Publications by authors named "Andrea De Micheli"

31 Publications

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

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

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

Universal and selective interventions to promote good mental health in young people: Systematic review and meta-analysis.

Eur Neuropsychopharmacol 2020 12 6;41:28-39. Epub 2020 Nov 6.

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

Promotion of good mental health in young people is important. Our aim was to evaluate the consistency and magnitude of the efficacy of universal/selective interventions to promote good mental health. A systematic PRISMA/RIGHT-compliant meta-analysis (PROSPERO: CRD42018088708) search of Web of Science until 04/31/2019 identified original studies comparing the efficacy of universal/selective interventions for good mental health vs a control group, in samples with a mean age <35 years. Meta-analytical random-effects model, heterogeneity statistics, assessment of publication bias, study quality and sensitivity analyses investigated the efficacy (Hedges' g=effect size, ES) of universal/selective interventions to promote 14 good mental health outcomes defined a-priori. 276 studies were included (total participants: 159,508, 79,142 interventions and 80,366 controls), mean age=15.0 (SD=7.4); female=56.0%. There was a significant overall improvement in 10/13 good mental health outcome categories that could be meta-analysed: compared to controls, interventions significantly improved (in descending order of magnitude) mental health literacy (ES=0.685, p<0.001), emotions (ES=0.541, p<0.001), self-perceptions and values (ES=0.49, p<0.001), quality of life (ES=0.457, p=0.001), cognitive skills (ES=0.428, p<0.001), social skills (ES=0.371, p<0.001), physical health (ES=0.285, p<0.001), sexual health (ES=0.257, p=0.017), academic/occupational performance (ES=0.211, p<0.001) and attitude towards mental disorders (ES=0.177, p=0.006). Psychoeducation was the most effective intervention for promoting mental health literacy (ES=0.774, p<0.001) and cognitive skills (ES=1.153, p=0.03). Physical therapy, exercise and relaxation were more effective than psychoeducation and psychotherapy for promoting physical health (ES=0.498, p<0.001). In conclusion, several universal/selective interventions can be effective to promote good mental health in young people. Future research should consolidate and extend these findings.
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http://dx.doi.org/10.1016/j.euroneuro.2020.10.007DOI Listing
December 2020

Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma.

Dis Model Mech 2020 10 30;13(10). Epub 2020 Oct 30.

Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA

Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells, but their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported that this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here, we describe a single-cell transcriptomic atlas of the main cell types of the mouse uterus and epithelial subset transcriptome and evaluate the contribution of epithelial cells expressing the transcription factor PAX8 to the homeostatic regeneration and malignant transformation of adult endometrial epithelium. According to lineage tracing, PAX8 epithelial cells are responsible for long-term maintenance of both luminal and glandular epithelium. Furthermore, multicolor tracing shows that individual glands and contiguous areas of luminal epithelium are formed by clonal cell expansion. Inactivation of the tumor suppressor genes and in PAX8 cells, but not in FOXJ1 cells, leads to the formation of neoplasms with features of serous endometrial carcinoma, one of the most aggressive types of human endometrial malignancies. Taken together, our results show that the progeny of single PAX8 cells represents the main source of regeneration of the adult endometrial epithelium. They also provide direct experimental genetic evidence for the key roles of the P53 and RB pathways in the pathogenesis of serous endometrial carcinoma and suggest that PAX8 cells represent the cell of origin of this neoplasm.
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http://dx.doi.org/10.1242/dmm.047035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648606PMC
October 2020

Lower speech connectedness linked to incidence of psychosis in people at clinical high risk.

Schizophr Res 2021 02 18;228:493-501. Epub 2020 Sep 18.

Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK.

Background: Formal thought disorder is a cardinal feature of psychotic disorders, and is also evident in subtle forms before psychosis onset in individuals at clinical high-risk for psychosis (CHR-P). Assessing speech output or assessing expressive language with speech as the medium at this stage may be particularly useful in predicting later transition to psychosis.

Method: Speech samples were acquired through administration of the Thought and Language Index (TLI) in 24 CHR-P participants, 16 people with first-episode psychosis (FEP) and 13 healthy controls. The CHR-P individuals were then followed clinically for a mean of 7 years (s.d. = 1.5) to determine if they transitioned to psychosis. Non-semantic speech graph analysis was used to assess the connectedness of transcribed speech in all groups.

Results: Speech was significantly more disconnected in the FEP group than in both healthy controls (p < .01) and the CHR-P group (p < .05). Results remained significant when IQ was included as a covariate. Significant correlations were found between speech connectedness measures and scores on the TLI, a manual assessment of formal thought disorder. In the CHR-P group, lower scores on two measures of speech connectedness were associated with subsequent transition to psychosis (8 transitions, 16 non-transitions; p < .05).

Conclusion: These findings support the utility and validity of speech graph analysis methods in characterizing speech connectedness in the early phases of psychosis. This approach has the potential to be developed into an automated, objective and time-efficient way of stratifying individuals at CHR-P according to level of psychosis risk.
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http://dx.doi.org/10.1016/j.schres.2020.09.002DOI Listing
February 2021

Outreach and support in South-London (OASIS) 2001-2020: Twenty years of early detection, prognosis and preventive care for young people at risk of psychosis.

Eur Neuropsychopharmacol 2020 10 10;39:111-122. Epub 2020 Sep 10.

