psychosis: A confirmatory efficacy trial.

Early Interv Psychiatry 2021 Aug 23. Epub 2021 Aug 23.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuropsychiatry and Behavior, University of California, Los Angeles, California, USA.

Aims: Young people with attenuated psychotic symptoms (APS), brief intermittent psychosis, and/or genetic risk and functional deterioration are at high risk for developing psychotic disorders. In a prior trial, family-focused therapy for clinical high risk youth (FFT-CHR) was more effective than brief psychoeducation in reducing APS severity over 6 months. This 7-site trial will compare the efficacy of FFT-CHR to a psychoeducational and supportive intervention (enhanced care) on APS and social functioning in CHR individuals over 18 months.

Methods: Participants (N = 220, ages 13-25 years) with a CHR syndrome will be randomly assigned to FFT-CHR (18 1-h sessions of family psychoeducation and communication/problem-solving skills training) or enhanced care (3 1-h family psychoeducational sessions followed by 5 individual support sessions), both given over 6 months. Participants will rate their weekly progress during treatment using a mobile-enhanced online platform. Family communication will be assessed in a laboratory interactional task at baseline and post-treatment. Independent evaluators will assess APS (primary outcome) and psychosocial functioning (secondary outcome) every 6 months over 18 months.

Results: We hypothesize that, compared to enhanced care, FFT-CHR will be associated with greater improvements in APS and psychosocial functioning over 18 months. Secondarily, improvements in family communication over 6 months will mediate the relationship between treatment condition and primary and secondary outcomes over 18 months. The effects of FFT-CHR are predicted to be greater in individuals with higher baseline risk for psychosis conversion.

Conclusions: Results of the trial will inform treatment guidelines for individuals at high risk for psychosis.
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http://dx.doi.org/10.1111/eip.13208DOI Listing
August 2021

Anxiety in youth at clinical high-risk for psychosis: A two-year follow-up.

Schizophr Res 2021 10 20;236:87-88. Epub 2021 Aug 20.

Hotchkiss Brain Institute and Mathison Centre for Mental Health Research and Education, Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.schres.2021.08.014DOI Listing
October 2021

Computerized Assessment of Psychosis Risk.

J Psychiatr Brain Sci 2021 29;6(3). Epub 2021 Jun 29.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21228, USA.

Early detection and intervention with young people at clinical high risk (CHR) for psychosis is critical for prevention efforts focused on altering the trajectory of psychosis. Early CHR research largely focused on validating clinical interviews for detecting at-risk individuals; however, this approach has limitations related to: (1) specificity (i.e., only 20% of CHR individuals convert to psychosis) and (2) the expertise and training needed to administer these interviews is limited. The purpose of our study is to develop the computerized assessment of psychosis risk (CAPR) battery, consisting of behavioral tasks that require minimal training to administer, can be administered online, and are tied to the neurobiological systems and computational mechanisms implicated in psychosis. The aims of our study are as follows: (1A) to develop a psychosis-risk calculator through the application of machine learning (ML) methods to the measures from the CAPR battery, (1B) evaluate group differences on the risk calculator score and test the hypothesis that the risk calculator score of the CHR group will differ from help-seeking and healthy controls, (1C) evaluate how baseline CAPR battery performance relates to symptomatic outcome two years later (i.e., conversion and symptomatic worsening). These aims will be explored in 500 CHR participants, 500 help-seeking individuals, and 500 healthy controls across the study sites. This project will provide a next-generation CHR battery, tied to illness mechanisms and powered by cutting-edge computational methods that can be used to facilitate the earliest possible detection of psychosis risk.
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http://dx.doi.org/10.20900/jpbs.20210011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302046PMC
June 2021

Discriminatory experiences predict neuroanatomical changes and anxiety among healthy individuals and those at clinical high risk for psychosis.

Neuroimage Clin 2021 6;31:102757. Epub 2021 Jul 6.

