Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, ...stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p < 5E-8), although seven loci were suggestive (p < 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 ≤ p ≤ 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer's Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep-wake behavior, and psychiatric disorders.
Depression is a prevalent and severe disorder associated with considerable stigma. This stigma contributes to the suffering and impedes help seeking behaviour of those affected. Stigma can be ...influenced by causal beliefs about depression and personal contact with people suffering from depression. The aim of this study was to investigate (1) the associations between beliefs about the aetiology of depression and personal / perceived stigma, as well as (2) a possible moderating effect of personal contact with people with depression on these associations.
Stigma, causal beliefs, and contact with depression were assessed in a representative online survey among German adults (N = 5,000). Multiple regression analyses were performed with contact levels (unaffected vs. personally affected (diagnosed) vs. personally affected (undiagnosed) vs. affected by relatives with depression vs. persons who treat depression) and causal beliefs (biogenetic vs. psychosocial vs. lifestyle) as predictor variables for personal and perceived stigma as dependent variables.
Higher personal stigma was associated with lifestyle causal beliefs (p < .001, f² = 0.07), lower personal stigma with biogenetic (p = .006, f² = 0.01) and psychosocial (p < .001, f² = 0.02) causal beliefs. A positive interaction between psychosocial beliefs and the contact group "relatives" (p = .039) further suggests that this contact group does not benefit so strongly from psychosocial causal beliefs regarding personal stigma. Higher perceived stigma was associated with psychosocial (p < .001, f² = 0.01) and lifestyle (p < .011, f² = 0.01) causal beliefs. Regarding contact levels, the "unaffected" had significantly higher personal stigma scores than each of the other contact groups (p < .001). The contact group "affected (diagnosed)" had significantly higher perceived stigma scores than "unaffected".
The available data show that anti-stigma campaigns should clearly communicate, that depression is not caused by an unfavorable lifestyle. In general, psychosocial or biological explanatory models should be explained. Especially for the target group "relatives of depressive patients", who can be an important support for patients, education about biogenetic explanatory models should be provided. However, it is important to note that causal beliefs are only one of many factors that impact on stigma.
Research concerning the association between use of antidepressants and incidence of suicide has yielded inconsistent results and is the subject of considerable controversy. The first aim is to ...describe trends in the use of antidepressants and rates of suicide in Europe, adjusted for gross domestic product, alcohol consumption, unemployment, and divorce. The second aim is to explore if any observed reduction in the rate of suicide in different European countries preceded the trend for increased use of antidepressants.
Data were obtained for 29 European countries between 1980 and 2009. Pearson correlations were used to explore the direction and magnitude of associations. Generalized linear mixed models and Poisson regression distribution were used to clarify the effects of antidepressants on suicide rates, while an autoregressive adjusted model was used to test the interaction between antidepressant utilization and suicide over two time periods: 1980-1994 and 1995-2009.
An inverse correlation was observed in all countries between recorded Standardised Death Rate (SDR) for suicide and antidepressant Defined Daily Dosage (DDD), with the exception of Portugal. Variability was marked in the association between suicide and alcohol, unemployment and divorce, with countries depicting either a positive or a negative correlation with the SDR for suicide. Every unit increase in DDD of an antidepressant per 1000 people per day, adjusted for these confounding factors, reduces the SDR by 0.088. The correlation between DDD and suicide related SDR was negative in both time periods considered, albeit more pronounced between 1980 and 1994.
Suicide rates have tended to decrease more in European countries where there has been a greater increase in the use of antidepressants. These findings underline the importance of the appropriate use of antidepressants as part of routine care for people diagnosed with depression, therefore reducing the risk of suicide.
Whether α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) expression is reduced in early Alzheimer's disease is controversial. Using (-)-18FFlubatine PET, Sabri, Meyer et al. report α4β2-nAChR ...deficiency in mild Alzheimer's dementia, especially within the basal forebrain-cortical and septohippocampal cholinergic projections. Reduced α4β2-nAChR availability correlates with impaired episodic memory and executive function/working memory.