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

This study aims to describe twenty years of early detection, prognosis and preventive care in the Outreach and Support In South-London (OASIS) mental health service for individuals at Clinical High risk of psychosis (CHR-P). The study presents a comprehensive analysis of the 2001- 2020 activity of the OASIS team encompassing core domains: (i) service characteristics, (ii) detection, (iii) prognosis, (iv) treatment and (v) clinical research. The analyses employed descriptive statistics, population-level data, the epidemiological incidence of psychosis, Kaplan Meier failure functions and Greenwood 95% CIs and Electronic Health Records. OASIS is part of the South London and Maudsley (SLaM) NHS trust, the largest European mental health provider, serving a total urban population of 1,358,646 individuals (population aged 16-35: 454,525). Incidence of psychosis in OASIS's catchment area ranges from 58.3 to 71.9 cases per 100,000 person-years, and it is higher than the national average of 41.5 cases per 100,000 person-year. OASIS is a standalone, NHS-funded, multidisciplinary (team leader, consultant and junior psychiatrists, clinical psychologists, mental health professionals), transitional (for those aged 14-35 years) community mental health service with a yearly caseload of 140 CHR-P individuals. OASIS regularly delivers a comprehensive service promotion outreach to several local community organisations. Referrals to OASIS (2366) are made by numerous agencies; about one-third of the referrals eventually met CHR-P criteria. Overall, 600 CHR-P individuals (55.33% males, mean age 22.63 years, white ethnicity 46.44%) have been under the care of the OASIS service: 80.43% met attenuated psychotic symptoms, 18.06% brief and limited intermittent psychotic symptoms and 1.51% genetic risk and deterioration CHR-P criteria. All CHR-P individuals were offered cognitive behavioural therapy and psychosocial support; medications were used depending on individual needs. The cumulative risk of psychosis at ten years was 0.365 (95%CI 0.302-0.437). At six years follow-up, across two-third of individuals non-transitioning to psychosis, 79.24% still displayed some mental health problem, and only 20.75% achieved a complete clinical remission. Research conducted at OASIS encompassed clinical, prognostic, neurobiological and interventional studies and leveraged local, national and international infrastructures; over the past ten years, OASIS-related research attracted about £ 50 million of grant income, with 5,922 citations in the international databases. Future developments may include broadening OASIS to prevent other serious mental disorders beyond psychosis and fostering translational risk prediction and interventional research. With a twenty-years activity, OASIS' cutting-edge quality of preventive care, combined with translational research innovations, consolidated the service as a leading reference model for evidence-based prevention of psychosis worldwide.
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http://dx.doi.org/10.1016/j.euroneuro.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540251PMC
October 2020

Single-cell transcriptomic analysis identifies extensive heterogeneity in the cellular composition of mouse Achilles tendons.

Am J Physiol Cell Physiol 2020 11 2;319(5):C885-C894. Epub 2020 Sep 2.

Hospital for Special Surgery, New York, New York.

Tendon is a dense connective tissue that stores and transmits forces between muscles and bones. Cellular heterogeneity is increasingly recognized as an important factor in the biological basis of tissue homeostasis and disease, yet little is known about the diversity of cell types that populate tendon. To address this, we determined the heterogeneity of cell populations within mouse Achilles tendons using single-cell RNA sequencing. In assembling a transcriptomic atlas of Achilles tendons, we identified 11 distinct types of cells, including three previously undescribed populations of tendon fibroblasts. Prior studies have indicated that pericytes, which are found in the vasculature of tendons, could serve as a potential source of progenitor cells for adult tendon fibroblasts. Using trajectory inference analysis, we provide additional support for the notion that pericytes are likely to be at least one of the progenitor cell populations for the fibroblasts that compose adult tendons. We also modeled cell-cell interactions and identified previously undescribed ligand-receptor signaling interactions involved in tendon homeostasis. Our novel and interactive tendon atlas highlights previously underappreciated heterogeneity between and within tendon cell populations. The atlas also serves as a resource to further the understanding of tendon extracellular matrix assembly and maintenance and in the design of therapies for tendinopathies.
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http://dx.doi.org/10.1152/ajpcell.00372.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701267PMC
November 2020

Musculoskeletal Consequences of COVID-19.

J Bone Joint Surg Am 2020 07;102(14):1197-1204

Hospital for Special Surgery, New York, NY.

Coronavirus disease 2019 (COVID-19) is an emerging pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the majority of patients who become infected with SARS-CoV-2 are asymptomatic or have mild symptoms, some patients develop severe symptoms that can permanently detract from their quality of life. SARS-CoV-2 is closely related to SARS-CoV-1, which causes severe acute respiratory syndrome (SARS). Both viruses infect the respiratory system, and there are direct and indirect effects of this infection on multiple organ systems, including the musculoskeletal system. Epidemiological data from the SARS pandemic of 2002 to 2004 identified myalgias, muscle dysfunction, osteoporosis, and osteonecrosis as common sequelae in patients with moderate and severe forms of this disease. Early studies have indicated that there is also considerable musculoskeletal dysfunction in some patients with COVID-19, although long-term follow-up studies have not yet been conducted. The purpose of this article was to summarize the known musculoskeletal pathologies in patients with SARS or COVID-19 and to combine this with computational modeling and biochemical signaling studies to predict musculoskeletal cellular targets and long-term consequences of the SARS-CoV-2 infection.
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http://dx.doi.org/10.2106/JBJS.20.00847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508274PMC
July 2020

Intranasal oxytocin increases heart-rate variability in men at clinical high risk for psychosis: a proof-of-concept study.

Transl Psychiatry 2020 07 12;10(1):227. Epub 2020 Jul 12.

Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, SE5 8AF, UK.

Autonomic nervous system (ANS) dysfunction (i.e., increased sympathetic and/or decreased parasympathetic activity) has been proposed to contribute to psychosis vulnerability. Yet, we still lack directed therapeutic strategies that improve ANS regulation in psychosis or at-risk states. The oxytocin system constitutes a potential therapeutic target, given its role in ANS regulation. However, whether intranasal oxytocin ameliorates autonomic regulation during emerging psychosis is currently unknown. We pooled together two datasets, one of 30 men at clinical high risk for psychosis (CHR-P), and another of 17 healthy men, who had participated in two double-blinded, placebo-controlled, randomised, crossover MRI studies with similar protocols. All participants self-administered 40 IU of intranasal oxytocin or placebo using a nasal spray. We recorded pulse plethysmography during a period of 8 min at about 1 h post dosing and estimated heart rate (HR) and high-frequency HR variability (HF-HRV), an index of cardio-parasympathetic activity. CHR-P and healthy men did not differ at resting HR or HF-HRV under placebo. We found a significant condition × treatment effect for HF-HRV, showing that intranasal oxytocin, compared with placebo, increased HF-HRV in CHR-P but not in healthy men. The main effects of treatment and condition were not significant. In this proof-of-concept study, we show that intranasal oxytocin increases cardio-parasympathetic activity in CHR-P men, highlighting its therapeutic potential to improve autonomic regulation in this clinical group. Our findings support the need for further research on the preventive and therapeutic potential of intranasal oxytocin during emerging psychosis, where we lack effective treatments.
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http://dx.doi.org/10.1038/s41398-020-00890-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354990PMC
July 2020

A reference single-cell transcriptomic atlas of human skeletal muscle tissue reveals bifurcated muscle stem cell populations.

