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Data de publicació electrònica: 11-03-2023 There is evidence linking ADHD to a reduced life expectancy. The mortality rate in individuals with ADHD is twice that of the general population and it is associated with several factors, such as unhealthy lifestyle behaviors, social adversity, and mental health problems that may in turn increase mortality rates. Since ADHD and lifespan are heritable, we used data from genome-wide association studies (GWAS) of ADHD and parental lifespan, as proxy of individual lifespan, to estimate their genetic correlation, identify genetic loci jointly associated with both phenotypes and assess causality. We confirmed a negative genetic correlation between ADHD and parental lifespan (rg = −0.36, P = 1.41e−16). Nineteen independent loci were jointly associated with both ADHD and parental lifespan, with most of the alleles that increased the risk for ADHD being associated with shorter lifespan. Fifteen loci were novel for ADHD and two were already present in the original GWAS on parental lifespan. Mendelian randomization analyses pointed towards a negative causal effect of ADHD liability on lifespan (P = 1.54e−06; Beta = −0.07), although these results were not confirmed by all sensitivity analyses performed, and further evidence is required. The present study provides the first evidence of a common genetic background between ADHD and lifespan, which may play a role in the reported effect of ADHD on premature mortality risk. These results are consistent with previous epidemiological data describing reduced lifespan in mental disorders and support that ADHD is an important health condition that could negatively affect future life outcomes. This work was supported by the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, 2017SGR-00444 and 2017SGR-1461), the Instituto de Salud Carlos III (PI18/01788, P19/01224, PI20/00041, PI21/00612, PI22/00464, FI18/00285 to LVR and CP22/00128 to MSA), the Ministry of Science, Innovation and Universities (IJC2018-035346-I to MSA and RYC2021-031324-I to JCD); the European Regional Development Fund (ERDF), the European Union H2020 Programme (H2020/2014–2020) under grant agreements no. 728018 (Eat2beNICE), no. 848228 (DISCOvERIE) and no. 2020604 (TIMESPAN) and the ECNP Network ‘ADHD across the Lifespan’ and “la Marató de TV3” (202228-30 and 202228-31). SSR was supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; Grant Number T29KT0526 and T32IR5226), and NIH/NIDA DP1DA054394. AAP was supported by NIH grant P50DA037844 and R01AA029688 and Tobacco-Related Disease Research Program Grant number: 28IR-0070.

Objective To validate the Delirium Diagnostic Tool (DDT-Pro) in a SNF and compare its performance to the 4 A's Test (4AT) in real life conditions. Methods Prospective cross-sectional study of 262 consecutively admitted adults to a SNF, independently assessed by psychiatrists using DSM-5 delirium criteria and by geriatricians using the DDT-Pro (0–9 points) and 4AT (0–12 points). Results 141 (53.8%) participants had dementia and 79 (30.1%) had delirium. DDT-Pro and 4AT were moderately correlated (−0.59). Accuracies against DSM-5 diagnosis ranged from 80 to 85% and were comparable between tools regardless of dementia. Recommended delirium cutoff for the DDT-Pro (≤6) had 77.2% sensitivity, 84% specificity, and NPV = 89.5% and 4AT (≥4) had 54.4% sensitivity and 92.9% specificity, with lower specificity in the dementia subsample. DDT-Pro sensitivity increased (84.8%) at ≤7cutoff. Sensitivity and specificity of all DDT-Pro and 2/4 4AT items displayed gradients along severity levels, but two dichotomously rated 4AT items had low positivity. The tools had low concordance (p Conclusions DDT-Pro is valid to detect delirium in SNF population where simple, structured tools with high sensitivity are needed. DDT-Pro items assess the three core domains of delirium as a continuous measure and may have advantages over the 4AT.

[Background] Mitochondrial DNA (mtDNA) encodes 37 genes necessary for synthesizing 13 essential subunits of the oxidative phosphorylation system. mtDNA alterations are known to cause mitochondrial disease (MitD), a clinically heterogeneous group of disorders that often present with neuropsychiatric symptoms. Understanding the nature and frequency of mtDNA alterations in health and disease could be a cornerstone in disentangling the relationship between biochemical findings and clinical symptoms of brain disorders. This systematic review aimed to summarize the mtDNA alterations in human brain tissue reported to date that have implications for further research on the pathophysiological significance of mtDNA alterations in brain functioning., [Methods] We searched the PubMed and Embase databases using distinct terms related to postmortem human brain and mtDNA up to June 10, 2021. Reports were eligible if they were empirical studies analysing mtDNA in postmortem human brains., [Findings] A total of 158 of 637 studies fulfilled the inclusion criteria and were clustered into the following groups: MitD (48 entries), neurological diseases (NeuD, 55 entries), psychiatric diseases (PsyD, 15 entries), a miscellaneous group with controls and other clinical diseases (5 entries), ageing (20 entries), and technical issues (5 entries). Ten entries were ascribed to more than one group. Pathogenic single nucleotide variants (pSNVs), both homo- or heteroplasmic variants, have been widely reported in MitD, with heteroplasmy levels varying among brain regions; however, pSNVs are rarer in NeuD, PsyD and ageing. A lower mtDNA copy number (CN) in disease was described in most, but not all, of the identified studies. mtDNA deletions were identified in individuals in the four clinical categories and ageing. Notably, brain samples showed significantly more mtDNA deletions and at higher heteroplasmy percentages than blood samples, and several of the deletions present in the brain were not detected in the blood. Finally, mtDNA heteroplasmy, mtDNA CN and the deletion levels varied depending on the brain region studied., [Interpretation] mtDNA alterations are well known to affect human tissues, including the brain. In general, we found that studies of MitD, NeuD, PsyD, and ageing were highly variable in terms of the type of disease or ageing process investigated, number of screened individuals, studied brain regions and technology used. In NeuD and PsyD, no particular type of mtDNA alteration could be unequivocally assigned to any specific disease or diagnostic group. However, the presence of mtDNA deletions and mtDNA CN variation imply a role for mtDNA in NeuD and PsyD. Heteroplasmy levels and threshold effects, affected brain regions, and mitotic segregation patterns of mtDNA alterations may be involved in the complex inheritance of NeuD and PsyD and in the ageing process. Therefore, more information is needed regarding the type of mtDNA alteration, the affected brain regions, the heteroplasmy levels, and their relationship with clinical phenotypes and the ageing process., Hospital Universitari Institut Pere Mata; Institut d'Investigació Sanitària Pere Virgili; Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (PI18/00514).

This work was supported by the Spanish Ministry of Science and Innovation. Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI17/00997, PI19/01024, PI20/00721), co-financed by ERDF Funds from the European Commission, “A way of making Europe”, CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds. European Union Seventh Framework Program under grant agreements FP7-4-HEALTH-2009-2.2.1-2-241909 (Project EU-GEI), FP7- HEALTH-2013-2.2.1-2-603196 (Project PSYSCAN), and FP7- HEALTH-2013-2.2.1-2- 602478 (Project METSY); and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement No 115916, Project PRISM, and grant agreement No 777394, Project AIMS-2-TRIALS), Fundación Familia Alonso, Fundación Alicia Koplowitz, and Fundación Mutua Madrileña. We are grateful to Paloma Pantoja for her assistance in the design of the figures. A.A.-B. holds a Rio Hortega Grant from Instituto de Salud Carlos III (CM20/00114). C.M.D.-C. holds a Juan Rodés Grant from Instituto de Salud Carlos III (JR19/00024)., Andreu-Bernabeu, Á., Díaz-Caneja, C.M., Costas, J., De Hoyos, L., Stella, C., Gurriarán, X., Alloza, C., Fañanás, L., Bobes, J., González-Pinto, A., Crespo-Facorro, B., Martorell, L., Vilella, E., Muntané, G., Nacher, J., Molto, M.D., Aguilar, E.J., Parellada, M., Arango, C., González-Peñas, J.

