Publications by authors named "Paolo Fusar-Poli"

330 Publications

Mental disorders and risk of COVID-19-related mortality, hospitalisation, and intensive care unit admission: a systematic review and meta-analysis.

Lancet Psychiatry 2021 Jul 15. Epub 2021 Jul 15.

University Psychiatric Hospital Campus Duffel, Duffel, Belgium; Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Antwerp, Belgium. Electronic address:

Background: Mental disorders might be a risk factor for severe COVID-19. We aimed to assess the specific risks of COVID-19-related mortality, hospitalisation, and intensive care unit (ICU) admission associated with any pre-existing mental disorder, and specific diagnostic categories of mental disorders, and exposure to psychopharmacological drug classes.

Methods: In this systematic review and meta-analysis, we searched Web of Science, Cochrane, PubMed, and PsycINFO databases between Jan 1, 2020, and March 5, 2021, for original studies reporting data on COVID-19 outcomes in patients with psychiatric disorders compared with controls. We excluded studies with overlapping samples, studies that were not peer-reviewed, and studies written in languages other than English, Danish, Dutch, French, German, Italian, and Portuguese. We modelled random-effects meta-analyses to estimate crude odds ratios (OR) for mortality after SARS-CoV-2 infection as the primary outcome, and hospitalisation and ICU admission as secondary outcomes. We calculated adjusted ORs for available data. Heterogeneity was assessed using the I statistic, and publication bias was tested with Egger regression and visual inspection of funnel plots. We used the GRADE approach to assess the overall strength of the evidence and the Newcastle Ottawa Scale to assess study quality. We also did subgroup analyses and meta-regressions to assess the effects of baseline COVID-19 treatment setting, patient age, country, pandemic phase, quality assessment score, sample sizes, and adjustment for confounders. This study is registered with PROSPERO, CRD42021233984.

Findings: 841 studies were identified by the systematic search, of which 33 studies were included in the systematic review and 23 studies in the meta-analysis, comprising 1 469 731 patients with COVID-19, of whom 43 938 had mental disorders. The sample included 130 807 females (8·9% of the whole sample) and 130 373 males (8·8%). Nine studies provided data on patient race and ethnicity, and 22 studies were rated as high quality. The presence of any mental disorder was associated with an increased risk of COVID-19 mortality (OR 2·00 [95% CI 1·58-2·54]; I=92·66%). This association was also observed for psychotic disorders (2·05 [1·37-3·06]; I=80·81%), mood disorders (1·99 [1·46-2·71]; I=68·32%), substance use disorders (1·76 [1·27-2·44]; I=47·90%), and intellectual disabilities and developmental disorders (1·73 [1·29-2·31]; I=90·15%) but not for anxiety disorders (1·07 [0·73-1·56]; I=11·05%). COVID-19 mortality was associated with exposure to antipsychotics (3·71 [1·74-7·91]; I=90·31%), anxiolytics (2·58 [1·22-5·44]; I=96·42%), and antidepressants (2·23 [1·06-4·71]; I=95·45%). For psychotic disorders, mood disorders, antipsychotics, and anxiolytics, the association remained significant after adjustment for age, sex, and other confounders. Mental disorders were associated with increased risk of hospitalisation (2·24 [1·70-2·94]; I=88·80%). No significant associations with mortality were identified for ICU admission. Subgroup analyses and meta-regressions showed significant associations of baseline COVID-19 treatment setting (p=0·013) and country (p<0·0001) with mortality. No significant associations with mortality were identified for other covariates. No evidence of publication bias was found. GRADE assessment indicated high certainty for crude mortality and hospitalisation, and moderate certainty for crude ICU admission.

Interpretation: Pre-existing mental disorders, in particular psychotic and mood disorders, and exposure to antipsychotics and anxiolytics were associated with COVID-19 mortality in both crude and adjusted models. Although further research is required to determine the underlying mechanisms, our findings highlight the need for targeted approaches to manage and prevent COVID-19 in at-risk patient groups identified in this study.

Funding: None.

Translations: For the Italian, French and Portuguese translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2215-0366(21)00232-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285121PMC
July 2021

Probability of Transition to Psychosis in Individuals at Clinical High Risk: An Updated Meta-analysis.

JAMA Psychiatry 2021 Jul 14. Epub 2021 Jul 14.

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

Importance: Estimating the current likelihood of transitioning from a clinical high risk for psychosis (CHR-P) to psychosis holds paramount importance for preventive care and applied research.

Objective: To quantitatively examine the consistency and magnitude of transition risk to psychosis in individuals at CHR-P.

Data Sources: PubMed and Web of Science databases until November 1, 2020. Manual search of references from previous articles.

Study Selection: Longitudinal studies reporting transition risks in individuals at CHR-P.

Data Extraction And Synthesis: Meta-analysis compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines; independent data extraction, manually and through digitalization of Kaplan-Meier curves.

Main Outcome And Measures: Primary effect size was cumulative risk of transition to psychosis at 0.5, 1, 1.5, 2, 2.5, 3, 4, and more than 4 years' follow-up, estimated using the numbers of individuals at CHR-P transitioning to psychosis at each time point. These analyses were complemented by meta-analytical Kaplan-Meier curves and speed of transition to psychosis (hazard rate). Random-effects meta-analysis, between-study heterogeneity analysis, study quality assessment, and meta-regressions were conducted.

Results: A total of 130 studies and 9222 individuals at CHR-P were included. The mean (SD) age was 20.3 (4.4) years, and 5100 individuals (55.3%) were male. The cumulative transition risk was 0.09 (95% CI, 0.07-0.10; k = 37; n = 6485) at 0.5 years, 0.15 (95% CI, 0.13-0.16; k = 53; n = 7907) at 1 year, 0.20 (95% CI, 0.17-0.22; k = 30; n = 5488) at 1.5 years, 0.19 (95% CI, 0.17-0.22; k = 44; n = 7351) at 2 years, 0.25 (95% CI, 0.21-0.29; k = 19; n = 3114) at 2.5 years, 0.25 (95% CI, 0.22-0.29; k = 29; n = 4029) at 3 years, 0.27 (95% CI, 0.23-0.30; k = 16; n = 2926) at 4 years, and 0.28 (95% CI, 0.20-0.37; k = 14; n = 2301) at more than 4 years. The cumulative Kaplan-Meier transition risk was 0.08 (95% CI, 0.08-0.09; n = 4860) at 0.5 years, 0.14 (95% CI, 0.13-0.15; n = 3408) at 1 year, 0.17 (95% CI, 0.16-0.19; n = 2892) at 1.5 years, 0.20 (95% CI, 0.19-0.21; n = 2357) at 2 years, 0.25 (95% CI, 0.23-0.26; n = 1444) at 2.5 years, 0.27 (95% CI, 0.25-0.28; n = 1029) at 3 years, 0.28 (95% CI, 0.26-0.29; n = 808) at 3.5 years, 0.29 (95% CI, 0.27-0.30; n = 737) at 4 years, and 0.35 (95% CI, 0.32-0.38; n = 114) at 10 years. The hazard rate only plateaued at 4 years' follow-up. Meta-regressions showed that a lower proportion of female individuals (β = -0.02; 95% CI, -0.04 to -0.01) and a higher proportion of brief limited intermittent psychotic symptoms (β = 0.02; 95% CI, 0.01-0.03) were associated with an increase in transition risk. Heterogeneity across the studies was high (I2 range, 77.91% to 95.73%).

Conclusions And Relevance: In this meta-analysis, 25% of individuals at CHR-P developed psychosis within 3 years. Transition risk continued increasing in the long term. Extended clinical monitoring and preventive care may be beneficial in this patient population.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8281006PMC
July 2021

Disparities in Screening and Treatment of Cardiovascular Diseases in Patients With Mental Disorders Across the World: Systematic Review and Meta-Analysis of 47 Observational Studies.

