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The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to similar to 0.7% of the variance in depression in Rotterdam Study and up to similar to 1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples. Molecular Psychiatry (2011) 16, 773-783; doi:10.1038/mp.2010.65; published online 22 June 2010

Dysfunctional self-schemas are assumed to play an important role in suicidal ideation. According to recent information-processing models, it is important to differentiate between 'explicit' beliefs and automatic associations. Explicit beliefs stem from the weighting of propositions and their corresponding 'truth' values, while automatic associations reflect more simple associations in memory. Both types of associations are assumed to have different functional properties and both may be involved in suicidal ideation. Thus far, studies into self-schemas and suicidal ideation focused on the more explicit, consciously accessible traces of self-schemas and predominantly relied on self-report questionnaires or interviews. To complement these 'explicit' findings and more directly tap into self-schemas, this study investigated automatic self-associations in a large scale community sample that was part of the Netherlands Study of Depression and Anxiety (NESDA). The results showed that automatic self-associations of depression and anxiety were indeed significantly related to suicidal ideation and past suicide attempt. Moreover, the interactions between automatic self-depressive (anxious) associations and explicit self-depressive (anxious) beliefs explained additional variance over and above explicit self-beliefs. Together these results provide an initial insight into one explanation of why suicidal patients might report difficulties in preventing and managing suicidal thoughts. © 2009 The Author(s).

The present study compared blood pressure levels between subjects with clinical anxiety and depressive disorders with healthy controls. Cross-sectional data were obtained in a large cohort study, the Netherlands Study of Depression and Anxiety (N=2981). Participants were classified as controls (N=590) or currently or remittedly depressed or anxious subjects (N=2028), of which 1384 were not and 644 were using antidepressants. Regression analyses calculated the contributions of anxiety and depressive disorders and antidepressant use to diastolic and systolic blood pressures, after controlling for multiple covariates. Heart rate and heart rate variability measures were subsequently added to test whether effects of anxiety/depression or medication were mediated by vagal control over the heart. Higher mean diastolic blood pressure was found among the current anxious subjects (β=0.932; P=0.03), although anxiety was not significantly related to hypertension risk. Remitted and current depressed subjects had a lower mean systolic blood pressure (β=-1.74, P=0.04 and β=-2.35, P=0.004, respectively) and were significantly less likely to have isolated systolic hypertension than controls. Users of tricyclic antidepressants had higher mean systolic and diastolic blood pressures and were more likely to have hypertension stage 1 (odds ratio: 1.90; 95% CI: 0.94 to 3.84; P=0.07) and stage 2 (odds ratio: 3.19; 95% CI: 1.35 to 7.59; P=0.008). Users of noradrenergic and serotonergic working antidepressants were more likely to have hypertension stage 1. This study shows that depressive disorder is associated with low systolic blood pressure and less hypertension, whereas the use of certain antidepressants is associated with both high diastolic and systolic blood pressures and hypertension. (Hypertension. 2009;53:631-638.) © 2009 American Heart Association, Inc.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 × 10

Background: Although anxiety disorders are prevalent in older adults, randomized controlled trials of treatment effectiveness for late-life anxiety are scarce and have focused primarily on the effectiveness of psychotherapeutic interventions. However, recent findings suggest that in some cases, pharmacological treatment may be more beneficial for late-life anxiety disorders. As yet, there have been no systematic studies investigating prognostic factors for the outcome of cognitive behavioral therapy (CBT) and pharmacotherapy for late-life anxiety. The objective of the present study was to study long-term treatment outcomes and to explore differential predictors for both short-term and long-term treatment outcomes of sertraline and CBT for late-life anxiety disorders. Methods: Participants of a randomized controlled trial (RCT) comparing sertraline and CBT for the treatment of late-life anxiety were contacted one year after completing their treatment, so that predictors for both short-term and long-term treatment outcome could be established. Results: Sertraline showed a greater reduction of symptoms than CBT on anxiety (Hamilton Anxiety Rating Scale; HARS) and worry (Worry Domain Questionnaire) ratings at one-year follow-up. The strongest predictor for short-term CBT outcome was poor perceived health, explaining 40% of the variance in post-treatment residual gain scores on the HARS. The strongest predictor for long-term CBT outcome was neuroticism, explaining 20% of the variance in residual gain scores at one-year follow-up. Analyses revealed no significant predictors for treatment outcome in sertraline participants. Conclusions: Our study suggests that long-term use of sertraline might be more beneficial for late-life anxiety than a 15-week CBT program. Poor perceived health and neuroticism are predictive of less improvement after CBT in anxious older adults. Implications of these findings are discussed. © 2009 International Psychogeriatric Association.