Department of Psychology, Yale University, New Haven, CT, USA; Department of Psychiatry, Yale University, New Haven, CT, USA.

Individuals face discrimination based on characteristics including race/ethnicity, gender, age, and disability. Discriminatory experiences (DE) are associated with poor psychological health in the general population and with worse outcomes among individuals at clinical high risk for psychosis (CHR). Though the brain is sensitive to stress, and brain structural change is a well-documented precursor to psychosis, potential relationships between DE and brain structure among CHR or healthy individuals are not known. This report assessed whether lifetime DE are associated with cortical thinning and clinical outcomes across time, after controlling for discrimination-related demographic factors among CHR individuals who ultimately do (N = 57) and do not convert to psychosis (N = 451), and healthy comparison (N = 208) participants in the North American Prodrome Longitudinal Study 2. Results indicate that DE are associated with thinner cortex across time in several cortical areas. Thickness in several right hemisphere regions partially mediates associations between DE and subsequent anxiety symptoms, but not attenuated positive symptoms of psychosis. This report provides the first evidence to date of an association between DE and brain structure in both CHR and healthy comparison individuals. Results also suggest that thinner cortex across time in areas linked with DE may partially explain associations between DE and cross-diagnostic indicators of psychological distress.
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http://dx.doi.org/10.1016/j.nicl.2021.102757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283423PMC
September 2021

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis.

Mol Psychiatry 2021 Nov 24;26(11):6833-6844. Epub 2021 May 24.

Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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 (FA) 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 FA in adolescence, and 4% lower FA by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FA or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosis-regardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development.
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http://dx.doi.org/10.1038/s41380-021-01128-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611104PMC
November 2021

Full speed ahead on indicated prevention of psychosis.

World Psychiatry 2021 Jun;20(2):223-224

Department of Psychiatry, Washington University School of Medicine, Washington, WA, USA.

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http://dx.doi.org/10.1002/wps.20851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129831PMC
June 2021

Increased face detection responses on the mooney faces test in people at clinical high risk for psychosis.

NPJ Schizophr 2021 May 17;7(1):26. Epub 2021 May 17.

Yale University, New Haven, CT, USA.

Identifying state-sensitive measures of perceptual and cognitive processes implicated in psychosis may allow for objective, earlier, and better monitoring of changes in mental status that are predictive of an impending psychotic episode, relative to traditional self-report-based clinical measures. To determine whether a measure of visual perception that has demonstrated sensitivity to the clinical state of schizophrenia in multiple prior studies is sensitive to features of the at-risk mental state, we examined differences between young people identified as being at clinical high risk for psychosis (CHR; n = 37) and non-psychiatric matched controls (n = 29) on the Mooney Faces Test (MFT). On each trial of the MFT, participants report whether they perceive a face in a degraded face image. The CHR group reported perceiving a greater number of faces in both upright and inverted MFT stimuli. Consistent with prior work, males reported more faces on the MFT than females in both conditions. However, the finding of greater reported face perception among CHR subjects was robustly observed in the female CHR group relative to the female control group. Among male CHR participants, greater reported face perception was related to increased perceptual abnormalities. These preliminary results are consistent with a small but growing literature suggesting that heightened perceptual sensitivity may characterize individuals at increased clinical risk for psychosis. Further studies are needed to determine the contributions of specific perceptual, cognitive, and motivational mechanisms to the findings.
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http://dx.doi.org/10.1038/s41537-021-00156-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129098PMC
May 2021

Attenuated Psychosis Syndrome Should Be Moved to the Main Section in DSM-5-TR.

JAMA Psychiatry 2021 08;78(8):821-822

Department of Psychiatry, Yale University, New Haven, Connecticut.

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http://dx.doi.org/10.1001/jamapsychiatry.2021.0838DOI Listing
August 2021

Life Event Stress and Reduced Cortical Thickness in Youth at Clinical High Risk for Psychosis and Healthy Control Subjects.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Apr 28. Epub 2021 Apr 28.