Am J Psychiatry 2021 Jul 14:appiajp202121010031. Epub 2021 Jul 14.

Neurosciences Department (Solmi, Miola), Padua Neuroscience Center (Solmi), Department of General Psychology (Poddighe), and Department of Philosophy, Sociology, Education, and Applied Psychology (Delogu), University of Padua, Italy; Early Psychosis: Interventions and Clinical Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Solmi, Fusar-Poli); Psychiatry Department, University of Ottawa, Ottawa (Fiedorowicz); Department of Clinical Medicine, Faculty of Health Sciences, UiT-Arctic University of Norway, Tromsø (Høye); Division of Mental Health and Substance Abuse, University Hospital of North Norway, Tromsø (Høye); Center for Clinical Documentation and Evaluation (SKDE), Tromsø (Høye, Heiberg); Physiotherapy Department, South London and Maudsley NHS Foundation Trust, and Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Stubbs); Cambridge Centre for Sport and Exercise Science, Anglia Ruskin University, Cambridge, U.K. (Smith); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, and School of Medical Sciences, Örebro University, Örebro, Sweden (Larsson); Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark, and Department of Clinical Sciences, Lund University, Lund, Sweden (Attar); Department of Psychiatry, Aalborg University Hospital, and Department of Clinical Medicine, Aalborg University, Aalborg, Denmark (Nielsen); Centre for Innovation in Mental Health-Developmental Lab, School of Psychology, University of Southampton, and NHS Trust, Southampton, U.K. (Cortese); Hassenfeld Children's Hospital at NYU Langone, New York University Child Study Center, New York (Cortese); Division of Psychiatry and Applied Psychology, School of Medicine, University of Nottingham, Nottingham, U.K. (Cortese); Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea (Shin); National Institute for Health Research, Maudsley Biomedical Research Centre, and OASIS Service, South London and Maudsley NHS Foundation Trust, London (Fusar-Poli); Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy (Fusar-Poli); Division of Psychology and Mental Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, U.K. (Firth); NICM Health Research Institute, Western Sydney University, Westmead, Australia (Firth); Department of Psychiatry, University of British Columbia, Vancouver (Yatham); Department of Psychiatry, University of Toronto, and Centre for Addiction and Mental Health, Toronto (Castle, Seeman); IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia (Carvalho); Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Charité University Medicine Berlin, Berlin (Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y. (Correll); and Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, N.Y. (Correll).

Objective: This study used meta-analysis to assess disparities in cardiovascular disease (CVD) screening and treatment in people with mental disorders, a group that has elevated CVD incidence and mortality.

Methods: The authors searched PubMed and PsycInfo through July 31, 2020, and conducted a random-effect meta-analysis of observational studies comparing CVD screening and treatment in people with and without mental disorders. The primary outcome was odds ratios for CVD screening and treatment. Sensitivity analyses on screening and treatment separately and on specific procedures, subgroup analyses by country, and by controlling for confounding by indication, as well as meta-regressions, were also run, and publication bias and quality were assessed.

Results: Forty-seven studies (N=24,400,452 patients, of whom 1,283,602 had mental disorders) from North America (k=26), Europe (k=16), Asia (k=4), and Australia (k=1) were meta-analyzed. Lower rates of screening or treatment in patients with mental disorders emerged for any CVD (k=47, odds ratio=0.773, 95% CI=0.742, 0.804), coronary artery disease (k=34, odds ratio=0.734, 95% CI=0.690, 0.781), cerebrovascular disease (k=8, odds ratio=0.810, 95% CI=0.779, 0.842), and other mixed CVDs (k=11, odds ratio=0.839, 95% CI=0.761, 0.924). Significant disparities emerged for any screening, any intervention, catheterization or revascularization in coronary artery disease, intravenous thrombolysis for stroke, and treatment with any and with specific medications for CVD across all mental disorders (except for CVD medications in mood disorders). Disparities were largest for schizophrenia, and they differed across countries. Median study quality was high (Newcastle-Ottawa Scale score, 8); higher-quality studies found larger disparities, and publication bias did not affect results.

Conclusions: People with mental disorders, and those with schizophrenia in particular, receive less screening and lower-quality treatment for CVD. It is of paramount importance to address underprescribing of CVD medications and underutilization of diagnostic and therapeutic procedures across all mental disorders.
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http://dx.doi.org/10.1176/appi.ajp.2021.21010031DOI Listing
July 2021

Antipsychotics and Attenuated Psychosis Syndrome: Transdiagnostic assessment and discontinuation strategies.

Schizophr Res 2021 Jun 30. Epub 2021 Jun 30.

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

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http://dx.doi.org/10.1016/j.schres.2021.06.030DOI Listing
June 2021

Early detection of bipolar disorders and treatment recommendations for help-seeking adolescents and young adults: Findings of the Early Detection and Intervention Center Dresden.

Int J Bipolar Disord 2021 Jul 2;9(1):23. Epub 2021 Jul 2.

Department of Psychiatry and Psychotherapy, Carl Gustav Carus University Hospital, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.

Background: Early identification and intervention of individuals with risk factors for or subtle prodromal symptoms of bipolar disorders (BD) may improve the illness course and prevent adverse long-term consequences.

Methods: We examined sociodemographic, clinical and psychopathological characteristics of help-seeking adolescents and young adults who consulted the Early Detection and Intervention Center Dresden at the University of Dresden (Germany) and presented with or without pre-defined at-risk criteria for BD. The standardized diagnostic procedure for all help-seeking youth included a comprehensive psychiatric history and a structured clinical interview. When BD at-risk state was suspected, early detection instruments (EPIbipolar, BPSS-FP) were applied. Treatment recommendations were formulated in multi-professional case conferences.

Results: Out of 890 help-seeking persons between 05/2009 and 04/2018, 582 (65%) completed the diagnostic process. Of these, 24 (4%) had manifest BD and 125 (21%) fulfilled at-risk BD criteria (age = 23.9 ± 0.6 years, female = 62%). Of the pre-defined main risk factors, family history for BD was reported in 22% of the at-risk persons, (hypo-)mania risk state in 44%, and increasing cyclothymic mood swings with increased activity in 48%. The most common secondary risk factors were decreased psychosocial functioning (78%), lifetime diagnosis of depressive disorder (67%) and specific sleep/circadian rhythm disturbances (59%). Substance use was very common in subjects at-risk for BD (cannabis = 50%, alcohol = 33%) and highest in patients with BD (cannabis = 75%, alcohol = 40%). Psychiatric treatment history, including psychopharmacological therapy, was similar between the groups, while treatment recommendations differed, with more advice for psychotherapy and antidepressants in the at-risk group with a lifetime diagnosis of depression and more advice for specialized BD treatment including mood stabilizers in patients with BD.

Conclusion: This analysis on the phenomenology of different BD at-risk stages suggests that early detection of individuals presenting with suggested risk factors for the development of BD is feasible in help-seeking young people. Future research should further develop/test stage-specific prevention and early targeted intervention approaches that were described in a naturalistic setting.
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http://dx.doi.org/10.1186/s40345-021-00227-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253866PMC
July 2021

A Pilot Study on Covid and Autism: Prevalence, Clinical Presentation and Vaccine Side Effects.

Brain Sci 2021 Jun 28;11(7). Epub 2021 Jun 28.

Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy.