Skelet Muscle 2020 07 6;10(1):19. Epub 2020 Jul 6.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14853, USA.

Single-cell RNA-sequencing (scRNA-seq) facilitates the unbiased reconstruction of multicellular tissue systems in health and disease. Here, we present a curated scRNA-seq dataset of human muscle samples from 10 adult donors with diverse anatomical locations. We integrated ~ 22,000 single-cell transcriptomes using Scanorama to account for technical and biological variation and resolved 16 distinct populations of muscle-resident cells using unsupervised clustering of the data compendium. These cell populations included muscle stem/progenitor cells (MuSCs), which bifurcated into discrete "quiescent" and "early-activated" MuSC subpopulations. Differential expression analysis identified transcriptional profiles altered in the activated MuSCs including genes associated with aging, obesity, diabetes, and impaired muscle regeneration, as well as long non-coding RNAs previously undescribed in human myogenic cells. Further, we modeled ligand-receptor cell-communication interactions and observed enrichment of the TWEAK-FN14 pathway in activated MuSCs, a characteristic signature of muscle wasting diseases. In contrast, the quiescent MuSCs have enhanced expression of the EGFR receptor, a recognized human MuSC marker. This work provides a new benchmark reference resource to examine human muscle tissue heterogeneity and identify potential targets in MuSC diversity and dysregulation in disease contexts.
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http://dx.doi.org/10.1186/s13395-020-00236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336639PMC
July 2020

Acute oxytocin effects in inferring others' beliefs and social emotions in people at clinical high risk for psychosis.

Transl Psychiatry 2020 06 22;10(1):203. Epub 2020 Jun 22.

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

Social deficits are key hallmarks of the Clinical High Risk for Psychosis (CHR-P) state and of established psychotic disorders, and contribute to impaired social functioning, indicating a potential target for interventions. However, current treatments do not significantly ameliorate social impairments in CHR-P individuals. Given its critical role in social behaviour and cognition, the oxytocinergic (OT) system is a promising target for novel interventions in CHR-P subjects. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using functional magnetic resonance imaging (fMRI) on two occasions, once after 40IU self-administered intranasal OT and once after placebo. A modified version of the Sally-Anne task was used to assess brain activation during inferring others' beliefs and social emotions. The Reading the Mind in the Eyes Test was acquired prior to the first scan to test whether OT effects were moderated by baseline social-emotional abilities. OT did not modulate behavioural performances but reduced activation in the bilateral inferior frontal gyrus compared with placebo while inferring others' social emotions. Furthermore, the relationship between brain activation and task performance after OT administration was moderated by baseline social-emotional abilities. While task accuracy during inferring others' social emotion increased with decreasing activation in the left inferior frontal gyrus in CHR-P individuals with low social-emotional abilities, there was no such relationship in CHR-P individuals with high social-emotional abilities. Our findings may suggest that acute OT administration enhances neural efficiency in the inferior frontal gyrus during inferring others' social emotions in those CHR-P subjects with low baseline social-emotional abilities.
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http://dx.doi.org/10.1038/s41398-020-00885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308367PMC
June 2020

Real-World Clinical Outcomes Two Years After Transition to Psychosis in Individuals at Clinical High Risk: Electronic Health Record Cohort Study.

Schizophr Bull 2020 Apr 18. Epub 2020 Apr 18.

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

The objective of this study is to describe the 2-year real-world clinical outcomes after transition to psychosis in patients at clinical high-risk. The study used the clinical electronic health record cohort study including all patients receiving a first index primary diagnosis of nonorganic International Classification of Diseases (ICD)-10 psychotic disorder within the early psychosis pathway in the South London and Maudsley (SLaM) National Health Service (NHS) Trust from 2001 to 2017. Outcomes encompassed: cumulative probability (at 3, 6, 12, and 24 months) of receiving a first (1) treatment with antipsychotic, (2) informal admission, (3) compulsory admission, and (4) treatment with clozapine and (5) numbers of days spent in hospital (at 12 and 24 months) in patients transitioning to psychosis from clinical high-risk services (Outreach and Support in south London; OASIS) compared to other first-episode groups. Analyses included logistic and 0-inflated negative binomial regressions. In the study, 1561 patients were included; those who had initially been managed by OASIS and had subsequently transitioned to a first episode of psychosis (n = 130) were more likely to receive antipsychotic medication (at 3, 6, and 24 months; all P < .023), to be admitted informally (at all timepoints, all P < .004) and on a compulsory basis (at all timepoints, all P < .013), and to have spent more time in hospital (all timepoints, all P < .007) than first-episode patients who were already psychotic when seen by the OASIS service (n = 310), or presented to early intervention services (n = 1121). The likelihood of receiving clozapine was similar across all groups (at 12/24 months, all P < .101). Transition to psychosis from a clinical high-risk state is associated with severe real-world clinical outcomes. Prevention of transition to psychosis should remain a core target of future research. The study protocol was registered on www.researchregistry.com; researchregistry5039).
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http://dx.doi.org/10.1093/schbul/sbaa040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505186PMC
April 2020

Prenatal and perinatal risk and protective factors for psychosis: a systematic review and meta-analysis.

Lancet Psychiatry 2020 05 24;7(5):399-410. Epub 2020 Mar 24.

Early Psychosis: Interventions and Clinical-detection (EPIC) Laboratory, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; National Institute for Health Research Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK; Outreach And Support in South London (OASIS) Service, South London and Maudsley NHS Foundation Trust, London, UK; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. Electronic address:

Background: Prenatal and perinatal insults are implicated in the aetiopathogenesis of psychotic disorders but the consistency and magnitude of their associations with psychosis have not been updated for nearly two decades. The aim of this systematic review and meta-analysis was to provide a comprehensive and up-to-date synthesis of the evidence on the association between prenatal or perinatal risk and protective factors and psychotic disorders.

