Publications by authors named "Mara Parellada"

147 Publications

Examining facial emotion recognition as an intermediate phenotype for psychosis: Findings from the EUGEI study.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Sep 16;113:110440. Epub 2021 Sep 16.

Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain; Department of Psychiatry, Hospital Clínico Universitario de Valencia, INCLIVA, School of Medicine, Universidad de Valencia, Valencia, Spain.

Background: Social cognition impairments, such as facial emotion recognition (FER), have been acknowledged since the earliest description of schizophrenia. Here, we tested FER as an intermediate phenotype for psychosis using two approaches that are indicators of genetic risk for schizophrenia: the proxy-genetic risk approach (family design) and the polygenic risk score for schizophrenia (PRS-SCZ).

Methods: The sample comprised 2039 individuals with schizophrenia, 2141 siblings, and 2049 healthy controls (HC). The Degraded Facial Affect Recognition Task (DFAR) was applied to measure the FER accuracy. Schizotypal traits in siblings and HC were assessed using the Structured Interview for Schizotypy-Revised (SIS-R). The PRS-SCZ was trained using the Psychiatric Genomics Consortium results. Regression models were applied to test the association of DFAR with psychosis risk, SIS-R, and PRS-SCZ.

Results: The DFAR-total scores were lower in individuals with schizophrenia than in siblings (RR = 0.97 [95% CI 0.97, 0.97]), who scored lower than HC (RR = 0.99 [95% CI 0.99-1.00]). The DFAR-total scores were negatively associated with SIS-R total scores in siblings (B = -2.04 [95% CI -3.72, -0.36]) and HC (B = -2.93 [95% CI -5.50, -0.36]). Different patterns of association were observed for individual emotions. No significant associations were found between DFAR scores and PRS-SCZ.

Conclusions: Our findings based on a proxy genetic risk approach suggest that FER deficits may represent an intermediate phenotype for schizophrenia. However, a significant association between FER and PRS-SCZ was not found. In the future, genetic mechanisms underlying FER phenotypes should be investigated trans-diagnostically.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110440DOI Listing
September 2021

A Phase II Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Arbaclofen Administered for the Treatment of Social Function in Children and Adolescents With Autism Spectrum Disorders: Study Protocol for AIMS-2-TRIALS-CT1.

Front Psychiatry 2021 24;12:701729. Epub 2021 Aug 24.

Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Autism Spectrum Disorder (ASD or autism) is characterized by difficulties in social communication and interaction, which negatively impact on individuals and their families' quality of life. Currently no pharmacological interventions have been shown to be effective for improving social communication in autism. Previous trials have indicated the potential of arbaclofen for improving social function among autistic children and adolescents with fluent speech. The AIMS2TRIALS-Clinical Trial 1 (AIMS-CT1) will examine whether arbaclofen is superior to placebo in improving social function and other secondary outcomes over 16 weeks, along with safety and tolerability profiles. AIMS-CT1 is an international, multi-site, double-blind, parallel group Phase II randomized clinical trial. It will include 130 males and females aged 5:0-17:11 years, with a diagnosis of ASD and fluent speech. Eligible participants will be randomized on a ratio of 1:1 for a 16-week treatment period. Medication will be titrated over 5 weeks. The primary outcome is the effect on social function from weeks 0 to 16 measured on the Socialization domain of the Vineland Adaptive Behavior Scales, 3rd edition. Secondary outcome measures include the CGI-S (Clinical Global Impression-Severity), CGI-I (Clinical Global Impression-Improvement), other areas of adaptive function, social communication and other autism symptoms, co-occurring behavior problems and health-related quality of life. Genetic and electrophysiological markers will be examined as potential stratifiers for treatment response. Exploratory novel digital technologies will also be used to measure change, examining simultaneously the validity of digital biomarkers in natural environments. The safety and tolerability of the drug will also be examined. Our protocol is very closely aligned with a parallel Canadian trial of 90 participants (ARBA Study, US NCT number: NCT03887676) to allow for secondary combined analyses. Outcomes will be compared using both an Intent-to-reat and Per Protocol approach. The outcomes of this trial, combined with the parallel Canadian trial, will contribute to the evidence base for medications used to help social difficulties among young autistic individuals; demonstrate the capabilities of the AIMS-2-TRIALS network of academic centers to deliver clinical trials; and support future drug development. EudraCT number: 2018-000942-21 and ClinicalTrials.gov registry number: NCT03682978. Currently under protocol v.7.2, dated 20.11.2020.
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http://dx.doi.org/10.3389/fpsyt.2021.701729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421761PMC
August 2021

Fronto-Parietal Gray Matter Volume Loss Is Associated with Decreased Working Memory Performance in Adolescents with a First Episode of Psychosis.