Department of Psychology, Emory University, Atlanta, Georgia.

Background: A decline in cortical thickness during early life appears to be a normal neuromaturational process. Accelerated cortical thinning has been linked with conversion to psychosis among individuals at clinical high risk for psychosis (CHR-P). Previous research indicates that exposure to life event stress (LES) is associated with exaggerated cortical thinning in both healthy and clinical populations, and LES is also linked with conversion to psychosis in CHR-P. To date, there are no reports on the relationship of LES with cortical thickness in CHR-P. This study examines this relationship and whether LES is linked with cortical thinning to a greater degree in individuals at CHR-P who convert to psychosis compared with individuals at CHR-P who do not convert and healthy control subjects.

Methods: Controlling for age and gender (364 male, 262 female), this study examined associations between LES and baseline cortical thickness in 436 individuals at CHR-P (375 nonconverters and 61 converters) and 190 comparison subjects in the North American Prodrome Longitudinal Study.

Results: Findings indicate that prebaseline cumulative LES is associated with reduced baseline cortical thickness in several regions among the CHR-P and control groups. Evidence suggests that LES is a risk factor for thinner cortex to the same extent across diagnostic groups, while CHR-P status is linked with thinner cortex in select regions after accounting for LES.

Conclusions: This research provides additional evidence to support the role of LES in cortical thinning in both healthy youth and those at CHR-P. Potential underlying mechanisms of the findings and implications for future research are discussed.
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http://dx.doi.org/10.1016/j.bpsc.2021.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551305PMC
April 2021

Visual cortical plasticity and the risk for psychosis: An interim analysis of the North American Prodrome Longitudinal Study.

Schizophr Res 2021 04 2;230:26-37. Epub 2021 Mar 2.

VA San Francisco Healthcare System, San Francisco, CA, USA; Department of Psychiatry and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

Background: Adolescence/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.

Methods: An 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.

Results: Input-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.

Conclusions: Input-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.
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http://dx.doi.org/10.1016/j.schres.2021.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328744PMC
April 2021

Genetic and clinical analyses of psychosis spectrum symptoms in a large multiethnic youth cohort reveal significant link with ADHD.

Transl Psychiatry 2021 01 28;11(1):80. Epub 2021 Jan 28.

Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.

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) 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.
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http://dx.doi.org/10.1038/s41398-021-01203-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844241PMC
January 2021

The association between migrant status and transition in an ultra-high risk for psychosis population.

Soc Psychiatry Psychiatr Epidemiol 2021 Jun 5;56(6):943-952. Epub 2021 Jan 5.

Department of Psychiatry, University Hospital Jena, Jena, Germany.

Purpose: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder.

Methods: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model.

Results: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51).

Conclusions: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.
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http://dx.doi.org/10.1007/s00127-020-02012-6DOI Listing
June 2021

A randomized Phase II trial evaluating efficacy, safety, and tolerability of oral BI 409306 in attenuated psychosis syndrome: Design and rationale.

Early Interv Psychiatry 2021 10 22;15(5):1315-1325. Epub 2020 Dec 22.

Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, USA.

Aim: Attenuated psychosis syndrome (APS), a condition for further study in the Diagnostic and Statistical Manual of Mental Disorders-5, comprises psychotic symptoms that are qualitatively similar to those observed in schizophrenia but are less severe. Patients with APS are at high risk of converting to first-episode psychosis (FEP). As evidence for effective pharmacological interventions in APS is limited, novel treatments may provide symptomatic relief and delay/prevent psychotic conversion. This trial aims to investigate the efficacy, safety, and tolerability of BI 409306, a potent and selective phosphodiesterase-9 inhibitor, versus placebo in APS. Novel biomarkers of psychosis are being investigated.

