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Despite achieving clinical remission, patients with depression encounter difficulties to return to their premorbid psychosocial functioning. Cognitive dysfunction has been proposed to be a primary mediator of functional impairment. Therefore, the new non-pharmacological procognitive strategy INtegral Cognitive REMediation for Depression (INCREM) has been developed with the aim of targeting cognitive and psychosocial functioning.This is a single-blind randomized controlled clinical trial with three treatment arms. Fifty-two depressed patients in clinical remission, with psychosocial difficulties and cognitive impairment, were randomly assigned to receive INCREM intervention, Psychoeducation programme, or treatment as usual. Patients were assessed before and after the study period, and six months after. The primary outcome was the change from baseline of patients' psychosocial functioning. Changes in cognitive functioning and other variables were considered secondary outcomes.The analysis showed a significant improvement in psychosocial functioning in the INCREM group, especially six months after the intervention, compared to patients who received the psychoeducation programme. An improvement in cognitive performance was also observed in the INCREM group.This study includes a small sample size due to the anticipated end of the clinical trial because of the COVID-19 pandemic.These results provide preliminary evidence on the feasibility and potential efficacy of the INCREM program to improve not only cognitive performance but also psychosocial functioning in clinically remitted depressed patients, and such improvement is maintained six months after. It can be speculated that the maintenance is mediated by the cognitive enhancement achieved with INCREM.

Background The COVID-19 pandemic had and still have a major impact on adolescent mental health and consequently on suicidal behavior. However, few studies have investigated whether the pandemic has changed the patterns and the triggers of suicidality peaks in adolescents, e.g., seasonal patterns or family conflicts. We hypothesized that the pandemic modified suicidality rates: an increment of suicide attempts would be observed in the first semester of the academic year during COVID-19 pandemic compared to the same period of previous academic year; and the precipitating factors would be more related to social stressors during the pandemic school year. Methods A retrospective cross-sectional study was conducted to assess the precipitating factors, also including school-related factors and cognitive skills, of suicide attempts of adolescents occurred in the first and second semesters of the year before the pandemic lockdown (study periods 1 and 2) and the year after (study periods 3 and 4). Results The sample consisted of 85 adolescents aged between 12 and 17 recruited consecutively from March 2019 to March 2021 at emergency ward because of suicide attempt. Forty-eight adolescents (55.3% of the sample) were attended before the lockdown (pre-pandemic group) and 38 (44.7%) the year after. The results showed a higher proportion of suicide attempts in girls in period 4 (Sept 2020-Mar 2021) compared to the rest of periods (p = 0.026). The multinomial regression models showed a significant increase in the frequency of suicide attempts in the first semester of the pandemic academic year compared to the second semester of the pre-pandemic year, with depressive symptoms being a significant contributing factor (p = 0.04). Additionally, social triggers and age were found to be significant risk factors for suicide attempts in the first semester of the pandemic academic year compared to the same semester of the pre-pandemic year (p = 0.006 and p = 0.01, respectively). Conclusions During the pandemic, suicide attempts in girls increased more significantly in the first semester than in the previous year, and it was associated with greater severity of depressive symptoms. Social relations in back-to-school after the lockdown was a relevant trigger of suicide attempts in adolescents.

Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR

The COVID-19 pandemic is having a major impact on the mental health of adolescents, leading to suicidal behaviors. However, it remains to be clarified whether the COVID-19 pandemic has changed the psychiatric profile of adolescent suicide attempters. Methods: a retrospective observational analytical study was conducted to assess age, gender and clinical characteristics of adolescents attempting suicide during the year before and the year after the global lockdown. Results: ninety adolescents (12–17 y.o.) were recruited consecutively from February 2019 to March 2021 at the emergency ward for having attempted suicide. Fifty-two (57.8%) attended before the lockdown (pre-pandemic group) and thirty-eight (42.2%) the year after (pandemic group). There were significant differences in diagnostic categories between the periods (p = 0.003). Adjustment and conduct disorders were more frequent in the pre-pandemic group, while anxiety and depressive disorders were more prevalent during the pandemic. Although the severity of suicide attempts did not show significant differences between the two study periods (0.7), the generalized linear model showed that the suicide attempt severity was significantly associated with current diagnosis (p = 0.01). Conclusions: the psychiatric profile of adolescents attempting suicide was different before and during the COVID-19 pandemic. During the pandemic, the proportion of adolescents with a prior psychiatric history was lower, and most of them were diagnosed with depressive and anxiety disorders. These diagnoses were also associated with a greater severity in the intentionality of suicide attempt, regardless of the study period.