Methods: In this systematic review and meta-analysis, we searched the Web of Science database for articles published up to July 20, 2019. We identified cohort and case-control studies examining the association (odds ratio [OR]) between prenatal and perinatal factors and any International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) non-organic psychotic disorder with a healthy comparison group. Other inclusion criteria were enough data available to do the analyses, and non-overlapping datasets. We excluded reviews, meta-analyses, abstracts or conference proceedings, and articles with overlapping datasets. Data were extracted according to EQUATOR and PRISMA guidelines. Extracted variables included first author, publication year, study type, sample size, type of psychotic diagnosis (non-affective psychoses or schizophrenia-spectrum disorders, affective psychoses) and diagnostic instrument (DSM or ICD and version), the risk or protective factor, and measure of association (primary outcome). We did random-effects pairwise meta-analyses, Q statistics, I index, sensitivity analyses, meta-regressions, and assessed study quality and publication bias. The study protocol was registered at PROSPERO, CRD42017079261.

Findings: 152 studies relating to 98 risk or protective factors were eligible for analysis. Significant risk factors were: maternal age younger than 20 years (OR 1·17) and 30-34 years (OR 1·05); paternal age younger than 20 years (OR 1·31) and older than 35 years (OR 1·28); any maternal (OR 4·60) or paternal (OR 2·73) psychopathology; maternal psychosis (OR 7·61) and affective disorder (OR 2·26); three or more pregnancies (OR 1·30); herpes simplex 2 (OR 1·35); maternal infections not otherwise specified (NOS; OR 1·27); suboptimal number of antenatal visits (OR 1·83); winter (OR 1·05) and winter to spring (OR 1·05) season of birth in the northern hemisphere; maternal stress NOS (OR 2·40); famine (OR 1·61); any famine or nutritional deficits in pregnancy (OR 1·40); maternal hypertension (OR 1·40); hypoxia (OR 1·63); ruptured (OR 1·86) and premature rupture (OR 2·29) of membranes; polyhydramnios (OR 3·05); definite obstetric complications NOS (OR 1·83); birthweights of less than 2000 g (OR 1·84), less than 2500 g (OR 1·53), or 2500-2999 g (OR 1·23); birth length less than 49 cm (OR 1·17); small for gestational age (OR 1·40); premature birth (OR 1·35), and congenital malformations (OR 2·35). Significant protective factors were maternal ages 20-24 years (OR 0·93) and 25-29 years (OR 0·92), nulliparity (OR 0·91), and birthweights 3500-3999 g (OR 0·90) or more than 4000 g (OR 0·86). The results were corrected for publication biases; sensitivity and meta-regression analyses confirmed the robustness of these findings for most factors.

Interpretation: Several prenatal and perinatal factors are associated with the later onset of psychosis. The updated knowledge emerging from this study could refine understanding of psychosis pathogenesis, enhance multivariable risk prediction, and inform preventive strategies.

Funding: None.
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http://dx.doi.org/10.1016/S2215-0366(20)30057-2DOI Listing
May 2020

Single-Cell Analysis of the Muscle Stem Cell Hierarchy Identifies Heterotypic Communication Signals Involved in Skeletal Muscle Regeneration.

Cell Rep 2020 03;30(10):3583-3595.e5

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Electronic address:

Muscle regeneration relies on the regulation of muscle stem cells (MuSCs) through paracrine signaling interactions. We analyzed muscle regeneration in mice using single-cell RNA sequencing (scRNA-seq) and generated over 34,000 single-cell transcriptomes spanning four time-points. We identified 15 distinct cell types including heterogenous populations of muscle stem and progenitor cells. We resolved a hierarchical map of these myogenic cells by trajectory inference and observed stage-specific regulatory programs within this continuum. Through ligand-receptor interaction analysis, we identified over 100 candidate regeneration-associated paracrine communication pairs between MuSCs and non-myogenic cells. We show that myogenic stem/progenitor cells exhibit heterogeneous expression of multiple Syndecan proteins in cycling myogenic cells, suggesting that Syndecans may coordinate myogenic fate regulation. We performed ligand stimulation in vitro and confirmed that three paracrine factors (FGF2, TGFβ1, and RSPO3) regulate myogenic cell proliferation in a Syndecan-dependent manner. Our study provides a scRNA-seq reference resource to investigate cell communication interactions in muscle regeneration.
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http://dx.doi.org/10.1016/j.celrep.2020.02.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091476PMC
March 2020

Preventive Treatments for Psychosis: Umbrella Review (Just the Evidence).

Front Psychiatry 2019 11;10:764. Epub 2019 Dec 11.

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

Indicated primary prevention in young people at Clinical High Risk for Psychosis (CHR-P) is a promising avenue for improving outcomes of one of the most severe mental disorders but their effectiveness has recently been questioned. Umbrella review. A multi-step independent literature search of Web of Science until January 11, 2019, identified interventional meta-analyses in CHR-P individuals. The individual randomised controlled trials that were analysed by the meta-analyses were extracted. A review of ongoing trials and a simulation of living meta-analysis complemented the analysis. Seven meta-analyses investigating preventive treatments in CHR-P individuals were included. None of them produced pooled effect sizes across psychological, pharmacological, or other types of interventions. The outcomes analysed encompassed risk of psychosis onset, the acceptability of treatments, the severity of attenuated positive/negative psychotic symptoms, depression, symptom-related distress, social functioning, general functioning, and quality of life. These meta-analyses were based on 20 randomised controlled trials: the vast majority defined the prevention of psychosis onset as their primary outcome of interest and only powered to large effect sizes. There was no evidence to favour any preventive intervention over any other (or control condition) for improving any of these clinical outcomes. Caution is required when making clinical recommendations for the prevention of psychosis in individuals at risk. Prevention of psychosis from a CHR-P state has been, and should remain, the primary outcome of interventional research, refined and complemented by other clinically meaningful outcomes. Stagnation of knowledge should promote innovative and collaborative research efforts, in line with the progressive and incremental nature of medical knowledge. Advancements will most likely be associated with the development of new experimental therapeutics that are ongoing along with the ability to deconstruct the high heterogeneity within CHR-P populations. This would require the estimation of treatment-specific effect sizes through living individual participant data meta-analyses, controlling risk enrichment during recruitment, statistical power, and embedding precision medicine within youth mental health services that can accommodate sequential prognosis and advanced trial designs. The evidence-based challenges and proposed solutions addressed by this umbrella review can inform the next generation of research into preventive treatments for psychosis.
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http://dx.doi.org/10.3389/fpsyt.2019.00764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917652PMC
December 2019

What is good mental health? A scoping review.