Smoking prevalence in schizophrenia is considerably larger than in general population, playing an important role in early mortality. We compared the polygenic contribution to smoking in schizophrenic patients and controls to assess if genetic factors may explain the different prevalence. Polygenic risk scores (PRSs) for smoking initiation and four genetically correlated traits were calculated in 1108 schizophrenic patients (64.4% smokers) and 1584 controls (31.1% smokers). PRSs for smoking initiation, educational attainment, body mass index and age at first birth were associated with smoking in patients and controls, explaining a similar percentage of variance in both groups. Attention-deficit hyperactivity disorder (ADHD) PRS was associated with smoking only in schizophrenia. This association remained significant after adjustment by psychiatric cross-disorder PRS. A PRS combining all the traits was more explanative than smoking initiation PRS alone, indicating that genetic susceptibility to the other traits plays an additional role in smoking behaviour. Smoking initiation PRS was also associated with schizophrenia in the whole sample, but the significance was lost after adjustment for smoking status. This same pattern was observed in the analysis of specific SNPs at the CHRNA5-CHRNA3-CHRNB4 cluster associated with both traits. Overall, the results indicate that the same genetic factors are involved in smoking susceptibility in schizophrenia and in general population and are compatible with smoking acting, directly or indirectly, as a risk factor for schizophrenia that contributes to the high prevalence of smoking in these patients. The contrasting results for ADHD PRS may be related to higher ADHD symptomatology in schizophrenic patients.

[Background] Discoidin domain receptor tyrosine kinase 1 (DDR1) is present in multiple types of epithelial cells and is highly expressed in the nervous system. Previous studies have revealed that DDR1 is involved in schizophrenia (SCZ). Although the expression of DDR1 in oligodendrocytes has been described, its role in brain myelination is not well understood. In this study, we aimed to explore the coexpression network of DDR1 in the human brain and to compare the list of DDR1 coexpressing genes with the list of genes containing single nucleotide polymorphisms (SNPs) that are associated with SCZ., [Materials and Methods] We used a weighted gene coexpression network analysis (WGCNA) of a dataset from four brain areas (the dorsolateral prefrontal cortex, primary motor cortex, hippocampus, and striatum) and from four different intervals (I) of life (I-1 = 10–38 weeks postconception, I-2 ≥0 to < 6 years, I-3 ≥ 6 to < 40 years, and I-4 ≥ 40 years of age). We compared the list of genes that are associated with SCZ in the GWAS Catalog with the list of genes coexpressing with DDR1 in each interval., [Results] Our study revealed that DDR1 was coexpressed with oligodendrocyte-related genes mainly in I-2 (adjP = 5.66e-24) and I-3 (adjP = 2.8e-114), which coincided with the coexpression of DDR1 with myelination-related genes (adjP = 9.04e-03 and 2.51e-08, respectively). DDR1 was also coexpressed with astrocyte-related genes in I-1 (adjP = 1.11e-71), I-2 (adjP = 2.12e-20) and I-4 (adjP = 9.93e-52) and with type 2 microglia-related genes in I-1 (adjP = 2.84e-08), I-2 (adjP = 5.68e-16) and I-4 (adjP = 3.66e-10). Moreover, we observed significant enrichment of SCZ susceptibility genes within the coexpression modules containing DDR1 in I-1 and I-4 (P = 1e-04 and 0.0037, respectively), during which the DDR1 module showed the highest association with the astrocytes., [Conclusions] Our study confirmed that DDR1 is coexpressed with oligodendrocyte- and myelin-related genes in the human brain but suggests that DDR1 may contribute mainly to SCZ risk through its role in other glial cell types, such as astrocytes., This work was supported by funds from the Catalan Agency of Research and Universities, AGAUR (2017SGR-00444 to EV and 2017SGR-00880 to AN), the Spanish Instituto de Salud Carlos III (predoctoral fellowship, FI19/00268, to SA) and Universitat Rovira i Virgili (2021OPEN Call).

AIM In the current cross-sectional study, we aimed to explore whether thyroid function or thyroid autoimmunity are associated with psychopathological symptoms and social functioning in patients with early psychosis. We hypothesized that psychopathological severity is greater in those patients with positive thyroid autoimmunity. METHODS We studied 70 outpatients with early psychosis (

Objectives: Previous studies suggest that childhood trauma, stressful life events, and cannabis use are associated with psychosis. We aimed to explore whether these environmental factors have an effect on hypothalamic–pituitary–adrenal (HPA) axis indices in recent-onset psychosis. Methods: We studied 56 recent-onset psychosis outpatients and 47 healthy controls. Childhood trauma was assessed with the Childhood Trauma Questionnaire. Stressful life events were assessed with the Holmes-Rahe Social Readjustment Scale. Cannabis use was assessed by semistructured interviews. Several HPA axis measures were analysed in saliva: cortisol awakening response (CAR), diurnal cortisol slope, and dexamethasone suppression test ratio (DSTR) after 0.25 mg of dexamethasone. Multiple linear regression analyses were conducted to explore the contribution of environmental factors to each HPA axis measure while adjusting for covariates (diagnosis, age, gender, smoking, body mass index and treatments). Results: There were no significant differences in HPA axis measures between diagnostic groups. Cannabis use was associated with a more flattened diurnal cortisol slope (standardized β = 0.21, p = 0.038), independent of recent-onset psychosis diagnosis. No associations were found between environmental factors and other HPA axis measures (CAR, DSTR). Conclusions: Our study provides evidence for the effect of cannabis exposure in cortisol secretion patterns in both healthy controls and recent-onset psychosis patients.

Objective Mild cognitive impairment (MCI) and dementia (DEM) are prevalent in skilled nursing facilities (SNFs), confounding delirium detection. We report characteristics of delirium in an SNF to ascertain distinguishing features for delirium diagnosis, despite challenges of comorbidity with MCI and DEM. Methods Cross-sectional study of 200 consecutive patients from an SNF in Catalunya, Spain, assessed within the first 24 to 48 admission hours by independent experts with Spanish-Informant Questionnaire on Cognitive Decline in the Elderly (for MCI-DEM), Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) delirium criteria, and Delirium Rating Scale Revised-98 (DRS-R98) for delirium phenomenology. Delirium characteristics were modeled in successive steps, according to the presence of delirium and MCI-DEM, with analysis of variance (ANOVA), receiver operator characteristic analyses, and conditional logistic regression. Results The final model produced symptoms that represented each of the three delirium core domains (ie, cognitive, higher order thinking, and circadian). The DRS-R98 items rated these symptoms as moderate-severe attention/vigilance, mild-severe language, and moderate-severe sleep-wake cycle alterations. The delirium discriminant accuracy of the three symptoms together was high: 84.6% in the MCI-DEM group to 92.8% in the No MCI-DEM group. Conclusions Impairments of attention, language, and sleep-wake cycle indicate delirium in SNF patients regardless of the underlying MCI-DEM status. Because delirium is underdetected in SNFs, where nursing staff/patient ratios are low, brief simple tools that measure these symptoms could potentially enhance delirium detection.

Metacognitive training (MCT) improves cognitive biases in psychosis. We aimed to explore whether the effectiveness of the combination of psychoeducation and MCT group treatments on cognitive biases differed if the combination was started by psychoeducation or by MCT. Fourty-nine stable patients with a recent-onset psychosis were randomized to two different sequences: MCT + psychoeducation vs psychoeducation + MCT. Cognitive biases, psychopathology symptoms, insight and functioning were assessed. Cognitive biases and depressive symptoms improved with both group interventions, without differential effects between both sequences. Our study suggests that MCT and psychoeducation are useful in improving cognitive biases and depressive symptoms in recent-onset psychosis.