Up to 20% of the cases of anorexia nervosa (AN) are chronic and treatment-resistant. Recently, the efficacy of deep brain stimulation (DBS) for severe cases of AN has been explored, with studies showing an improvement in body mass index and other psychiatric outcomes. While the effects of DBS on cognitive domains have been studied in patients with other neurological and psychiatric conditions so far, no evidence has been gathered in AN.Eight patients with severe, chronic, treatment-resistant AN received DBS either to the nucleus accumbens (NAcc) or subcallosal cingulate (SCC; four subjects on each target). A comprehensive battery of neuropsychological and clinical outcomes was used before and 6-month after surgery.Although Body Mass Index (BMI) did not normalise, statistically significant improvements in BMI, quality of life, and performance on cognitive flexibility were observed after 6 months of DBS. Changes in BMI were related to a decrease in depressive symptoms and an improvement in memory functioning.These findings, although preliminary, support the use of DBS in AN, pointing to its safety, even for cognitive functioning; improvements of cognitive flexibility are reported. DBS seems to exert changes on cognition and mood that accompany BMI increments. Further studies are needed better to determine the impact of DBS on cognitive functions.

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Contains fulltext : 248376.pdf (Publisher’s version ) (Open Access) For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Consortium presents the largest-ever mega-analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1-90 years old (47% females). We observed significant patterns of greater male than female between-subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene-environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex-specific vulnerability to disorders.

Background: Cognitive impairment has been reported in patients with Major Depressive Disorder (MDD). This study aims to explore the association between lifestyle habits and health-related factors and the presence of cognitive symptoms in MDD patients. Methods: Demographic, clinical, health-related variables and cognitive scores measured with the Cambridge Neuropsychological Test Automated Battery (CANTAB) were compared between 74 patients with current MDD and 68 healthy controls (HC). To test the hypothesis of associated factors to cognitive symptoms, multivariate backward stepwise linear regression models were run. Results: Significant neuropsychological deficits were evident in MDD compared with HC in the global cognitive index (F=8.29; df=1, 140; p=0.005). In the regression analysis performed on MDD and HC, years of schooling (β=-0.11; p=

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

Alterations in cognitive performance have been described in patients with major depressive disorder (MDD). However, the specific risk factors of these changes are not yet known. This study aimed to explore whether inmunometabolic parameters are related to cognitive performance in MDD in comparison to healthy controls (HC) Methods: Sample consisted of 84 MDD patients and 78 HC. Both groups were compared on the results of cognitive performance measured with the Cambridge Neuropsychological Test Automated Battery (CANTAB), the presence of metabolic syndrome (MetS) and an inflammatory/oxidative index calculated by a principal component analysis of peripheral biomarkers (tumor necrosis factor, C-reactive protein and 4-hydroxynonenal). A multiple linear regression was carried out, to study the relationship between inmunometabolic variables and the global cognitive performance, being the latter the dependent variable. Results: Significant differences were obtained in the inflammatory/oxidative index between both groups (F(1157)= 12.93; p < .001), also in cognitive performance (F(1157)= 56.75; p < .001). The inmunometabolic covariate regression model (i.e., condition (HC/MDD), sex, age and medication loading, MetS, inflammatory/oxidative index and the interaction between MetS and inflammatory/oxidative index) was statistically significant (F(7157)= 11.24; p < .01) and explained 31% of variance. The condition, being either MDD or HD, (B=˗0.97; p < .001), age (B=˗0.28; p < .001) and the interaction between inflammatory/oxidative index and MetS (B=˗0.38; p = .02) were factors associated to cognitive performance. Limitations: Sample size was relatively small. The cross-sectional design of the study limits the possibilities of analysis. Conclusions: Our results provide evidence on the conjoint influence of metabolic and inflammatory dysregulation on cognitive dysfunction in MDD patients. In this way, our study opens a line of research in immunometabolic agents to deal with cognitive decline associated with MDD, This study was supported in part by grants from the Carlos III Health Institute through the Ministry of Science, Innovation and Universities (PI15/00662, PI15/0039, PI15/00204, PI19/01040), co-funded by the European Regional Development Fund (ERDF) “A way to build Europe”, CIBERSAM, and the Catalan Agency for the Management of University and Research Grants (AGAUR 2017 SGR 1247). We also thank CERCA Programme/ Generalitat de Catalunya for institutional support. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. MJP was funded with a Miguel Servet II contract until 2020 (CP16/00020) from the Carlos III Health Institute through the Spanish Ministry of Health. YSC work is supported by the FPI predoctoral grant (FPI 2016/17) from Universidad Autonoma de Madrid. The authors would like to acknowledge the support of the research participants, who helped to make this work possible. We thank Tamara Oliva and Marta Martín for technical assistance

Background: The evolution of cognitive performance throughout the lifespan in bipolar disorder (BD) is understudied. This cross-sectional study aims to describe the cognitive performance across age groups. Methods: A sample of 654 participants was recruited for this study (BD = 432 and healthy controls -HC- =222). Three subgroups, divided according to age range (18 to 35, 36 to 49, and >= 50 years old) were analyzed after administering a comprehensive neuropsychological battery including six cognitive domains. Demographic, clinical, and psychosocial functioning data were also analyzed. Generalized linear models (GLM) with age, diagnostic group, and age x group as main effects were carried out to examine their potential association on cognitive domains. Subsequently, a GLM in the BD sample was conducted to analyze interactions of several clinical variables by age on each cognitive domain.Results: Main effects of diagnostic group and age were found in all cognitive domains. Significant group x age effect interaction was found for attention domain (p = 0.02) demonstrating a worse cognitive evolution across age in BD, driven by older age, but not in HC. Significant interaction effects of higher number of manic episodes and older age were also found in attention and verbal memory. Older age was also associated with a longer duration of illness, higher number of episodes, more somatic comorbidities, and poorer psychosocial functioning.Conclusions: These results suggest that older age was associated with a selective cognitive decline in BD in the attentional domain. These findings highlight the importance of developing interventions targeting cognitive dysfunction throughout the BD adulthood lifespan.