: Several neurobiological mechanisms have been proposed to support the hypothesis of a higher COVID-19 risk in individuals with autism spectrum disorder (ASD). However, no real-world data are available on this population. : We compared the period prevalence (March-May 2020) and symptom presentation of COVID-19 infections between a sample of individuals with severe ASD ( = 36) and the staff personnel ( = 35) of two specialized centers. Anti-SARS-Cov-2 antibody positivity was used as a proxy of infection. Additionally, we evaluated vaccine side effects in the same groups. : No significant difference was found between the prevalence of COVID-19 positivity between autistic participants and staff personnel. Levels of antibodies against the spike protein and the receptor binding domain were not significantly different between autistic and staff participants. The level of antibodies against the N-terminal domain were higher in autistic individuals. There was a significant difference between the prevalence of symptomatic COVID-19 in autistic participants (9.1%) compared to staff personnel (92.3%). The most frequent side effect among autistic participants was light fever. The present study provides preliminary data on COVID-19 transmission and presentation in ASD. Our data do not support the hypothesis of a higher susceptibility and severity of COVID-19 in people with ASD.
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http://dx.doi.org/10.3390/brainsci11070860DOI Listing
June 2021

Longitudinal outcome of attenuated positive symptoms, negative symptoms, functioning and remission in people at clinical high risk for psychosis: a meta-analysis.

EClinicalMedicine 2021 Jun 16;36:100909. Epub 2021 Jun 16.

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

Background: Little is known about clinical outcomes other than transition to psychosis in people at Clinical High-Risk for psychosis (CHR-P). Our aim was to comprehensively meta-analytically evaluate for the first time a wide range of clinical and functional outcomes beyond transition to psychosis in CHR-P individuals.

Methods: PubMed and Web of Science were searched until November 2020 in this PRISMA compliant meta-analysis (PROSPERO:CRD42020206271). Individual longitudinal studies conducted in individuals at CHR-P providing data on at least one of our outcomes of interest were included. We carried out random-effects pairwise meta-analyses, meta-regressions, and assessed publication bias and study quality. Analyses were two-tailed with α=0.05.

Findings: 75 prospective studies were included (n=5,288, age=20.0 years, females=44.5%). Attenuated positive symptoms improved at 12 (Hedges' g=0.753, 95%CI=0.495-1.012) and 24 (Hedges' g=0.836, 95%CI=0.463-1.209), but not ≥36 months (Hedges' g=0.315. 95%CI=-0.176-0.806). Negative symptoms improved at 12 (Hedges' g=0.496, 95%CI=0.315-0.678), but not 24 (Hedges' g=0.499, 95%CI=-0.137-1.134) or ≥36 months (Hedges' g=0.033, 95%CI=-0.439-0.505). Depressive symptoms improved at 12 (Hedges' g=0.611, 95%CI=0.441-0.782) and 24 (Hedges' g=0.583, 95%CI=0.364-0.803), but not ≥36 months (Hedges' g=0.512 95%CI=-0.337-1.361). Functioning improved at 12 (Hedges' g=0.711, 95%CI=0.488-0.934), 24 (Hedges' g=0.930, 95%CI=0.553-1.306) and ≥36 months (Hedges' g=0.392, 95%CI=0.117-0.667). Remission from CHR-P status occurred in 33.4% (95%CI=22.6-44.1%) at 12 months, 41.4% (95%CI=32.3-50.5%) at 24 months and 42.4% (95%CI=23.4-61.3%) at ≥36 months. Heterogeneity across the included studies was significant and ranged from I=53.6% to I=96.9%. The quality of the included studies (mean±SD) was 4.6±1.1 (range=2-8).

Interpretation: CHR-P individuals improve on symptomatic and functional outcomes over time, but these improvements are not maintained in the longer term, and less than half fully remit. Prolonged duration of care may be needed for this patient population to optimize outcomes.

Funding: None.
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http://dx.doi.org/10.1016/j.eclinm.2021.100909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219991PMC
June 2021

Developing and Validating an Individualized Clinical Prediction Model to Forecast Psychotic Recurrence in Acute and Transient Psychotic Disorders: Electronic Health Record Cohort Study.

Schizophr Bull 2021 Jun 26. Epub 2021 Jun 26.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Acute and transient psychotic disorders (ATPDs) include short-lived psychotic episodes with a high probability of developing psychotic recurrences. Clinical care for ATPD is currently limited by the inability to predict outcomes. Real-world electronic health record (EHR)-based retrospective cohort study STROBE/RECORD compliant included all individuals accessing the South London and Maudsley NHS Trust between 2006 and 2017 and receiving a first diagnosis of ATPD (F23, ICD-10). After imputing missing data, stepwise and LASSO Cox regression methods employing a priori predictors (n = 23) were compared to develop and internally validate an individualized risk prediction model to forecast the risk of psychotic recurrences following TRIPOD guidelines. The primary outcome was prognostic accuracy (area under the curve [AUC]). 3018 ATPD individuals were included (average age = 33.75 years, 52.7% females). Over follow-up (average 1042 ± 1011 days, up to 8 years) there were 1160 psychotic recurrences (events). Stepwise (n = 12 predictors) and LASSO (n = 17 predictors) regression methods yielded comparable prognostic accuracy, with an events per variable ratio >100 for both models. Both models showed an internally validated adequate prognostic accuracy from 4 years follow-up (AUC 0.70 for both models) and good calibration. A refined model was adapted in view of the new ICD-11 criteria on 307 subjects with polymorphic ATPD, showing fair prognostic accuracy at 4 years (AUC: stepwise 0.68; LASSO 0.70). This study presents the first clinically based prediction model internally validated to adequately predict long-term psychotic recurrence in individuals with ATPD. The model can be automatable in EHRs, supporting further external validations and refinements to improve its prognostic accuracy.
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http://dx.doi.org/10.1093/schbul/sbab070DOI Listing
June 2021

Neurocognitive Functioning in Individuals at Clinical High Risk for Psychosis: A Systematic Review and Meta-analysis.

JAMA Psychiatry 2021 Jun 16. Epub 2021 Jun 16.

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

Importance: Neurocognitive functioning is a potential biomarker to advance detection, prognosis, and preventive care for individuals at clinical high risk for psychosis (CHR-P). The current consistency and magnitude of neurocognitive functioning in individuals at CHR-P are undetermined.

Objective: To provide an updated synthesis of evidence on the consistency and magnitude of neurocognitive functioning in individuals at CHR-P.

Data Sources: Web of Science database, Cochrane Central Register of Reviews, and Ovid/PsycINFO and trial registries up to July 1, 2020.

Study Selection: Multistep literature search compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology performed by independent researchers to identify original studies reporting on neurocognitive functioning in individuals at CHR-P.

Data Extraction And Synthesis: Independent researchers extracted the data, clustering the neurocognitive tasks according to 7 Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) domains and 8 CHR-P domains. Random-effect model meta-analyses, assessment of publication biases and study quality, and meta-regressions were conducted.

Main Outcomes And Measures: The primary effect size measure was Hedges g of neurocognitive functioning in individuals at CHR-P (1) compared with healthy control (HC) individuals or (2) compared with individuals with first-episode psychosis (FEP) or (3) stratified for the longitudinal transition to psychosis.

Results: A total of 78 independent studies were included, consisting of 5162 individuals at CHR-P (mean [SD; range] age, 20.2 [3.3; 12.0-29.0] years; 2529 [49.0%] were female), 2865 HC individuals (mean [SD; range] age, 21.1 [3.6; 12.6-29.2] years; 1490 [52.0%] were female), and 486 individuals with FEP (mean [SD; range] age, 23.0 [2.0; 19.1-26.4] years; 267 [55.9%] were female). Compared with HC individuals, individuals at CHR-P showed medium to large deficits on the Stroop color word reading task (g = -1.17; 95% CI, -1.86 to -0.48), Hopkins Verbal Learning Test-Revised (g = -0.86; 95% CI, -1.43 to -0.28), digit symbol coding test (g = -0.74; 95% CI, -1.19 to -0.29), Brief Assessment of Cognition Scale Symbol Coding (g = -0.67; 95% CI, -0.95 to -0.39), University of Pennsylvania Smell Identification Test (g = -0.55; 95% CI, -0.97 to -0.12), Hinting Task (g = -0.53; 95% CI, -0.77 to -0.28), Rey Auditory Verbal Learning Test (g = -0.50; 95% CI, -0.78 to -0.21), California Verbal Learning Test (CVLT) (g = -0.50; 95% CI, -0.64 to -0.36), and National Adult Reading Test (g = -0.52; 95% CI, -1.01 to -0.03). Individuals at CHR-P were less impaired than individuals with FEP. Longitudinal transition to psychosis from a CHR-P state was associated with medium to large deficits in the CVLT task (g = -0.58; 95% CI, -1.12 to -0.05). Meta-regressions found significant effects for age and education on processing speed.