Abstract
In early Alzheimer's dementia, there is a need for PET biomarkers of disease progression with close associations to cognitive dysfunction that may aid to predict further cognitive decline and neurodegeneration. Amyloid biomarkers are not suitable for that purpose. The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) are widely abundant in the human brain. As neuromodulators they play an important role in cognitive functions such as attention, learning and memory. Post-mortem studies reported lower expression of α4β2-nAChRs in more advanced Alzheimer's dementia. However, there is ongoing controversy whether α4β2-nAChRs are reduced in early Alzheimer's dementia. Therefore, using the recently developed α4β2-nAChR-specific radioligand (−)-18F-flubatine and PET, we aimed to quantify the α4β2-nAChR availability and its relationship to specific cognitive dysfunction in mild Alzheimer's dementia. Fourteen non-smoking patients with mild Alzheimer's dementia, drug-naïve for cholinesterase therapy, were compared with 15 non-smoking healthy controls matched for age, sex and education by applying (−)-18F-flubatine PET together with a neuropsychological test battery. The one-tissue compartment model and Logan plot method with arterial input function were used for kinetic analysis to obtain the total distribution volume (VT) as the primary, and the specific binding part of the distribution volume (VS) as the secondary quantitative outcome measure of α4β2-nAChR availability. VS was determined by using a pseudo-reference region. Correlations between VT within relevant brain regions and Z-scores of five cognitive functions (episodic memory, executive function/working memory, attention, language, visuospatial function) were calculated. VT (and VS) were applied for between-group comparisons. Volume of interest and statistical parametric mapping analyses were carried out. Analyses revealed that in patients with mild Alzheimer's dementia compared to healthy controls, there was significantly lower VT, especially within the hippocampus, fronto-temporal cortices, and basal forebrain, which was similar to comparisons of VS. VT decline in Alzheimer's dementia was associated with distinct domains of impaired cognitive functioning, especially episodic memory and executive function/working memory. Using (−)-18F-flubatine PET in patients with mild Alzheimer's dementia, we show for the first time a cholinergic α4β2-nAChR deficiency mainly present within the basal forebrain-cortical and septohippocampal cholinergic projections and a relationship between lower α4β2-nAChR availability and impairment of distinct cognitive domains, notably episodic memory and executive function/working memory. This shows the potential of (−)-18F-flubatine as PET biomarker of cholinergic α4β2-nAChR dysfunction and specific cognitive decline. Thus, if validated by longitudinal PET studies, (−)-18F-flubatine might become a PET biomarker of progression of neurodegeneration in Alzheimer's dementia.
Abstract
Background
Despite well-established guidelines for managing major depressive disorder, its extensive disability burden persists. This Value of Treatment mission from the European Brain ...Council aimed to elucidate the nature and extent of “gaps” between best-practice and current-practice care, specifically to:
1.
Identify current treatment gaps along the care pathway and determine the extent of these gaps in comparison with the stepped-care model and
2.
Recommend policies intending to better meet patient needs (i.e., minimize treatment gaps).
Methods
After agreement upon a set of relevant treatment gaps, data pertaining to each gap were gathered and synthesized from several sources across six European countries. Subsequently, a modified Delphi approach was undertaken to attain consensus among an expert panel on proposed recommendations for minimizing treatment gaps.
Results
Four recommendations were made to increase the depression diagnosis rate (from ~50% episodes), aiming to both increase the number of patients seeking help, and the likelihood of a practitioner to correctly detect depression. These should reduce time to treatment (from ~1 to ~8 years after illness onset) and increase rates of treatment; nine further recommendations aimed to increase rates of treatment (from ~25 to ~50% of patients currently treated), mainly focused on targeting the best treatment to each patient. To improve follow-up after treatment initiation (from ~30 to ~65% followed up within 3 months), seven recommendations focused on increasing continuity of care. For those not responding, 10 recommendations focused on ensuring access to more specialist care (currently at rates of ~5–25% of patients).
Conclusions
The treatment gaps in depression care are substantial and concerning, from the proportion of people not entering care pathways to those stagnating in primary care with impairing and persistent illness. A wide range of recommendations can be made to enhance care throughout the pathway.
Stigma is one of the most significant constraints on people living with depression. There is a lack of validated scales in Portugal to measure depression stigma; therefore, the Depression Stigma ...Scale (DSS) is essential to the depression stigma research in Portugal.
We developed the adaptation process with the ITC Guidelines for Translation and Adapting Tests taken into consideration. We collected the sample as part of the OSPI program-Optimizing suicide prevention programs and their implementation in Europe, specifically within the application in Portugal, and included 1693 participants. Floor-ceiling effects and response ranges were analyzed, and we calculated Cronbach alphas, and Confirmatory Analysis. Validity evidence was tested with two well-documented hypotheses, using data on gender and depression symptoms.
The sample was well comparable with the general Portuguese population, indicating its representativeness. We identified a three-factor structure in each subscale (personal and perceived stigma): weak-not-sick, discrimination, and dangerous/unpredictable, with good model fit results. The Cronbach's alphas were satisfactory, and validity was confirmed.
This study established the validity and demonstrated good psychometric properties of the DSS in the Portuguese population. The validation of the DSS can be beneficial in exploring stigma predictors and evaluating the effectiveness of stigma reduction interventions.
fMRI and EEG are complimentary methods for the analysis of brain activity since each method has its strength where the other one has limits: The spatial resolution is thus in the range of millimeters ...with fMRI and the time resolution is in the range of milliseconds with EEG. For a comprehensive understanding of brain activity in target detection, nine healthy subjects (age 24.2 ± 2.9) were investigated with simultaneous EEG (27 electrodes) and fMRI using an auditory oddball paradigm. As a first step, event-related potentials, measured inside the scanner, have been compared with the potentials recorded in a directly preceding session in front of the scanner. Attenuated amplitudes were found inside the scanner for the earlier N1/P2 component but not for the late P300 component. Second, an independent analysis of the localizations of the fMRI activations and the current source density as revealed by low resolution electromagnetic tomography (LORETA) has been done. Concordant activations were found in most regions, including the temporoparietal junction (TPJ), the supplementary motor area (SMA)/anterior cingulate cortex (ACC), the insula, and the middle frontal gyrus, with a mean Euclidean distance of 16.0 ± 6.6 mm between the BOLD centers of gravity and the LORETA-maxima. Finally, a time-course analysis based on the current source density maxima was done. It revealed different time-course patterns in the left and right hemisphere with earlier activations in frontal and parietal regions in the right hemisphere. The results suggest that the combination of EEG and fMRI permits an improved understanding of the spatiotemporal dynamics of brain activity.