Eur Neuropsychopharmacol 2020 02 31;31:33-46. Epub 2019 Dec 31.

Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands.

Promotion of good mental health in young people with and without mental disorders has received little empirical research attention and interventions for improving mental health in young people are not well established. This situation could be explained among other reasons due to the difficulties to define and operationalise what good mental health is. The current manuscript, produced by the European College of Neuropsychopharmacology Thematic Working Group on the Prevention of Mental Disorders and Mental Health Promotion (ECNP TWG PMD-MHP), presents a critical review of the available operationalizations for good mental health. A pragmatic conceptual operationalisation of good mental health is a much-needed step towards more standardised research in this field. Good mental health can be defined as a state of well-being that allows individuals to cope with the normal stresses of life and function productively. Universal and selective interventions are suitable to promote mental health. Core domains that define good mental health encompass: (i) mental health literacy, (ii) attitude towards mental disorders, (iii) self-perceptions and values, (iv) cognitive skills, (v) academic/ occupational performance, (vi) emotions, (vii) behaviours, (viii) self-management strategies, (ix) social skills, (x) family and significant relationships (xi) physical health, (xii) sexual health, (xiii) meaning of life, (xiv) and quality of life. These domains should be widely traceable in the literature and can be used to conduct further empirical research in the field of good mental health. Such data can lead to more robust evidence to identify and establish the pathways to follow in order to improve mental health.
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http://dx.doi.org/10.1016/j.euroneuro.2019.12.105DOI Listing
February 2020

Unmet needs for treatment in 102 individuals with brief and limited intermittent psychotic symptoms (BLIPS): implications for current clinical recommendations.

Epidemiol Psychiatr Sci 2019 Nov 19;29:e67. Epub 2019 Nov 19.

National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK.

Aims: To investigate clinical outcomes and unmet needs in individuals at Clinical High Risk for Psychosis presenting with Brief and Limited Intermittent Psychotic Symptoms (BLIPS).

Methods: Prospective naturalistic long-term (up to 9 years) cohort study in individuals meeting BLIPS criteria at the Outreach And Support In South-London (OASIS) up to April 2016. Baseline sociodemographic and clinical characteristics, specific BLIPS features, preventive treatments received and clinical outcomes (psychotic and non-psychotic) were measured. Analyses included Kaplan Meier survival estimates and Cox regression methods.

Results: One hundred and two BLIPS individuals were followed up to 9 years. Across BLIPS cases, 35% had an abrupt onset; 32% were associated with acute stress, 45% with lifetime trauma and 20% with concurrent illicit substance use. The vast majority (80%) of BLIPS individuals, despite being systematically offered cognitive behavioural therapy for psychosis, did not fully engage with it and did not receive the minimum effective dose. Only 3% of BLIPS individuals received the appropriate dose of cognitive behavioural therapy. At 4-year follow-up, 52% of the BLIPS individuals developed a psychotic disorder, 34% were admitted to hospital and 16% received a compulsory admission. At 3-year follow-up, 52% of them received an antipsychotic treatment; at 4-year follow-up, 26% of them received an antidepressant treatment. The presence of seriously disorganising and dangerous features was a strong poor prognostic factor.

Conclusions: BLIPS individuals display severe clinical outcomes beyond their very high risk of developing psychosis and show poor compliance with preventive cognitive behavioural therapy. BLIPS individuals have severe needs for treatment that are not met by current preventive strategies.
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http://dx.doi.org/10.1017/S2045796019000635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061208PMC
November 2019

Pan-London Network for Psychosis-Prevention (PNP).

Front Psychiatry 2019 11;10:707. Epub 2019 Oct 11.

National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, United Kingdom.

The empirical success of the Clinical High Risk for Psychosis (CHR-P) paradigm is determined by the concurrent integration of efficient detection of cases at-risk, accurate prognosis, and effective preventive treatment within specialized clinical services. The characteristics of the CHR-P services are relatively under-investigated. A Pan-London Network for psychosis prevention (PNP) was created across urban CHR-P services. These services were surveyed to collect the following: description of the service and catchment area, outreach, service users, interventions, and outcomes. The results were analyzed with descriptive statistics and Kaplan Meier failure function. The PNP included five CHR-P services across two NHS Trusts: Outreach and Support In South-London (OASIS) in Lambeth and Southwark, OASIS in Croydon and Lewisham, Tower Hamlets Early Detection Service (THEDS), City & Hackney At-Risk Mental State Service (HEADS UP) and Newham Early Intervention Service (NEIS). The PNP serves a total population of 2,318,515 Londoners (830,889; age, 16-35 years), with a yearly recruitment capacity of 220 CHR-P individuals (age, 22.55 years). Standalone teams (OASIS and THEDS) are more established and successful than teams that share their resources with other mental health services (HEADS UP, NEIS). Characteristics of the catchment areas, outreach and service users, differ across PNP services; all of them offer psychotherapy to prevent psychosis. The PNP is supporting several CHR-P translational research projects. The PNP is the largest CHR-P clinical network in the UK; it represents a reference benchmark for implementing detection, prognosis, and care in the real-world clinical routine, as well as for translating research innovations into practice.
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http://dx.doi.org/10.3389/fpsyt.2019.00707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798006PMC
October 2019

Clinical-learning versus machine-learning for transdiagnostic prediction of psychosis onset in individuals at-risk.

Transl Psychiatry 2019 10 17;9(1):259. Epub 2019 Oct 17.