Internationally, there was a warning of the risk of increased domestic violence during lockdown due to the COVID-19 pandemic, including child-to-parent violence. The objective of our study was to assess the prevalence of different violent behaviors from children to parents during pre-lockdown, lockdown and immediately after, between March 14 and June 20, 2020, and to assess differences in behaviors between pre-lockdown and lockdown and between pre-lockdown and post-lockdown.The researchers developed a survey with closed questions about different violent behaviors of the children (poor responses, insults and physical aggression). This was distributed with the CAWI methodology during the months of August and September 2020 to a sample of Spanish parents stratified by autonomous communities. 1,500 families with 1,927 adolescents aged 12 to 18 years participated. The frequency of responses obtained between the pre-lockdown and lockdown and between pre-lockdown and post-lockdown was compared through the Mac Nemar test for comparison of related samples.The prevalences of poor responses, insults and aggressions in a pre-lockdown setting were 30.1%, 3.8% and 0.6%, respectively. Poor responses and insults increased significantly between pre-lockdown and lockdown (p0.001) and between pre-lockdown and post-lockdown (p0.001) in all autonomous communities, age groups, genders, occupation type of the adolescent and type of household. No statistically significant differences were found in physical aggression for the periods evaluated. Single-parent families, adolescents residing in subsidized housing and those without an occupation or education ("NEET") exhibited more violent behavior in the three periods.Lockdown led to an increase in nonphysical violent behaviors, which were maintained to the end, warning of the potentially persistent risks of lockdown in this age group, especially in vulnerable families.A nivel internacional se alertó de riesgo de aumento de violencia doméstica, durante el confinamiento debido a la pandemia por COVID-19, incluyendo violencia filioparental. El objetivo de nuestro estudio fue valorar la prevalencia de diferentes conductas violentas de hijos adolescentes a padres en los periodos pre-confinamiento, confinamiento e inmediatamente después del confinamiento producido entre el 14 de marzo y el 20 de junio de 2020, y valorar diferencias en las conductas entre pre y confinamiento, y entre pre y post-confinamiento.Los investigadores elaboraron una encuesta con preguntas cerradas acerca de diferentes conductas violentas (malas respuestas, insultos y agresión física) de los hijos. Esta fue distribuida con metodología CAWI durante los meses de agosto y septiembre de 2020 a una muestra de padres españoles estratificada por comunidades autónomas. Participaron 1.500 familias con 1.927 hijos entre 14 y 18 años. Se comparó la frecuencia de respuestas obtenidas entre el momento pre-confinamiento y durante el confinamiento, y entre pre y post confinamiento, a través de la prueba de Mc Nemar para comparación de muestras relacionadas.Las prevalencias encontradas de malas respuestas, insultos y agresiones en situación previa al confinamiento fueron del 30,1%, 3,8% y 0,6% respectivamente. Las malas respuestas e insultos aumentaron de forma altamente significativa entre el pre y el confinamiento (p0,001), y entre el pre y post-confinamiento (p0,001), en todas las comunidades autónomas, franjas de edad, sexo, tipo de ocupación del adolescente y tipo de vivienda. No se hallaron diferencias estadísticamente significativas en las agresiones físicas en los periodos evaluados. Las familias monoparentales, los adolescentes residentes en viviendas cedidas y aquellos sin ocupación ni estudios (“ninis”) presentaban valores porcentualmente más elevados de conductas violentas en los tres periodos.El confinamiento supuso un incremento de conductas violentas no físicas, que se mantuvieron al cesar el mismo, alertando de los riesgos del confinamiento en esta franja de edad, potencialmente persistente, en especial en familias vulnerables.

Cognitive impairment has been associated with both childhood adversity and abnormalities of hypothalamic-pituitary-adrenal (HPA) axis function. An interaction exists between the functional polymorphism rs1360780 in the FKBP5 gene and childhood maltreatment, influencing a variety of clinical outcomes. Our goal was to study the relationship between different types of childhood trauma, HPA axis functionality, rs1360780 genotype and cognitive function in 198 healthy individuals who participated in the study. We obtained clinical data, childhood maltreatment scores and neurocognitive performance by clinical assessment; HPA negative feedback was analysed using the dexamethasone suppression test ratio (DSTR) after administration of 0.25 mg of dexamethasone; and the FKBP5 rs1360780 polymorphism was genotyped in DNA obtained from blood samples. The results showed a significant influence of physical neglect on measures of neurocognition as well as an interaction between the DSTR and physical and emotional neglect. Regarding social cognition, a significant association was found with sexual and physical abuse as well as with rs1360780 risk-allele carrier status. Moreover, an interaction between the rs1360780 genotype and the presence of physical abuse was significantly associated with social cognition results. Our results suggest a specific impact of different kinds of childhood maltreatment on measures of neurocognition and social cognition, which might be influenced by HPA axis reactivity and genetic variants in HPA axis-related genes such as FKBP5. Disentangling the relationship between these elements and their influence on cognitive performance might help identify susceptible individuals with higher stress vulnerability and develop preventive interventions.

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap—pleiotropy—between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder., This work was supported by Ministerio de Ciencia e Innovación, Spain, the Agencia Estatal de Investigación (AEI) and the Fondo Europeo de Desarrollo Regional (FEDER) with project grants BFU2016-77961-P and PGC2018-101927-B-I00 to EB and AN, respectively, by the Spanish National Institute of Bioinformatics (PT17/0009/0020 to AN), the Direcció General de Recerca, the Generalitat de Catalunya (2017SGR444 to EV, 2017SGR702 to EB and 2017SGR880 to AN) and the “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000792-M).

In spite of extensive work, inconsistent findings and lack of specificity in most neuroimaging techniques used to examine age- and gender-related patterns in brain tissue microstructure indicate the need for additional research. Here, we performed the largest Multi-component T

Aim Quality of life (QoL) has been widely studied in people with schizophrenia. In the early phases of psychosis, it remains often impaired even after the remission of psychotic symptoms. The aim of this study was to explore QoL and social functioning during the first year after a first-episode psychosis (FEP), and to study potential moderating effects of stress measures. Methods Here, 61 FEP subjects and 55 healthy controls (HCs) were included. Sociodemographic data and clinical variables were collected through a semi-structured interview. Stress measures, social functioning and QoL were assessed with the Holmes-Rahe Social Readjustment Rating Scale, the Perceived Stress Scale, the Social Adaptation Self-Scale and the Euro-QoL-5D, respectively. Analysis of variance was employed with repeated measures and a mediation analysis at baseline and at 1-year follow-up was carried out. Results Patients reported lower QoL, poorer social functioning and more stress than HC. FEP patients significantly improved in QoL and stress measures over time, but not in social functioning. Perceived stress mediated the association between poorer social functioning and lower QoL. Conclusions Social functioning at baseline may determine QoL over a 1-year follow-up period. Despite the improvement in most measures, patients do not achieve the level of well-being as the healthy group.

Background:Borderline personality disorder (BPD) usually begins in adolescence and manifests itself in adult life. Early intervention can improve the prognosis or reduce its severity. Nevertheless, there are currently few studies of adolescent patients with severe emotion instability and borderline personality traits.Aims:To evaluate the effectiveness of the Systems Training for Emotional Predictability and Problem Solving (STEPPS) programme in a sample of 21 adolescents (aged 13–17 years) in the Child and Adolescents Mental Health Center of Tarragona in Spain.Method:We evaluated BPD traits using the Diagnostic Interview for Borderline Disorder-Revised (DIB-R) and the Global Clinical Impression Scale of Illness Severity for TLP (CGI-TLP). We compared pre- and post-treatment scores for the DIB-R, CGI-GI scale, general psychopathology using the Personality Inventory for Adolescents (PAI-A) and impulsivity with the Barratt Impulsivity Scale (BIS-11). The therapeutic objectives were evaluated with the Borderline Estimate Severity over Time (BEST) scale.Results:There was a statistically significant improvement in the scores for the affective area and in the total score of the DIB-R, a decrease in the percentage of patients who failed to meet criteria for BPD, and an improvement (although not statistically significant) in the scores of the BEST scale throughout the treatment. The results of the CGI-GI scale showed global improvement in almost 72% of patients.Conclusion:Our study suggests that STEPPS can be an effective treatment to improve BPD symptoms and is very useful in community settings with limited resources in which efficient treatment alternatives must be sought. However, this conclusion must be interpreted with caution, as there is no comparison control group.

Objective:It has been hypothesised that neuropsychiatric symptoms, including psychosis, can be the result of a milder brain bioenergetic defect produced by mitochondrial dysfunction; however, mitochondrial dysfunction can be present in other organs or systems. The aim of the study was to investigate whether clinical conditions associated with mitochondrial disorders (CAMDs) were frequently present in schizophrenia.Methods:A previously used questionnaire regarding the CAMDs was administered to patients and controls in a direct interview with a trained psychiatrist. The frequencies of CAMDs in 164 patients with schizophrenia were compared to those in 156 age- and sex-matched controls.Results:Severe fatigue, seizures, constipation and diabetes were significantly more frequent in patients with schizophrenia than in control subjects and apparently not related to pharmacological treatment.Conclusion:The results of the present study suggest that multi-systemic mitochondrial dysfunction may be an underlying mechanism involved in schizophrenia.