The use of deep brain stimulation (DBS) in treatment resistant patients with schizophrenia is of considerable current interest, but where to site the electrodes is challenging. This article reviews rationales for electrode placement in schizophrenia based on evidence for localized brain abnormality in the disorder and the targets that have been proposed and employed to date. The nucleus accumbens and the subgenual anterior cingulate cortex are of interest on the grounds that they are sites of potential pathologically increased brain activity in schizophrenia and so susceptible to the local inhibitory effects of DBS; both sites have been employed in trials of DBS in schizophrenia. Based on other lines of reasoning, the ventral tegmental area, the substantia nigra pars reticulata and the habenula have also been proposed and in some cases employed. The dorsolateral prefrontal cortex has not been suggested, probably reflecting evidence that it is underactive rather than overactive in schizophrenia. The hippocampus is also of theoretical interest but there is no clear functional imaging evidence that it shows overactivity in schizophrenia. On current evidence, the nucleus accumbens may represent the strongest candidate for DBS electrode placement in schizophrenia, with the substantia nigra pars reticulata also showing promise in a single case report; the ventral tegmental area is also of potential interest, though it remains untried.

Brain structural abnormalities and low educational attainment are consistently associated with major depressive disorder (MDD), yet there has been little research investigating the complex interaction of these factors. Brain structural alterations may represent a vulnerability or differential susceptibility marker, and in the context of low educational attainment, predict MDD. We tested this moderation model in a large multisite sample of 1958 adults with MDD and 2921 controls (aged 18 to 86) from the ENIGMA MDD working group. Using generalized linear mixed models and within-sample split-half replication, we tested whether brain structure interacted with educational attainment to predict MDD status. Analyses revealed that cortical thickness in a number of occipital, parietal, and frontal regions significantly interacted with education to predict MDD. For the majority of regions, models suggested a differential susceptibility effect, whereby thicker cortex was more likely to predict MDD in individuals with low educational attainment, but less likely to predict MDD in individuals with high educational attainment. Findings suggest that greater thickness of brain regions subserving visuomotor and social-cognitive functions confers susceptibility to MDD, dependent on level of educational attainment. Longitudinal work, however, is ultimately needed to establish whether cortical thickness represents a preexisting susceptibility marker. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Despite the considerable amount of research evidence on the significant role of subjective happiness on mental health, there is no psychometric study of the Subjective Happiness Scale (SHS) in psychiatric samples. This study was aimed at exploring the psychometric properties of the SHS in a Spanish sample of patients with depressive disorders. Participants were 174 patients with a depressive disorder (70% diagnosed as major depressive disorder) who completed the SHS, the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16), and the EQ-5D Visual Analogue Scale (EQ-5D VAS). Depressive symptoms were also assessed by means of the 17-item Hamilton Depression Rating Scale (HDRS17) and the Clinical Global Impression-Severity (CGI-S) Scale. Dimensionality, internal consistency reliability, construct validity, and responsiveness to change of the SHS were examined. Confirmatory factor analysis replicated the original one-factor structure of the scale. The SHS exhibited good-to-excellent results for internal consistency (α = 0.83) and for convergent [EQ-5D VAS (r = 0.71)] and divergent [QIDS-SR16 (r = −0.72), HDRS17 (r = −0.60) and CGI-S (r = −0.61)] construct validity. The ability of the SHS to differentiate between depression severity levels as well as its responsiveness to clinical change were both highly satisfactory (p &lt, 0.001 in both cases). The SHS retained the soundness of psychometric properties showed in non-clinical samples in a sample of patients with depressive disorders, which supports its use as a reliable and valid outcome measure in the treatment of such disorders.

Although pharmacotherapy is considered the first-line treatment for bipolar disorders (BD), adjunctive psychoeducation has proven its effectiveness in improving self-management of the disease and reducing relapse rates. Few studies have evaluated the effect of brief group psychoeducation on pragmatic variables, such as the number of hospitalizations. The aim of the present study was to assess the mid-term effect of a four-session group psychoeducation on course-related variables in BD. Thirty-two individuals with BD were included in the study. Sixteen were exposed to psychoeducation and were matched to sixteen nonexposed individuals who received their usual treatment. Both groups were compared on insight, treatment adherence, change in the number of hospitalizations and visits to the emergency services, occurrence rate after intervention, and time to the first psychiatric hospitalization and the first urgent attendance. There was a significant reduction in the mean number of hospitalizations and urgent attendances in the exposed group in comparison to the nonexposed group. The first urgent attendance was significantly sooner in the nonexposed cohort. There were no differences between groups in any of the other variables. This intervention has shown benefits for pragmatic variables of the disease course and may be a feasible and cost-effective intervention to routinely implement in the management of BD.