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Predicting the onset of psychosis in individuals at-risk is based on robust prognostic model building methods including a priori clinical knowledge (also termed clinical-learning) to preselect predictors or machine-learning methods to select predictors automatically. To date, there is no empirical research comparing the prognostic accuracy of these two methods for the prediction of psychosis onset. In a first experiment, no improved performance was observed when machine-learning methods (LASSO and RIDGE) were applied-using the same predictors-to an individualised, transdiagnostic, clinically based, risk calculator previously developed on the basis of clinical-learning (predictors: age, gender, age by gender, ethnicity, ICD-10 diagnostic spectrum), and externally validated twice. In a second experiment, two refined versions of the published model which expanded the granularity of the ICD-10 diagnosis were introduced: ICD-10 diagnostic categories and ICD-10 diagnostic subdivisions. Although these refined versions showed an increase in apparent performance, their external performance was similar to the original model. In a third experiment, the three refined models were analysed under machine-learning and clinical-learning with a variable event per variable ratio (EPV). The best performing model under low EPVs was obtained through machine-learning approaches. The development of prognostic models on the basis of a priori clinical knowledge, large samples and adequate events per variable is a robust clinical prediction method to forecast psychosis onset in patients at-risk, and is comparable to machine-learning methods, which are more difficult to interpret and implement. Machine-learning methods should be preferred for high dimensional data when no a priori knowledge is available.
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http://dx.doi.org/10.1038/s41398-019-0600-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797779PMC
October 2019

Neurochemical effects of oxytocin in people at clinical high risk for psychosis.

Eur Neuropsychopharmacol 2019 05 28;29(5):601-615. Epub 2019 Mar 28.

Early Psychosis: Interventions & Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 16 De Crespigny Park, London SE5 8AF, UK; National Institute for Health Research (NIHR) Biomedical Research Centre (BRC), South London and Maudsley NHS Foundation Trust, London, UK; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy; Outreach and Support in South London (OASIS) Service, South London and Maudsley NHS Foundation Trust, London, UK.

Alterations in neurochemical metabolites are thought to play a role in the pathophysiology of psychosis onset. Oxytocin, a neuropeptide with prosocial and anxiolytic properties, modulates glutamate neurotransmission in preclinical models but its neurochemical effects in people at high risk for psychosis are unknown. We used proton magnetic resonance spectroscopy (H-MRS) to examine the effects of intranasal oxytocin on glutamate and other metabolites in people at Clinical High Risk for Psychosis (CHR-P) in a double-blind, placebo-controlled, crossover design. 30 CHR-P males were studied on two occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on the concentration of glutamate, glutamate+glutamine and other metabolites (choline, N-acetylaspartate, myo-inositol) scaled to creatine were examined in the left thalamus, anterior cingulate cortex (ACC) and left hippocampus, starting approximately 75, 84 and 93 min post-dosing, respectively. Relative to placebo, administration of oxytocin was associated with an increase in choline levels in the ACC (p=.008, Cohen's d = 0.54). There were no other significant effects on metabolite concentrations (all p>.05). Our findings suggest that, at ∼75-99 min post-dosing, a single dose of intranasal oxytocin does not alter levels of neurochemical metabolites in the thalamus, ACC, or hippocampus in those at CHR-P, aside from potential effects on choline in the ACC.
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http://dx.doi.org/10.1016/j.euroneuro.2019.03.008DOI Listing
May 2019

Unmet needs in patients with brief psychotic disorders: Too ill for clinical high risk services and not ill enough for first episode services.

Eur Psychiatry 2019 04 15;57:26-32. Epub 2019 Jan 15.

Early Psychosis: Interventions & Clinical-detection (EPIC) lab, Department of Psychosis Studies, King's College London, Institute of Psychiatry Psychology and Neuroscience, London, United Kingdom; OASIS Service, South London and the Maudsley NHS Foundation Trust, London, United Kingdom; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. Electronic address:

Background: Patients with acute and transient psychotic disorders (ATPDs) are by definition remitting, but have a high risk of developing persistent psychoses, resembling a subgroup of individuals at Clinical High Risk for Psychosis (CHR-P). Their pathways to care, treatment offered and long-term clinical outcomes beyond risk to psychosis are unexplored. We conducted an electronic health record-based retrospective cohort study including patients with ATPDs within the SLaM NHS Trust and followed-up to 8 years.

Methods: A total of 2561 ATPDs were included in the study. A minority were detected (8%) and treated (18%) by Early Intervention services (EIS) and none by CHR-P services. Patients were offered a clinical follow-up of 350.40 ± 589.90 days. The cumulative incidence of discharges was 40% at 3 months, 60% at 1 year, 69% at 2 years, 77% at 4 years, and 82% at 8 years. Treatment was heterogeneous: the majority of patients received antipsychotics (up to 52%), only a tiny minority psychotherapy (up to 8%).

Results: Over follow-up, 32.88% and 28.54% of ATPDS received at least one mental health hospitalization or one compulsory hospital admission under the Mental Health Act, respectively. The mean number of days spent in psychiatric hospital was 66.39 ± 239.44 days.

Conclusions: The majority of ATPDs are not detected/treated by EIS or CHR-P services, receive heterogeneous treatments and short-term clinical follow-up. ATPDs have a high risk of developing severe clinical outcomes beyond persistent psychotic disorders and unmet clinical needs that are not targeted by current mental health services.
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http://dx.doi.org/10.1016/j.eurpsy.2018.12.006DOI Listing
April 2019

Oxytocin modulates hippocampal perfusion in people at clinical high risk for psychosis.

Neuropsychopharmacology 2019 06 9;44(7):1300-1309. Epub 2019 Jan 9.

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

Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20-35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22-28 and at 30-36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.
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http://dx.doi.org/10.1038/s41386-018-0311-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784972PMC
June 2019

Transcatheter aortic valve replacement in the setting of left atrial appendage thrombus.

Interact Cardiovasc Thorac Surg 2018 12;27(6):842-849

Department of Cardiothoracic Surgery, New York Presbyterian-Weill Cornell Medicine, New York, NY, USA.

Objectives: Left atrial appendage thrombus (LAT) was an exclusion criterion in the seminal transcatheter aortic valve replacement (TAVR) trials; however, such patients do undergo TAVR in the 'real-world' setting. This study sought to analyse outcomes after TAVR in patients with LAT or spontaneous echo contrast (SEC).

Methods: All patients undergoing TAVR at our institution between March 2009 and December 2014 were prospectively analysed. The presence of LAT or SEC was determined via a retrospective chart review. Primary outcomes included 30-day and 1-year neurological events as well as mortality.