J Clin Med 2021 Aug 31;10(17). Epub 2021 Aug 31.

Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, 28040 Madrid, Spain.

Cognitive maturation during adolescence is modulated by brain maturation. However, it is unknown how these processes intertwine in early onset psychosis (EOP). Studies examining longitudinal brain changes and cognitive performance in psychosis lend support for an altered development of high-order cognitive functions, which parallels progressive gray matter (GM) loss over time, particularly in fronto-parietal brain regions. We aimed to assess this relationship in a subsample of 33 adolescents with first-episode EOP and 47 matched controls over 2 years. Backwards stepwise regression analyses were conducted to determine the association and predictive value of longitudinal brain changes over cognitive performance within each group. Fronto-parietal GM volume loss was positively associated with decreased working memory in adolescents with psychosis (frontal left (B = 0.096, = 0.008); right (B = 0.089, = 0.015); parietal left (B = 0.119, = 0.007), right (B = 0.125, = 0.015)) as a function of age. A particular decrease in frontal left GM volume best predicted a significant amount (22.28%) of the variance of decreased working memory performance over time, accounting for variance in age (14.9%). No such association was found in controls. Our results suggest that during adolescence, EOP individuals seem to follow an abnormal neurodevelopmental trajectory, in which fronto-parietal GM volume reduction is associated with the differential age-related working memory dysfunction in this group.
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http://dx.doi.org/10.3390/jcm10173929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432087PMC
August 2021

Identification of as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data.

Front Pharmacol 2021 13;12:729474. Epub 2021 Aug 13.

Department of Basic Clinical Practice, Pharmacology Unit, University of Barcelona, Barcelona, Spain.

Antipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An integrative gene expression analysis was performed in four different mouse tissues (striatum, liver, pancreas and adipose) after risperidone or olanzapine treatment. The analytical approach combined the identification of the gene co-expression modules related to AP treatment, gene set enrichment analysis and protein-protein interaction network construction. We found several co-expression modules of genes involved in glucose and lipid homeostasis, hormone regulation and other processes related to metabolic impairment. Among these genes, , which encodes an acetyltransferase involved in transcriptional regulation, was identified as the most important hub gene overlapping the networks of both APs. Then, we explored the genetically predicted expression levels in a cohort of 226 patients with first-episode psychosis who were being treated with APs to further assess the association of this gene with metabolic alterations. The expression levels were significantly associated with increases in body weight, body mass index, total cholesterol levels, low-density lipoprotein cholesterol levels and triglyceride concentrations after 6 months of AP treatment. Taken together, our analysis identified as a key gene in AP-induced metabolic abnormalities, indicating that the dysregulation of function could be important in the development of these side effects. However, more studies are needed to disentangle the role of this gene in the mechanism of action of APs.
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http://dx.doi.org/10.3389/fphar.2021.729474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414590PMC
August 2021

The prevention of relapses in first episodes of schizophrenia: The 2EPs Project, background, rationale and study design.

Rev Psiquiatr Salud Ment (Engl Ed) 2021 Jul-Sep;14(3):164-176

Grupo de Investigación en Neuropsicofarmacología y Psicobiología, Departamento de Neurociencias, Universidad de Cádiz, Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, CIBERSAM, Cádiz, Spain.

Up to 80% of first-episode psychosis patients suffer a relapse within five years of the remission. Relapse should be an important focus of prevention given the potential harm to the patient and family. It threatens to disrupt their psychosocial recovery, increases the risk of resistance to treatment and has been associated with greater direct and indirect costs for society. Based on a previous project entitled "Genotype-phenotype and environment. Application to a predictive model in first psychotic episodes" (PEPs Project), the project "Clinical and neurobiological determinants of second episodes of schizophrenia. Longitudinal study of first episode of psychosis" was designed, also known as the 2EPs Project. It aimed to identify and characterize those factors that predict a relapse within the years immediately following a first episode. This project has focused on following the clinical course, with neuropsychological assessments, biological and neuroanatomical measures, genetic adherence and physical health monitoring in order to compare a subgroup of patients with a second episode to another group of patients which remains in remission. The main objective of the present article is to describe the rationale of the 2EPs Project, explaining the measurement approach adopted and providing an overview of the selected clinical and functional measures. 2EPs Project is a multicenter, coordinated, naturalistic, longitudinal follow-up study over three years in a Spanish sample of patients in remission after a first-psychotic episode of schizophrenia. It is closely monitoring the clinical course of the cases recruited to compare the subgroup of patients with a second episode to that which remains in remission. The sample is composed of 223 subjects recruited from 15 clinical centres in Spain with experience of the preceding PEPs Study project, albeit 2EPs being an expanded version with new basic groups in biological research. From the total sample recruited, 63 patients presented a relapse (44%). 2EPs arose to characterize first episodes in an exhaustive, novel and multimodal way, thus contributing towards the development of a predictive model of relapse. Identifying the characteristics of patients who relapse could improve early detection and intervention.
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http://dx.doi.org/10.1016/j.rpsmen.2021.08.001DOI Listing
May 2020

The impact of COVID-19 lockdown on child and adolescent mental health: systematic review.

