Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.

Feasibility and Effectiveness of Memory Specificity Training in Depressed Outpatients: A Pilot Study.

BACKGROUND: Research has shown that depressed patients suffer from reduced autobiographical memory specificity (rAMS). This cognitive phenomenon is associated with the maintenance and recurrence of depressive symptoms. OBJECTIVES: This pilot study aims to investigate the feasibility and effectiveness of a relatively new group-based intervention (Memory Specificity Training; MeST) that aims to reduce rAMS in an outpatient setting. METHODS: Twenty-six depressed outpatients received MeST during the waiting period prior to psychotherapy. The Client Satisfaction Questionnaire (CSQ-8) was used to measure client satisfaction after the training. The Autobiographical Memory Test (AMT) was used to measure memory specificity before and after the training. Depressive symptoms were measured using the Beck Depression Inventory (BDI-II) and the Montgomery Asberg Depression Rating Scale (MADRS), before and after the training, and at a 3-month follow-up. RESULTS: Participants as well as trainers were positive about the use of MeST. Participants also showed an increase in memory specificity and a decrease in depressive symptoms. CONCLUSIONS: This study suggests that MeST is feasible in an outpatient setting, that it increases autobiographical memory specificity and that it may decrease depressive symptoms. A randomized controlled trial is recommended to examine MeST and its effects on autobiographical memory specificity, depressive symptoms and depressive relapse more extensively. Copyright © 2015 John Wiley & Sons, Ltd. Key Practitioner Message: Research suggests that modification of rAMS can advance recovery and reduce the chance of developing a depression relapse. However, most existing psychotherapies for depression do not include these specific interventions. This is the first study to show that MeST in an outpatient setting is feasible and can lead to an increase in autobiographical memory specificity and that it may decrease depressive symptoms. A larger scale randomized controlled trial is required to examine whether the addition of MeST to care as usual decreases depressive symptoms more effectively than care as usual without MeST, and to examine whether subgroups of patients benefit specifically from this intervention (e.g. patients with more severely decreased memory specificity).

Anxiety and new onset of cardiovascular disease: critical review and meta-analysis.

BACKGROUND: Anxiety has been associated with new-onset cardiovascular disease (CVD), but the quality of this relationship is unclear. Only if anxiety is a causal, independent cardiovascular risk factor might it be a target for CVD prevention. AIMS: To determine and examine the independent association and causality between anxiety and incident CVD. METHOD: PubMed, EMBASE and PsycINFO databases were searched up to October 2013. A review of Hill's criteria for causality and random effects meta-analysis were conducted of prospective, population-based studies examining anxiety and incident CVD in people free from CVD at baseline. RESULTS: The meta-analysis comprised 37 papers (n = 1 565 699). The follow-up ranged from 1 to 24 years. Anxiety was associated with a 52% increased incidence of CVD (hazard ratio = 1.52, 95% CI 1.36-1.71). The risk seemed independent of traditional risk factors and depression. The evaluation of Hill's criteria largely argued in favour of causality. CONCLUSIONS: Anxiety may be of interest for CVD prevention. Future research should examine biological and behavioural underpinnings of the association in order to identify targets for intervention.

Baseline Severity as a Moderator of the Waiting List-Controlled Association of Cognitive Behavioral Therapy With Symptom Change in Social Anxiety Disorder: A Systematic Review and Individual Patient Data Meta-analysis.

Importance: Social anxiety disorder (SAD) can be adequately treated with cognitive behavioral therapy (CBT). However, there is a large gap in knowledge on factors associated with prognosis, and it is unclear whether symptom severity predicts response to CBT for SAD. Objective: To examine baseline SAD symptom severity as a moderator of the association between CBT and symptom change in patients with SAD. Data Sources: For this systematic review and individual patient data meta-analysis (IPDMA), PubMed, PsycInfo, Embase, and the Cochrane Library were searched from January 1, 1990, to January 13, 2023. Primary search topics were social anxiety disorder, cognitive behavior therapy, and randomized controlled trial. Study Selection: Inclusion criteria were randomized clinical trials comparing CBT with being on a waiting list and using the Liebowitz Social Anxiety Scale (LSAS) in adults with a primary clinical diagnosis of SAD. Data Extraction and Synthesis: Authors of included studies were approached to provide individual-level data. Data were extracted by pairs of authors following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, and risk of bias was assessed using the Cochrane tool. An IPDMA was conducted using a 2-stage approach for the association of CBT with change in LSAS scores from baseline to posttreatment and for the interaction effect of baseline LSAS score by condition using random-effects models. Main Outcomes and Measures: The main outcome was the baseline to posttreatment change in symptom severity measured by the LSAS. Results: A total of 12 studies including 1246 patients with SAD (mean [SD] age, 35.3 [10.9] years; 738 [59.2%] female) were included in the meta-analysis. A waiting list-controlled association between CBT and pretreatment to posttreatment LSAS change was found (b = -20.3; 95% CI, -24.9 to -15.6; P < .001; Cohen d = -0.95; 95% CI, -1.16 to -0.73). Baseline LSAS scores moderated the differences between CBT and waiting list with respect to pretreatment to posttreatment symptom reductions (b = -0.22; 95% CI, -0.39 to -0.06; P = .009), indicating that individuals with severe symptoms had larger waiting list-controlled symptom reductions after CBT (Cohen d = -1.13 [95% CI, -1.39 to -0.88] for patients with very severe SAD; Cohen d = -0.54 [95% CI, -0.80 to -0.29] for patients with mild SAD). Conclusions and Relevance: In this systematic review and IPDMA, higher baseline SAD symptom severity was associated with greater (absolute but not relative) symptom reductions after CBT in patients with SAD. The findings contribute to personalized care by suggesting that clinicians can confidently offer CBT to individuals with severe SAD symptoms.

Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey.

AIMS: The association between antidepressant use and risk of cardiovascular disease (CVD) remains controversial, particularly in initially healthy samples. Given that antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are now prescribed not only for depression, but also for a wide range of conditions, this issue has relevance to the general population. We assessed the association between antidepressant medication use and future risk of CVD in a representative sample of community-dwelling adults without known CVD. METHODS AND RESULTS: A prospective cohort study of 14 784 adults (aged 52.4 ± 11.9 years, 43.9% males) without a known history of CVD was drawn from the Scottish Health Surveys. Of these study participants, 4.9% reported the use of antidepressant medication. Incident CVD events (comprising CVD death, non-fatal myocardial infarction, coronary surgical procedures, stroke, and heart failure) over 8-year follow-up were ascertained by a linkage to national registers; a total of 1434 events were recorded. The use of tricyclic antidepressants (TCAs) was associated with elevated risk of CVD [multivariate-adjusted hazard ratio (HR) = 1.35, 95% confidence interval (CI), 1.03-1.77] after accounting for a range of covariates. There was a non-significant association between TCA use and coronary heart disease events (969 events, multivariate-adjusted HR = 1.24, 95% CI, 0.87-1.75). The use of SSRIs was not associated with CVD. Neither class of drug was associated with all-cause mortality risk. CONCLUSION: Although replication is required, the increased risk of CVD in men and women taking TCAs was not explained by existing mental illness, which suggests that this medication is associated with an excess disease burden.

The bidirectional relationship between anxiety disorders and alcohol use disorders in adults: Findings from a longitudinal population-based study.

BACKGROUND: Anxiety disorders (AD) and alcohol use disorder (AUD) frequently co-occur, but the temporal order of the association is unclear. We have determined the association between AD and the presence and first-onset of AUD, and vice versa. METHODS: Data were used from n = 6.646 participants and four measurement waves (baseline, 3-, 6- and 9-years) of the Netherlands Mental Health Survey and Incidence Study 2 (NEMESIS-2), a cohort study of the Dutch general population aged 18-64 years. AD and AUD were assessed with the Composite International Diagnostic Interview 3.0. Multilevel logistic autoregressive models were controlled for previous-wave AD or AUD, sociodemographics (Model 1), smoking and clinical factors (Model 2). RESULTS: People with AUD had a higher risk of present (OR = 1.65, 95 % CI 1.11-2.43; Model 2) and first-onset (OR = 2.03, 95 % CI 1.17-3.51; Model 2) AD in 3-years follow-up intervals than people without AUD. Vice versa, people with AD also had a higher sociodemographics-adjusted risk of present and first-onset AUD over 3-years follow-up intervals, but these associations attenuated into insignificance after adjustment for smoking and clinical variables. Limitations For statistical power reasons we were not able to analyze 9-year follow-up data or distinguish between AD and AUD types. CONCLUSIONS: Our results indicate a bidirectional relationship between AD and AUD; especially those with severe AD (medication use, comorbid depression) are at risk of developing AUD. Health care professionals should focus on prevention of AD in AUD patients and prevention of AUD in patients with (more severe) AD. Further research should investigate the mechanisms underlying the observed associations.

Anxiety, Mental Stress, and Sudden Cardiac Arrest: Epidemiology, Possible Mechanisms and Future Research.

Sudden cardiac arrest (SCA) is a leading cause of mortality and morbidity in affluent societies, which underscores the need to identify persons at risk. The etiology of SCA is however complex, with predisposing and precipitating factors interacting. Although anxiety and mental stress have been linked to SCA for decades, their precise role and impact remain unclear and the biological underpinnings are insufficiently understood. In this paper, we systematically reviewed various types of observational studies (total n = 20) examining the association between anxiety or mental stress and SCA. Multiple methodological considerations challenged the summarizing and interpretation of the findings. For anxiety, the overall picture suggests that it predisposes for SCA in physically healthy populations (unadjusted OR = 2.44; 95% CI: 1.06-5.59; n = 3). However, in populations at risk for SCA (n = 4), associations were heterogeneous but not significant. Anxiety may partly predispose to SCA by contributing to other risk factors such as cardiovascular disease and diabetes mellitus via mechanisms such as unhealthy lifestyle and metabolic abnormalities. Mental stress appears to precipitate SCA, presumably by more directly impacting on the cardiac ion channels that control the heart's electrical properties. This may lead to ventricular fibrillation, the arrhythmia that underlies SCA. To advance this field of research, experimental studies that unravel the underlying biological mechanisms are deemed important, and most easily designed for mental stress as a precipitating factor because of the short timeframe. These proof-of-concept studies should examine the whole pathway from the brain to the autonomic nervous system, and eventually to cardiac ion channels. Ultimately, such studies may facilitate the identification of persons at risk and the development of novel preventive strategies.

Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring.

Currently, there is a lack of international and national guidelines or consensus documents with specific recommendations for electrocardiogram (ECG) screening and monitoring during antidepressant treatment. To make a proper estimation of the risk of cardiac arrhythmias and sudden (cardiac) death during antidepressant use, both the drug and patient-specific factors should be taken into account; however, solid evidence on how this should be done in clinical practice is lacking. Available recommendations on the management of QT(c) prolongation (with antidepressant treatment) emphasize that special attention should be given to high-risk patients; however, clinicians are in need of more concrete suggestions about how to select patients for ECG screening and monitoring. Based on a review of the literature, a Dutch multidisciplinary expert panel aimed to formulate specific guidelines to identify patients at risk for cardiac arrhythmias and sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepressant use. These relative contributions of risk factors could not be determined since no systematic reviews or meta-analyses quantitatively addressed this topic. Because evidence was insufficient, additional expert opinion was used to formulate recommendations. This resulted in readily applicable recommendations for clinical practice for selection of high-risk patients for ECG screening and monitoring. ECG screening and monitoring is recommended before and following the start of QTc-prolonging antidepressants in the presence of vulnerability to QTc prolongation or two or more risk factors (age > 65 years, female sex, concomitant use of a QTc-prolonging drug or concomitant use of a drug that influences the metabolism of a QTc-prolonging drug, cardiac disease, excessive dosing and specific electrolyte disturbances).

Depression, anxiety and 6-year risk of cardiovascular disease.

OBJECTIVE: Depression and anxiety are considered etiological factors in cardiovascular disease (CVD), though their relative contribution and differentiation by clinical characteristics have not been studied intensively. We examined 6-year associations between depressive and anxiety disorders, clinical characteristics and newly-developed CVD. METHODS: DSM-IV diagnoses were established in 2510 CVD-free participants of the Netherlands Study of Depression and Anxiety. Data on subtype, severity, and psychoactive medication were collected. The 6-year incidence of CVD was assessed using Cox regression analyses adjusted for sociodemographic, health and lifestyle factors. RESULTS: One-hundred-six subjects (4.2%) developed CVD. Having both current depressive and anxiety disorders (HR=2.86, 95%CI 1.49-5.49) or current depression only (HR=2.30; 95%CI 1.10-4.80) was significantly associated with increased CVD incidence, whereas current anxiety only (HR=1.48; 95%CI 0.74-2.96) and remitted disorders (HR=1.48; 95%CI 0.80-2.75) were not associated. Symptom severity was associated with increased CVD onset (e.g., Inventory of Depressive Symptomatology per SD increase: HR=1.51; 95%CI 1.25-1.83). Benzodiazepine use was associated with additional CVD risk (HR=1.95; 95%CI 1.16-3.31). CONCLUSIONS: Current depressive (but not anxiety) disorder independently contributed to CVD in our sample of initially CVD-free participants. CVD incidence over 6years of follow-up was particularly increased in subjects with more symptoms, and in those using benzodiazepines.

Associations between life stress and subclinical cardiovascular disease are partly mediated by depressive and anxiety symptoms.

BACKGROUND: Stress experienced during childhood or adulthood has been associated with cardiovascular disease (CVD), but it is not clear whether associations are already prevalent on a subclinical cardiovascular level. This study investigates associations between indicators of life stress and subclinical CVD, and whether these are mediated by depression and anxiety. METHODS: Subjects were 650 participants of the Netherlands Study of Depression and Anxiety, aged 20-66 years, with or without (27.5%) depressive and anxiety disorders. Life stress included childhood trauma, negative life events and recently experienced daily hassles or job strain. Subclinical CVD was measured as 1) carotid atherosclerosis (intima-media thickness and the presence of plaques) using B-mode ultrasonography, and 2) central arterial stiffness (heart rate normalized augmentation index) using calibrated radial applanation tonometry. RESULTS: Increased central arterial stiffness was shown in subjects who had experienced childhood trauma (per SD increase: ß=.07; p=.01), or reported recently experienced daily hassles (per SD increase: ß=.06; p=.02), negative life events (per SD increase: ß=.05; p=.03), or job strain (high versus low: ß=.09; p=.01). Associations between life stress and arterial stiffness appeared to be partly mediated by severity of depressive and anxiety symptoms. No significant associations were found for childhood life events, nor between indicators of life stress and carotid atherosclerosis. CONCLUSIONS: Childhood trauma and recent life stress were associated with increased central arterial stiffness. This suggests that life stress - partly via depression and anxiety - might enhance the development and progression of CVD.