Results: Of the 369 patients undergoing TAVR, 3.8% (14) were found to have LAT and 6.8% (25) were found to have SEC, and they were separately compared to patients who did not have LAT or SEC. Significant differences were noted between groups with regard to preoperative renal function, atrial fibrillation and ejection fraction. Preoperative atrial fibrillation was the only independent predictor of LAT. No perioperative complications were associated with the presence of LAT or SEC. Specifically, no patient with LAT or SEC experienced a postoperative neurological event. While neither LAT nor SEC was an independent predictor of 30-day mortality, LAT was an independent predictor of 1-year mortality (odds ratio 3.573, 95% confidence interval 1.040-12.28; P = 0.042).

Conclusions: The current study suggests that TAVR may be performed in patients with LAT and SEC with a low risk of embolic complications. While neither was an independent predictor of 30-day mortality, LAT was an independent predictor of 1-year mortality. Larger studies are needed to better study this phenomenon.
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http://dx.doi.org/10.1093/icvts/ivy189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328003PMC
December 2018

Long term outcomes of acute and transient psychotic disorders: The missed opportunity of preventive interventions.

Eur Psychiatry 2018 08 19;52:126-133. Epub 2018 May 19.

Early Psychosis: Interventions and Clinical Detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, 16 De Crespigny Park, SE5 8AF, London, United Kingdom; OASIS Service, South London and Maudsley NHS Foundation Trust, 190 Kennington Ln, Lambeth, SE11, London, United Kingdom; National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, De Crespigny Park, Camberwell, SE5 8AF, London, United Kingdom; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Background: Acute and transient psychotic disorders (ATPD) are characterized by an acute onset and a remitting course, and overlap with subgroups of the clinical high-risk state for psychosis. The long-term course and outcomes of ATPD are not completely clear.

Methods: Electronic health record-based retrospective cohort study, including all patients who received a first index diagnosis of ATPD (F23, ICD-10) within the South London and Maudsley (SLaM) National Health Service Trust, between 1 st April 2006 and 15th June 2017. The primary outcome was risk of developing persistent psychotic disorders, defined as the development of any ICD-10 diagnoses of non-organic psychotic disorders. Cumulative risk of psychosis onset was estimated through Kaplan-Meier failure functions (non-competing risks) and Greenwood confidence intervals.

Results: A total of 3074 patients receiving a first index diagnosis of ATPD (F23, ICD-10) within SLaM were included. The mean follow-up was 1495 days. After 8-year, 1883 cases (61.26%) retained the index diagnosis of ATPD; the remaining developed psychosis. The cumulative incidence (Kaplan-Meier failure function) of risk of developing any ICD-10 non-organic psychotic disorder was 16.10% at 1-year (95%CI 14.83-17.47%), 28.41% at 2-year (95%CI 26.80-30.09%), 33.96% at 3-year (95% CI 32.25-35.75%), 36.85% at 4-year (95%CI 35.07-38.69%), 40.99% at 5-year (95% CI 39.12-42.92%), 42.58% at 6-year (95%CI 40.67-44.55%), 44.65% at 7-year (95% CI 42.66-46.69%), and 46.25% at 8-year (95% CI 44.17-48.37%). The cumulative risk of schizophrenia-spectrum disorder at 8-year was 36.14% (95% CI 34.09-38.27%).

Conclusions: Individuals with ATPD have a very high risk of developing persistent psychotic disorders and may benefit from early detection and preventive treatments to improve their outcomes.
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http://dx.doi.org/10.1016/j.eurpsy.2018.05.004DOI Listing
August 2018

Semistructured Interview for Bipolar At Risk States (SIBARS).

Psychiatry Res 2018 06 24;264:302-309. Epub 2018 Apr 24.

Early Psychosis: Interventions & Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry Psychology and Neuroscience, King's College London, London, UK; Department of Psychiatry and Psychotherapy, Philipps-University, Rudolf-Bultmann-Str. 8, Marburg 35039, Germany.

The external prognostic accuracy of Bipolar At Risk (BAR) criteria is undetermined and no psychometric tools are available to measure them. We present here three studies that overcome these limitations. Study 1 and 2 investigated the prognostic accuracy (Harrell's C) of the original BAR and revised Bipolar At Risk States (BARS) criteria respectively for the prediction of bipolar disorders, using a retrospective cohort of individuals at Clinical High Risk for Psychosis (CHR-P). Study 3 validated externally the prognostic accuracy of a newly developed Semistructured Interview of At Risk Bipolar States (SIBARS) in an independent prospective CHR-P cohort. In study 1 (n = 205), those meeting BAR criteria had an increased risk of developing bipolar disorders (HR = 5.30) relative to those not meeting them, but the prognostic accuracy was poor (Harrell's C = 0.659). In study 2 (n = 205), those meeting the refined BARS criteria had a higher risk of developing bipolar disorders than those not meeting them (HR = 12.364), with an adequate prognostic accuracy (Harrell's C = 0.777). Study 3 (n = 71) confirmed that SIBARS criteria had an adequate prognostic accuracy (Harrell's C = 0.742) and clinical utility. Overall, these findings suggest that the SIBARS could be used for the detection of individuals at risk of developing bipolar disorders in CHR-P services.
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http://dx.doi.org/10.1016/j.psychres.2018.03.074DOI Listing
June 2018

Formal thought disorder in people at ultra-high risk of psychosis.

BJPsych Open 2017 Jul 14;3(4):165-170. Epub 2017 Jul 14.

, PhD, Department of Psychosis Studies, Biomedical Research Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Background: Formal thought disorder is a cardinal feature of psychosis. However, the extent to which formal thought disorder is evident in ultra-high-risk individuals and whether it is linked to the progression to psychosis remains unclear.

Aims: Examine the severity of formal thought disorder in ultra-high-risk participants and its association with future psychosis.

Method: The Thought and Language Index (TLI) was used to assess 24 ultra-high-risk participants, 16 people with first-episode psychosis and 13 healthy controls. Ultra-high-risk individuals were followed up for a mean duration of 7 years (s.d.=1.5) to determine the relationship between formal thought disorder at baseline and transition to psychosis.

Results: TLI scores were significantly greater in the ultra-high-risk group compared with the healthy control group (effect size (ES)=1.2), but lower than in people with first-episode psychosis (ES=0.8). Total and negative TLI scores were higher in ultra-high-risk individuals who developed psychosis, but this was not significant. Combining negative TLI scores with attenuated psychotic symptoms and basic symptoms predicted transition to psychosis (=0.04; ES=1.04).

