Publications by authors named "David Fraguas"

60 Publications

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

Humanization in mental health plans in Spain.

Rev Psiquiatr Salud Ment 2021 Sep 4. Epub 2021 Sep 4.

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

Introduction: Mental health (MH) care has important challenges, especially in the field of humanization. Our objectives were to identify the humanization measures in MH plans of the Spanish autonomous communities (CCAA) and the priorities to be developed in this area.

Material And Methods: A large and multidisciplinary group of people involved in MH care participated in a consensus, according to a modified Delphi method, based on «design thinking», in three phases: (1) identification of humanization measures in MH plans of CCAA; (2) analysis of the implementation of these measures; and (3) identification of humanization priorities in MH.

Results: Fourteen of the 17 CCAA have current MH plans. They contained four types of humanization measures: (1) improvement of the quality of care; (2) promotion of user participation; (3) campaigns against stigma and discrimination; (4) caring for especially vulnerable people. Implementation of measures ranged from 6.3% (i.e.: specific budget) to 100%, with an average of 64.1%. We identified priority issues, operationalized in 5 proposals: (1) information campaigns; (2) multidisciplinary meeting forums; (3) platforms of support entities; (4) strategies on MH education; (5) humanization in study plans.

Conclusions: Some MH plans include humanization among their objectives, but partially. The implementation of humanization proposals such as those identified in this study is essential to achieve a high-quality MH care.
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http://dx.doi.org/10.1016/j.rpsm.2021.08.003DOI Listing
September 2021

Cognitive clusters in first-episode psychosis.

Schizophr Res 2021 Sep 1;237:31-39. Epub 2021 Sep 1.

Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, Department of Medicine, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Biomedical Research Networking Centre in Mental Health (CIBERSAM), Spain. Electronic address:

Impairments in a broad range of cognitive domains have been consistently reported in some individuals with first-episode psychosis (FEP). Cognitive deficits can be observed during the prodromal stage. However, the course of cognitive deficits is still unclear. The aim of this study was to identify cognitive subgroups over time and to compare their sociodemographic, clinical and functional profiles. A total of 114 patients with Schizophrenia Spectrum Disorders were included in the present study. We assessed subjects through psychiatric scales and eight neuropsychological tests at baseline and at two-year follow-up visit. We performed the Partition Around Medoids algorithm with all cognitive variables. Furthermore, we performed a logistic regression to identify the predictors related to the different cognitive clusters at follow-up. Two distinct subgroups were found: the first cluster characterized by cognitive impairment and a second cluster had relatively intact cognition in comparison with norms. Up to 54.7% of patients with cognitive deficits at baseline tended to improve during the first two years of treatment. Patients with intact cognition at follow-up had a higher socioeconomic status, later age of onset, lower negative symptoms and a higher cognitive reserve (CR) at baseline. CR and age of onset were the baseline variables that predicted cognitive impairment. This research allows us to obtain a better understanding of the heterogeneous profile of psychotic disorders. Identifying the characteristics of patients who will present a cognitive impairment could improve early detection and intervention. These results suggest that enhancing CR could contribute to improving the course of the illness.
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http://dx.doi.org/10.1016/j.schres.2021.08.021DOI Listing
September 2021

First episode psychosis longitudinal cohort studies: The CIBERSAM FEP cohort.

Eur Neuropsychopharmacol 2021 Jul 17;51:132-133. Epub 2021 Jul 17.

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

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http://dx.doi.org/10.1016/j.euroneuro.2021.06.011DOI Listing
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

The role of depression in the prediction of a "late" remission in first-episode psychosis: An analysis of the OPTiMiSE study.

Schizophr Res 2021 05 7;231:100-107. Epub 2021 Apr 7.

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

Objective: The identification of predictors of psychosis remission could guide early clinical decision-making for treatment of first-episode schizophrenia (FES).

Methods: We analyzed two non-independent subsamples of patients with FES ages 18-40 years from the OPTiMiSE study dataset to investigate the demographic and clinical factors that might help to differentiate "late" remitters (i.e., not in remission at week 2 or 4, but achieving remission within a 10-week follow-up period) from non-remitters within the same period.

Results: Subsample 1 included 216 individuals (55 females, mean age 25.9 years) treated with amisulpride in an open-label design who were not in remission at week 2. Early symptomatic response between baseline and week 2 (odds ratio (OR) = 4.186, 95% confidence interval (CI) = 2.082-8.416, p < 0.001) and older age (OR = 1.081, 95% CI = 1.026-1.138, p = 0.003) were the only variables significantly associated with a higher probability of psychosis remission at week 4. Subsample 2 was composed of the 72 participants (19 females, mean age 25.1 years) who were not in remission at week 4 and completed a 6-week double-blind randomized trial comparing continuation of amisulpride with switch to olanzapine. Depression at baseline (as measured with the Calgary Depression Scale for Schizophrenia) was significantly associated with a nearly 3-fold lower likelihood of psychosis remission during the 10-week follow-up (hazard ratio = 2.865, 95% CI = 1.187-6.916, p = 0.019).