The relationship between childhood attention-deficit/hyperactivity disorder (c-ADHD) and psychosis has been understudied. Cognitive dysfunction is a core feature of both disorders, but no previous study has investigated whether first-episode psychosis (FEP) with c-ADHD (FEP-ADHD+) presents a different cognitive profile than FEP without c-ADHD (FEP-ADHD−). One hundred and thirty-three FEP outpatients were screened for c-ADHD through a diagnostic interview and underwent a comprehensive clinical and cognitive assessment with the MATRICS Consensus Cognitive Battery (MCCB). Cognitive differences among FEP groups, and a group of 65 healthy controls (HCs) were analysed by multivariate analysis of covariance. Nearly 25% of FEP fulfilled criteria for c-ADHD. Both FEP groups performed worse than HCs in speed processing, executive function and social cognition, but only the FEP-ADHD+group was significantly more impaired than the HC group in attention (F = 4.35; p = 0.04). Only the Trail Making Test A (TMT-A) (F = 6.99; p = 0.01) within the domain of processing speed and the Neuropsychological Assessment Battery (NAB) (F = 6.46; p = 0.01) within the domain of executive function reliably differentiated the two clinical groups. The FEP groups did not differ in the severity of psychopathology, but the FEP-ADHD+reported fewer years of education than the FEP-ADHD− and were more likely to use tobacco and cannabis and to require higher doses of antipsychotics to achieve a clinical response. In conclusion, we found a gradient of severity in cognitive performance between groups, with FEP-ADHD+ having the greatest cognitive impairment. Our results suggest that FEP-ADHD+ represents a subgroup with a worse prognosis than FEP-ADHD−.

Altres ajuts: This study was supported in part by grants from the European Regional Development Fund (ERDF) "A way to build Europe", the Fundació La Marató de TV3 (092230/092231), CIBERSAM. Samples from patients included in this study were processed and preserved by the Biobank IISPV and the Biobank HUB-ICO-IDIBELL, integrated in the Spanish National Biobanks Network (PT17/0015/0024) and Xarxa Banc de Tumors. The funders had no role in the study design,data collection and analysis, decision to publish, or preparation of the manuscript. Sleep plays a crucial role in cognitive processes. Sleep and wake memory consolidation seem to be regulated by glucocorticoids, pointing out the potential role of the hypothalamic-pituitary-adrenal (HPA) axis in the relationship between sleep quality and cognitive abilities. Trait anxiety is another factor that is likely to moderate the relationship between sleep and cognition, because poorer sleep quality and subtle HPA axis abnormalities have been reported in people with high trait anxiety. The current study aimed to explore whether HPA axis activity or trait anxiety moderate the relationship between sleep quality and cognitive abilities in healthy individuals. We studied 203 healthy individuals. We measured verbal and visual memory, working memory, processing speed, attention and executive function. Sleep quality was assessed with the Pittsburgh Sleep Quality Index. Trait anxiety was assessed with the State-Trait Anxiety Inventory. HPA axis measures included the cortisol awakening response (CAR), diurnal cortisol slope and cortisol levels during the day. Multiple linear regression analyses explored the relationship between sleep quality and cognition and tested potential moderating effects by HPA axis measures and trait anxiety. Poor sleep quality was associated with poorer performance in memory, processing speed and executive function tasks. In people with poorer sleep quality, a blunted CAR was associated with poorer verbal and visual memory and executive functions, and higher cortisol levels during the day were associated with poorer processing speed. Trait anxiety was a moderator of visual memory and executive functioning. These results suggest that subtle abnormalities in the HPA axis and higher trait anxiety contribute to the relationship between lower sleep quality and poorer cognitive functioning in healthy individuals.

Background: Mitochondrial dysfunction and an elevation of lactate are observed in patients with schizophrenia (SZ). However, it is unknown whether mitochondrial dysfunction is associated with the presence of mitochondrial DNA (mtDNA) alterations and comorbid clinical conditions. We aimed to identify systemic mitochondrial abnormalities in blood samples of patients with SZ that may have a high impact on the brain due to its high bioenergetic requirements. Methods: Case/control study between 57 patients with SZ and 33 healthy controls (HCs). We measured lactate levels at baseline, during 15 min of exercise (at 5, 10 and 15 min) and at rest. We also evaluated the presence of clinical conditions associated with mitochondrial disorders (CAMDs), measured the neutrophil to lymphocyte ratio (NLR, a subclinical inflammatory marker), and analyzed mtDNA variation and copy number. Results: Linear models adjusting for covariates showed that patients with SZ exhibited higher elevation of lactate than HCs during exercise but not at baseline or at rest. In accordance, patients showed higher number of CAMDs and lower mtDNA copy number. Interestingly, CAMDs correlated with both lactate levels and mtDNA copy number, which in turn correlated with the NLR. Finally, we identified 13 putative pathogenic variants in the mtDNA of 11 participants with SZ not present in HCs, together with a lactate elevation during exercise that was significantly higher in these 11 carriers than in the noncarriers. Conclusions: These results are consistent with systemic mitochondrial malfunctioning in SZ and pinpoint lactate metabolism and mtDNA as targets for potential therapeutic treatments., This work was supported by the Instituto de Salud Carlos III of the Spanish Ministry of Science and Innovation in Spain (grant numbers PS09/01052, PI12/01885, PI18/00514 and FEDER to L.M.). HT was the recipient of an FI-DGR, and GM was the recipient of a BP-DGR scholarship; both are from the Generalitat de Catalunya.

Suicidability has been associated with neuroticism and psychoticism, but its role during perinatal period has not been analyzed. We explore the association between personality dimensions, depressive symptoms, and other psychosocial variables in postpartum suicidal ideation. A cohort of 1795 healthy Spanish women from the general population was assessed for suicidal ideation (EPDS-Item10) in early postpartum, 8 and 32 weeks postpartum. Sociodemographic, obstetric, and reproductive variables, psychiatric history, social support, stressful life-events during pregnancy, depressive symptoms (EPDS), and the Eysenck's personality dimensions (EPQ-RS) were also assessed at baseline. A major depressive episode (DSM-IV) was confirmed in women with EPDS>10 at follow-up assessments. Descriptive, bivariate, and multivariate analyses were conducted. Adjusted logistic regression analysis was reported as odds ratio (ORs) with 95% confidence intervals (CIs). Seven percent of mothers reported suicidal ideation during the first 8 months postpartum. Sixty-two percent of women with suicidal ideation had a major depressive episode at 8 weeks, and 70% at 32 weeks postpartum. Neuroticism and psychoticism predicted suicidal ideation throughout the first 2 weeks after delivery (OR, 1.03; 95%CI 1.01-1.06; and OR, 1.03; 95%CI 1.01-1.05 respectively). Early postpartum depressive symptoms (OR 1.2; 95%CI 1.11-1.26), personal psychiatric history (OR 2.1; 95%CI 1.33-3.27), and stressful life events during pregnancy (OR 1.88; 95%CI 1.12-3.16) also emerged as predictors of postpartum suicidal ideation. Analysis of women for postpartum suicidal ideation should include not only psychiatric symptoms but also psychosocial assessment (i.e., covering psychiatric history, stressful events, or long-standing personality vulnerabilities) in order to identify those in need of early psychosocial or psychiatric care.

A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs—including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1—providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services. Electronic supplementary material The online version of this article (10.1007/s10519-018-9902-6) contains supplementary material, which is available to authorized users.

Introduction Schizotypy has been proposed to be the expression of genetic vulnerability to schizophrenia. The available literature shows cognitive similarities between schizotypy and schizophrenia, with mildly impaired performance being associated with schizotypy. This study aims to determine the relationship between schizotypy and cognitive performance in siblings of patients with psychosis. Methods Schizotypal features and cognitive performance on a neuropsychological battery were compared between 48 siblings of patients with psychosis and 44 healthy controls. The relationships between schizotypy and cognitive performance were analysed by controlling the condition of being a sibling. Results Siblings showed poorer performance on vigilance/sustained attention (M = 37.6; SD = 7.1) and selective attention/interference control/working memory (M = 23.28; SD = 2.7) tasks. The variance in vigilance/sustained attention performance was explained, at 30%, by the interpersonal factor of schizotypy on the suspiciousness dimension and the condition of being a sibling. Conclusions Interpersonal features of schizotypy in siblings of patients with psychosis are associated with deficits in vigilance/sustained attention performance.