Eur Child Adolesc Psychiatry 2021 Aug 18. Epub 2021 Aug 18.

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

COVID-19 was declared a pandemic in March 2020, resulting in many countries worldwide calling for lockdowns. This study aimed to review the existing literature on the effects of the lockdown measures established as a response to the COVID-19 pandemic on the mental health of children and adolescents. Embase, Ovid, Global Health, PsycINFO, Web of Science, and pre-print databases were searched in this PRISMA-compliant systematic review (PROSPERO: CRD42021225604). We included individual studies reporting on a wide range of mental health outcomes, including risk and protective factors, conducted in children and adolescents (aged ≤ 19 years), exposed to COVID-19 lockdown. Data extraction and quality appraisal were conducted by independent researchers, and results were synthesised by core themes. 61 articles with 54,999 children and adolescents were included (mean age = 11.3 years, 49.7% female). Anxiety symptoms and depression symptoms were common in the included studies and ranged 1.8-49.5% and 2.2-63.8%, respectively. Irritability (range = 16.7-73.2%) and anger (range = 30.0-51.3%), were also frequently reported by children and adolescents. Special needs and the presence of mental disorders before the lockdown, alongside excessive media exposure, were significant risk factors for anxiety. Parent-child communication was protective for anxiety and depression. The COVID-19 lockdown has resulted in psychological distress and highlighted vulnerable groups such as those with previous or current mental health difficulties. Supporting the mental health needs of children and adolescents at risk is key. Clinical guidelines to alleviate the negative effects of COVID-19 lockdown and public health strategies to support this population need to be developed.
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http://dx.doi.org/10.1007/s00787-021-01856-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371430PMC
August 2021

Imputing the Number of Responders from the Mean and Standard Deviation of CGI-Improvement in Clinical Trials Investigating Medications for Autism Spectrum Disorder.

Brain Sci 2021 Jul 9;11(7). Epub 2021 Jul 9.

Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, 81675 Munich, Germany.

Introduction: Response to treatment, according to Clinical Global Impression-Improvement (CGI-I) scale, is an easily interpretable outcome in clinical trials of autism spectrum disorder (ASD). Yet, the CGI-I rating is sometimes reported as a continuous outcome, and converting it to dichotomous would allow meta-analysis to incorporate more evidence.

Methods: Clinical trials investigating medications for ASD and presenting both dichotomous and continuous CGI-I data were included. The number of patients with at least much improvement (CGI-I ≤ 2) were imputed from the CGI-I scale, assuming an underlying normal distribution of a latent continuous score using a primary threshold θ = 2.5 instead of θ = 2, which is the original cut-off in the CGI-I scale. The original and imputed values were used to calculate responder rates and odds ratios. The performance of the imputation method was investigated with a concordance correlation coefficient (CCC), linear regression, Bland-Altman plots, and subgroup differences of summary estimates obtained from random-effects meta-analysis.

Results: Data from 27 studies, 58 arms, and 1428 participants were used. The imputation method using the primary threshold (θ = 2.5) had good performance for the responder rates (CCC = 0.93 95% confidence intervals [0.86, 0.96]; β of linear regression = 1.04 [0.95, 1.13]; bias and limits of agreements = 4.32% [-8.1%, 16.74%]; no subgroup differences χ = 1.24, -value = 0.266) and odds ratios (CCC = 0.91 [0.86, 0.96]; β = 0.96 [0.78, 1.14]; bias = 0.09 [-0.87, 1.04]; χ = 0.02, -value = 0.894). The imputation method had poorer performance when the secondary threshold (θ = 2) was used.

Discussion: Assuming a normal distribution of the CGI-I scale, the number of responders could be imputed from the mean and standard deviation and used in meta-analysis. Due to the wide limits of agreement of the imputation method, sensitivity analysis excluding studies with imputed values should be performed.
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http://dx.doi.org/10.3390/brainsci11070908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305379PMC
July 2021

The Role of Premorbid IQ and Age of Onset as Useful Predictors of Clinical, Functional Outcomes, and Recovery of Individuals with a First Episode of Psychosis.

J Clin Med 2021 Jun 2;10(11). Epub 2021 Jun 2.

Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Gregorio Marañón Health Research Institute (IiSGM), Hospital General Universitario Gregorio Marañón, Research Networking Center for Mental Health Network (CIBERSAM), School of Medicine, Complutense University of Madrid (UCM), 28007 Madrid, Spain.

Background: premorbid IQ (pIQ) and age of onset are predictors of clinical severity and long-term functioning after a first episode of psychosis. However, the additive influence of these variables on clinical, functional, and recovery rates outcomes is largely unknown.

Methods: we characterized 255 individuals who have experienced a first episode of psychosis in four a priori defined subgroups based on pIQ (low pIQ < 85; average pIQ ≥ 85) and age of onset (early onset < 18 years; adult onset ≥ 18 years). We conducted clinical and functional assessments at baseline and at two-year follow-up. We calculated symptom remission and recovery rates using the Positive and Negative Symptoms of Schizophrenia Schedule (PANSS) and the Global Assessment Functioning (GAF or Children-GAF). We examined clinical and functional changes with pair-wise comparisons and two-way mixed ANOVA. We built hierarchical lineal and logistic regression models to estimate the predictive value of the independent variables over functioning or recovery rates.

Results: early-onset patients had more severe positive symptoms and poorer functioning than adult-onset patients. At two-year follow-up, only early-onset with low pIQ and adult-onset with average pIQ subgroups differed consistently, with the former having more negative symptoms ( = 0.59), poorer functioning ( = 0.82), lower remission (61% vs. 81.1%), and clinical recovery (34.1% vs. 62.2%).

Conclusions: early-onset individuals with low pIQ may present persistent negative symptoms, lower functioning, and less recovery likelihood at two-year follow-up. Intensive cognitive and functional programs for these individuals merit testing to improve long-term recovery rates in this subgroup.
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http://dx.doi.org/10.3390/jcm10112474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199787PMC
June 2021

Mental health impact of the first wave of COVID-19 pandemic on Spanish healthcare workers: A large cross-sectional survey.

Rev Psiquiatr Salud Ment (Engl Ed) 2021 Apr-Jun;14(2):90-105

Center for Public Health Psychiatry, Universitair Psychiatrisch Centrum, KU Leuven, Leuven, Belgium.

Introduction: Healthcare workers are vulnerable to adverse mental health impacts of the COVID-19 pandemic. We assessed prevalence of mental disorders and associated factors during the first wave of the pandemic among healthcare professionals in Spain.

Methods: All workers in 18 healthcare institutions (6 AACC) in Spain were invited to web-based surveys assessing individual characteristics, COVID-19 infection status and exposure, and mental health status (May 5 - September 7, 2020). We report: probable current mental disorders (Major Depressive Disorder-MDD- [PHQ-8≥10], Generalized Anxiety Disorder-GAD- [GAD-7≥10], Panic attacks, Posttraumatic Stress Disorder -PTSD- [PCL-5≥7]; and Substance Use Disorder -SUD-[CAGE-AID≥2]. Severe disability assessed by the Sheehan Disability Scale was used to identify probable "disabling" current mental disorders.

Results: 9,138 healthcare workers participated. Prevalence of screen-positive disorder: 28.1% MDD; 22.5% GAD, 24.0% Panic; 22.2% PTSD; and 6.2% SUD. Overall 45.7% presented any current and 14.5% any disabling current mental disorder. Workers with pre-pandemic lifetime mental disorders had almost twice the prevalence than those without. Adjusting for all other variables, odds of any disabling mental disorder were: prior lifetime disorders (TUS: OR=5.74; 95%CI 2.53-13.03; Mood: OR=3.23; 95%CI:2.27-4.60; Anxiety: OR=3.03; 95%CI:2.53-3.62); age category 18-29 years (OR=1.36; 95%CI:1.02-1.82), caring "all of the time" for COVID-19 patients (OR=5.19; 95%CI: 3.61-7.46), female gender (OR=1.58; 95%CI: 1.27-1.96) and having being in quarantine or isolated (OR= 1.60; 95CI:1.31-1.95).

Conclusions: One in seven Spanish healthcare workers screened positive for a disabling mental disorder during the first wave of the COVID-19 pandemic. Workers reporting pre-pandemic lifetime mental disorders, those frequently exposed to COVID-19 patients, infected or quarantined/isolated, female workers, and auxiliary nurses should be considered groups in need of mental health monitoring and support.
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http://dx.doi.org/10.1016/j.rpsmen.2021.05.003DOI Listing
June 2021

Examining the association between exposome score for schizophrenia and functioning in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

Eur Psychiatry 2021 Mar 19;64(1):e25. Epub 2021 Mar 19.