Conclusions And Relevance: Findings from this meta-analysis support neurocognitive dysfunction as a potential detection and prognostic biomarker in individuals at CHR-P. These findings may advance clinical research and inform preventive approaches.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.1290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209603PMC
June 2021

Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies.

Mol Psychiatry 2021 Jun 2. Epub 2021 Jun 2.

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

Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11-34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7-16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9-25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14-29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15-23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17-48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20-41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20-34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20-33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21-46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.
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http://dx.doi.org/10.1038/s41380-021-01161-7DOI Listing
June 2021

Cortical gray matter reduction precedes transition to psychosis in individuals at clinical high-risk for psychosis: A voxel-based meta-analysis.

Schizophr Res 2021 06 22;232:98-106. Epub 2021 May 22.

Department of Child and Adolescent Psychiatry and Psychology, 2017SGR881, Institute of Neuroscience, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; Fundació Clínic per a la Recerca Biomèdica (FCRB), Esther Koplowitz Centre, Rosselló 153, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Rosselló 149, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain. Electronic address:

Gray matter and cortical thickness reductions have been documented in individuals at clinical high-risk for psychosis and may be more pronounced in those who transition to psychosis. However, these findings rely on small samples and are inconsistent across studies. In this review and meta-analysis we aimed to investigate neuroanatomical correlates of clinical high-risk for psychosis and potential predictors of transition, using a novel meta-analytic method (Seed-based d Mapping with Permutation of Subject Images) and cortical mask, combining data from surface-based and voxel-based morphometry studies. Individuals at clinical high-risk for psychosis who later transitioned to psychosis were compared to those who did not and to controls, and included three statistical maps. Overall, individuals at clinical high-risk for psychosis did not differ from controls, however, within the clinical high-risk for psychosis group, transition to psychosis was associated with less cortical gray matter in the right temporal lobe (Hedges' g = -0.377), anterior cingulate and paracingulate (Hedges' g = -0.391). These findings have the potential to help refine prognostic and etiopathological research in early psychosis.
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http://dx.doi.org/10.1016/j.schres.2021.05.008DOI Listing
June 2021

Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: an umbrella review.

World Psychiatry 2021 Jun;20(2):244-275

Neurosciences Department, University of Padua, Padua, Italy.

Top-tier evidence on the safety/tolerability of 80 medications in children/adolescents with mental disorders has recently been reviewed in this jour-nal. To guide clinical practice, such data must be combined with evidence on efficacy and acceptability. Besides medications, psychosocial inter-ventions and brain stimulation techniques are treatment options for children/adolescents with mental disorders. For this umbrella review, we systematically searched network meta-analyses (NMAs) and meta-analyses (MAs) of randomized controlled trials (RCTs) evaluating 48 medications, 20 psychosocial interventions, and four brain stimulation techniques in children/adolescents with 52 different mental disorders or groups of mental disorders, reporting on 20 different efficacy/acceptability outcomes. Co-primary outcomes were disease-specific symptom reduction and all-cause discontinuation ("acceptability"). We included 14 NMAs and 90 MAs, reporting on 15 mental disorders or groups of mental disorders. Overall, 21 medications outperformed placebo regarding the co-primary outcomes, and three psychosocial interventions did so (while seven outperformed waiting list/no treatment). Based on the meta-analytic evidence, the most convincing efficacy profile emerged for amphetamines, methylphenidate and, to a smaller extent, behavioral therapy in attention-deficit/hyperactivity disorder; aripiprazole, risperidone and several psychosocial interventions in autism; risperidone and behavioral interventions in disruptive behavior disorders; several antipsychotics in schizophrenia spectrum disorders; fluoxetine, the combination of fluoxetine and cognitive behavioral therapy (CBT), and interpersonal therapy in depression; aripiprazole in mania; fluoxetine and group CBT in anxiety disorders; fluoxetine/selective serotonin reuptake inhibitors, CBT, and behavioral therapy with exposure and response prevention in obsessive-compulsive disorder; CBT in post-traumatic stress disorder; imipramine and alarm behavioral intervention in enuresis; behavioral therapy in encopresis; and family therapy in anorexia nervosa. Results from this umbrella review of interventions for mental disorders in children/adolescents provide evidence-based information for clinical decision making.
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http://dx.doi.org/10.1002/wps.20881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129843PMC
June 2021

Preventive psychiatry: a blueprint for improving the mental health of young people.

World Psychiatry 2021 Jun;20(2):200-221

Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, CA, USA.

Preventive approaches have latterly gained traction for improving mental health in young people. In this paper, we first appraise the conceptual foundations of preventive psychiatry, encompassing the public health, Gordon's, US Institute of Medicine, World Health Organization, and good mental health frameworks, and neurodevelopmentally-sensitive clinical staging models. We then review the evidence supporting primary prevention of psychotic, bipolar and common mental disorders and promotion of good mental health as potential transformative strategies to reduce the incidence of these disorders in young people. Within indicated approaches, the clinical high-risk for psychosis paradigm has received the most empirical validation, while clinical high-risk states for bipolar and common mental disorders are increasingly becoming a focus of attention. Selective approaches have mostly targeted familial vulnerability and non-genetic risk exposures. Selective screening and psychological/psychoeducational interventions in vulnerable subgroups may improve anxiety/depressive symptoms, but their efficacy in reducing the incidence of psychotic/bipolar/common mental disorders is unproven. Selective physical exercise may reduce the incidence of anxiety disorders. Universal psychological/psychoeducational interventions may improve anxiety symptoms but not prevent depressive/anxiety disorders, while universal physical exercise may reduce the incidence of anxiety disorders. Universal public health approaches targeting school climate or social determinants (demographic, economic, neighbourhood, environmental, social/cultural) of mental disorders hold the greatest potential for reducing the risk profile of the population as a whole. The approach to promotion of good mental health is currently fragmented. We leverage the knowledge gained from the review to develop a blueprint for future research and practice of preventive psychiatry in young people: integrating universal and targeted frameworks; advancing multivariable, transdiagnostic, multi-endpoint epidemiological knowledge; synergically preventing common and infrequent mental disorders; preventing physical and mental health burden together; implementing stratified/personalized prognosis; establishing evidence-based preventive interventions; developing an ethical framework, improving prevention through education/training; consolidating the cost-effectiveness of preventive psychiatry; and decreasing inequalities. These goals can only be achieved through an urgent individual, societal, and global level response, which promotes a vigorous collaboration across scientific, health care, societal and governmental sectors for implementing preventive psychiatry, as much is at stake for young people with or at risk for emerging mental disorders.
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http://dx.doi.org/10.1002/wps.20869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129854PMC
June 2021

Universal and Selective Interventions to Prevent Poor Mental Health Outcomes in Young People: Systematic Review and Meta-analysis.