Objective: To determine whether patients with different types of anxiety disorder (panic disorder, social phobia, generalized anxiety disorder) have higher heart rate and lower heart rate variability compared with healthy controls in a sample that was sufficiently powered to examine the confounding effects of lifestyle and antidepressants. Methods: The standard deviation of the normal-to-normal intervals (SDNN), heart rate (HR), and respiratory sinus arrhythmia (RSA) were measured in 2059 subjects (mean age = 41.7 years, 66.8% female) participating in The Netherlands Study of Depression and Anxiety (NESDA). Based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) and Composite International Diagnostic Interview (CIDI), NESDA participants were classified as healthy controls (n = 616), subjects with an anxiety diagnosis earlier in life (n = 420), and subjects with current anxiety diagnosis (n = 1059). Results: Current anxious subjects had a significantly lower SDNN and RSA compared with controls. RSA was also significantly lower in remitted anxious subjects compared with controls. These associations were similar across the three different types of anxiety disorders. Adjustment for lifestyle had little impact. However, additional adjustment for antidepressant use reduced all significant associations between anxiety and HRV to nonsignificant. Anxious subjects who used a tricyclic antidepressant, a selective serotonin reuptake inhibitor, or another antidepressant showed significantly lower mean SDNN and RSA compared with controls (effect sizes = 0.20-0.80 for SDNN and 0.42-0.79 for RSA). Nonmedicated anxious subjects did not differ from controls in mean SDNN and RSA. Conclusion: This study shows that anxiety disorders are associated with significantly lower HR variability, but the association seems to be driven by the effects of antidepressants Copyright © 2009 by the American Psychosomatic Society.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

The Netherlands Study of Depression and Anxiety (NESDA) is a multi-site naturalistic cohort study to: (1) describe the long-term course and consequences of depressive and anxiety disorders, and (2) to integrate biological and psychosocial research paradigms within an epidemiological approach in order to examine (interaction between) predictors of the long-term course and consequences. Its design is an eight-year longitudinal cohort study among 2981 participants aged 18 through 65 years. The sample consists of 1701 persons with a current (six-month recency) diagnosis of depression and/ or anxiety disorder, 907 persons with life-time diagnoses or at risk because of a family history or subthreshold depressive or anxiety symptoms, and 373 healthy controls. Recruitment took place in the general population, in general practices (through a three-stage screening procedure), and in mental health organizations in order to recruit persons reflecting various settings and developmental stages of psychopathology. During a four-hour baseline assessment including written questionnaires, interviews, a medical examination, a cognitive computer task and collection of blood and saliva samples, extensive information was gathered about key (mental) health outcomes and demographic, psychosocial, clinical, biological and genetic determinants. Detailed assessments will be repeated after one, two, four and eight years of follow-up. The findings of NESDA are expected to provide more detailed insight into (predictors of) the long-term course of depressive and anxiety disorders in adults. Besides its scientific relevance, this may contribute to more effective prevention and treatment of depressive and anxiety disorders. Copyright © 2008 John Wiley & Sons, Ltd.

To identify the genomic regions that confer risk and protection for major depressive disorder (MDD) in humans, large-scale studies are needed. Such studies should collect multiple phenotypes, DNA, and ideally, biological material that allows gene expression analysis, transcriptomic, proteomic, and metabolomic studies. In this paper, we briefly review linkage studies of MDD and then describe the large-scale nationwide biological sample collection in Dutch twin families from the Netherlands Twin Register (NTR) and in participants in the Netherlands Study of Depression and Anxiety (NESDA). Within these studies, 1862 participants with a diagnosis of MDD and 1857 controls at low liability for MDD have been selected for genome-wide genotyping by the US Foundation for the National Institutes of Health Genetic Association Information Network. Stage 1 genome-wide association results are scheduled to be accessible before the end of 2007. Genome-wide association results are open-access and can be viewed at the dbGAP web portal (http://www.ncbi.nlm.nih.gov). Approved users can download the genotype and phenotype data, which have been made available as of 9 October 2007.

Context: It has been hypothesized that depression is associated with lower heart rate variability and decreased cardiac vagal control. This may play an important role in the risk of cardiovascular diseaseamongdepressed individuals. Objective: To determine whether heart rate variability was lower in depressed individuals than in healthy controls in a large adult sample. Design: Cross-sectional analyses from a large depression cohort study. Setting: The Netherlands Study of Depression and Anxiety. Participants: Two thousand three hundred seventy-three individuals (mean age, 41.8 years; 66.8% female) who participated in the Netherlands Study of Depression and Anxiety. Included were 524 controls, 774 individuals with a diagnosis of major depressive disorder (MDD) earlier in life (remitted MDD), and 1075 individuals with current MDD based on the Composite International Diagnostic Interview. This sample was sufficiently powered to examine the confounding effects of lifestyle, comorbid anxiety, and antidepressants. Main Outcome Measures: The standard deviation of normal-to-normal beats (SDNN) and cardiac vagal control, as indexed by respiratory sinus arrhythmia (RSA), were measured during 11/2 hours of ambulatory recording of electrocardiograms and thorax impedance. Multivariate analyses were conducted to compare SDNN and RSA across depression groups after adjustment for demographics, health, lifestyle, comorbid anxiety, and psychoactive medication. Results: Individuals with remitted and current MDD had a lower mean SDNN and RSA compared with controls (SDNN, 3.1-5.7 milliseconds shorter, P ≤ .02; RSA, 5.1-7.1 milliseconds shorter, P < .001; effect size, 0.125-0.269). Comorbid anxiety and lifestyle did not reduce these associations. However, accounting for psychoactive medication removed the association with SDNN and strongly attenuated the association with RSA. Depressed individuals who were using selective serotonin reuptake inhibitors, tricyclic antidepressants, or ot