Biomedical Research Networking Centre in Mental Health (CIBERSAM), Barcelona, Spain.

Background: A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls.

Methods: This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate.

Results: ES-SCZ was associated with the GAF dimensions in patients (symptom: B = -1.53, p-value = 0.001; disability: B = -1.44, p-value = 0.001), siblings (symptom: B = -3.07, p-value < 0.001; disability: B = -2.52, p-value < 0.001), and healthy controls (symptom: B = -1.50, p-value < 0.001; disability: B = -1.31, p-value < 0.001). The results remained the same after adjusting for PRS-SCZ. The degree of associations of ES-SCZ with both symptom and disability dimensions were higher in unaffected siblings than in patients and controls. By analyzing an independent dataset (the Genetic Risk and Outcome of Psychosis study), we replicated the results observed in the patient group.

Conclusions: Our findings suggest that ES-SCZ shows promise for enhancing risk prediction and stratification in research practice. From a clinical perspective, ES-SCZ may aid in efforts of clinical characterization, operationalizing transdiagnostic clinical staging models, and personalizing clinical management.
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http://dx.doi.org/10.1192/j.eurpsy.2021.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080213PMC
March 2021

Migration history and risk of psychosis: results from the multinational EU-GEI study.

Psychol Med 2021 Feb 10:1-13. Epub 2021 Feb 10.

Univ Paris Est Creteil (UPEC), AP-HP, Hôpitaux Universitaires « H. Mondor », DMU IMPACT, INSERM, IMRB, Fondation FondaMental, F-94010Creteil, France.

Background: Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration.

Methods: We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models.

Results: In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06-2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02-3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03-1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672-2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose-response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06-96.47, p = 0.007).

Conclusions: The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.
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http://dx.doi.org/10.1017/S003329172000495XDOI Listing
February 2021

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Department of Psychiatry, Dokuz Eylül University, School of Medicine, Izmir, Turkey.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-020-00969-zDOI Listing
January 2021

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Department of Psychiatry, Dokuz Eylül University, School of Medicine, Izmir, Turkey.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-020-00969-zDOI Listing
January 2021

Mental health impact of the first wave of COVID-19 pandemic on Spanish healthcare workers: A large cross-sectional survey.

Rev Psiquiatr Salud Ment (Engl Ed) 2021 Apr-Jun;14(2):90-105. Epub 2020 Dec 10.

Center for Public Health Psychiatry, Universitair Psychiatrisch Centrum, KU Leuven, Leuven, Belgium.

Introduction: Healthcare workers are vulnerable to adverse mental health impacts of the COVID-19 pandemic. We assessed prevalence of mental disorders and associated factors during the first wave of the pandemic among healthcare professionals in Spain.

Methods: All workers in 18 healthcare institutions (6 AACC) in Spain were invited to web-based surveys assessing individual characteristics, COVID-19 infection status and exposure, and mental health status (May 5 - September 7, 2020). We report: probable current mental disorders (Major Depressive Disorder-MDD- [PHQ-8≥10], Generalized Anxiety Disorder-GAD- [GAD-7≥10], Panic attacks, Posttraumatic Stress Disorder -PTSD- [PCL-5≥7]; and Substance Use Disorder -SUD-[CAGE-AID≥2]. Severe disability assessed by the Sheehan Disability Scale was used to identify probable "disabling" current mental disorders.

Results: 9,138 healthcare workers participated. Prevalence of screen-positive disorder: 28.1% MDD; 22.5% GAD, 24.0% Panic; 22.2% PTSD; and 6.2% SUD. Overall 45.7% presented any current and 14.5% any disabling current mental disorder. Workers with pre-pandemic lifetime mental disorders had almost twice the prevalence than those without. Adjusting for all other variables, odds of any disabling mental disorder were: prior lifetime disorders (TUS: OR=5.74; 95%CI 2.53-13.03; Mood: OR=3.23; 95%CI:2.27-4.60; Anxiety: OR=3.03; 95%CI:2.53-3.62); age category 18-29 years (OR=1.36; 95%CI:1.02-1.82), caring "all of the time" for COVID-19 patients (OR=5.19; 95%CI: 3.61-7.46), female gender (OR=1.58; 95%CI: 1.27-1.96) and having being in quarantine or isolated (OR= 1.60; 95CI:1.31-1.95).

Conclusions: One in seven Spanish healthcare workers screened positive for a disabling mental disorder during the first wave of the COVID-19 pandemic. Workers reporting pre-pandemic lifetime mental disorders, those frequently exposed to COVID-19 patients, infected or quarantined/isolated, female workers, and auxiliary nurses should be considered groups in need of mental health monitoring and support.
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http://dx.doi.org/10.1016/j.rpsm.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726524PMC
June 2021

Bumetanide Oral Liquid Formulation for the Treatment of Children and Adolescents with Autism Spectrum Disorder: Design of Two Phase III Studies (SIGN Trials).