Harv Rev Psychiatry 2021 May-Jun 01;29(3):196-215

From the Early Psychosis: Interventions and Clinical-Detection (EPIC) Laboratory, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London (Drs. Salazar de Pablo, De Micheli, Catalan, Verdino, Di Maggio, Radua, Provenzani, Montealegre, Signorini, and Fusar-Poli, and Mr. Oliver); Departments of Child and Adolescent Psychiatry (Dr. Salazar de Pablo) and of Psychosis Studies (Drs. Bonoldi and Baccaredda Boy), Institute of Psychiatry, Psychology & Neuroscience, King's College London; Institute of Psychiatry and Mental Health. Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), CIBERSAM, Madrid (Drs. Salazar de Pablo and Arango); National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London (Drs. De Micheli and Fusar-Poli); Department of Brain and Behavioral Sciences, University of Pavia (Drs. Di Maggio, Provenzani, Ruzzi, Calorio, Nosari, Di Marco, Famularo, Molteni, Filosi, Mensi, Balottin, Politi, and Fusar-Poli); Neurosciences Department, University of Padova (Dr. Solmi); Mental Health Department, Biocruces Bizkaia Health Research Institute, Basurto University Hospital, Facultad de Medicina y Odontología, Campus de Leioa, University of the Basque Country, UPV/EHU, Barakaldo, Bizkaia, Spain (Dr. Catalan); Department of Molecular and Developmental Medicine, Division of Psychiatry, University of Siena (Dr. Verdino); Imaging of Mood- and Anxiety-Related Disorders (IMARD) group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Barcelona (Dr. Radua); Department of Clinical Neuroscience, Centre for Psychiatric Research and Education, Karolinska Institutet, Stockholm (Dr. Radua); Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Mondino Foundation, Child and Adolescent Neuropsychiatric Unit (Dr. Mensi); Department of Paediatrics, Yonsei University College of Medicine, Seoul (Dr. Shin); Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY (Dr. Correll); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Dr. Correll); Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY (Dr. Correll); Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin (Dr. Correll); OASIS service, South London and Maudsley NHS Foundation Trust, London (Dr. Fusar-Poli).

Background: Much is not known about the efficacy of interventions to prevent poor mental health outcomes in young people by targeting either the general population (universal prevention) or asymptomatic individuals with high risk of developing a mental disorder (selective prevention).

Methods: We conducted a PRISMA/MOOSE-compliant systematic review and meta-analysis of Web of Science to identify studies comparing post-test efficacy (effect size [ES]; Hedges' g) of universal or selective interventions for poor mental health outcomes versus control groups, in samples with mean age <35 years (PROSPERO: CRD42018102143). Measurements included random-effects models, I2 statistics, publication bias, meta-regression, sensitivity analyses, quality assessments, number needed to treat, and population impact number.

Results: 295 articles (447,206 individuals; mean age = 15.4) appraising 17 poor mental health outcomes were included. Compared to control conditions, universal and selective interventions improved (in descending magnitude order) interpersonal violence, general psychological distress, alcohol use, anxiety features, affective symptoms, other emotional and behavioral problems, consequences of alcohol use, posttraumatic stress disorder features, conduct problems, tobacco use, externalizing behaviors, attention-deficit/hyperactivity disorder features, and cannabis use, but not eating-related problems, impaired functioning, internalizing behavior, or sleep-related problems. Psychoeducation had the highest effect size for ADHD features, affective symptoms, and interpersonal violence. Psychotherapy had the highest effect size for anxiety features.

Conclusion: Universal and selective preventive interventions for young individuals are feasible and can improve poor mental health outcomes.
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http://dx.doi.org/10.1097/HRP.0000000000000294DOI Listing
May 2021

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis.

JAMA Psychiatry 2021 Jul;78(7):753-766

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.

Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).

Design, Setting, And Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.

Main Outcomes And Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).

Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001).

Conclusions And Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.0638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100913PMC
July 2021

Prognostic Accuracy of DSM-5 Attenuated Psychosis Symptoms in Adolescents: Prospective Real-World 5-Year Cohort Study.

Schizophr Bull 2021 May 3. Epub 2021 May 3.

Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

There is limited research in adolescents at risk for psychosis. The new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition attenuated psychosis syndrome (DSM-5 APS) criteria have not been validated in this group. We conducted a RECORD-compliant, real-world, prospective, 5-year cohort study addressing clinical profile, transition to psychosis, and prognostic accuracy of DSM-5 APS in help-seeking inpatient/outpatient adolescents accessing Children and Adolescent Neuropsychiatric services at IRCCS Mondino Foundation (Pavia, Lombardy, Italy) between 2012 and 2019. About 243 adolescents (31 early-onset psychosis [EOP]; 110 meeting DSM-5 APS criteria, DSM-5 APS; 102 not meeting psychotic or DSM-5 APS criteria, non-APS) were included. At baseline, DSM-5 APS adolescents (aged 15.4 ± 1.6) had on average 2.3 comorbid disorders (higher than EOP/non-APS, P < .001). DSM-5 APS adolescents had an intermediate psychopathological profile between non-APS/EOP (P < .001) and worsen Clinical Global Impression-Severity than non-APS (P < .001). DSM-5 APS functioning was intermediate between non-APS and EOP. 39.1% of DSM-5 APS were treated with psychotropic drugs (average = 64 days); 53.6% received psychotherapy. Follow-up of DSM-5 APS and non-APS groups lasted 33 and 26 months, respectively (median). The cumulative risk of transition at 1-5 years was 13%, 17%, 24.2%, 26.8%, and 26.8% in the DSM-5 APS group, 0%, 0%, 3.2%, 3.2%, and 3.2% in the non-APS group. The 5-year prognostic accuracy of the DSM-5 APS in adolescent was adequate (area under the curve = 0.77; Harrell's C = 0.736, 95%CI 0.697-0.775), with high sensitivity (91.3%) and suboptimal specificity (63.2%). The DSM-5 APS diagnosis can be used to detect help-seeking adolescents at risk of psychosis and predict their long-term outcomes. Future research should consolidate these findings.
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http://dx.doi.org/10.1093/schbul/sbab041DOI Listing
May 2021

Gender differences in clinical presentation and illicit substance use during first episode psychosis: a natural language processing, electronic case register study.

BMJ Open 2021 04 20;11(4):e042949. Epub 2021 Apr 20.

Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, London, UK.

Objective: To determine whether gender differences in symptom presentation at first episode psychosis (FEP) remain even when controlling for substance use, age and ethnicity, using natural language processing applied to electronic health records (EHRs).

Design, Setting And Participants: Data were extracted from EHRs of 3350 people (62% male patients) who had presented to the South London and Maudsley NHS Trust with a FEP between 1 April 2007 and 31 March 2017. Logistic regression was used to examine gender differences in the presentation of positive, negative, depressive, mania and disorganisation symptoms.

Exposures For Observational Studies: Gender (male vs female).

Main Outcomes And Measures: Presence of positive, negative, depressive, mania and disorganisation symptoms at initial clinical presentation.

Results: Eight symptoms were significantly more prevalent in men (poverty of thought, negative symptoms, social withdrawal, poverty of speech, aggression, grandiosity, paranoia and agitation). Conversely, tearfulness, low energy, reduced appetite, low mood, pressured speech, mood instability, flight of ideas, guilt, mutism, insomnia, poor concentration, tangentiality and elation were more prevalent in women than men. Negative symptoms were more common among men (OR 1.85, 95% CI 1.33 to 2.62) and depressive and manic symptoms more common among women (OR 0.30, 95% CI 0.26 to 0.35). After adjustment for illicit substance use, the strength of associations between gender and negative, manic and depression symptoms increased, whereas gender differences in aggression, agitation, paranoia and grandiosity became insignificant.

Conclusions: There are clear gender differences in the clinical presentation of FEP. Our findings suggest that gender can have a substantial influence on the nature of clinical presentation in people with psychosis, and that this is only partly explained by exposure to illicit substance use.
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http://dx.doi.org/10.1136/bmjopen-2020-042949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061860PMC
April 2021

Risk and protective factors for cannabis, cocaine, and opioid use disorders: An umbrella review of meta-analyses of observational studies.

Neurosci Biobehav Rev 2021 07 15;126:243-251. Epub 2021 Mar 15.