Background:Although pharmacogenetics for major depressive disorder (MDD) is gaining momentum, the role of genetics in differences in response to antidepressant treatment is controversial, as they depend on multifactorial and polygenic phenotypes. Previous studies focused on the genes of the serotonergic system, leaving apart other pathological factors such as the inflammatory pathway. The main objective of the study was to assess whether treatment response might be associated with specific inflammation-related genetic variants or their methylation status.Methods:41 SNPs in 8 inflammatory genes: interleukin (IL) 1-β, IL2, IL6, IL6R, IL10, IL18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were genotyped in 153 patients with MDD, who were evaluated with the Mausdley Staging Method to determine treatment response profiles. Pyrosequencing reactions and methylation quantification were performed in a PyroMark Q24 in 5 selected CpG islands of IL1- β, IL6 and IL6R. Linear and logistic regression analyses were conducted, including age and gender as covariates using PLINK 1.07.Results:Allelic distribution of IL1- β rs1143643 was significantly associated with MSM scores (FDR corrected p = 0.04). Allelic distribution of IL6R rs57569414 showed a trend towards significance with MSM scores (p = 0.002; FDR corrected p = 0.07). Haplotype analyses showed associations between allelic combinations of IL1-β and IL10 with treatment response (FDR corrected p < 0.01). Methylation percentage of treatment responders was only higher in an IL6R CpG island (p < 0.05).Conclusions:These exploratory findings suggest that IL1-β and, marginally, IL6R polymorphisms may affect treatment response in major depression. If confirmed, these results may account for the heterogeneous phenotypes of major depression that underlie differences in treatment response.

Objective and subjective cognitive measures are altered in major depressive disorder (MDD), but there is a poor correlation between them. This study aims to explore such discrepancy and the characteristics explaining this phenomenon. 229 patients with MDD subdivided into remitted (n = 57), partially remitted (n = 90) and acute (n = 82) underwent a clinical interview, completed self-report questionnaires and a neuropsychological assessment. The association between objective and subjective cognition was evaluated in the areas of attention and memory. Also, dependent measures of concordance and self-appraisal were calculated for each patient. Potential predictors of these outcomes were evaluated through regression analysis. Depressive symptoms correlated negatively with objective but especially with subjective cognition. Patients in an acute episode showed a significant correlation between objective and subjective attention/ memory measures, but also the greatest underestimation of their cognitive performance. In those with fewer depressive symptoms, objective and subjective cognition showed poor correspondence between them. In the regression analyses with the full MDD sample, higher scores on depressive symptoms, intelligence quotient and executive functions predicted lower self-appraisal. Objective and subjective cognition show poor concordance in MDD patients, especially in those with residual mood symptoms. Higher executive functions also explain this discrepancy. Assessments of both subjective cognitive complaints and objective performance seem necessary as they may be measuring different aspects of cognitive functioning. (c) 2018 Elsevier B.V. and ECNP. All rights reserved.

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER) Altres ajuts: Generalitat de Catalunya. Programa CERCA Altres ajuts: Instituto de Salud Carlos III (CIBERSAM i CIBERNED) Altres ajuts: Fundació "La Caixa" Altres ajuts: Grífols SA (GR@ACE project) Neuropsychiatric symptoms (NPS) have been recently addressed as risk factors of conversion to Alzheimer's disease (AD) and other dementia types in patients diagnosed with Mild Cognitive Impairment (MCI). Our aim was to determine profiles based on the prominent NPS in MCI patients and to explore the predictive value of these profiles on conversion to specific types of dementia. A total of 2137 MCI patients monitored in a memory clinic were included in the study. Four NPS profiles emerged (classes), which were defined by preeminent symptoms: Irritability, Apathy, Anxiety/Depression and Asymptomatic. Irritability and Apathy were predictors of conversion to dementia (HR = 1.43 and 1.56, respectively). Anxiety/depression class showed no risk effect of conversion when compared to Asymptomatic class. Irritability class appeared as the most discriminant neuropsychiatric condition to identify non-AD converters (i.e., frontotemporal dementia, vascular dementia, Parkinson's disease and dementia with Lewy Bodies). The findings revealed that consistent subgroups of MCI patients could be identified among comorbid basal NPS. The preeminent NPS showed to behave differentially on conversion to dementia, beyond AD. Therefore, NPS should be used as early diagnosis facilitators, and should also guide clinicians to detect patients with different illness trajectories in the progression of MCI.