Methods: In this Phase II, multinational, double-blind, parallel-group trial, randomized (1:1) patients will receive BI 409306 50 mg or placebo twice daily for 52 weeks. Patients (n = 300) will be enrolled to determine time to remission of APS, time to FEP, change in everyday functional capacity (Schizophrenia Cognition Rating Scale), and change from baseline in Brief Assessment of Cognition composite score and Positive and Negative Syndrome Scale scores. Potential biomarkers of psychosis under investigation include functional measures of brain activity and automated speech analyses. Safety is being assessed throughout.

Conclusions: This trial will determine whether BI 409306 is superior to placebo in achieving sustainable remission of APS and improvements in cognition and functional capacity. These advances may provide evidence-based treatment options for symptomatic relief in APS. Furthermore, the study will assess the effect of BI 409306 on psychotic conversion and explore the identification of patients at risk for conversion using novel biomarkers.
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http://dx.doi.org/10.1111/eip.13083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451588PMC
October 2021

Duration of Untreated Psychosis: Getting Both the Timing and the Sample Right.

Am J Psychiatry 2020 12;177(12):1183

Department of Psychiatry and Connecticut Mental Health Center, Yale University School of Medicine, New Haven, Conn. (Woods, McGlashan); Orygen, National Centre of Excellence in Youth Mental Health, University of Melbourne, Parkville, Australia (Yung, McGorry).

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http://dx.doi.org/10.1176/appi.ajp.2020.20040389DOI Listing
December 2020

Reliability of mismatch negativity event-related potentials in a multisite, traveling subjects study.

Clin Neurophysiol 2020 12 22;131(12):2899-2909. Epub 2020 Oct 22.

San Francisco Veterans Affairs Healthcare System, San Francisco, CA, United States; Department of Psychiatry, University of California, San Francisco, CA, United States. Electronic address:

Objective: To determine the optimal methods for measuring mismatch negativity (MMN), an auditory event-related potential (ERP), and quantify sources of MMN variance in a multisite setting.

Methods: Reliability of frequency, duration, and double (frequency + duration) MMN was determined from eight traveling subjects, tested on two occasions at eight laboratory sites. Deviant-specific variance components were estimated for MMN peak amplitude and latency measures using different ERP processing methods. Generalizability (G) coefficients were calculated using two-facet (site and occasion), fully-crossed models and single-facet (occasion) models within each laboratory to assess MMN reliability.

Results: G-coefficients calculated from two-facet models indicated fair (0.4 < G<=0.6) duration MMN reliability at electrode Fz, but poor (G < 0.4) double and frequency MMN reliability. Single-facet G-coefficients averaged across laboratory resulted in improved reliability (G > 0.5). MMN amplitude reliability was greater than latency reliability, and reliability with mastoid referencing significantly outperformed nose-referencing.

Conclusions: EEG preprocessing methods have an impact on the reliability of MMN amplitude. Within site MMN reliability can be excellent, consistent with prior single site studies.

Significance: With standardized data collection and ERP processing, MMN can be reliably obtained in multisite studies, providing larger samples sizeswithin rare patient groups.
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http://dx.doi.org/10.1016/j.clinph.2020.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323616PMC
December 2020

Social decline in the psychosis prodrome: Predictor potential and heterogeneity of outcome.

Schizophr Res 2021 01 31;227:44-51. Epub 2020 Oct 31.

Division of Psychiatry Research, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, United States; Institute of Behavioral Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States; Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York 11549, United States; Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York 11549, United States. Electronic address:

Background: While an established clinical outcome of high importance, social functioning has been emerging as possibly having a broader significance to the evolution of psychosis and long term disability. In the current study we explored the association between social decline, conversion to psychosis, and functional outcome in individuals at clinical high risk (CHR) for psychosis.