There is a scarcity of studies investigating the effect of sex on the clinical and treatment characteristics of first-admitted patients with first-episode psychosis (FEP). The reasons for using cannabis and the effect of cannabis on clinical features have not received enough attention either. We aim therefore, to investigate sex differences in the reasons for cannabis use and to determine the effects of sex, cannabis use and their interaction on clinical variables at admission and at discharge from the inpatient unit. 204 first-admitted FEPs in two inpatient units in Spain were included. The reasons for using cannabis were determined using the Dixon questionnaire. Clinical variables were compared between sexes and between cannabis users and non-users. Cannabis use was more frequent in males, but females were more likely to smoke cannabis to “feel relaxed”. There was a main effect of sex on positive psychotic symptoms and antipsychotics dose and an interaction effect of cannabis and sex on global functioning at discharge .Our findings show sex differences in the reasons for cannabis use and in some clinical and treatment characteristics among FEP patients. More studies focusing on gender perspectives are needed to develop more individualized treatments.

[Background] Studies evaluating leptin levels in patients with first-episode psychoses (FEP) have been inconclusive, and apparently, the high levels of leptin reported in patients with schizophrenia may be associated with weight gain. The aim of this study was to evaluate leptin levels at the early stages of the disease and the relationship between leptin and lifestyle habits, stress-related variables and metabolic parameters., [Methods] In total, 14 at-risk mental state (ARMS) patients, 39 FEP patients, 32 psychotic patients in the critical period (CP) and 21 healthy controls (HCs) were assessed. Anthropometric and biochemical parameters, as well as dietary intake, physical activity, stress-related variables and symptomatology, were collected., [Results] Leptin levels were higher in the ARMS, FEP and CP patients than in the HCs. After controlling for age, sex, BMI, physical exercise, tobacco use and dietary intake, the highest differences in leptin levels were observed between the ARMS patients and HCs (p = 0.025). In the whole sample, leptin levels were positively correlated with BMI (p < 0.001), waist circumference (p < 0.001), insulin levels (p = 0.020), levels of the inflammatory marker IL-6 (p = 0.007) and energy intake (p = 0.043) and negatively correlated with HDL cholesterol (p = 0.018). Interestingly, energy intake and food craving scores were positively correlated with levels of leptin only in females (p = 0.022 and p = 0.036, respectively)., [Discussion] The present study detected increased leptin levels in the early stages of psychosis and significant correlations between leptin levels and anthropometric, lipid, hormone, and cytokine parameters. We found higher leptin levels in women, and we identified dietary intake habits associated with leptin exclusively in females that advocate considering sex in future studies., Funding for this study was provided by Fundació la Marató de TV3 (grants numbers 092230, 092231) and from the Instituto de Salud Carlos III (grant number PI10/01607). GM was the recipient of a BP-DGR scholarship from the Generalitat de Catalunya. LO and JL have received a personal grant to support their research activity (SLT002/16/0125 and SLT006/17/00012, respectively). The Health Department of the Generalitat de Catalunya also supported this study.

Background Previous studies have shown associations between obsessive-compulsive disorder (OCD) and hypothalamic-pituitary-adrenal axis activity (HPA). We aimed to investigate the association between obsessive-compulsive (OC) symptoms and HPA axis functionality in a non-clinical sample and to explore whether there are sex differences in this relationship. Methods One hundred eighty-three healthy individuals without any psychiatric diagnosis (80 men, 103 women; mean age 41.3 ± 17.9 years) were recruited from the general population. The Obsessive-Compulsive Inventory Revised (OCI-R) was used to assess OC symptoms. State-trait anxiety, perceived stress, and stressful life events were also assessed. Saliva cortisol levels were determined at 6 time points (awakening, 30 and 60 min post-awakening, 10:00 a.m., 23:00 p.m. and 10:00 a.m. the following day of 0.25 mg dexamethasone intake [that occurred at 23:00 p.m.]). Three HPA axis measures were calculated: cortisol awakening response (CAR), cortisol diurnal slope, and cortisol suppression ratio after dexamethasone (DSTR). Multiple linear regression analyses were used to explore the association between OC symptoms and HPA axis measures while adjusting for covariates. Our main analyses were focused on OCI-R total score, but we also explored associations with specific OC symptom dimensions. Results No significant differences were observed between males and females in OC symptoms, anxiety measures, stress, or cortisol measures. In the multiple linear regression analyses between overall OC symptoms and HPA axis measures, a female sex by OC symptoms significant interaction (standardized beta = − 0.322; p = 0.023) for the CAR (but not cortisol diurnal slope nor DSTR) was found. Regarding specific symptom dimensions, two other sex interactions were found: a blunted CAR was associated with obsessing symptoms in women, whereas a more flattened diurnal cortisol slope was associated with ordering symptoms in men. Conclusions There are sex differences in the association between OC symptoms and HPA axis measures in healthy individuals.

Ascertaining the clinical consequences of BRCA1 and BRCA2 variants of uncertain significance (VUS) is currently indispensable for providing effective genetic counseling and preventive actions for families with hereditary breast and ovarian cancer (HBOC). To this end, we conducted a combination of in silico prediction and cDNA splicing analyses of 13 BRCA1 and 10 BRCA2 VUS identified in our cohort as well as a case-control analysis in a population-based sample of 10 recurrent VUS. We observed consistent results between the in silico predictions and sequencing analyses for all analyzed VUS. An abnormal cDNA pattern was observed for variants c.212+1G>A and c.5278-1G>A in BRCA1 and c.516+2T>A and c.8168A>G in BRCA2 according to in silico splicing prediction. A case-control study of VUS confirmed the polymorphisms of the c.67+62A>G, c.7008-62A>G and c.8851G>A BRCA2 variants previously published. c.4068G>A in the BRCA2 gene can also be considered a polymorphism due to its occurrence at a frequency greater than 1% in our population. Our study shows that employing population-based analysis and a combination of several in silico methods yields highly accurate information, resulting in a reliable tool for selecting variants for cDNA sequencing analysis in routine cancer genetic counseling units.

The results of previous cross-sectional studies suggest that free thyroxine (FT4) levels are associated with cognitive abilities (particularly attention/vigilance) during the early stages of psychosis. We aimed to explore whether hypothalamic-pituitary-thyroid hormones predict cognitive changes in a 1-year longitudinal study following first episodes of psychosis (FEP). We studied 36 FEP patients and a control group of 50 healthy subjects (HS). Plasma levels of thyroid-stimulating hormone (TSH) and FT4 were measured. Cognitive assessment was performed with the MATRICS Cognitive Consensus Cognitive Battery (MCCB). FEP patients were assessed twice (baseline and after 1year), whereas HS were assessed only once. We compared cognitive changes at 1year between three groups based on baseline FT4 levels: 1) lowest quartile (Q1, FT41.16ng/dL); 2) medium quartiles (Q2-Q3, FT4 1.16-1.54ng/dL); and 3) highest quartile (Q4, FT41.54ng/dL). No differences in TSH or FT4 levels were found between HS and FEP patients. All participants had FT4 levels within the normal range. HS outperformed FEP patients in all cognitive tasks. In relation to the relationship between FT4 levels and cognitive changes, a U-shaped pattern was observed: FEP patients from the middle quartiles (Q2-Q3) improved in attention/vigilance, whereas both extreme quartiles (Q1 and Q4) showed a worsening in this cognitive domain over time. Patients with lower FT4 (Q1) showed poorer baseline attention; therefore, lower baseline FT4 levels predicted a poorer prognosis in terms of attention performance. Our study suggests that baseline FT4 levels are associated with changes in attention and vigilance performance over one year in FEP patients.