Conclusion: Our results reinforce the importance of assessing depressive symptoms in people with FES and support the relevance of an early response (as early as 2 weeks) as a predictor of clinical outcome in this population.

Clinical Trials Registration: ClinicalTrials.gov identifier: NCT01248195, https://clinicaltrials.gov/ct2/show/NCT01248195.
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http://dx.doi.org/10.1016/j.schres.2021.03.010DOI Listing
May 2021

Methodologic and Reporting Issues in Published Meta-analysis-Reply.

JAMA Pediatr 2021 Jun;175(6):644-645

Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Department of Child and Adolescent Psychiatry, Universidad Complutense School of Medicine, Madrid, Spain.

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http://dx.doi.org/10.1001/jamapediatrics.2021.0013DOI Listing
June 2021

Assessment of School Anti-Bullying Interventions: A Meta-analysis of Randomized Clinical Trials.

JAMA Pediatr 2021 Jan;175(1):44-55

Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), School of Medicine, Universidad Complutense, Madrid, Spain.

Importance: Bullying is a prevalent and modifiable risk factor for mental health disorders. Although previous studies have supported the effectiveness of anti-bullying programs; their population impact and the association of specific moderators with outcomes are still unclear.

Objective: To assess the effectiveness of school anti-bullying interventions, their population impact, and the association between moderator variables and outcomes.

Data Sources: A search of Ovid MEDLINE, ERIC, and PsycInfo databases was conducted using 3 sets of search terms to identify randomized clinical trials (RCTs) assessing anti-bullying interventions published from database inception through February 2020. A manual search of reference lists of articles included in previous systematic reviews and meta-analyses was also performed.

Study Selection: The initial literature search yielded 34 798 studies. Included in the study were articles that (1) assessed bullying at school; (2) assessed the effectiveness of an anti-bullying program; (3) had an RCT design; (4) reported results; and (5) were published in English. Of 16 707 studies identified, 371 met the criteria for review of full-text articles; 77 RCTs were identified that reported data allowing calculation of effect sizes (ESs). Of these, 69 independent trials were included in the final meta-analysis database.

Data Extraction And Synthesis: Random-effects and meta-regression models were used to derive Cohen d values with pooled 95% CIs as estimates of ES and to test associations between moderator variables and ES estimates. Population impact number (PIN), defined as the number of children in the total population for whom 1 event may be prevented by an intervention, was used as an estimate of the population impact of universal interventions targeting all students, regardless of individual risk.

Main Outcomes And Measures: The main outcomes are the effectiveness (measured by ES) and the population impact (measured by the PIN) of anti-bullying interventions on the following 8 variable categories: overall bullying, bullying perpetration, bullying exposure, cyberbullying, attitudes that discourage bullying, attitudes that encourage bullying, mental health problems (eg, anxiety and depression), and school climate as well as the assessment of potential assocations between trial or intervention characteristics and outcomes.

Results: This study included 77 samples from 69 RCTs (111 659 participants [56 511 in the intervention group and 55 148 in the control group]). The weighted mean (range) age of participants in the intervention group was 11.1 (4-17) years and 10.8 (4-17) years in the control group. The weighted mean (range) proportion of female participants in the intervention group was 49.9% (0%-100%) and 50.5% (0%-100%) in the control group. Anti-bullying interventions were efficacious in reducing bullying (ES, -0.150; 95% CI, -0.191 to -0.109) and improving mental health problems (ES, -0.205; 95% CI, -0.277 to -0.133) at study end point, with PINs for universal interventions that target the total student population of 147 (95% CI, 113-213) and 107 (95% CI, 73-173), respectively. Duration of intervention was not statistically significantly associated with intervention effectiveness (mean [range] duration of interventions, 29.4 [1 to 144] weeks). The effectiveness of anti-bullying programs did not diminish over time during follow-up (mean [range] follow-up, 30.9 [2-104] weeks).

Conclusions And Relevance: Despite the small ESs and some regional differences in effectiveness, the population impact of school anti-bullying interventions appeared to be substantial. Better designed trials that assess optimal intervention timing and duration are warranted.
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http://dx.doi.org/10.1001/jamapediatrics.2020.3541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607493PMC
January 2021

The impact of cognitive reserve, cognition and clinical symptoms on psychosocial functioning in first-episode psychoses.

Psychol Med 2020 Sep 9:1-12. Epub 2020 Sep 9.

Barcelona Clinic Schizophrenia Unit, Hospital Clinic of Barcelona, Neuroscience Institute, University of Barcelona, Spain.