Early Psychosis: Interventions and Clinical-Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology, London, UK; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy; Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; Outreach and Support in South London (OASIS) Service, South London and Maudsley NHS Foundation Trust, London, UK.

Several meta-analyses of observational studies have addressed the association between risk and protective factors and cannabis/cocaine/opioid use disorders, but results are conflicting. No umbrella review has ever graded the credibility of this evidence (not significant/weak/suggestive/highly suggestive/convincing). We searched Pubmed-MEDLINE/PsycInfo, last search September 21, 2020. We assessed the quality of meta-analyses with the AMSTAR-2 tool. Out of 3,072 initial references, five were included, providing 19 associations between 12 putative risk/protective factors and cannabis/cocaine/opioid use disorders (cases: 4539; N = 1,118,872,721). While 84 % of the associations were statistically significant, none was convincing. One risk factor (smoking) had highly suggestive evidence for association with nonmedical use of prescription opioid medicines (OR = 3.07, 95 %CI:2.27 to 4.14). Convincing evidence emerged in sensitivity analyses on antisocial behavior and cannabis use disoder (OR 3.34, 95 %CI 2.53-4.41). Remaining associations had weak evidence. The quality of meta-analyses was rated as moderate in two (40 %), low in one (20 %), and critically low in two (40 %). Future research is needed to better profile risk/protective factors for cannabis/cocaine/opioid use disorders disorders informing preventive approaches.
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http://dx.doi.org/10.1016/j.neubiorev.2021.03.014DOI Listing
July 2021

Severe mental illness and European COVID-19 vaccination strategies.

Lancet Psychiatry 2021 05 17;8(5):356-359. Epub 2021 Feb 17.

IMRB Translational Neuropsychiatry Lab, Université Paris Est Creteil, Creteil, France; Department of Psychiatry and Addictology, Hôpitaux Universitaires Henri Mondor, Créteil, France; Fondation FondaMental, Creteil, France.

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http://dx.doi.org/10.1016/S2215-0366(21)00046-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906735PMC
May 2021

Corrigendum to "Real-world long-term outcomes in individuals at clinical risk for psychosis: The case for extending duration of care" [EClinicalMedicine 28 (2020) 100,578].

EClinicalMedicine 2021 Feb 4;32:100729. Epub 2021 Feb 4.

OASIS service, South London and Maudsley NHS Foundation Trust, London, United Kingdom.

[This corrects the article DOI: 10.1016/j.eclinm.2020.100578.].
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http://dx.doi.org/10.1016/j.eclinm.2021.100729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868808PMC
February 2021

Third external replication of an individualised transdiagnostic prediction model for the automatic detection of individuals at risk of psychosis using electronic health records.

Schizophr Res 2021 02 5;228:403-409. Epub 2021 Feb 5.

Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley National Health Service (NHS) Foundation Trust, London, United Kingdom; OASIS Service, South London and Maudsley National Health Service (NHS) Foundation Trust, London, United Kingdom; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Background: Primary indicated prevention is a key target for reducing the incidence and burden of schizophrenia and related psychotic disorders. An individualised, clinically-based transdiagnostic model for the detection of individuals at risk of psychosis has been developed and validated in two large, urban healthcare providers. We tested its external validity in a geographically and demographically different non-urban population.

Method: Retrospective EHR cohort study. All individuals accessing secondary healthcare provided by Oxford Health NHS Foundation Trust between 1st January 2011 and 30th November 2019 and receiving a primary index diagnosis of a non-psychotic or non-organic mental disorder were considered eligible. The previously developed model was applied to this database and its external prognostic accuracy was measured with Harrell's C.

Findings: The study included n = 33,710 eligible individuals, with an average age of 27.7 years (SD = 19.8), mostly white (92.0%) and female (57.3%). The mean follow-up was 1863.9 days (SD = 948.9), with 868 transitions to psychosis and a cumulative incidence of psychosis at 6 years of 2.9% (95%CI: 2.7-3.1). Compared to the urban development database, Oxford Health was characterised by a relevant case mix, lower incidence of psychosis, different distribution of baseline predictors, higher proportion of white females, and a lack of specialised clinical services for at risk individuals. Despite these differences the model retained an adequate prognostic performance (Harrell's C = 0.79, 95%CI: 0.78-0.81), with no major miscalibration.

Interpretation: The transdiagnostic, individualised, clinically-based risk calculator is transportable outside urban healthcare providers. Further research should test transportability of this risk prediction model in an international setting.
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http://dx.doi.org/10.1016/j.schres.2021.01.005DOI Listing
February 2021

Viewpoint | European COVID-19 exit strategy for people with severe mental disorders: Too little, but not yet too late.

Brain Behav Immun 2021 05 23;94:15-17. Epub 2021 Jan 23.

Translational Neuropsychiatry Lab, Université Paris Est Creteil (UPEC), INSERM U955, IMRB, F-94010 Creteil, France; Département Medico-Universitaire de Psychiatrie et d'Addictologie (DMU ADAPT), AP-HP, Hopital Henri Mondor, F-94010 Creteil, France; Fondation FondaMental, Creteil, France. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2021.01.008DOI Listing
May 2021

Establishing a clinical service to prevent psychosis: What, how and when? Systematic review.

Transl Psychiatry 2021 01 13;11(1):43. Epub 2021 Jan 13.

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

The first rate-limiting step to successfully translate prevention of psychosis in to clinical practice is to establish specialised Clinical High Risk for Psychosis (CHR-P) services. This study systematises the knowledge regarding CHR-P services and provides guidelines for translational implementation. We conducted a PRISMA/MOOSE-compliant (PROSPERO-CRD42020163640) systematic review of Web of Science to identify studies until 4/05/2020 reporting on CHR-P service configuration, outreach strategy and referrals, service user characteristics, interventions, and outcomes. Fifty-six studies (1998-2020) were included, encompassing 51 distinct CHR-P services across 15 countries and a catchment area of 17,252,666 people. Most services (80.4%) consisted of integrated multidisciplinary teams taking care of CHR-P and other patients. Outreach encompassed active (up to 97.6%) or passive (up to 63.4%) approaches: referrals came mostly (90%) from healthcare agencies. CHR-P individuals were more frequently males (57.2%). Most (70.6%) services accepted individuals aged 12-35 years, typically assessed with the CAARMS/SIPS (83.7%). Baseline comorbid mental conditions were reported in two-third (69.5%) of cases, and unemployment in one third (36.6%). Most services provided up to 2-years (72.4%), of clinical monitoring (100%), psychoeducation (81.1%), psychosocial support (73%), family interventions (73%), individual (67.6%) and group (18.9%) psychotherapy, physical health interventions (37.8%), antipsychotics (87.1%), antidepressants (74.2%), anxiolytics (51.6%), and mood stabilisers (38.7%). Outcomes were more frequently ascertained clinically (93.0%) and included: persistence of symptoms/comorbidities (67.4%), transition to psychosis (53.5%), and functional status (48.8%). We provide ten practical recommendations for implementation of CHR-P services. Health service knowledge summarised by the current study will facilitate translational efforts for implementation of CHR-P services worldwide.
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http://dx.doi.org/10.1038/s41398-020-01165-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807021PMC
January 2021

Development of a probability calculator for psychosis risk in children, adolescents, and young adults.

Psychol Med 2021 Jan 12:1-9. Epub 2021 Jan 12.

Department of Psychiatry, Brain Behavior Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA19104, USA.

Background: Assessment of risks of illnesses has been an important part of medicine for decades. We now have hundreds of 'risk calculators' for illnesses, including brain disorders, and these calculators are continually improving as more diverse measures are collected on larger samples.