J Autism Dev Disord 2021 Aug;51(8):2959-2972

University Paris-Sud, Univ. Paris-Descartes, AP-HP, INSERM U1178, Paris, France.

There are currently no approved pharmacological treatments to improve social reciprocity and limit repetitive and rigid behaviors in autism spectrum disorder (ASD). We describe the design of two Phase III studies evaluating the efficacy/safety of bumetanide oral liquid formulation in ASD. These are international, multicenter, randomized, double-blind, placebo-controlled studies in children and adolescents with ASD aged 7 to 17 years (n = 200; study 1), or younger children with ASD aged 2 to 6 years (n = 200; study 2). The primary endpoint of each is change in Childhood Autism Rating Scale 2 total raw score after 6 months. These studies could contribute to the first pharmacological treatment to improve social reciprocity and limit repetitive and rigid behaviors in children and adolescents with ASD.
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http://dx.doi.org/10.1007/s10803-020-04709-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254707PMC
August 2021

[Patient care, right to information and consent for minors in situations of parental conflict. Clinical guidelines in the context of Spanish legislation].

An Pediatr (Engl Ed) 2021 May 29;94(5):338.e1-338.e7. Epub 2020 Oct 29.

Servicio de Psiquiatría del Niño y Adolescente, Instituto de Psiquiatría y Salud Mental, Hospital General Universitario Gregorio Marañón, IiSGM, CIBERSAM, Facultad de Medicina, Universidad Complutense, Madrid, España.

Among the main social and legislative changes as regards family matters that have taken place in Spain in the last few years, are included: (i) the gradual increase in legal disputes between parents, and (ii) the introduction of Law 26/2015 on Child Protection, which modified Law 41/2002 on the Freedom of the Patient. These searched for a balance between the rights of minors and the powers of the parents, particularly when the former had not reached 16 years or had sufficient maturity or, having reached it, the decision puts their life or health at severe risk. Likewise, it has led to a jurisprudence that determines that, for any minor, there are particularly sensitive, "special" or "important" health care actions, such as psychotherapy or surgical treatments, which require, with exceptions, the consent of both parents for it to be carried out. All this, however, subject to the discretion of the doctor responsible, who must always look after the best interests of the minor. For this reason, healthcare for minors, occasionally, lead to complex conflicts as regards information and consent by the parents, particularly when they do not agree. A review is presented on the current legislative framework and the main legal concepts that regulate the healthcare of minors as regards information and consent relative to health, as well a healthcare protocol for the care of minors in situations of conflict between parents, developed in the Gregorio Marañón Hospital of Madrid, and endorsed by the Official Medical Collegiate of Madrid.
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http://dx.doi.org/10.1016/j.anpedi.2020.09.007DOI Listing
May 2021

Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway.

Psychol Med 2020 Oct 19:1-13. Epub 2020 Oct 19.

Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain.

Background: There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.

Methods: We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.

Results: The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).

Conclusions: The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
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http://dx.doi.org/10.1017/S0033291720003748DOI Listing
October 2020

A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

Psychol Med 2020 Oct 13:1-7. Epub 2020 Oct 13.

Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain.

Background: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation.

Methods: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses.

Results: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences.

Conclusions: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.
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http://dx.doi.org/10.1017/S0033291720003578DOI Listing
October 2020

Influence of BDNF and MTHFR polymorphisms on hippocampal volume in first-episode psychosis.

Schizophr Res 2020 09 26;223:345-352. Epub 2020 Sep 26.

Biomedical Research Networking Center for Mental Health Network (CIBERSAM), Spain; Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón School of Medicine, Universidad Complutense, IiSGM, Madrid, Spain.

Background: The BDNF and MTHFR genes are independently linked to the pathogenesis of schizophrenia and its neuroimaging correlates. The aim of this study was to explore, for the first time, the individual and interactional effects of the Val66Met and C677T polymorphisms on hippocampal atrophy in first-episode psychosis (FEP).

Method: Multi-site case-control study based on clinical, genetic (rs 6265, rs 1801133) and structural magnetic resonance imaging data from 98 non-affective FEP patients and 117 matched healthy controls (HC). Hippocampal volume was estimated using FreeSurfer software and this volume was compared between diagnostic (FEP vs HC) and genotype (Val66Met, C677T) groups. The BDNF Val66Met x MTHFR C677T effect on hippocampal volume was further evaluated through stratified analyses.