Background: Functional impairment is a defining feature of psychotic disorders. A range of factors has been shown to influence functioning, including negative symptoms, cognitive performance and cognitive reserve (CR). However, it is not clear how these variables may affect functioning in first-episode psychosis (FEP) patients. This 2-year follow-up study aimed to explore the possible mediating effects of CR on the relationship between cognitive performance or specific clinical symptoms and functional outcome.

Methods: A prospective study of non-affective FEP patients was performed (211 at baseline and 139 at follow-up). CR was entered in a path analysis model as potential mediators between cognitive domains or clinical symptoms and functioning.

Results: At baseline, the relationship between clinical variables or cognitive performance and functioning was not mediated by CR. At follow-up, the effect of attention (p = 0.003) and negative symptoms (p = 0.012) assessed at baseline on functioning was partially mediated by CR (p = 0.032 and 0.016), whereas the relationship between verbal memory (p = 0.057) and functioning was mediated by CR (p = 0.014). Verbal memory and positive and total subscales of PANSS assessed at follow-up were partially mediated by CR and the effect of working memory on functioning was totally mediated by CR.

Conclusions: Our results showed the influence of CR in mediating the relationship between cognitive domains or clinical symptoms and functioning in FEP. In particular, CR partially mediated the relationship between some cognitive domains or clinical symptoms and functioning at follow-up. Therefore, CR could improve our understanding of the long-term functioning of patients with a non-affective FEP.
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http://dx.doi.org/10.1017/S0033291720002226DOI Listing
September 2020

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

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
July 2020

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Mol Psychiatry 2020 Feb 3. Epub 2020 Feb 3.

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p = 6.73 × 10). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.
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http://dx.doi.org/10.1038/s41380-020-0654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396297PMC
February 2020

Dietary Interventions for Autism Spectrum Disorder: A Meta-analysis.

Pediatrics 2019 11 4;144(5). Epub 2019 Oct 4.

Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón and School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.

Context: Dietary interventions such as restrictive diets or supplements are common treatments for young people with autism spectrum disorder (ASD). Evidence for the efficacy of these interventions is still controversial.

Objective: To assess the efficacy of specific dietary interventions on symptoms, functions, and clinical domains in subjects with ASD by using a meta-analytic approach.

Data Sources: Ovid Medline, PsycINFO, Embase databases.

Study Selection: We selected placebo-controlled, double-blind, randomized clinical trials assessing the efficacy of dietary interventions in ASD published from database inception through September 2017.

Data Extraction: Outcome variables were subsumed under 4 clinical domains and 17 symptoms and/or functions groups. Hedges' adjusted g values were used as estimates of the effect size of each dietary intervention relative to placebo.

Results: In this meta-analysis, we examined 27 double-blind, randomized clinical trials, including 1028 patients with ASD: 542 in the intervention arms and 486 in the placebo arms. Participant-weighted average age was 7.1 years. Participant-weighted average intervention duration was 10.6 weeks. Dietary supplementation (including omega-3, vitamin supplementation, and/or other supplementation), omega-3 supplementation, and vitamin supplementation were more efficacious than the placebo at improving several symptoms, functions, and clinical domains. Effect sizes were small (mean Hedges' g for significant analyses was 0.31), with low statistical heterogeneity and low risk of publication bias.

Limitations: Methodologic heterogeneity among the studies in terms of the intervention, clinical measures and outcomes, and sample characteristics.

Conclusions: This meta-analysis does not support nonspecific dietary interventions as treatment of ASD but suggests a potential role for some specific dietary interventions in the management of some symptoms, functions, and clinical domains in patients with ASD.
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http://dx.doi.org/10.1542/peds.2018-3218DOI Listing
November 2019

Risperidone administered during adolescence induced metabolic, anatomical and inflammatory/oxidative changes in adult brain: A PET and MRI study in the maternal immune stimulation animal model.

Eur Neuropsychopharmacol 2019 07 20;29(7):880-896. Epub 2019 Jun 20.

Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; CIBER de Salud Mental (CIBERSAM), Madrid, Spain.

Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.
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http://dx.doi.org/10.1016/j.euroneuro.2019.05.002DOI Listing
July 2019

Neuroanatomical deficits shared by youth with autism spectrum disorders and psychotic disorders.

Hum Brain Mapp 2019 04 19;40(5):1643-1653. Epub 2018 Dec 19.

Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Autism spectrum disorders (ASD) and early-onset psychosis (EOP) are neurodevelopmental disorders that share genetic, clinical and cognitive facets; it is unclear if these disorders also share spatially overlapping cortical thickness (CT) and surface area (SA) abnormalities. MRI scans of 30 ASD, 29 patients with early-onset first-episode psychosis (EO-FEP) and 26 typically developing controls (TD) (age range 10-18 years) were analyzed by the FreeSurfer suite to calculate vertex-wise estimates of CT, SA, and cortical volume. Two publicly available datasets of ASD and EOP (age range 7-18 years and 5-17 years, respectively) were used for replication analysis. ASD and EO-FEP had spatially overlapping areas of cortical thinning and reduced SA in the bilateral insula (all p's < .00002); 37% of all left insular vertices presenting with significant cortical thinning and 20% (left insula) and 61% (right insula) of insular vertices displaying decreased SA overlapped across both disorders. In both disorders, SA deficits contributed more to cortical volume decreases than reductions in CT did. This finding, as well as the novel finding of an absence of spatial overlap (for ASD) or marginal overlap (for EOP) of deficits in CT and SA, was replicated in the two nonoverlapping independent samples. The insula appears to be a region with transdiagnostic vulnerability for deficits in CT and SA. The finding of nonexistent or small spatial overlap between CT and SA deficits in young people with ASD and psychosis may point to the involvement of common aberrant early neurodevelopmental mechanisms in their pathophysiology.
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http://dx.doi.org/10.1002/hbm.24475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865706PMC
April 2019

Oxidative Stress and Inflammation in First-Episode Psychosis: A Systematic Review and Meta-analysis.

Schizophr Bull 2019 06;45(4):742-751

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

Despite mixed findings, increasing evidence suggests that people with first-episode psychosis (FEP) show increased pro-inflammatory and pro-oxidative status. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to conduct a systematic literature search of cross-sectional studies comparing in vivo inflammatory and oxidative blood markers between FEP patients and healthy controls. We analyzed 61 independent samples from 59 publications, including 3002 patients with FEP (ie, patients with FEP, early psychosis, first-episode schizophrenia or early schizophrenia) and 2806 controls. After controlling for multiple comparisons, our meta-analysis showed that total antioxidant status and docosahexaenoic acid levels were significantly lower in FEP patients than in controls, whereas levels of homocysteine, interleukin-6 and tumor necrosis factor alpha were significantly higher in FEP patients than in controls. This suggests that FEP patients had reduced antioxidant status and a pro-inflammatory imbalance, and that these biological processes may be targets for managing FEP.
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http://dx.doi.org/10.1093/schbul/sby125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581144PMC
June 2019

Predictors of Placebo Response in Pharmacological Clinical Trials of Negative Symptoms in Schizophrenia: A Meta-regression Analysis.

Schizophr Bull 2019 01;45(1):57-68

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

We conducted a meta-regression analysis of all double-blind, randomized, placebo-controlled clinical trials (DBRCTs) reporting effects of drug and placebo on negative symptoms in people with stable schizophrenia and predominant or prominent negative symptoms to assess predictors of placebo response in these individuals. We used Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines for systematic reviews and meta-analyses to conduct a systematic literature search to identify DBRCTs assessing treatment efficacy on negative symptoms, as primary outcome, in patients with stable schizophrenia and predominant or prominent negative symptoms. We used Cohen's d, with 95% CIs, as the effect size measure for placebo response, based on negative symptom change scores from baseline to endpoint (range 4 to 24 wk) in the placebo-treated group. We included 18 DBRCTs from 17 publications, assessing the effect of 13 drugs vs placebo on negative symptoms and comprising 998 patients, in the meta-regression analyses. Overall, drugs showed greater efficacy than placebo in reducing negative symptoms, with small effect size (Cohen's d: 0.208, P = .020). Placebo response was significant (P < .001) and clinically relevant (Cohen's d: 2.909), but there was significant heterogeneity and high risk of publication bias. Multivariable meta-regression analyses showed that larger numbers of arms in the trial, larger numbers of study sites and industry sponsorship were significant moderators of placebo response in this population. Our results suggest that some clinical trial design and operational factors affect the level of placebo response in such studies, thus highlighting the need for designs better suited to assess these outcomes.
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http://dx.doi.org/10.1093/schbul/sbx192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293224PMC
January 2019

Oxidative Stress and Inflammation in Early Onset First Episode Psychosis: A Systematic Review and Meta-Analysis.

Int J Neuropsychopharmacol 2017 06;20(6):435-444

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

Background: People with schizophrenia and other psychosis show increased proinflammatory and prooxidative status. However, the few studies that have specifically assessed oxidative and inflammatory markers in early onset psychosis (onset before age 18) have shown contradictory results.

Methods: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews and meta-analyses were used to conduct a systematic literature search to detect studies comparing inflammatory and oxidative markers in early onset psychosis patients and healthy controls.