DDR1 has been linked to schizophrenia (SZ) and myelination. Here, we tested whether DDR1 variants in people at risk for SZ influence white matter (WM) structural variations and cognitive processing speed (PS). First, following a case-control design (Study 1), SZ patients (N = 1193) and controls (N = 1839) were genotyped for rs1264323 and rs2267641 at DDR1, and the frequencies were compared. We replicated the association between DDR1 and SZ (rs1264323, adjusted P = 0.015). Carriers of the rs1264323AA combined with the rs2267641AC or CC genotype are at risk to develop SZ compared to the other genotype combinations. Second, SZ patients (Study 2, N = 194) underwent an evaluation of PS using the Trail Making Test (TMT) and DDR1 genotyping. To compare PS between DDR1 genotype groups, we conducted an analysis of covariance (including rs1264323 as a covariate) and found that SZ patients with the rs2267641CC genotype had decreased PS compared to patients with the AA and AC genotypes. Third, 54 patients (Study 3) from Study 2 were selected based on rs1264323 genotype to undergo reevaluation, including a DTI-MRI brain scan. To test for associations between PS, WM microstructure and DDR1 genotype, we first localized those WM regions where fractional anisotropy (FA) was correlated with PS and tested whether FA showed differences between the rs1264323 genotypes. SZ patients with the rs1264323AA genotype showed decreased FA in WM regions associated with decreased PS. We conclude that DDR1 variants may confer a risk of SZ through WM microstructural alterations leading to cognitive dysfunction.

Postpartum depression (PPD) is a common mood disorder that occurs after delivery with a prevalence of approximately 10%. Recent reports have related placental corticotropin-releasing hormone (pCRH) to postpartum depressive symptoms. The aim of this study was to determine whether pCRH, ACTH, and cortisol (measured 48 h after delivery) and glucocorticoid and mineralocorticoid receptor genotypes (NR3C1 and NR3C2) and their interaction are associated with PPD. A longitudinal 32-week prospective study of five hundred twenty-five Caucasian depression-free women that were recruited from obstetric units at two Spanish general hospitals immediately after delivery. Of the women included in the sample, forty-two (8%) developed PPD. A strong association between PPD and the interaction between the pCRH and NR3C2 rs2070951 genotype was observed. The mean level of pCRH in rs2070951GG carriers with PPD was 56% higher than the mean in the CG and CC genotype groups (P

Aim Quality of life (QoL) and social functioning have emerged as good predictors of the outcome of psychotic disorders. Poor QoL and social functioning are usually present before the onset of the first episode of psychosis. Our study aimed to explore the relationship between social adaptation and QoL in young people at risk of psychosis (ultra-high-risk, UHR) and healthy controls (HCs), and to investigate potential mediating effects of stress measures (perceived stress, stressful life events). Methods The study included 55 UHR subjects and 40 HC. Social functioning was assessed with the Social Adaptation Self-evaluation Scale (SASS). Stress measures included the assessment of stressful life events and perceived stress. We compared stress and QoL measures between UHR and HC, and also compared UHR with low or normal social adaptation. A mediation analysis was performed to explore whether stress measures mediated the relationship between social adaptation and QoL. Results UHR were less frequently employed and reported more stress, poorer QoL and lower social adaptation than HC. QoL and social adaptation were associated with stress measures. UHR with low social adaptation reported more perceived stress and less QoL than UHR with normal social adaptation and HC. Perceived stress mediated the relationship between social adaptation and QoL. Conclusions Social adaptation is less developed in UHR subjects than in healthy subjects and has a negative impact on quality of life. This association is mediated by perceived stress.

The objective of this study is to describe the frequency and type of victimization in a Spanish child and adolescent clinical ADHD sample and to analyze the association between the types of victimization and the severity of the symptoms. The sample is composed of 106 outpatients in treatment for ADHD, according to Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria. Symptom severity was measured by the Conners-3 scales. ADHD and comorbid diagnostics were evaluated with the Mini-Kid interview. The victimization experiences were studied using the Juvenile Victimization Questionnaire (JVQ). Children with child maltreatment history showed a greater intensity of hyperactivity/impulsivity, aggression and behavioral disorders as well as depression and anxiety disorders. The presence of peer victimization was associated with inattention, learning disorders, executive functioning, and relationship problems. Episodes of victimization should be considered in the treatment of the ADHD. Child maltreatment history is more associated with hyperactivity-impulsivity symptoms, while peer victimization is more associated with attentional symptoms.

Background There is a lack of studies investigating the dose-response effect of childhood trauma, recent events and cannabis use on recent psychosis. This study aims to determine the relationship between the level of exposure to stress factors and cannabis use with psychosis and to determine the combination effect among these factors in predicting a psychotic disorder. Methods 146 recent onset psychotic (ROP) patients and 61 healthy controls were included. Childhood trauma was evaluated using the childhood trauma questionnaire (CTQ) and recent events using the Holmes-Rahe social readjustment scale. The pattern of cannabis use was assessed by a detailed interview. A hierarchical multiple regression was run in order to determine both the cumulative and independent contribution of each factor in predicting a psychotic disorder. Results The highest levels of exposure to childhood trauma and cannabis were associated with psychosis while neither low nor high recent event exposure was associated. The combined effect of risk factors yielded a significant association with psychosis (×2 = 86.76, p Conclusions Our study provides evidence for a cumulative and a dose-response effect of environmental factors on recent psychosis. Considering that cannabis use and stress are highly prevalent in the population with psychosis, investigations of their relationships are needed to implement targeted prevention and treatment strategies.

Hypothalamic-pituitary-adrenal (HPA) axis alterations in at-risk mental states (ARMS) resemble those observed in established psychosis but are less consistent. We aimed to explore HPA axis abnormalities in both first-episode psychosis (FEP) and ARMS patients, while controlling for psychopathological symptoms. We studied 21 ARMS, 34 FEP patients and 34 healthy subjects. Clinical assessment included psychopathological symptoms (positive, negative, disorganized, excited and depressive symptoms) and stress measures. Saliva cortisol levels were determined at awakening, 30' and 60' post-awakening, 10:00 h, 23:00 h and 10:00 h on the day after the administration of 0.25 mg of dexamethasone, which occurred at 23:00 h. Three HPA axis measures were calculated: cortisol awakening response (CAR), cortisol diurnal slope and cortisol suppression ratio of the dexamethasone suppression test (DST). There were no significant differences between groups in HPA axis measures. However, when exploring the relationship between HPA axis measures and psychopathological symptoms, in ARMS subjects (but not FEP patients), a flatter cortisol slope was associated with more prominent negative symptoms, whereas a blunted CAR was associated with excited symptoms. Although no significant differences in HPA axis measures were found between diagnostic groups, subtle abnormalities in the CAR or circadian cortisol rhythmicity might be important for the phenotype of ARMS individuals.

Strategies for the early detection of autism spectrum disorders (ASD) in people with intellectual developmental disorder (IDD) are urgently needed, but few specific tools have been developed. The present study examines the psychometric properties of the EVTEA-DI, a Spanish adaptation of the PDD-MRS, in a large randomized sample of 979 adults with IDD. Factorial solution analysis suggested a three-factor solution (stereotyped behavior, communication, and social behavior). The EVTEA-DI showed good reliability and convergent validity when compared to the Childhood Autism Rating Scale. Discriminative validity analysis resulted in an acceptable global sensitivity of 70% and a high specificity of 90%. The EVTEA-DI proved to be a valid screening tool in ASD assessment of the adult Spanish population with IDD.