Special Issue: The ENIGMA Consortium: the first 10 years.-- Karolinska Schizophrenia Project (KaSP)., Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., National Institute of Mental Health, Grant/Award Numbers: MH104284, MH116147, R01MH113619, R01 MH090553, R01MH117014, R01MH042191; Karolinska Institutet; Stockholm County Council; Southern and Eastern Norway Regional Health Authority; German Centre for Cardiovascular Research; DZHK; Siemens Healthineers; University of Queensland; US National Institute of Child Health and Human Development, Grant/Award Number: RO1HD050735; Australian National Health and Medical Research Council; Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Institute on Drug Abuse, Grant/Award Numbers: UL1 TR000153, 1 U24 RR025736-01, 1 U24 RR021992; Brain Injury Fund Research Grant Program; Indiana State Department of Health Spinal Cord; Parents Against Childhood Epilepsy; Epilepsy Therapy Project, Fight Against Childhood Epilepsy and Seizures; Epilepsy Foundation; American Epilepsy Society; Knut and Alice Wallenberg Foundation; European Community's Horizon 2020 Programme; Vici Innovation Program; NWO Brain & Cognition Excellence Program; Netherlands Organization for Scientific Research; Hersenstichting Nederland; Netherlands Organization for Health Research and Development; Geestkracht Programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; Universiteit Utrecht; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; National Center for Advancing Translational Sciences; National Institutes of Health; National Center for Research Resources; Consortium grant, Grant/Award Number: U54 EB020403; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Number: G0500092; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; the Research Council, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Swedish Research Council; European Community's Seventh Framework Programme, Grant/Award Number: 602450; King's College London; South London and Maudsley NHS Foundation Trust; Biomedical Research Centre; National Institute for Health Research.

The most recent evidence suggest that cognitive dysfunction is a nuclear symptom of major depressive disorder (MDD), which in turn mediates the psychosocial functioning of depressed patients. However, few studies have determined whether cognitive disturbances are observable in the first stages of the disorder as some authors have described the worse cognitive performance in both first episode and recurrently depressed patients, others have reported small impairments across most cognitive domains. Such disparity may be accounted for by a great heterogeneity of cognitive profiles among patients that have not been taken much into account. The chapter goes on to briefly review the history of cognitive performance in MDD and to discuss the necessity of determining the cognitive dysfunction in the early stages of the disorder. The chapter concludes with the consideration of cognitive impairment alongside core depressive symptoms to direct efforts toward full recovery of patients from the very beginning of MDD.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

Treatment-resistant auditory verbal hallucinations (TRAVH) are a relatively prevalent and devastating symptom in patients with schizophrenia (SCZ). Even though their pathological mechanisms are poorly understood, they seem to differ from those underlying non-hallucinating SCZ.& nbsp; In this study, we characterise structural brain changes in SCZ patients with TRAVH. With respect to nonhallucinating patients and healthy controls, we studied macrostructural grey matter changes through cortical thickness and subcortical volumetric data. Additionally, we analysed microstructural differences across groups using intracortical and subcortical mean diffusivity data. This latter imaging metric has been claimed to detect incipient neuronal damage, as water can diffuse more freely in regions with reduced neural density.& nbsp; We found brain macrostructrural and microstructural alterations in SCZ patients with TRAVH (n = 29), both with respect to non-hallucinating (n = 20) patients and healthy controls (n = 27). Importantly, a microstructural & ndash;rather than a macrostructural & ndash; compromise was found in key brain regions such as the ventral ACC, the NAcc and the hippocampus. These microstructural alterations correlated, in turn, with clinical severity. TRAVH patients also showed accentuated age-related cortical deterioration and an abnormal longitudinal loss of cortical integrity over a one-year period.& nbsp; These findings highlight the potential role of microstructural imaging biomarkers in SCZ. Notably, they could be used both to detect and to monitor subtle grey matter alterations in critical brain regions such as deep brain stimulation targets. Moreover, our results support the existence of a more aggressive and active pathological mechanism in patients with TRAVH, providing new insight into the aetiology of this debilitating illness.

Delineating age-related cortical trajectories in healthy individuals is critical given the association of cortical thickness with cognition and behaviour. Previous research has shown that deriving robust estimates of age-related brain morphometric changes requires large-scale studies. In response, we conducted a large-scale analysis of cortical thickness in 17,075 individuals aged 3-90 years by pooling data through the Lifespan Working group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium. We used fractional polynomial (FP) regression to characterize age-related trajectories in cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma (LMS) method. Inter-individual variability was estimated using meta-analysis and one-way analysis of variance. Overall, cortical thickness peaked in childhood and had a steep decrease during the first 2-3 decades of life; thereafter, it showed a gradual monotonic decrease which was steeper in men than in women particularly in middle-life. Notable exceptions to this general pattern were entorhinal, temporopolar and anterior cingulate cortices. Inter-individual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results reconcile uncertainties about age-related trajectories of cortical thickness; the centile values provide estimates of normative variance in cortical thickness, and may assist in detecting abnormal deviations in cortical thickness, and associated behavioural, cognitive and clinical outcomes.

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalised on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine the age-related morphometric trajectories of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum early in life; the volume of the basal ganglia showed a gradual monotonic decline thereafter while the volumes of the thalamus, amygdala and the hippocampus remained largely stable (with some degree of decline in thalamus) until the sixth decade of life followed by a steep decline thereafter. The lateral ventricles showed a trajectory of continuous enlargement throughout the lifespan. Significant age-related increase in inter-individual variability was found for the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to derive risk predictions for the early identification of diverse clinical phenotypes.