Results: Seven studies met criteria for the qualitative analysis. Four studies met criteria for meta-analysis, comprising an overall sample of 261 early onset psychosis patients and 246 healthy controls. Six independent meta-analyses were performed for catalase, glutathione, glutathione peroxidase, superoxide dismutase, total antioxidant status, and cell/DNA oxidative damage. No significant differences were found between early onset psychosis patients and controls in any of the parameters assessed. Heterogeneity among studies was high. Qualitative analysis of individual studies showed an association of inflammatory and oxidative markers with clinical, cognitive, and neurobiological outcomes, especially in longitudinal assessments.

Conclusions: Despite the lack of significant differences between early onset psychosis patients and controls in the oxidative markers assessed in the meta-analyses, results based on individual studies suggest that greater inflammation and oxidative stress might lead to poorer outcomes in patients with first episodes of early onset psychosis.
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http://dx.doi.org/10.1093/ijnp/pyx015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452799PMC
June 2017

Atypical age-dependency of executive function and white matter microstructure in children and adolescents with autism spectrum disorders.

Eur Child Adolesc Psychiatry 2017 Nov 26;26(11):1361-1376. Epub 2017 Apr 26.

Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Executive function (EF) performance is associated with measurements of white matter microstructure (WMS) in typical individuals. Impaired EF is a hallmark symptom of autism spectrum disorders (ASD) but it is unclear how impaired EF relates to variability in WMS. Twenty-one male youth (8-18 years) with ASD and without intellectual disability and twenty-one typical male participants (TP) matched for age, intelligence quotient, handedness, race and parental socioeconomic status were recruited. Five EF domains were assessed and several DTI-based measurements of WMS [fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD)] were estimated for eighteen white matter tracts. The ASD group had lower scores for attention (F = 8.37, p = 0.006) and response inhibition (F = 13.09, p = 0.001). Age-dependent changes of EF performance and WMS measurements were present in TP but attenuated in the ASD group. The strongest diagnosis-by-age effect was found for forceps minor, left anterior thalamic radiation and left cingulum angular bundle (all p's ≤ 0.002). In these tracts subjects with ASD tended to have equal or increased FA and/or reduced MD and/or RD at younger ages while controls had increased FA and/or reduced MD and/or RD thereafter. Only for TP individuals, increased FA in the left anterior thalamic radiation was associated with better response inhibition, while reduced RD in forceps minor and left cingulum angular bundle was related to better problem solving and working memory performance respectively. These findings provide novel insight into the age-dependency of EF performance and WMS in ASD, which can be instructive to cognitive training programs.
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http://dx.doi.org/10.1007/s00787-017-0990-2DOI Listing
November 2017

Gene-environment interaction as a predictor of early adjustment in first episode psychosis.

Schizophr Res 2017 11 2;189:196-203. Epub 2017 Mar 2.

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

Background: This study aims to explore the gene-environment interaction hypothesis applied to pre-symptomatic neurodevelopmental phenotypes of first episode psychosis (FEP), that is, genetic factors might increase vulnerability to the effects of environmental adverse conditions occurring at later stages of development.

Methods: We constructed a schematic 'two-hit' model, with Val/Val homozygosity for the catechol-O-methyltransferase (COMT) Val158Met polymorphism as the 'first hit' and history of obstetric complications and parental socioeconomic status as 'second hits'. Early adjustment, measured using the Premorbid Adjustment Scale, was considered the main outcome. The study population comprised 221 adolescents and adults with FEP and 191 sex- and age-matched controls.

Results: The interaction between the Val/Val COMT genotype and a positive history of obstetric complications plus low parental socioeconomic status was significantly associated with poorer early adjustment. These results were observed both in FEP individuals and in controls, and remained significant after controlling for age, sex, and diagnosis.

Conclusions: Individuals carrying Val/Val seem to be more sensitive to the synergistic effect of environmental factors acting early in neurodevelopment, which leads to vulnerability phenotypes such as impaired early adjustment.
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http://dx.doi.org/10.1016/j.schres.2017.02.021DOI Listing
November 2017

Switching long acting antipsychotic medications to aripiprazole long acting once-a-month: expert consensus by a panel of Italian and Spanish psychiatrists.

Expert Opin Drug Saf 2016 9;15(4):449-55. Epub 2016 Mar 9.

r Casa di Cura Neuropsichiatrica e Comunità Terapeutica-Genzano , University of Rome and Villa Von Siebenthal , Rome , Italy.

Introduction: Aripiprazole long acting once-monthly (AOM) is a long acting atypical antipsychotic with proven efficacy in schizophrenia and with a pharmacological and a side effect profile that is different from other antipsychotics. These and other characteristics make AOM a possible alternative in patients requiring a change in long acting antipsychotic treatment due to issues such as lack of efficacy or persistent side effects. Both clinical and pharmacological factors should be considered when switching antipsychotics, and specific guidelines for long acting antipsychotic switching that address all these factors are needed.