Subjects with a psychotic disorder show mild to moderate cognitive impairment, which is an important determinant of functional outcome. The underlying biological process of cognitive impairment in psychosis is unclear. We aimed to explore whether hypothalamic-pituitary-thyroid axis hormones or thyroid autoimmunity modulate cognitive functioning in subjects with early psychosis.We studied 70 patients with a psychotic disorder (3years of illness) and a control group of 37 healthy subjects (HS). Plasma levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroid-peroxidase (TPO-Abs) and thyroglobulin antibodies (TG-Abs) were determined. Cognitive assessment was performed with the MATRICS Cognitive Consensus Cognitive Battery. We also explored the relationship between thyroid variables and cognition in three subgroups of psychotic patients: psychosis not otherwise specified, affective psychosis (bipolar disorder or schizoaffective disorder) and non-affective psychosis (schizophrenia or schizophreniphorm disorder).In patients with early psychosis, higher FT4 levels (but not TSH or thyroid antibodies) were associated with better cognitive performance in attention/vigilance and overall cognition. The relationship between FT4 levels and the attention/vigilance domain remained significant in a multivariate analysis after adjusting for education level, age, gender, substance use, and benzodiazepine and antipsychotic treatments. We did not find a significant association between FT4 and cognitive performance in HS. In the exploratory analysis by psychotic subtypes, subjects with affective psychosis had increased FT4 levels and better cognitive profile than those with non-affective psychosis.Our study suggests that FT4 levels are associated with cognitive abilities (attention/vigilance and overall cognition) in individuals with early psychosis.

Controversy exists about the role of parent psychopathology in persistence and severity of attention deficit hyperactivity disorder (ADHD) symptoms in their children. Here we aimed to analyse the potential association between the severity of ADHD symptoms in children and the presence of psychiatric and ADHD symptoms in their biological parents. Seventy-three triads of children and their parents who were in active treatment for their diagnosed ADHD were evaluated in our Child and Adolescent Mental Health Centers. The mental health of the parents was also assessed. The general psychopathology of the parents was evaluated using the Symptom Checklist-90-R (SCL-90-R), and symptoms of hyperactivity were examined using the Adult ADHD Self-Report Scale (ASRS v.1.1). The severity of symptoms in children was assessed using the ADHD Rating Scale-IV (ADHD-RS-IV). Variables that could have affected the clinical development of ADHD such as sex, evolution time, age, academic level and the presence of comorbidities were controlled. The severity of the symptoms in children with ADHD was significantly related to the psychiatric history of their mother, the younger age of the child and the presence of a comorbid conduct disorder in the child. We discussed the importance of screening for parental psychopathology in clinical practice.

Clinical conditions commonly associated with mitochondrial disorders (CAMDs) are often present in autism spectrum disorders (ASD) and intellectual disability (ID). Therefore, the mitochondrial dysfunction hypothesis has been proposed as a transversal mechanism that may function in both disorders. Here, we investigated the presence of conditions associated with mitochondrial disorders and mitochondrial DNA (mtDNA) alterations in 122 subjects who presented ASD with ID (ASD group), 115 subjects who presented ID but not ASD (ID group) and 112 healthy controls (HC group). We assessed in the three study groups the presence of the clinical conditions through a questionnaire and the mtDNA content of two mitochondrial genes, MT-ND1 and MT-ND4, by qPCR. The mtDNA sequences of 98 ASD and 95 ID subjects were obtained by mtDNA-targeted next generation sequencing and analysed through the MToolBox pipeline to identify mtDNA mutations. Subjects with ASD and ID showed higher frequencies of constipation, edema, seizures, vision alterations, strabismus and sphincter incontinence than HCs subjects. ASD and ID subjects showed significantly lower mtDNA content than HCs in both MT-ND1 and MT-ND4 genes. In addition, we identified 49 putative pathogenic variants with a heteroplasmy level higher than 60%: 8 missense, 29 rRNA and 12 tRNA variants. A total of 28.6% of ASD and 30.5% of ID subjects carried at least one putative pathogenic mtDNA mutation. The high frequency of CAMDs, the low mtDNA content and the presence of putative pathogenic mtDNA mutations observed in both ASD and ID subjects are evidence of mitochondrial dysfunction in ASD and ID.

Objective To review the scientific literature about the relationship between impairment on smooth pursuit eye movements and schizophrenia. Methods Narrative review that includes historical articles, reports about basic and clinical investigation, systematic reviews, and meta-analysis on the topic. Results Up to 80% of schizophrenic patients have impairment of smooth pursuit eye movements. Despite the diversity of test protocols, 65% of patients and controls are correctly classified by their overall performance during this pursuit. The smooth pursuit eye movements depend on the ability to anticipate the target's velocity and the visual feedback, as well as on learning and attention. The neuroanatomy implicated in smooth pursuit overlaps to some extent with certain frontal cortex zones associated with some clinical and neuropsychological characteristics of the schizophrenia, therefore some specific components of smooth pursuit anomalies could serve as biomarkers of the disease. Due to their sedative effect, antipsychotics have a deleterious effect on smooth pursuit eye movements, thus these movements cannot be used to evaluate the efficacy of the currently available treatments. Conclusion Standardized evaluation of smooth pursuit eye movements on schizophrenia will allow to use specific aspects of that pursuit as biomarkers for the study of its genetics, psychopathology, or neuropsychology.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor that is activated by fibrillar collagens. Here, we review the expression and role of DDR1 in the central nervous system (CNS). In a murine model, DDR1 is expressed in oligodendrocytes in the developing brain and during remyelination. In human adult brain tissue, DDR1 is detected in a similar pattern as other classical myelin proteins such as myelin basic protein (MBP). Up to 50 transcripts of DDR1 have been detected in human tissues, of which 5 isoforms have been identified. In the human brain, all 5 isoforms are detectable, but DDR1b is the most highly expressed, and DDR1c is coexpressed with myelin genes. DDR1 sequence variants have been associated with psychiatric disorders, and upregulation of this gene occurs in gliomas. Moreover, mutations in DDR1 have been found in tumors of Schwann cells, which are the myelinating cells of the peripheral nervous system. All these data suggest that DDR1 plays a role in myelination and is relevant to neuropsychiatric diseases.

Impairment of language abilities is a common feature in autistic individuals. Heterozygous mutations in the Forkhead Box P2 (FOXP2) gene lead to a severe spoken language disorder. Recently, several studies have pinpointed the involvement of common variants of the Contactin-Associated Protein-Like 2 (CNTNAP2) gene, whose transcription is regulated by the product of FOXP2, in several disorders characterized by language impairments such as autism, specific language impairment (SLI), and selective mutism (SM). In the present study, common variants of the FOXP2 and the CNTNAP2 genes were analyzed through a case-control association study in 322 Spanish autistic patients and 524 controls. The results of this study suggest that common variants of FOXP2 are unlikely to contribute to autism susceptibility, in agreement with previous findings. Furthermore, we failed to replicate in our sample a previous association finding of two single nucleotide polymorphisms (rs2710102 and rs7794745) in the CNTNAP2 gene with autism. No evidence for the association of these genes with language traits was observed in our analysis.

Hyperprolactinaemia is a significant side effect of antipsychotic medications and may cause sexual dysfunction. The aim of our study was to assess the effect of switching from long-acting injectable (LAI) risperidone to paliperidone palmitate (PP) on sexual function and prolactin levels in patients with psychosis. We carried out a prospective observational study during a 3-month period that involved 11 patients with psychosis treated with risperidone-LAI who suffered from hyperprolactinaemia and who were then switched to PP. Two assessments were completed: the first one before the switch and the second one 3 months after the switch. These assessments measured sexual function using the Arizona Sexual Experience Scale and assessed prolactin levels. Our results showed a significant decrease in serum prolactin levels (P=0.041). We observed a four-fold reduction in clinically significant sexual dysfunction that is suggestive of benefit, although the sample size is too small to be sure. Our study suggests that prolactin levels seem to decrease after switching from risperidone-LAI to PP in patients with a psychotic disorder.

We studied the patterns and predictors of long-acting injectable (LAI) antipsychotic (AP) use in the treatment of schizophrenia and the effect of introducing a new LAI (paliperidone palmitate [paliperidone-LAI]) in the Spanish province of Tarragona.This noninterventional, naturalistic, retrospective study included electronic medical record data from a large population-based database of 1,646 patients who were diagnosed with schizophrenia according to ICD-10 criteria and treated between January 2011 and December 2013.During the study period, 42.0% of patients were treated with an LAI AP. The most frequently prescribed initial LAI was risperidone (52.0% of patients). A total of 23% of patients initially treated with an oral AP were switched to an LAI AP, a change that was associated with younger age (P = .001), undifferentiated schizophrenia (P = .015), substance abuse (P.001), and neuropsychiatric comedication with the following agents: anticonvulsants (P = .004), anticholinergics (P.001), and hypnotics/sedatives (P = .03). The change from an oral AP to paliperidone-LAI was predicted by younger age (P.001). Overall, 27.5% of patients switched to another LAI AP, and paliperidone-LAI was the preferred option in 64.7% of cases. The most frequent change involved patients taking risperidone-LAI, many of whom transitioned to paliperidone-LAI (85.0% of cases), particularly patients with a disease duration5 years (P = .019).There was a progressive increase in the use of LAI formulations in our catchment area. These agents were preferentially prescribed to patients with chronic disease and a history of substance abuse, as well as patients receiving neuropsychiatric comedication. One-month LAI formulations were commonly used in young patients.