Deep brain stimulation (DBS) has been found to be effective in treatment resistant neurological and psychiatric disorders. So far there has been only one completed trial in schizophrenia, in which seven treatment resistant patients received DBS in the subgenual anterior cingulate cortex (sgACC, N = 4) or the nucleus accumbens (NAc, N = 3); four met symptomatic response criteria over the trial period. Six patients underwent 18 F-FDG PET at baseline and after at least 6 months of stimulation. Individual patient analysis indicated that DBS to both the sgACC and NAc was associated with local and distant changes in glucose metabolism. Increments and decrements of brain activity were observed in regions that included the medial prefrontal cortex, the dorsolateral prefrontal cortex, the anterior cingulate cortex, the caudate nucleus, the NAc, the hippocampus and the thalamus. Increased activity appeared to be associated with clinical improvement. These preliminary findings suggest that DBS acts by modulating cerebral activity in the cortico-basal-thalamic-cortical circuit in patients with schizophrenia who show improvement in psychotic symptoms.

Background: Previous magnetic resonance spectroscopic (MRS) studies have reported brain metabolic abnormalities in Major Depressive Disorder (MDD). Nevertheless, results have been inconsistent, focusing on fully developed major depression neglecting first episode patients (FED). Longitudinal studies have also been rare and with short follow-up periods. The aim of the current study was to investigate the differences between healthy controls and first episode patients at baseline, together with changes of metabolites after 1 year follow-up in the ventromedial prefrontal cortex. Methods: H-1-MRS images were obtained from 64 healthy controls and 31 FED patients using a 3T Philips Achieva scanner and processed with TARQUIN software at baseline and after 1 year. Examined metabolites included Glx (corresponding to Glu + Gln-peak), Glu, NAAG, myo-Ins, Cr, GSH and GABA. Clinical improvement was assessed by HDRS-17 scale. Differences in the concentrations of metabolites were evaluated by MANOVA/MANCOVA and GLM repeated measures for longitudinal changes. Results: FED patients had significantly decreased glutamate levels at baseline (p < 0.05) along with significantly elevated GABA (p < 0.01) compared to healthy controls. At the follow up, myo- Ins levels were significantly increased compared to baseline (p < 0.05). Limitations: The limited sample size, together with the unexpectedly high response rate after treatment (83%) might suggest decreased representativeness of the sample. Conclusions: Results indicate glutamatergic and GABAergic changes taking place within the ventromedial prefrontal region even at the early stage of depression prior to any medication treatment.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research. ENIGMA MDD work is supported by NIH grants U54 EB020403 (Thompson), R01 MH116147 (Thompson), and R01 MH117601 (Jahanshad & Schmaal). LS was supported by an NHMRC Career Development Fellowship (1140764). AFFDIS cohort: this study was funded by the University Medical Center Goettingen (UMG Startfoerderung) and the research team is supported by German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung, BMBF: 01 ZX 1507, “PreNeSt - e:Med”). Barcelona cohort: MJP is funded by the Ministerio de Ciencia e Innovación of the Spanish Government and by the Instituto de Salud Carlos III through a ‘Miguel Servet’ research contract (CP16–0020); National Research Plan (Plan Estatal de I + D + I 2016–2019); and co-financed by the European Regional Development Fund (ERDF). BRC DeCC cohort: CHYF is supported by NIHR BRC. Calgary cohort: supported by Canadian Institutes for Health Research, Branch Out Neurological Foundation. Cardiff cohort: supported by the Medical Research Council (grant G 1100629) and the National Center for Mental Health (NCMH), funded by Health Research Wales (HS/14/20). CLING cohort: this study was partially supported by the Deutsche Forschungsgemeinschaft (DFG) via grants to OG (GR1950/5–1 and GR1950/10–1). CODE cohort: Henrik Walter is supported by a grant of the Deutsche Forschungsgemeinschaft (WA 1539/4–1). The CODE cohort was collected from studies funded by Lundbeck and the German Research Foundation (WA 1539/4–1, SCHN 1205/3–1, SCHR443/11–1). DIP-Groningen cohort: this study was supported by the Gratama Foundation, the Netherlands (2012/35 to NG). Edinburgh cohort: The research leading to these results was supported by IMAGEMEND, which received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602450. This paper reflects only the author’s views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award 104036/Z/14/Z. FOR2107-Marburg cohort: funded by the German Research Foundation (DFG, grant FOR2107 KR 3822/7–2 to AK; FOR2107 KI 588/14–2 to TK and FOR2107 JA 1890/7–2 to AJ). Houston cohorts: supported in part by NIMH grant R01 085667 and the Dunn Research Foundation. JCS is supported by the Pat Rutherford, Jr. Endowed Chair in Psychiatry. IMH Study cohort: supported by funding from NHG (SIG/15012) and NMRC CISSP (2018). Melbourne cohort: funded by National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (Principal Investigator BJH) and 1024570 (Principal Investigator CGD). Minnesota cohort: the study was funded by the National Institute of Mental Health (K23MH090421; Dr. Cullen) and Biotechnology Research Center (P41 RR008079; Center for Magnetic Resonance Research), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, and the Minnesota Medical Foundation. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. Münster cohort: funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5–1 and DA1151/5–2 to UD; SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). NESDA cohort: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10–000–1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. Pharmo cohort: supported by ERA-NET PRIOMEDCHILD FP 6 (EU) grant 11.32050.26. PSYABM-NORMENT: supported by the Research Council of Norway (project number 229135). The South East Norway Health Authority Research Funding (project number 2015052). The Department of Psychology, University of Oslo, Norway. San Francisco cohort: supported by NIH/NCCIH 1R61AT009864–01A1. NIMH R01MH085734. SHIP and SHIP-trend cohorts: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Stanford cohorts: this work was supported by NIH grant R37 MH101495. The BiDirect Study was supported by grants from the German Federal Ministry of Education and Research (BMBF; grants FKZ-01ER0816 and FKZ-01ER1506). MDS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. TCH is supported by NIMH grant 5K01MH117442. EJWVS, JL, and TFB are supported by European Research Council grant no. ERC-ADG-2014–671084 INSOMNIA. TFB is supported by a VU University Amsterdam University Research Fellowship 2016–2017. JL is supported by a VU University Amsterdam University Research Fellowship 2017–2018.