Conclusions: TLI is beneficial in evaluating formal thought disorder in ultra-high-risk participants, and complements existing instruments for the evaluation of psychopathology in this group.

Declaration Of Interests: None.

Copyright And Usage: © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.
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http://dx.doi.org/10.1192/bjpo.bp.116.004408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509964PMC
July 2017

Diagnostic and Prognostic Significance of DSM-5 Attenuated Psychosis Syndrome in Services for Individuals at Ultra High Risk for Psychosis.

Schizophr Bull 2018 02;44(2):264-275

OASIS Service, South London and the Maudsley NHS Foundation Trust, London, UK.

Background: The diagnostic and prognostic significance of the DSM-5-defined Attenuated Psychosis Syndrome (DSM-5-APS) in individuals undergoing an ultra high risk (UHR) clinical assessment for suspicion of psychosis risk is unknown.

Methods: Prospective cohort study including all consecutive help-seeking individuals undergoing both a DSM-5-APS and a Comprehensive Assessment of At Risk Mental States (CAARMS 12/2006) assessment for psychosis risk at the Outreach and Support in South London (OASIS) UHR service (March 2013-April 2014). The diagnostic significance of DSM-5-APS was assessed with percent overall agreement, prevalence bias adjusted kappa, Bowker's test, Stuart-Maxwell test, residual analysis; the prognostic significance with Cox regression, Kaplan-Meier failure function, time-dependent area under the curve (AUC) and net benefits analysis. The impact of specific revisions of the DSM-5-APS was further tested.

Result: In 203 help-seeking individuals undergoing UHR assessment, the agreement between the DSM-5-APS and the CAARMS 12/2006 was only moderate (kappa 0.59). Among 142 nonpsychotic cases, those meeting DSM-5-APS criteria had a 5-fold probability (HR = 5.379) of developing psychosis compared to those not meeting DSM-5-APS criteria, with a 21-month cumulative risk of psychosis of 28.17% vs 6.49%, respectively. The DSM-5-APS prognostic accuracy was acceptable (AUC 0.76 at 24 months) and similar to the CAARMS 12/2006. The DSM-5-APS designation may be clinically useful to guide the provision of indicated interventions within a 7%-35% (2-year) range of psychosis risk. The removal of the criterion E or C of the DSM-5-APS may improve its prognostic performance and transdiagnostic value.

Conclusions: The DSM-5-APS designation may be clinically useful in individuals accessing clinical services for psychosis prevention.
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http://dx.doi.org/10.1093/schbul/sbx055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814820PMC
February 2018

Diagnostic and Prognostic Significance of Brief Limited Intermittent Psychotic Symptoms (BLIPS) in Individuals at Ultra High Risk.

Schizophr Bull 2017 01;43(1):48-56

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Brief Limited Intermittent Psychotic Symptoms (BLIPS) are key inclusion criteria to define individuals at ultra high risk for psychosis (UHR). Their diagnostic and prognostic significance is unclear.

Objectives: To address the baseline diagnostic relationship between BLIPS and the ICD-10 categories and examine the longitudinal prognostic impact of clinical and sociodemographic factors.

Methods: Prospective long-term study in UHR individuals meeting BLIPS criteria. Sociodemographic and clinical data, including ICD-10 diagnoses, were automatically drawn from electronic health records and analyzed using Kaplan-Meier failure function (1-survival), Cox regression models, bootstrapping methods, and Receiver Operating Characteristics (ROC) curve.

Results: Eighty BLIPS were included. At baseline, two-thirds (68%) of BLIPS met the diagnostic criteria for ICD-10 Acute and Transient Psychotic Disorder (ATPD), most featuring schizophrenic symptoms. The remaining individuals met ICD-10 diagnostic criteria for unspecified nonorganic psychosis (15%), mental and behavioral disorders due to use of cannabinoids (11%), and mania with psychotic symptoms (6%). The overall 5-year risk of psychosis was 0.54. Recurrent episodes of BLIPS were relatively rare (11%) but associated with a higher risk of psychosis (hazard ratio [HR] 3.98) than mono-episodic BLIPS at the univariate analysis. Multivariate analysis revealed that seriously disorganizing or dangerous features increased greatly (HR = 4.39) the risk of psychosis (0.89 at 5-year). Bootstrapping confirmed the robustness of this predictor (area under the ROC = 0.74).

Conclusions: BLIPS are most likely to fulfill the ATPD criteria, mainly acute schizophrenic subtypes. About half of BLIPS cases develops a psychotic disorder during follow-up. Recurrent BLIPS are relatively rare but tend to develop into psychosis. BLIPS with seriously disorganizing or dangerous features have an extreme high risk of psychosis.
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http://dx.doi.org/10.1093/schbul/sbw151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216865PMC
January 2017

Long-term outcome of a cohort of adults with autism and intellectual disability: A pilot prospective study.

Res Dev Disabil 2017 Jan 9;60:223-231. Epub 2016 Nov 9.

Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100 Pavia, Italy.

Background: Autism spectrum disorders (ASD) are a long-life condition frequently associated with intellectual disability. To date, long-term outcome has been investigated mostly in ASD people with average or above-average intelligence and there is a paucity of data about autistic adults with comorbid intellectual disability.

Aims: The aim of the present study is to assess long-term variations of adaptive abilities in a sample of autistic adults with intellectual disability and severe language impairment.

Methods And Procedures: 22 adults (17 males and 5 females) affected by autism and intellectual disability were recruited and evaluated after their admission in an Italian farm-community. Vineland Adaptive Behavior Scales (VABS) were used as outcome measure for adaptive abilities. After ten years the measurement was repeated in order to study the evolution of patients' skills along time. Additionally, sociodemographic variables, changes in medication and comorbidities were recorded.

Outcomes And Results: No statistically significant improvement neither deterioration was found according to VABS raw scores in the entire sample. On the contrary, a significant improvement was evident in standard scores for the Adaptive Behavior Composite Scale and for each domain.

Conclusions And Implications: In general, our patients remained stable in adaptive abilities. However, our results are not generalisable to the entire autistic population, but only to inpatients with autism and comorbid intellectual disability. New measures should be developed in order to better assess changes in this particular population.
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http://dx.doi.org/10.1016/j.ridd.2016.10.014DOI Listing
January 2017