Results: After applying Bonferroni correction, diagnosis showed a significant effect for adjusted left and right hippocampal volume (FEP < HC). Stratified analyses showed that the interactive effect contributed to adjusted hippocampal size in both the HC (left and right hippocampus) and FEP groups (right hippocampus); among BDNF Met carriers, those with the CT-TT genotype exhibited decreased hippocampal volume compared to individuals with the homozygous normal CC genotype.

Conclusions: Our results provide preliminary evidence indicating that the Val66Met x C677T interaction may be a potential genetic risk factor for reduced hippocampal size in both healthy controls and in patients with FEP. Further research in independent samples including different ethnic groups is warranted to confirm this new finding.
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http://dx.doi.org/10.1016/j.schres.2020.08.002DOI Listing
September 2020

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

JAMA Psychiatry 2021 Jan;78(1):47-63

Department of Psychiatry and Neuropsychology, School of Mental Health and Neuroscience, Maastricht University, the Netherlands.

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood.

Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia.

Design, Setting, And Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244.

Main Outcomes And Measures: Interregional profiles of group difference in cortical thickness between cases and controls.

Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders.

Conclusions And Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.
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http://dx.doi.org/10.1001/jamapsychiatry.2020.2694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450410PMC
January 2021

Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

Mol Autism 2020 08 26;11(1):66. Epub 2020 Aug 26.

Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany.

Background: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms.

Methods: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 .

Results: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain.

Limitations: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers.

Conclusions: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.
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http://dx.doi.org/10.1186/s13229-020-00372-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448339PMC
August 2020

Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype.

Am J Hum Genet 2020 09 5;107(3):555-563. Epub 2020 Aug 5.

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477006PMC
September 2020

Psychiatric comorbidities in Asperger syndrome are related with polygenic overlap and differ from other Autism subtypes.

Transl Psychiatry 2020 07 30;10(1):258. Epub 2020 Jul 30.

Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM), Facultad de Medicina, Universidad Complutense, Madrid, Spain.

There is great phenotypic heterogeneity within autism spectrum disorders (ASD), which has led to question their classification into a single diagnostic category. The study of the common genetic variation in ASD has suggested a greater contribution of other psychiatric conditions in Asperger syndrome (AS) than in the rest of the DSM-IV ASD subtypes (Non_AS). Here, using available genetic data from previously performed genome-wide association studies (GWAS), we aimed to study the genetic overlap between five of the most related disorders (schizophrenia (SCZ), major depression disorder (MDD), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorders (OCD) and anxiety (ANX)), and AS, comparing it with the overlap in Non_AS subtypes. A Spanish cohort of autism trios (N = 371) was exome sequenced as part of the Autism Sequencing Consortium (ASC) and 241 trios were extensively characterized to be diagnosed with AS following DSM-IV and Gillberg's criteria (N = 39) or not (N = 202). Following exome imputation, polygenic risk scores (PRS) were calculated for ASD, SCZ, ADHD, MDD, ANX, and OCD (from available summary data from Psychiatric Genomic Consortium (PGC) repository) in the Spanish trios' cohort. By using polygenic transmission disequilibrium test (pTDT), we reported that risk for SCZ (P= 0.008, corrected-P = 0.0409), ADHD (P = 0.021, corrected-P = 0.0301), and MDD (P = 0.039, corrected-P = 0.0501) is over-transmitted to children with AS but not to Non_AS. Indeed, agnostic clustering procedure with deviation values from pTDT tests suggested two differentiated clusters of subjects, one of which is significantly enriched in AS (P = 0.025). Subsequent analysis with S-Predixcan, a recently developed software to predict gene expression from genotype data, revealed a clear pattern of correlation between cortical gene expression in ADHD and AS (P < 0.001) and a similar strong correlation pattern between MDD and AS, but also extendable to another non-brain tissue such as lung (P < 0.001). Altogether, these results support the idea of AS being qualitatively distinct from Non_AS autism and consistently evidence the genetic overlap between AS and ADHD, MDD, or SCZ.
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http://dx.doi.org/10.1038/s41398-020-00939-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393162PMC
July 2020

The Positive and Negative Syndrome Scale for Schizophrenia Autism Severity Scale (PAUSS) in young people with autism and schizophrenia.

Rev Psiquiatr Salud Ment (Engl Ed) 2020 Jul - Sep;13(3):118-130. Epub 2020 Jul 20.

Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, CIBERSAM, IiSGM, School of Medicine, Universidad Complutense, Madrid, Spain.