Abstract Background Stigmatizing attitudes toward depression and toward help-seeking are important barriers for people with mental health problems to obtain adequate professional help. This study ...aimed to examine: (1) population attitudes toward depression and toward seeking professional help in four European countries; (2) the relation between depression stigma and attitudes toward help-seeking; (3) the relation between both attitudes and socio-demographic characteristics; and (4) differences in attitudes across countries. Methods A representative general population survey ( n =4011) was conducted in Germany, Hungary, Ireland, and Portugal, assessing attitudes toward depression and toward help-seeking, and a number of socio-demographic variables. Results Respondents showed a moderate degree of personal stigma toward depression and a strikingly higher degree of perceived stigma. Although a substantial majority showed openness to seek professional help, only half of the people perceived professional help as valuable. More negative attitudes were found in Hungary and were associated with male gender, older age, lower educational level and living alone. Also, personal stigma was related to less openness to and less perceived value of professional treatment. Limitations The survey was cross-sectional, so no causal inferences could be drawn. Conclusions Personal and perceived stigma toward depression deserves public health attention, since they impact upon the intention of people with depression to seek professional help. Public media campaigns should focus on the credibility of the mental health care sector, and target males, older people, and those with a lower educational level and living alone. The content of each campaign should be adapted to the cultural norms of the country for which it is intended.
The 'European Alliance Against Depression' community-based intervention approach simultaneously targets depression and suicidal behaviour by a multifaceted community based intervention and has been ...implemented in more than 115 regions worldwide. The two main aims of the European Union funded project "Optimizing Suicide Prevention Programmes and Their Implementation in Europe" were to optimise this approach and to evaluate its implementation and impact. This paper reports on the primary outcome of the intervention (the number of completed and attempted suicides combined as 'suicidal acts') and on results concerning process evaluation analysis. Interventions were implemented in four European cities in Germany, Hungary, Portugal and Ireland, with matched control sites. The intervention comprised activities with predefined minimal intensity at four levels: training of primary care providers, a public awareness campaign, training of community facilitators, support for patients and their relatives. Changes in frequency of suicidal acts with respect to a one-year baseline in the four intervention regions were compared to those in the four control regions (chi-square tests). The decrease in suicidal acts compared to baseline in the intervention regions (-58 cases, -3.26%) did not differ significantly (χ2 = 0.13; p = 0.72) from the decrease in the control regions (-18 cases, -1.40%). However, intervention effects differed between countries (χ2 = 8.59; p = 0.04), with significant effects on suicidal acts in Portugal (χ2 = 4.82; p = 0.03). The interviews and observations explored local circumstances in each site throughout the study. Hypothesised mechanisms of action for successful implementation were observed and drivers for 'added-value' were identified: local partnership working and 'in-kind' contributions; an approach which valued existing partnership strengths; and synergies operating across intervention levels. It can be assumed that significant events during the implementation phase had a certain impact on the observed outcomes. However, this impact was, of course, not proven.
Abstract In major depressive disorder (MDD), elevated theta current density in the rostral anterior cingulate (rACC), as estimated by source localization of scalp-recorded electroencenphalogram ...(EEG), has been associated with response to antidepressant treatments, whereas elevated frontal theta has been linked to non-response. This study used source localization to attempt to integrate these apparently opposite results and test, whether antidepressant response is associated with elevated rACC theta and non-response with elevated frontal theta and whether theta activity is a differential predictor of response to different types of commonly used antidepressants. In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, international, randomized, prospective practical trial, 1008 MDD participants were randomized to escitalopram, sertraline or venlafaxine-XR. The study also recruited 336 healthy controls. Treatment response and remission were established after eight weeks using the 17-item Hamilton Rating Scale for Depression (HRSD17 ). The resting-state EEG was assessed at baseline with eyes closed and source localization (eLORETA) was employed to extract theta from the rACC and frontal cortex. Patients with MDD had elevated theta in both frontal cortex and rACC, with small effect sizes. High frontal and rACC theta were associated with treatment non-response, but not with non-remission, and this effect was most pronounced in a subgroup with previous treatment failures. Low theta in frontal cortex and rACC are found in responders to antidepressant treatments with a small effect size. Future studies should investigate in more detail the role of previous treatment (failure) in the association between theta and treatment outcome.
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