Areas Covered: A panel of Italian and Spanish experts in psychiatry met to discuss the strategies for the switch to AOM in patients with schizophrenia. Real life clinical experiences were shared and the clinical strategies to improve the likelihood of success were discussed.

Expert Opinion: Due to its specific pharmacological and tolerability profile, AOM represents a suitable alternative for patients with schizophrenia requiring a switch to a new LAI treatment because of lack of efficacy or persistent side effects from another LAI. Possible strategies for the switch to AOM are presented in this expert consensus paper in an attempt to provide guidance throughout the entire switching process.
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http://dx.doi.org/10.1517/14740338.2016.1155553DOI Listing
December 2016

Should psychiatry deal only with mental disorders without an identified medical aetiology?

World Psychiatry 2016 Feb;15(1):22-3

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

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http://dx.doi.org/10.1002/wps.20283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780294PMC
February 2016

Functional deterioration from the premorbid period to 2 years after the first episode of psychosis in early-onset psychosis.

Eur Child Adolesc Psychiatry 2015 Dec 1;24(12):1447-59. Epub 2015 Mar 1.

Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, IiSGM, School of Medicine, Universidad Complutense, CIBERSAM, Ibiza 43, 28009, Madrid, Spain.

The aim of the study was to analyze changes in functional adjustment from childhood to 2 years after the first episode of psychosis (FEP) in patients with early-onset schizophrenia spectrum disorders (SSD) and affective psychoses (AFP) and a good or intermediate level of premorbid adjustment. We followed 106 adolescents (aged 12-17 years) with FEP for 2 years after recruitment. Premorbid adjustment in childhood was assessed in 98 patients with the childhood subscale of the Cannon-Spoor Premorbid Adjustment Scale (c-PAS). Global functioning was assessed 2 years after the FEP with the Children's Global Assessment Scale (c-GAS) or the Global Assessment of Functioning scale (GAF), as appropriate. Functional deterioration was defined as a downward shift in the level of functional adjustment from childhood to 2 years after the FEP. In patients with good or intermediate premorbid adjustment, functional deterioration was observed in 28.2 % (26.5 % of the AFP group, 29.4 % of the SSD group). Longer duration of untreated psychosis (Beta = 0.01; P = 0.01) and higher symptom severity at the FEP, as measured with the Clinical Global Impression Scale (Beta = 1.12; P = 0.02), significantly predicted the presence of functional deterioration, accounting for 21.4 % of the variance. Irrespective of diagnosis (SSD or AFP), almost one-third of adolescents with FEP and good or intermediate premorbid adjustment showed functional deterioration from the premorbid period to 2 years after the FEP.
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http://dx.doi.org/10.1007/s00787-015-0693-5DOI Listing
December 2015

Progressive brain changes in children and adolescents with early-onset psychosis: A meta-analysis of longitudinal MRI studies.

Schizophr Res 2016 06 31;173(3):132-139. Epub 2014 Dec 31.

Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, CIBERSAM, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), School of Medicine, Universidad Complutense, Madrid, Spain. Electronic address:

Background: Studies on longitudinal brain volume changes in patients with early-onset psychosis (EOP) are particularly valuable for understanding the neurobiological basis of brain abnormalities associated with psychosis. However, findings have not been consistent across studies in this population. We aimed to conduct a meta-analysis on progressive brain volume changes in children and adolescents with EOP.

Methods: A systematic literature search of magnetic resonance imaging (MRI) studies comparing longitudinal brain volume changes in children and adolescents with EOP and healthy controls was conducted. The annualized rates of relative change in brain volume by region of interest (ROI) were used as raw data for the meta-analysis. The effect of age, sex, duration of illness, and specific diagnosis on volume change was also evaluated.

Results: Five original studies with 156 EOP patients (mean age at baseline MRI in the five studies ranged from 13.3 to 16.6years, 67.31% males) and 163 age- and sex-matched healthy controls, with a mean duration of follow-up of 2.46years (range 2.02-3.40), were included. Frontal gray matter (GM) was the only region in which significant differences in volume change over time were found between patients and controls (Hedges' g -0.435, 95% confidence interval (CI): -0.678 to -0.193, p<0.001). Younger age at baseline MRI was associated with greater loss of temporal GM volume over time in patients as compared with controls (p=0.005). Within patients, a diagnosis of schizophrenia was related to greater occipital GM volume loss over time (p=0.001).

Conclusions: Compared with healthy individuals, EOP patients show greater progressive frontal GM loss over the first few years after illness onset. Age at baseline MRI and diagnosis of schizophrenia appear to be significant moderators of particular specific brain volume changes.
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http://dx.doi.org/10.1016/j.schres.2014.12.022DOI Listing
June 2016

Predictors of outcome in early-onset psychosis: a systematic review.

NPJ Schizophr 2015 4;1:14005. Epub 2015 Mar 4.