Background: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly. Methods: Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed). Findings: One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively). Interpretation: These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects. (C) 2019 The Authors. Published by Elsevier B.V.

Major Depressive Disorder (MDD) entails cognitive dysfunction in many cognitive domains, but it is still uncertain whether such deficits are present in the early stages. The purpose of the study is to determine the cognitive performance in first episode depression (FED) exploring the presence of different cognitive profiles, and the role of cognition in FED at baseline and long-term. Ninety subjects (18-50 years) were included, 50 patients with a FED and 40 healthy controls. Participants were assessed with a neuropsychological battery, covering language, attention, verbal memory, processing speed and executive domains. Neuropsychological group comparisons were performed with MANOVAs. A hierarchical cluster analysis was run to identify clusters of patients with similar neuropsychological performance. Two generalized linear models were built to predict baseline HDRS-17 and changes at 12 months. Patients performed significantly worse than healthy controls in language, attention/working memory, verbal memory, processing speed and executive functioning, with moderate to large effect sizes (0.5 - 1). Two clusters were found: cognitively preserved patients (n=37) and cognitively impaired patients (n=13). Large effect sizes of cognitive impairment in FED were observed between the two cognitive clusters (preserved and impaired). Depressive symptoms at baseline were predicted by verbal memory (p=0.003), while 12-month changes were predicted by executive function (p=0.041) and language (p=0.037). Cognitive performance predicted depressive symptoms at baseline and at follow-up, pointing to the usefulness of cognitive assessment even at the commencement of the illness. (C) 2018 Elsevier B.V. and ECNP. All rights reserved.

Cognitive symptoms play a central role in schizophrenia and are strongly associated with social functioning. Treatment with clozapine presents controversial results regarding its effects on cognition. The opposite effects of clozapine and n-desmethylclozapine (NDMC) on cholinergic system have been suggested to underlie these inconclusive findings. The aim of this study is to determine whether clozapine/NDMC ratio can predict cognitive performance in patients with treatment-resistant psychosis. Nineteen clinically stable patients with schizophrenia or schizoaffective disorder treated with clozapine monotherapy completed demographic and clinical interviews. For the purpose of the study, patients were assessed with a neuropsychological battery and on the same day a blood sampling was obtained from each patient to measure plasma levels of clozapine and NDMC. Our results showed that clozapine/NDMC ratio, but not clozapine or NDMC plasma levels separately, was a predictive factor of cognitive performance, specifically of executive functioning. Our results showed that lower clozapine/NDMC ratios are associated with better executive functioning in clinically stable patients. These findings could be interpreted by the different pharmacodynamic properties on cholinergic, dopaminergic and serotonergic systems of NDMC compared to clozapine.

Introduction The influence of age and gender in the electrical charge delivered in a given population was analysed using an electroconvulsive therapy (ECT) clinical database. Material and method An observational, prospective, longitudinal study with descriptive analysis was performed using data from a database that included total bilateral frontotemporal ECT carried out with a Mecta spECTrum 5000Q® in our hospital over 6 years. From 2006 to 2012, a total of 4337 ECT were performed on 187 patients. Linear regression using mixed effects analysis was weighted by the inverse of the number of ECT performed on each patient per year of treatment. Results The results indicate that age is related with changes in the required charge (P = .031), as such that the older the age a higher charge is needed. Gender is also associated with changes in charge (P = .014), with women requiring less charge than men, a mean of 87.3 mC less. When the effects of age and gender are included in the same model, both are significant (P = .0080 and P = .0041). Thus, for the same age, women require 99.0 mC less charge than men, and in both genders the charge increases by 2.3 mC per year. Conclusions From our study, it is concluded that the effect of age on the dosage of the electrical charge is even more significant when related to gender. It would be of interest to promote the systematic collection of data for a better understanding and application of the technique.