Background: Minor and mild-major depression are highly prevalent in primary care. There is insufficient evidence for the effectiveness of antidepressants in the treatment of minor and mild-major depression. We compared the effectiveness of usual primary care treatment, with or without antidepressants, in minor and mild-major depression. Methods: Apragmatic patient-randomized equivalence trial with 52 weeks follow-up was conducted in The Netherlands. In total, 59 primary care physicians (PCPs) recruited and treated 181 adult patients with minor or mild-major depression. Patients were randomized to four consultations within 3 months of usual care plus antidepressants (UCandAD) or usual care alone (UCnoAD). The Montgomery Åsberg Depression Rating Scale (MADRS) was used to assess changes in severity of depressive symptoms. The predefined equivalence margin was set at five points. Multilevel analysis was used to analyze the data. Secondary outcome measures were the Short-Form 36 (SF-36), and the Client Satisfaction Questionnaire (CSQ-8). Results: Patients received on average 3.0 (SD 1.4) 15-min consultations within 3 months with (n = 85) or without paroxetine (n = 96). Equivalence of UCandAD and UCnoAD was demonstrated in the intention-to-treat analyses as well as the per-protocol analysis after 6 weeks, but not at 13, 26 and 52 weeks follow-up. No statistical differences in effectiveness between treatment groups were found in the intention-to-treat analysis. No differences in the physical and mental functioning (SF-36) were found between the treatment groups. Patients allocated to UCandAD were slightly more satisfied with their treatment at 13 weeks follow-up (but not at 52 weeks follow-up) than patients allocated to UCnoAD. Preliminary analyses suggested that subgroups such as patients with mild-major (instead of a minor) depression might benefit from antidepressant treatment. Patients who were assigned to their preferred treatment (in particular to UCnoAD) were more o

Background. Co-morbidity within anxiety disorders, and between anxiety disorders and depression, is common. According to the theory of Gray and McNaughton, this co-morbidity is caused by recursive interconnections linking the brain regions involved in fear, anxiety and panic and by heritable personality traits such as neuroticism. In other words, co-morbidity can be explained by one disorder being an epiphenomenon of the other and by a partly shared genetic etiology. The aim of this paper is to evaluate the theory of Gray and McNaughton using the results of genetic epidemiological studies. Method. Twenty-three twin studies and 12 family studies on co-morbidity are reviewed. To compare the outcomes systematically, genetic and environmental correlations between disorders are calculated for the twin studies and the results from the family studies are summarized according to the method of Klein and Riso. Results. Twin studies show that co-morbidity within anxiety disorders and between anxiety disorders and depression is explained by a shared genetic vulnerability for both disorders. Some family studies support this conclusion, but others suggest that co-morbidity is due to one disorder being an epiphenomenon of the other. Conclusions. Discrepancies between the twin and family studies seem partly due to differences in used methodology. The theory of Gray and McNaughton that neuroticism is a shared risk factor for anxiety and depression is supported. Further research should reveal the role of recursive interconnections linking brain regions. A model is proposed to simultaneously investigate the influence of neuroticism and recursive interconnections on co-morbidity. © 2005 Cambridge University Press.

Background. Dissociation, defined as a disruption in usually integrated mental functions, is found not only in DSM-IV dissociative disorders, but also in post-traumatic stress disorder and eating disorders. Dissociative phenomena are also common in the general population, and may reflect a constitutionally determined cognitive style rather than a pathological trait acquired through experiencing adverse life events. In pathological dissociation, evidence has been presented for episodic memory dysfunction. In contrast, in high-dissociative subjects increased performance has been found for episodic memory and dual task performance. These findings have been linked to changes in working memory capacity. Method. In the present study, the authors sought to extend these findings by using functional magnetic resonance imaging during performance of two parametric working memory tasks. We tested 21 healthy low- and high-dissociative participants. Results. High-dissociative participants performed slightly better during both tasks. Imaging data showed that both groups activated similar networks for both tasks, i.e. (bilateral) dorsolateral (DL) and ventrolateral prefrontal cortex (PFC), parietal cortex, and supplementary motor area. Group x task interactions were found in the high-dissociative group in L DLPFC and L parietal cortex; in the low-dissociative group in R fusiform gyrus. The differences in the high-dissociative group were independent from performance differences, implying that high-dissociative subjects generally recruit this network to a greater extent. Conclusions. These results confirm earlier findings using a verbal WM task in high-dissociative participants, and are compatible with the conceptualization of non-pathological dissociation as an information-processing style, characterized by distinct attentional and mnemonic abilities. © 2004 Cambridge University Press.