Introduction: Schizophrenia spectrum disorders (SSD) share symptoms with autism spectrum disorders (ASD). Autistic phenotypic profiles in SSD may be associated with a poor prognosis. We aimed to assess the evidences for reliability and convergent validity of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Autism Severity Scale (PAUSS) in a sample of young people with ASD and SSD, and to use the PAUSS to explore correlates of "autistic profiles" in the SSD sample.

Materials And Methods: ASD (n=33, age=13-27 years) and SSD subjects (n=26, age=16-35 years) underwent PANSS, Autism Diagnostic Observation Schedule-Generic (ADOS-G), Autism Diagnostic Interview-Revised (ADI-R), and Social Responsiveness Scale (SRS) assessments. We derived PAUSS total/domain scores from the PANSS and applied these back-to-back with ADOS calibrated severity scores (CSS), ADI-R current behavior algorithm (CBA) scores, and SRS scores.

Results: Our results show evidence for an acceptable PAUSS score reliability and convergent validity both in the ASD and SSD samples. PAUSS total and socio-communication scores significantly correlated with ADOS Overall/Social Affect CSS, both in ASD and in SSD. SSD with higher PAUSS scores ("autistic-SSD") showed Overall/Social Affect CSS scores positioned in between ASD and "non-autistic SSD". The PAUSS total score was significantly associated with global functioning in SSD (adjusted R=0.311).

Conclusions: There seems to be evidence for the reliability and validity of PAUSS scores for quantifying autism symptom severity transdiagnostically and to identify "autistic phenotypes" in adolescents/young adults with SSD.
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http://dx.doi.org/10.1016/j.rpsm.2020.05.006DOI Listing
October 2021

Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups.

Am J Psychiatry 2020 09 16;177(9):834-843. Epub 2020 Jun 16.

The full list of authors in the ENIGMA working groups, author affiliations, author disclosures, and acknowledgments are provided in online supplements.

Objective: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data.

Methods: Structural T-weighted whole-brain MRI data from healthy control subjects (N=5,827) and from patients with ADHD (N=2,271), ASD (N=1,777), and OCD (N=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. The authors examined subcortical volume, cortical thickness, and cortical surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults, using linear mixed-effects models adjusting for age, sex, and site (and intracranial volume for subcortical and surface area measures).

Results: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood.

Conclusions: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.
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http://dx.doi.org/10.1176/appi.ajp.2020.19030331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296070PMC
September 2020

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Hum Brain Mapp 2020 May 18. Epub 2020 May 18.

Division of Psychological & Social Medicine and Developmental Neurosciences, Faculty of Medicine, Technischen Universität Dresden, Dresden, Germany.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
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http://dx.doi.org/10.1002/hbm.25029DOI Listing
May 2020

Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms.

Psychopharmacology (Berl) 2020 Jul 7;237(7):2151-2159. Epub 2020 May 7.

Dept. Clinical Foundations, Pharmacology Unit, University of Barcelona, Barcelona, Spain.

Introduction: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies.

Methods: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP.

Results: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1.

Conclusion: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.
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http://dx.doi.org/10.1007/s00213-020-05526-8DOI Listing
July 2020

Association study of candidate genes with obesity and metabolic traits in antipsychotic-treated patients with first-episode psychosis over a 2-year period.

J Psychopharmacol 2020 05 3;34(5):514-523. Epub 2020 Feb 3.

Department of Basic Clinical Practice, University of Barcelona, Barcelona, Spain.

Aims: Patients with a first episode of psychosis (FEP) often display different metabolic disturbances even independently of drug therapy. However, antipsychotic (AP) treatment, especially with second-generation APs, is strongly linked to weight gain, which increases patients' risk of developing obesity and other metabolic diseases. There is an important genetic risk component that can contribute to the appearance of these disturbances. The aim of the present study was to evaluate the effect of polymorphisms in selected candidate genes on obesity and other anthropometric and metabolic traits in 320 AP-treated FEP patients over the course of a 2-year follow-up.

Methods: These patients were recruited in the multicentre PEPs study (Phenotype-genotype and environmental interaction; Application of a predictive model in first psychotic episodes). A total of 127 validated single nucleotide polymorphisms (SNPs) in 18 candidate genes were included in the genetic analysis.

Results: After Bonferroni correction, SNPs in and were associated with obesity, abdominal circumference, triglycerides, HDL cholesterol, and/or percentage of glycated haemoglobin.

Conclusions: Although our results should be interpreted as exploratory, they support previous evidence of the impact of these candidate genes on obesity and metabolic status. Further research is required to gain a better knowledge of the genetic variants that can be considered relevant metabolic risk factors. The ability to identify FEP patients at higher risk for these metabolic disturbances would enable clinicians to better select and control their AP treatment.
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http://dx.doi.org/10.1177/0269881120903462DOI Listing
May 2020
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