Methods: 585 subjects collected in the North American Prodrome Longitudinal Study (NAPLS2) were divided into 236 Healthy Controls (HCs), and CHR subjects that developed psychosis (CHR + C, N = 79), or those that did not (Non-Converters, CHR-NC, N = 270). CHR + C subjects were further divided into those that experienced an atypical decline in social functioning prior to baseline (beyond typical impairment levels) when in min-to-late adolescence (CHR + C-SD, N = 39) or those that did not undergoing a decline (CHR + C-NSD, N = 40).

Results: Patterns of poor functional outcomes varied across the CHR subgroups: CHR-NC (Poor Social 36.3%, Role 42.2%) through CHR + C-NSD (Poor Social 50%, Poor Role 67.5%) to CHR + C-SD (Poor Social 76.9%, Poor Role 89.7%) functioning. The two Converter subgroups had comparable positive symptoms at baseline. At 12 months, the CHR + C-SD group stabilized, but social functioning levels remained significantly lower than the other two subgroups.

Conclusions: The current study demonstrates that pre-baseline social decline in mid-to-late adolescence predicts psychosis. In addition, we found that this social decline in converters is strongly associated with especially poor functional outcome and overall poorer prognosis. Role functioning, in contrast, has not shown similar predictor potential, and rather appears to be an illness indicator that worsens over time.
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http://dx.doi.org/10.1016/j.schres.2020.09.006DOI Listing
January 2021

Depression: An actionable outcome for those at clinical high-risk.

Schizophr Res 2021 01 29;227:38-43. Epub 2020 Oct 29.

Department of Psychiatry, Yale University, New Haven, CT, United States of America.

Comorbid diagnoses are common in youth who are at clinical high-risk (CHR) for developing psychosis, with depression being the most common. The aim of this paper is to examine depression over two years in a large sample of CHR youth who do not make the transition to psychosis, considering both categorical and dimensional ratings of depression severity. The sample consisted of 267 CHR youth who were followed for two years. Based on DSM-IV diagnoses over this time period, 100 CHR individuals never received a diagnosis of depression, 64 individuals continuously met criteria for depression, 92 individuals received a diagnosis of depression at one or more timepoints, and 11 participants had a diagnosis of depression only at 24-months. These groupings were supported by six-monthly ratings on the Calgary Depression Scale. The majority of this sample experienced a major depressive episode on more than one occasion, suggesting that depression and depressive symptoms identify a domain of substantial unmet clinical need. Recommendations are that depression in CHR youth and young adults should be monitored more frequently and that there is a need for clinical trials to address depression systematically in this vulnerable population.
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http://dx.doi.org/10.1016/j.schres.2020.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854482PMC
January 2021

Incorporating cortisol into the NAPLS2 individualized risk calculator for prediction of psychosis.

Schizophr Res 2021 01 9;227:95-100. Epub 2020 Oct 9.

Department of Psychology, Yale University, New Haven, CT, United States of America; Department of Psychiatry, Yale University, New Haven, CT, United States of America. Electronic address:

Background: Risk calculators are useful tools that can help clinicians and researchers better understand an individual's risk of conversion to psychosis. The North American Prodrome Longitudinal Study (NAPLS2) Individualized Risk Calculator has good predictive accuracy but could be potentially improved by the inclusion of a biomarker. Baseline cortisol, a measure of hypothalamic-pituitary-adrenal (HPA) axis functioning that is impacted by biological vulnerability to stress and exposure to environmental stressors, has been shown to be higher among individuals at clinical high-risk for psychosis (CHRP) who eventually convert to psychosis than those who do not. We sought to determine whether the addition of baseline cortisol to the NAPLS2 risk calculator improved the performance of the risk calculator.

Methods: Participants were drawn from the NAPLS2 study. A subset of NAPLS2 participants provided salivary cortisol samples. A multivariate Cox proportional hazards regression evaluated the likelihood of an individual's eventual conversion to psychosis based on demographic and clinical variables in addition to baseline cortisol levels.