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

Given the global burden of psychotic disorders, the identification of patients with early-onset psychosis (EOP; that is, onset before the age of 18) at higher risk of adverse outcome should be a priority. A systematic search of Pubmed, Embase, and PsycInfo (1980 through August 2014) was performed to identify longitudinal observational studies assessing correlates and/or predictors of clinical, functional, cognitive, and biological outcomes in EOP. Seventy-five studies were included in the review. Using multivariate models, the most replicated predictors of worse clinical, functional, cognitive, and biological outcomes in EOP were premorbid difficulties and symptom severity (especially of negative symptoms) at baseline. Longer duration of untreated psychosis (DUP) predicted worse clinical, functional, and cognitive outcomes. Higher risk of attempting suicide was predicted by greater severity of psychotic illness and of depressive symptoms at the first episode of psychosis. Age at onset and sex were not found to be relevant predictors of outcome in most multivariate models, whereas studies using bivariate analyses yielded inconsistent results. Lower intelligence quotient at baseline predicted lower insight at follow-up, worse functional outcomes, and a diagnostic outcome of schizophrenia. Biological predictors of outcome in EOP have been little studied and have not been replicated. Lower levels of antioxidants at baseline predicted greater brain volume changes and worse cognitive functioning at follow-up, whereas neuroimaging markers such as regional cortical thickness and gray matter volume at baseline predicted remission and better insight at follow-up, respectively. EOP patients with poorer premorbid adjustment and prominent negative symptoms at initial presentation are at risk of poor outcome. They should therefore be the target of careful monitoring and more intensive interventions to address whether the disease course can be modified in this especially severely affected group. Early intervention strategies to reduce DUP may also improve outcome in EOP.
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http://dx.doi.org/10.1038/npjschz.2014.5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849440PMC
June 2016

Pharmacogenetic study of second-generation antipsychotic long-term treatment metabolic side effects (the SLiM Study): rationale, objectives, design and sample description.

Rev Psiquiatr Salud Ment 2014 Oct-Dec;7(4):166-78. Epub 2014 Oct 19.

CIBER del área de Salud Mental (CIBERSAM), España; Servicio de Psiquiatría del Niño y del Adolescente, Departamento de Psiquiatría, Hospital General Universitario Gregorio Marañón, Facultad de Medicina, Universidad Complutense, IiSGM, Madrid, España.

Aim: Weight gain is an important and common side effect of second generation antipsychotics (SGAs). Furthermore, these drugs can induce other side effects associated with higher cardiovascular morbidity and mortality, such as insulin resistance, diabetes or metabolic syndrome. Preliminary studies show that inter-individual genetic differences produce varying degrees of vulnerability to the different SGA-induced side effects. The Second-generation antipsychotic Long-term treatment Metabolic side effects (SLiM) study aims to identify clinical, environmental and genetic factors that explain inter-individual differences in weight gain and metabolic changes in drug-naïve patients after six months of treatment with SGAs.

Materials And Methods: The SLIM study is a multicenter, observational, six-month pharmacogenetic study where a cohort of 307 drug-naïve paediatric and adult patients (age range 8.8-90.1 years) and a cohort of 150 age- and sex- matched healthy controls (7.8-73.2 years) were recruited.

Results: This paper describes the rationale, objectives and design of the study and provides a description of the sample at baseline.

Conclusions: Results from the SLiM study will provide a better understanding of the clinical, environmental, and genetic factors involved in weight gain and metabolic disturbances associated with SGA treatment.
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http://dx.doi.org/10.1016/j.rpsm.2014.05.004DOI Listing
October 2016

Second-generation antipsychotic use in children and adolescents: a six-month prospective cohort study in drug-naïve patients.

J Am Acad Child Adolesc Psychiatry 2014 Nov 2;53(11):1179-90,1190.e1-4. Epub 2014 Sep 2.

Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, and Centro de Investigación Biomédica En Red de Salud Mental (CIBERSAM), Madrid.

Objective: To assess weight and metabolic effects of 6 months of treatment with second-generation antipsychotics in naïve/quasi-naïve youths.

Method: This study looked at a nonrandomized, naturalistic, multicenter, inception cohort study of 279 patients aged 4 to 17 years (mean = 14.6 ± 2.9 years). Of those, 248 (88.8%) received a single antipsychotic (risperidone, olanzapine, or quetiapine) and completed 2 visits, and 178 (63.8%) completed the 6-month follow-up. Patients had schizophrenia-spectrum disorders (44.5%), mood-spectrum disorders (23.2%), disruptive behavioral disorders (17.3%), or other disorders (15.1%). Fifteen age- and gender-matched, healthy, nonmedicated individuals served as a comparison group.