The identification of mutations in genes encoding proteins of the synaptic neurexin–neuroligin pathway in different neurodevelopmental disorders, including autism and mental retardation, has suggested the presence of a shared underlying mechanism. A few mutations have been described so far and for most of them the biological consequences are unknown. To further explore the role of the NRXN1β gene in neurodevelopmental disorders, we have sequenced the coding exons of the gene in 86 cases with autism and mental retardation and 200 controls and performed expression analysis of DNA variants identified in patients. We report the identification of four novel independent mutations that affect nearby positions in two regions of the gene/protein: i) sequences important for protein translation initiation, c.− 3G>T within the Kozak sequence, and c.3G>T (p.Met1), at the initiation codon; and ii) the juxtamembrane region of the extracellular domain, p.Arg375Gln and p.Gly378Ser. These mutations cosegregate with different psychiatric disorders other than autism and mental retardation, such as psychosis and attention-deficit/hyperactivity disorder. We provide experimental evidence for the use of an alternative translation initiation codon for c.− 3G>T and p.Met1 mutations and reduced synaptic levels of neurexin-1β protein resulting from p.Met1 and p.Arg375Gln. The data reported here support a role for synaptic defects of neurexin-1β in neurodevelopmental disorders., The authors gratefully thank the participation of patients and their families; Dr. S. Sommer for providing the sequences of PCR primers; Dr. P. Scheiffele for helpful comments; R.J. Meléndez-Cadenas for excellent technical assistance; and Dr. Miguel Lucas for support. This work was funded by grants from the Instituto de Salud Carlos III (ISCIII; PI081446 to F.G.S.) and Junta de Andalucía (P07-CVI-02943 to F.G.S., P07-CVI-0270 to A.M-M. and P06-CVI-02392). R.J.C-G. is a recipient of a fellowship from ISCIII (FI08/00730).

OBJECTIVE: One of the hypotheses about the genetic factors that contribute to schizophrenia involves mitochondrial DNA (mtDNA), an approximately 16,569-base pair molecule inherited only from the mother. If this hypothesis were true, one would expect a higher frequency of schizophrenia among matrilineal relatives who share mtDNA with a schizophrenia patient than among relatives who do not. This article reports the risk of presenting with schizophrenia, other psychiatric disorders, and conditions related to mitochondrial disorders in relatives who share mtDNA with a schizophrenia patient versus those who do not. METHOD: We interviewed 100 schizophrenia patients (DSM-IV criteria) and 147 of their first-degree relatives from November 2007 to November 2009 to collect clinical data from patients and from both sides of each patient's pedigree. The study was conducted at of a psychiatric teaching hospital in Reus, Spain. Contingency tables were established, and odds ratios were calculated to estimate relative risk. RESULTS: Relatives who shared mtDNA with a schizophrenia patient had a higher risk of presenting with schizophrenia than those who did not share mtDNA (odds ratio [OR] = 3.05; 95% CI, 1.65-5.72; P < .001). Female but not male relatives who shared mtDNA with a schizophrenia patient also had a higher risk of unipolar depression (OR =10.19; 95% CI, 4.07-32.80; P < .001), panic attack (OR = 15.52; 95% CI, 2.41-643.6; P < .001), and other anxiety disorders (OR = 4.14; 95% CI, 1.84-9.71; P < .001). Some conditions frequently associated with mitochondrial disorders were also more frequent among female relatives who shared mtDNA with a schizophrenia patient than among those who did not. CONCLUSIONS: The results of this study support the hypothesis that mtDNA may be involved in schizophrenia. In females, mtDNA could also be involved in the development of other psychiatric and nonpsychiatric conditions. Further studies are needed to confirm the role of mtDNA in psychiatric disorders.

Neurotransmitter systems and neurotrophic factors can be considered strong candidates for autism spectrum disorder (ASD). The serotoninergic and dopaminergic systems are involved in neurotransmission, brain maturation and cortical organization, while neurotrophic factors (NTFs) participate in neurodevelopment, neuronal survival and synapses formation. We aimed to test the contribution of these candidate pathways to autism through a case-control association study of genes selected both for their role in central nervous system functions and for pathophysiological evidences.The study sample consisted of 326 unrelated autistic patients and 350 gender-matched controls from Spain. We genotyped 369 tagSNPs to perform a case-control association study of 37 candidate genes.A significant association was obtained between the DDC gene and autism in the single-marker analysis (rs6592961, P = 0.00047). Haplotype-based analysis pinpointed a four-marker combination in this gene associated with the disorder (rs2329340C-rs2044859T-rs6592961A-rs11761683T, P = 4.988e-05). No significant results were obtained for the remaining genes after applying multiple testing corrections. However, the rs167771 marker in DRD3, associated with ASD in a previous study, displayed a nominal association in our analysis (P = 0.023).Our data suggest that common allelic variants in the DDC gene may be involved in autism susceptibility.

Genome-wide association studies using several hundred thousand anonymous markers present limited statistical power. Alternatively, association studies restricted to common nonsynonymous single nucleotide polymorphisms (nsSNPs) have the advantage of strongly reducing the multiple testing problem, while increasing the probability of testing functional single nucleotide polymorphisms (SNPs).We performed a case-control association study of common nsSNPs in Galician (northwest Spain) samples using the Affymetrix GeneChip Human 20k cSNP Kit, followed by a replication study of the more promising results. After quality control procedures, the discovery sample consisted of 5100 nsSNPs at minor allele frequency5% analyzed in 476 schizophrenia patients and 447 control subjects. The replication sample consisted of 4069 cases and 15,128 control subjects of European origin. We also performed multilocus analysis, using aggregated scores of nsSNPs at liberal significance thresholds and cross-validation procedures.The 5 independent nsSNPs with false discovery rate q ≤ .25, as well as 13 additional nsSNPs at p.01 and located in functional candidate genes, were genotyped in the replication samples. One SNP, rs13107325, located at the metal ions transporter gene SLC39A8, reached significance in the combined sample after Bonferroni correction (trend test, p = 2.7 × 10(-6), allelic odds ratio = 1.32). This SNP presents minor allele frequency of 5% to 10% in many European populations but is rare outside Europe. We also confirmed the polygenic component of susceptibility.Taking into account that another metal ions transporter gene, SLC39A3, is associated to bipolar disorder, our findings reveal a role for brain metal homeostasis in psychosis.

The brain-derived neurotrophic factor (BDNF) is a major participant in the regulation of food intake and may play a role in the regulation of the stress response. We aimed to investigate whether there is a gene-environment interaction in the relationship between stress and BDNF Val66Met polymorphism in relation to dietary patterns in a sample of subjects with early psychosis.We studied 124 early psychotic disorder (PD) patients, 36 At-Risk Mental States (ARMS) and 62 healthy subjects (HS). Dietary patterns were examined by a dietician. Physical activity, life stress and perceived stress were assessed by validated questionnaires. BDNF Val66Met polymorphism (rs6265) was genotyped. A gene-environment interaction was tested with multiple linear regression analysis while adjusting for covariates.Perceived stress was not associated with calorie intake in HS. In ARMS subjects, Met-carriers who presented low-perceived stress were associated with increased caloric intake. Conversely, those who presented high-perceived stress were associated with reduced caloric intake. In PD, perceived stress was neither associated with increased calorie intake without an effect by BDNF genotype nor a gene-environment interaction. Perceived stress was associated with food craving in PD patients, independent of genotype, and in ARMS or HS who were Val homozygous.This study suggests that the common Val66Met polymorphism of the BDNF gene may modulate the relationship between life stress and calorie intake in subjects at risk for psychosis.