Results: A total of 417 NAPLS2 participants provided salivary cortisol and were included in the analysis. Higher levels of cortisol were predictive of conversion to psychosis in a univariate model (C-index = 0.59, HR = 21.5, p-value = 0.004). The inclusion of cortisol in the risk calculator model resulted in a statistically significant improvement in performance from the original risk calculator model (C-index = 0.78, SE = 0.028).

Conclusions: Salivary cortisol is an inexpensive and non-invasive biomarker that could improve individual predictions about conversion to psychosis and treatment decisions for CHR-P individuals.
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http://dx.doi.org/10.1016/j.schres.2020.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287972PMC
January 2021

Evidence of Slow Neural Processing, Developmental Differences and Sensitivity to Cannabis Effects in a Sample at Clinical High Risk for Psychosis From the NAPLS Consortium Assessed With the Human Startle Paradigm.

Front Psychiatry 2020 25;11:833. Epub 2020 Aug 25.

University of California, San Francisco, San Francisco, CA, United States.

Abstract: Biomarkers are important in the study of the prodromal period of psychosis because they can help to identify individuals at greatest risk for future psychotic illness and provide insights into disease mechanism underlying neurodevelopmental abnormalities. The biomarker abnormalities can then be targeted with treatment, with an aim toward prevention or mitigation of disease. The human startle paradigm has been used in translational studies of psychopathology including psychotic illness to assess preattentive information processing for over 50 years. In one of the largest studies to date in clinical high risk (CHR) for psychosis participants, we aimed to evaluate startle indices as biomarkers of risk along with the role of age, sex, treatment, and substance use in this population of high risk individuals.

Methods: Startle response reactivity, latency, and prepulse inhibition (PPI) were assessed in 543 CHR and 218 Normal Comparison (NC) participants between the ages of 12 and 35.

Results: At 1 year follow-up, 58 CHR participants had converted to psychosis. CHR and NC groups did not differ across any of the startle measures but those CHR participants who later converted to psychosis had significantly slower startle latency than did those who did not convert to psychosis, and this effect was driven by female CHR participants. PPI was significantly associated with age in the CHR, but not the NC, participants with the greatest positive age correlations present in those CHR participants who later converted to psychosis, consistent with a prior report. Finally, there was a significant group by cannabis use interaction due to greater PPI in cannabis users and opposite PPI group effects in users (CHR>NC) and non-users (NC>CHR).

Discussion: This is the first study to demonstrate a relationship of startle response latency to psychotic conversion in a CHR population. PPI is an important biomarker that may be sensitive to the neurodevelopmental abnormalities thought to be present in psychosis prone individuals and the effects of cannabis. The significant correlations with age in this sample as well as the finding of greater PPI in CHR cannabis users replicate findings from another large sample of CHR participants.
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http://dx.doi.org/10.3389/fpsyt.2020.00833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479820PMC
August 2020

Concordance and factor structure of subthreshold positive symptoms in youth at clinical high risk for psychosis.

Schizophr Res 2021 01 15;227:72-77. Epub 2020 Sep 15.

Department of Psychiatry, University of Calgary, Calgary, Alberta, Canada.

Prevailing models of psychosis risk incorporate positive subthreshold symptoms as defining features of risk or transition to psychotic disorders. Despite this, relatively few studies have focused on characterizing longitudinal symptom features, such as prevalence, concordance and structure, which may aid in refining methods and enhancing classification and prediction efforts. The present study aimed to fill these gaps using longitudinal 24-month follow-up data from the well-characterized NAPLS-2 multi-site investigation of youth at clinical high risk (CHR) who had (n = 86) and had not (n = 268) transitioned to a threshold psychotic disorder since baseline. At baseline, among sub-delusional ideas, unusual thought content and suspicious/persecutory thinking were very common in CHR youth, and were highly concordant. Perceptual abnormalities (P4) were also common across youth regardless of symptom course and eventual transition to psychosis. Grandiose ideas were rare. Exploratory factor analysis extracted two constituent factors at multiple follow-up intervals, but there was marked instability in the structure over 24 months, and clear indicators for a single positive symptom factor. Together these findings support suggestions to combine sub-delusional symptoms into a single symptom category for classification purposes, in efforts to reduce clinical heterogeneity and ease measurement burden.
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http://dx.doi.org/10.1016/j.schres.2020.08.014DOI Listing
January 2021

Associations between childhood adversity, cognitive schemas and attenuated psychotic symptoms.