Methods: We first replicated an existing psychosis risk calculator and then used our own sample to develop a similar calculator for use in recruiting 'psychosis risk' enriched community samples. We assessed 632 participants age 8-21 (52% female; 48% Black) from a community sample with longitudinal data on neurocognitive, clinical, medical, and environmental variables. We used this information to predict psychosis spectrum (PS) status in the future. We selected variables based on lasso, random forest, and statistical inference relief; and predicted future PS using ridge regression, random forest, and support vector machines.

Results: Cross-validated prediction diagnostics were obtained by building and testing models in randomly selected sub-samples of the data, resulting in a distribution of the diagnostics; we report the mean. The strongest predictors of later PS status were the Children's Global Assessment Scale; delusions of predicting the future or having one's thoughts/actions controlled; and the percent married in one's neighborhood. Random forest followed by ridge regression was most accurate, with a cross-validated area under the curve (AUC) of 0.67. Adjustment of the model including only six variables reached an AUC of 0.70.

Conclusions: Results support the potential application of risk calculators for screening and identification of at-risk community youth in prospective investigations of developmental trajectories of the PS.
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http://dx.doi.org/10.1017/S0033291720005231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273212PMC
January 2021

Early Intervention Services for First Episode of Psychosis in South London and the Maudsley (SLaM): 20 Years of Care and Research for Young People.

Front Psychiatry 2020 24;11:577110. Epub 2020 Nov 24.

COAST Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom.

Early Intervention for a first episode of Psychosis (EI) is essential to improve outcomes. There is limited research describing real-world implementation of EI services. Analysis of service characteristics, outcomes (described through a retrospective 2007-2017 Electronic Health Record (EHR) cohort study) and clinical research relating to the first 20 years of implementation of EI services in South London and Maudsley (SLaM) Trust. SLaM EI are standalone services serving 443,050 young individuals in South-London, where (2017) incidence of psychosis (58.3-71.9 cases per 100,000 person-years) is greater than the national average. From 2007-2017 (when the EHR was established), 1,200 individuals (62.67% male, mean age 24.38 years, 88.17% single; two-thirds of non-white ethnicity) received NICE-compliant EI care. Pathways to EI services came mainly (75.26%) through inpatient (39.83%) or community (19.33%) mental health services or Accident and Emergency departments (A&E) (16%). At 6 year follow-up 34.92% of patients were still being prescribed antipsychotics. The 3 month and 6 year cumulative proportions of those receiving clozapine were 0.75 and 7.33%; those compulsorily admitted to psychiatric hospitals 26.92 and 57.25%; those admitted to physical health hospitals 6.83 and 31.17%, respectively. Average 3 months and 6 year days spent in hospital were 0.82 and 1.85, respectively; mean 6 year attendance at A&E was 3.01. SLaM EI clinical research attracted £58 million grant income and numerous high-impact scientific publications. SLaM EI services represent one of the largest, most established services of its kind, and are a leading model for development of similar services in the UK and worldwide.
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http://dx.doi.org/10.3389/fpsyt.2020.577110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732476PMC
November 2020

Dynamic ElecTronic hEalth reCord deTection (DETECT) of individuals at risk of a first episode of psychosis: a case-control development and validation study.

Lancet Digit Health 2020 05 26;2(5):e229-e239. Epub 2020 Mar 26.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; OASIS, South London and Maudsley NHS Foundation Trust, London, UK; National Institute for Health Research Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK; South London and Maudsley NHS Foundation Trust, London, UK; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Background: Many individuals who will experience a first episode of psychosis (FEP) are not detected before occurrence, limiting the effect of preventive interventions. The combination of machine-learning methods and electronic health records (EHRs) could help address this gap.

Methods: This case-control development and validation study is based on EHR data from IBM Explorys. The IBM Explorys Platform holds standardised, longitudinal, de-identified, patient-level EHR data pooled from different health-care systems with distinct EHRs. The present EHR-based studies were retrospective, matched (1:1), case-control studies compliant with RECORD, STROBE, and TRIPOD statements. The study included individuals in the IBM Explorys database who at some point between 1990 and 2018 had a diagnosis of FEP followed by schizophrenia, and psychosis-free matched control individuals from a random subsample of the full cohort. For every individual in the FEP cohort, the individual in the control cohort was matched to have a similar date for inclusion in the database and a similar total observation time. Individuals in the FEP cohort had their index date defined as the first diagnosis of psychosis or the first prescription of antipsychotic medication. Individuals in the control cohort had their index date defined to occur the same number of days after inclusion in the database as their matching FEP individual. The FEP and control cohorts were both randomly split into development and validation datasets in a ratio of 7:3. The subset of individuals in the validation dataset who had all their health-care encounters at providers that were not seen in the development dataset made up the external validation subset. A novel recurrent neural network model was developed to predict the risk of FEP 1 year before the index date by employing demographics and medical events (in the categories diagnoses, prescriptions, procedures, encounters and admissions, observations, and laboratory test results) dynamically collected in the EHR as part of clinical routine. We named the recurrent neural network Dynamic ElecTronic hEalth reCord deTection (DETECT). The main outcomes were accuracy and area under receiver operating characteristic curve (AUROC). Decision-curve analyses and dynamic patient journey plots were used to evaluate clinical usefulness.

Findings: The FEP and control cohorts each comprised 72 860 individuals. 102 030 individuals (51 015 matching pairs) were randomly allocated to the development dataset and the remaining 43 690 to the validation dataset. In the validation dataset, 4770 individuals had all their encounters outside of the 118 790 health-care providers that were encountered in the development dataset. The data from these individuals made up the external validation subset. The median follow-up (observation time before index date) was 6·0 years (IQR 3·0-10·4). In the development dataset, DETECT's prognostic accuracy was 0·787 and AUROC was 0·868. In the validation dataset, DETECT's prognostic accuracy was 0·774 and AUROC was 0·856. In the external test subset, DETECT's balanced prognostic accuracy was 0·724 and AUROC was 0·799. Prevalence-adjusted decision-curve analyses suggested that DETECT was associated with a positive net benefit in two different scenarios for FEP detection.

Interpretation: DETECT showed adequate prognostic accuracy to detect individuals at risk of developing a FEP in primary and secondary care. Replication and refinement in a population-based setting are needed to consolidate these findings.

Funding: Lundbeck.
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http://dx.doi.org/10.1016/S2589-7500(20)30024-8DOI Listing
May 2020

Real-world long-term outcomes in individuals at clinical risk for psychosis: The case for extending duration of care.

EClinicalMedicine 2020 Nov 7;28:100578. Epub 2020 Oct 7.

OASIS service, South London and Maudsley NHS Foundation Trust, London, UK.

Background: Most services for individuals at Clinical High Risk for Psychosis (CHR-P) provide short-term clinical care. This study determines the real-world and long-term clinical outcomes beyond transition to psychosis in a large cohort of CHR-P individuals.

Method: Retrospective RECORD-compliant real-world Electronic Health Records (EHR) cohort study in secondary mental health care (the South London and the Maudsley -SLaM- NHS Foundation Trust). All CHR-P patients accessing the CHR-P service at SLaM in the period 2001-2018 were included. Main outcomes were long-term cumulative risk of first: (i) developing an ICD-10 psychotic disorder (primary outcome), receiving a treatment with (iia) antipsychotic medication, (iib) benzodiazepines, (iic) other psychotropic medications, (iid) psychotherapy, receiving an (iiia) informal or (iiib) compulsory admission into a mental health hospital, and the time to these events; (iiic) number of days spent in hospital and (iv) cumulative risk of death for any reason and age/gender Standardised Mortality Ratio (SMR). Data were extracted from the EHR and analysed with Kaplan Meier failure functions, Cox and zero-inflated negative binomial regressions.