Results: From baseline to 1 month, 3 months, and 6 months, all anthropometric measures increased significantly with each antipsychotic, that is, 6-month changes with risperidone (n = 157; 7.1 kg and 0.66 body mass index [BMI] z score), olanzapine (n = 44; 11.5 kg and 1.08 BMI z score), and quetiapine (n = 47; 6.3 kg and 0.54 BMI z score), but not in healthy control participants (-0.11 kg and 0.006 BMI z score). Fasting metabolic parameters increased significantly with risperidone (glucose [3.8] mg/dL, insulin [4.9] mU/L, homeostasis model assessment of insulin resistance [HOMA-IR: 1.2], triglycerides [15.6] mg/dL), and olanzapine (glucose [5.0] mg/dL, total cholesterol [21.2] mg/dL, and low-density lipoprotein cholesterol [44.6] mg/dL), but not with quetiapine or in healthy control participants. The percentage of research participants considered to be "at risk of adverse health outcome" increased during the 6 months from 8.9% to 29.2% for risperidone (p < .0001), 6.8% to 38.1% for olanzapine (p < .0001), and 6.3% to 4.0% for quetiapine (p = .91).

Conclusion: Olanzapine, quetiapine, and risperidone increase body weight but have different cardiometabolic side effect profiles and different temporal side effect patterns.
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http://dx.doi.org/10.1016/j.jaac.2014.08.009DOI Listing
November 2014

A longitudinal study on the relationship between duration of untreated psychosis and executive function in early-onset first-episode psychosis.

Schizophr Res 2014 Sep 15;158(1-3):126-33. Epub 2014 Jul 15.

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

Background: The relationship between duration of untreated psychosis (DUP) and executive function (EF) in patients with first-episode psychosis (FEP) is controversial. We aim to assess the influence of DUP on changes in EF over a 2-year period in subjects with early-onset FEP (first psychotic symptom before age 18) and less than 6 months of positive symptoms.

Methods: A total of 66 subjects were included in the study (19 females [28.8%], mean age 16.2 ± 1.6 years). The influence of DUP on changes in EF over the 2-year follow-up (expressed as a composite score of 5 cognitive abilities: attention, working memory, cognitive flexibility, response inhibition, and problem solving) was estimated using a multivariate linear regression model after removing the effect of intelligence quotient and controlling for age, gender, diagnosis, premorbid adjustment, severity of positive and negative symptoms at baseline, global functioning at baseline, and mean daily antipsychotic dosage during follow-up.

Results: Mean DUP was 65.0 ± 6.9 days (95% confidence interval [CI], 51.2, 78.8). Median DUP was 47.5 days (range 2-180 days). Negative symptoms at baseline was the only variable significantly associated with EF at baseline (10.9% of explained variance [e.v. 10.9%], p=0.007). Only shorter DUP (e.v. 8.7%, p=0.013) and greater severity of baseline negative symptoms (e.v. 10.0%, p=0.008) were significantly associated with greater improvement in EF.

Conclusions: In early-onset FEP, shorter DUP was associated with greater improvement in EF over a 2-year follow-up period.
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http://dx.doi.org/10.1016/j.schres.2014.06.038DOI Listing
September 2014

Differential neurodevelopmental trajectories in patients with early-onset bipolar and schizophrenia disorders.

Schizophr Bull 2014 Mar 26;40 Suppl 2:S138-46. Epub 2013 Dec 26.

*To whom correspondence should be addressed; Hospital General Universitario Gregorio Marañón, Ibiza 43, 28009 Madrid, Spain; tel: 34-914265006; fax: 34-91426004, e-mail:

Schizophrenia and bipolar disorders share not only clinical features but also some risk factors such as genetic markers and childhood adversity, while other risk factors such as urbanicity and obstetric complications seem to be specific to schizophrenia. An intriguing question is whether the well-established abnormal neurodevelopment present in many children and adolescents who eventually develop schizophrenia is also present in bipolar patients. The literature on adult bipolar patients is controversial. We report data on a subgroup of patients with pediatric-onset psychotic bipolar disorder who seem to share some developmental trajectories with patients with early-onset schizophrenia. These early-onset psychotic bipolar patients have low intelligence quotient, more neurological signs, reduced frontal gray matter at the time of their first psychotic episode, and greater brain changes than healthy controls in a pattern similar to early-onset schizophrenia cases. However, patients with early-onset schizophrenia seem to have more social impairment, developmental abnormalities (eg, language problems), and lower academic achievement in childhood than early-onset bipolar patients. We suggest that some of these abnormal developmental trajectories are more related to the phenotypic features (eg, early-onset psychotic symptoms) of these 2 syndromes than to categorically defined Diagnostic and Statistical Manual of Mental Disorders disorders.
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http://dx.doi.org/10.1093/schbul/sbt198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934406PMC
March 2014
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