Early Interv Psychiatry 2021 08 7;15(4):818-827. Epub 2020 Aug 7.

Department of Psychiatry and Behavioral Sciences, Emory School of Medicine, Atlanta, Georgia, USA.

Aim: Childhood Adversity (CA) is strongly linked to psychotic-like symptoms across the clinical spectrum, though the mechanisms underlying these associations remain poorly understood. Negative cognitive schemas are associated with both CA exposure and psychotic symptoms, highlighting the possibility that cognitive schemas may be a key risk pathway. The purpose of this study was to determine whether negative cognitive schemas mediate the association between CA and specific attenuated psychotic symptoms in a large sample of clinical-high risk youth. Given the variability in experiences that encompass CA (eg, abuse, neglect and poverty) and attenuated psychotic symptoms (eg, suspiciousness and perceptual abnormalities), we also tested whether these associations differ by CA type (threat vs deprivation) and attenuated positive psychotic symptom domain.

Methods: Data were collected from 531 clinical-high risk youth between 12 and 35 years of age (mean = 18.80, SD = 4.21) who completed a clinical assessment that included the Structured Interview of Prodromal Syndromes (SIPS), Childhood Trauma and Abuse scale and questionnaires on cognitive schemas and depressive symptoms.

Results: No direct effects of threat or deprivation exposure on any of the psychotic symptom domains were found. However, there was a unique indirect effect of threat, but not deprivation, on delusional thinking and suspiciousness through negative cognitive schemas about others.

Conclusion: Cognitive vulnerability in the form of negative schemas about others may be one mechanism linking childhood threat experiences and attenuated psychotic symptoms. The results underscore the importance of targeting negative schemas in interventions to mitigate psychosis risk.
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http://dx.doi.org/10.1111/eip.13017DOI Listing
August 2021

Deficits in auditory predictive coding in individuals with the psychosis risk syndrome: Prediction of conversion to psychosis.

J Abnorm Psychol 2020 Aug;129(6):599-611

Veterans Affairs San Francisco Healthcare System.

The mismatch negativity (MMN) event-related potential (ERP) component is increasingly viewed as a prediction error signal elicited when a deviant sound violates the prediction that a frequent "standard" sound will repeat. Support for this predictive coding framework emerged with the identification of the repetition positivity (RP), a standard stimulus ERP component that increases with standard repetition and is thought to reflect strengthening of the standard's memory trace and associated predictive code. Using electroencephalographic recordings, we examined the RP elicited by repeating standard tones presented during a traditional "constant standard" MMN paradigm in individuals with the psychosis risk syndrome (PRS; n = 579) and healthy controls (HC; n = 241). Clinical follow-up assessments identified PRS participants who converted to a psychotic disorder (n = 77) and PRS nonconverters who were followed for the entire 24-month clinical follow-up period and either remained symptomatic (n = 144) or remitted from the PRS (n = 94). In HC, RP linearly increased from early- to late-appearing standards within local trains of repeating standards (p < .0001), consistent with auditory predictive code/memory trace strengthening. Relative to HC, PRS participants showed a reduced RP across standards (p = .0056). PRS converters showed a relatively small RP deficit for early appearing standards relative to HC (p = .0.0107) and a more prominent deficit for late-appearing standards (p = .0006) relative to both HC and PRS-remitted groups. Moreover, greater RP deficits predicted shorter time to conversion in a subsample of unmedicated PRS individuals (p = .02). Thus, auditory predictive coding/memory trace deficits precede psychosis onset and predict future psychosis risk in PRS individuals. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430496PMC
August 2020

Enhancing Psychosis Risk Prediction Through Computational Cognitive Neuroscience.