Findings: 600 CHR-P patients (80.43% Attenuated Psychotic Symptoms, APS; 18.06%, Brief and Limited Intermittent Psychotic Symptoms, BLIPS, 1.51% Genetic Risk and Deterioration Syndrome) were included (mean age 22.63 years, range 13-36; 55.33% males; 46.44% white, mean duration of untreated attenuated psychotic symptoms 676.32 days, 1105.40 SD). The cumulative risk to first psychosis was 0.365 (95%CI 0.302-0.437) at 11 years; first antipsychotic 0.777 (95%CI 0.702-0.844) at 9 years; first benzodiazepine 0.259 (95%CI 0.183-0.359) at 12 years; first other types of medications 0.630 (95%CI 0.538-0.772) at 9 years; first psychotherapy 0.814 (95%CI 0.764-0.859) at 9 years; first informal admission 0.378 (95%CI 0.249-0.546) at 12 years; first compulsory admission 0.251 (95%CI 0.175-0.352) at 12 years; those admitted spent on average 94.84 (SD=169.94) days in hospital; the cumulative risk of death for any reason was 0.036 (95%CI 0.012-0.103) at 9 years, with an SMR of 3.9 (95%CI 1.20-6.6). Compared to APS, BLIPS had a higher risk of developing psychosis, being admitted compulsorily into hospital, receiving antipsychotics and benzodiazepines and lower probability of receiving psychotherapy. Other prognostic factors of long-term outcomes included age, symptoms severity, duration of untreated attenuated psychotic symptoms, ethnicity and employment status.

Interpretation: Duration of care provided by CHR-P services should be expanded to address long-term real-world outcomes.

Funding: This study was supported by the King's College London Confidence in Concept award from the Medical Research Council (MRC) (MC_PC_16048) to PF-P. GSP is supported by the Alicia Koplowitz Foundation. HB is supported by a National Institute for Health Research Maudsley Biomedical Research Centre studentship.
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http://dx.doi.org/10.1016/j.eclinm.2020.100578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700893PMC
November 2020

Risk and protective factors for alcohol and tobacco related disorders: An umbrella review of observational studies.

Neurosci Biobehav Rev 2021 02 25;121:20-28. Epub 2020 Nov 25.

IMPACT (Innovation in Mental and Physical Health and Clinical Treatment) Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia; Department of Psychiatry, University of Toronto, and the Centre for Addiction and Mental Health, Toronto, ON, Canada.

The credibility of evidence of various environmental risk factors for alcohol and tobacco use disorders (AUD/TUD) needs to be graded to identify groups to target with selective prevention. A systematic umbrella review was conducted (PubMed/PsycINFO), grading credibility of meta-analyses of prospective/retrospective observational cohort studies assessing risk/protective factors for AUD/TUD, applying established quantitative criteria. Sensitivity analyses were conducted. Quality of eligible meta-analyses was assessed with AMSTAR-2. Out of 8464 unique references, 80 full text articles were scrutinized, and 12 meta-analyses, corresponding to 21 individual estimates of 12 putative risk/protective factors (n = 241,300), were included. In main analyses no association had convincing nor highly suggestive evidence for AUD/TUD. Six associations had suggestive evidence for AUD, two for TUD. Among these, in sensitivity analyses without >1000 cases criterion, convincing evidence emerged for parental alcohol supply, and impulsivity traits in college students for AUD, and attention-deficit/hyperactivity disorder for TUD. Other associations were supported by weak evidence/were not nominally significant. Few risk factors identified at-risk groups where selective preventative strategies could be developed to prevent AUD/TUD.
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http://dx.doi.org/10.1016/j.neubiorev.2020.11.010DOI Listing
February 2021

The case for improved transdiagnostic detection of first-episode psychosis: Electronic health record cohort study.

Schizophr Res 2021 02 22;228:547-554. Epub 2020 Nov 22.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Background: Improving outcomes of a First Episode of Psychosis (FEP) relies on the ability to detect most individuals with emerging psychosis and treat them in specialised Early Intervention (EI) services. Efficacy of current detection strategies is undetermined.

Methods: RECORD-compliant clinical, 6-year, retrospective, transdiagnostic, lifespan-inclusive, Electronic Health Record (EHR) cohort study, representing real-world secondary mental healthcare in South London and Maudsley (SLaM) NHS. All individuals accessing SLaM in the period 2007-2017 and receiving any ICD-10 diagnosis other than persistent psychosis were included. Descriptive statistics, Kaplan-Meier curves, logistic regression, epidemiological incidence of psychosis in the general population were used to address pathways to care and detection power of EI services for FEP.

Results: A total of 106,706 individuals underwent the 6-year follow-up: they were mostly single (72.57%) males (50.51%) of white ethnicity (60.01%), aged on average 32.96 years, with an average Health Of the Nation Outcome Scale score of 11.12 and mostly affected with F40-48 Neurotic/stress-related/somatoform disorders (27.46%). Their transdiagnostic risk of developing a FEP cumulated to 0.072 (95%CI 0.067-0.077) at 6 years. Those individuals who developed a FEP (n = 1841) entered healthcare mostly (79.02%) through inpatient mental health services (29.76%), community mental health services (29.54%) or accident and emergency departments (19.50%); at the time of FEP onset, most of them (46.43%) were under the acute care pathway. Individuals contacting accident and emergency departments had an increased risk of FEP (OR 2.301, 95%CI 2.095-2.534, P < 0.001). The proportion of SLaM FEP cases that were eligible and under the care of EI services was 0.456 at any time. The epidemiological proportion of FEP cases in the sociodemographically-matched general population that was detected by EI service was 0.373.

Conclusions: More than half of individuals who develop a FEP remain undetected by current pathways to care and EI services. Improving detection strategies should become a mainstream area in the future generation of early psychosis research.
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http://dx.doi.org/10.1016/j.schres.2020.11.031DOI Listing
February 2021

The prevalence, odds and predictors of lifespan comorbid eating disorder among people with a primary diagnosis of bipolar disorders, and vice-versa: Systematic review and meta-analysis.

J Affect Disord 2021 02 13;280(Pt A):409-431. Epub 2020 Nov 13.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.

Background: There are scarce and discrepant data about the prevalence and correlates of co-occurring eating disorders (EDs) among people with a primary diagnosis of bipolar disorder (BD), and vice-versa, compelling a systematic review and meta-analysis on the matter.

Methods: MEDLINE/PsycINFO databases were systematically searched for original studies documenting BD⇌ED comorbidity across the lifespan, from inception up until April 20, 2020. Random-effects meta-analysis and meta-regression analyses were conducted, accounting for multiple moderators.

Results: Thirty-six studies involved 15,084 primary BD patients. Eleven studies encompassed 15,146 people with primary EDs. Binge eating disorder (BED) occurred in 12.5% (95%C.I.=9.4-16.6%, I=93.48%) of BDs, while 9.1% (95%C.I.=3.3-22.6%) of BEDs endorsed BD. Bulimia Nervosa (BN) occurred in 7.4% (95%C.I.=6-10%) of people with BD, whereas 6.7% (95%C.I.=12-29.2%) of subjects with BN had a diagnosis of BD. Anorexia Nervosa (AN) occurred in 3.8% (95%C.I.=2-6%) of people with BDs; 2% (95%C.I.=1-2%) of BD patients had a diagnosis of AN. Overall, BD patients with EDs had higher odds of being female vs. non-ED controls. Several moderators yielded statistically significant differences both within- and between different types of BDs and EDs.

Limitations: Scant longitudinal studies, especially across different EDs and pediatric samples. High heterogeneity despite subgroup comparisons. Limited discrimination of the quality of the evidence.

Conclusions: The rates of BD⇌ED comorbidity vary across different diagnostic groups, more than they do according to the "direction" of BD⇌ED. Further primary studies should focus on the risks, chronology, clinical impact, and management of the onset of intertwined BD⇌ED across different ages, promoting a continuum approach.
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http://dx.doi.org/10.1016/j.jad.2020.11.015DOI Listing
February 2021