Resumen Introduccion A partir de una base de datos clinica de terapia electroconvulsiva (TEC) se pretende corroborar la influencia de la edad y el genero en la carga electrica administrada en una poblacion determinada. Material y metodo Estudio observacional, prospectivo y longitudinal, con analisis descriptivo, de una base de datos que incluye el total de sesiones de TEC bilaterales frontotemporales realizadas con la Mecta spECTrum 5000Q ® entre 2006 y 2012. Es una muestra de 4.337 sesiones de TEC realizadas a 187 pacientes. Mediante regresion lineal de efectos mixtos se realiza un analisis ponderado por el inverso del numero de sesiones de TEC realizadas por cada paciente y por ano de tratamiento. Resultados Los resultados indican que la edad esta relacionada con cambios en la carga requerida (p = 0,031): a mayor edad, mayor aumento de carga. El genero tambien se relaciona con cambios en la carga (p = 0,014): las mujeres requeririan 87,3 mC menos de media que los hombres. Incluyendo los efectos de edad y genero en el mismo modelo, ambos resultan significativos (p = 0,0080 y p = 0,0041), de modo que a igualdad de edad, las mujeres requieren 99,0 mC menos de carga que los hombres, y en ambos generos aumenta la carga 2,3 mC por ano de edad. Conclusiones Del analisis se obtiene que el efecto de la edad en la dosificacion de la carga electrica es todavia mas significativo cuando se tiene en cuenta el genero. Es de interes promover la recogida sistematica de datos para un mejor conocimiento y aplicacion de la tecnica.

Despite safety concerns raised by the European Medicines Agency (EMA), evidence supporting QT-lengthening effects of escitalopram is far to be conclusive. We aimed to evaluate the relationship between escitalopram plasma levels (Escit-PL) and corrected QT-interval length (QTc-length) in 91 outpatients recruited from a hospital setting. Fifteen patients had an abnormally prolonged QTc-interval, and 3 had QTc-intervals >= 500 ms. No correlation between Escit-PL and QTc-length was found (r = 0.08; p = 0.45). Linear/logistic regression analyses were also conducted taking into account potential confounders such as age, gender, personal history of heart disease, medication load and concomitant use of antipsychotic/tricyclic antidepressants. Escit-PL did not predict either QTc-length or abnormally prolonged QTc-interval. Only antipsychotics/tricyclics use (adjusted beta = 0.26, SE = 9.1; p = 0.01) was an independent predictor of QTc-length (R (2) = 0.096, F = 4.68, df = 2,88; p = 0.01). Only antipsychotics/tricyclics use (OR 3.56 [95% CI 1.01-12.52]; p < 0.05) and medication load (OR 1.32 [95% CI 1.06-1.64]; p < 0.01) were significantly associated with an increased risk of abnormally prolonged QTc-interval (Omnibus test chi (2) = 9.5, df = 2; p < 0.01). Our study did not find a significant relationship between Escit-PL and QTc-length even when recognized modulating factors of the QT-interval were controlled for. Concomitant use of other potentially arrhythmogenic agents may help to explain the apparent link between escitalopram and QT prolongation previously suggested. The advisability of maintaining the EMA warning is once again called into question.

Altres ajuts: The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT) and NIH grant R01 MH116147 (PMT). LS is supported by an NHMRC MRFF Career Development Fellowship (APP1140764). We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. M-JvT was supported by a VENI grant (NWO grant number 016.156.077). UCSF: This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) to TTY; the National Institute of Mental Health (R01MH085734 to TTY; K01MH117442 to TCH) and by the American Foundation for Suicide Prevention (PDF-1-064-13) to TCH. Stanford: This work was supported by NIMH Grants R01MH59259 and R37101495 to IHG. MS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). Marburg: This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; KI 588/ 14-1, KI 588/14-2 to TK; KR 3822/7-1, KR 3822/7-2 to AK; JA 1890/ 7-1, JA 1890/7-2 to AJ). IMH-MDD: This work was supported by the National Healthcare Group Research Grant (SIG/15012) awarded to KS. Barcelona: This study was funded by two grants of the Fondo de Investigación Sanitaria from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The author is funded through 'Miguel Servet' research contract (CP16-0020), co-financed by the European Regional Development Fund (ERDF) (2016-2019). QTIM: We thank the twins and singleton siblings who gave generously of their time to participate in the QTIM study. We also thank the many research assistants, radiographers, and IT support staff for data acquisition and DNA sample preparation. This study was funded by White matter disturbances in major depressive disorder: a coordinated analysis across 20 international. . . 1521 the National Institute of Child Health & Human Development (RO1 HD050735); National Institute of Biomedical Imaging and Bioengineering (Award 1U54EB020403-01, Subaward 56929223); National Health and Medical Research Council, Australia (Project Grants 496682, 1009064). NIH ENIGMA-BD2K U54 EB020403 (Thompson); R01 MH117601 (Jahanshad/Schmaal). Magdeburg: M.L. and M.W. are funded by SFB 779. Bipolar Family Study: This study has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award (104036/Z/14/Z). Minnesota Adolescent Depression Study: The study was funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women's Health Seed Grant, University of Minnesota. Dublin: This study was supported by Science Foundation Ireland through a Stokes Professorhip grant to TF. MPIP: The MPIP Sample comprises patients included in the Recurrent Unipolar Depression (RUD) Case-Control study at the clinic of the Max Planck Institute of Psychiatry, Munich, German. The RUD study was supported by GlaxoSmithKline. Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T-1-weighted MRI data were processedwith a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1.Results: The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.