Schizophr Bull 2020 12;46(6):1346-1352

Departments of Psychology, Psychiatry, Medical Social Sciences, Institutes for Policy Research (IPR) and Innovations in Developmental Sciences (DevSci), Evanston and Chicago, IL.

Research suggests that early identification and intervention with individuals at clinical high risk (CHR) for psychosis may be able to improve the course of illness. The first generation of studies suggested that the identification of CHR through the use of specialized interviews evaluating attenuated psychosis symptoms is a promising strategy for exploring mechanisms associated with illness progression, etiology, and identifying new treatment targets. The next generation of research on psychosis risk must address two major limitations: (1) interview methods have limited specificity, as recent estimates indicate that only 15%-30% of individuals identified as CHR convert to psychosis and (2) the expertise needed to make CHR diagnosis is only accessible in a handful of academic centers. Here, we introduce a new approach to CHR assessment that has the potential to increase accessibility and positive predictive value. Recent advances in clinical and computational cognitive neuroscience have generated new behavioral measures that assay the cognitive mechanisms and neural systems that underlie the positive, negative, and disorganization symptoms that are characteristic of psychotic disorders. We hypothesize that measures tied to symptom generation will lead to enhanced sensitivity and specificity relative to interview methods and the cognitive intermediate phenotype measures that have been studied to date that are typically indicators of trait vulnerability and, therefore, have a high false positive rate for conversion to psychosis. These new behavioral measures have the potential to be implemented on the internet and at minimal expense, thereby increasing accessibility of assessments.
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http://dx.doi.org/10.1093/schbul/sbaa091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707066PMC
December 2020

Modeling perception and behavior in individuals at clinical high risk for psychosis: Support for the predictive processing framework.

Schizophr Res 2020 12 24;226:167-175. Epub 2020 Jun 24.

Yale University School of Medicine and the Connecticut Mental Health Center, New Haven, CT, United States of America. Electronic address:

Early intervention in psychotic spectrum disorders is critical for maximizing key clinical outcomes. While there is some evidence for the utility of intervention during the prodromal phase of the illness, efficacy of interventions is difficult to assess without appropriate risk stratification. This will require biomarkers that robustly help to identify risk level and are also relatively easy to obtain. Recent work highlights the utility of computer-based behavioral tasks for understanding the pathophysiology of psychotic symptoms. Computational modeling of performance on such tasks may be particularly useful because they explicitly and formally link performance and symptom expression. Several recent studies have successfully applied principles of Bayesian inference to understanding the computational underpinnings of hallucinations. Within this framework, hallucinations are seen as arising from an over-weighting of prior beliefs relative to sensory evidence. This view is supported by recently-published data from two tasks: the Conditioned Hallucinations (CH) task, which determines the degree to which participants use expectations in detecting a target tone; and a Sine-Vocoded Speech (SVS) task, in which participants can use prior exposure to speech samples to inform their understanding of degraded speech stimuli. We administered both of these tasks to two samples of participants at clinical high risk for psychosis (CHR; N = 19) and healthy controls (HC; N = 17). CHR participants reported both more conditioned hallucinations and more pre-training SVS detection. In addition, relationships were found between participants' performance on both tasks. On computational modeling of behavior on the CH task, CHR participants demonstrate significantly poorer recognition of task volatility as well as a trend toward higher weighting of priors. A relationship was found between this latter effect and performance on both tasks. Taken together, these results support the assertion that these two tasks may be driven by similar latent factors in perceptual inference, and highlight the potential utility of computationally-based tasks in identifying risk.
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http://dx.doi.org/10.1016/j.schres.2020.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774587PMC
December 2020
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