Hek, K.

Anxiety Disorders and Depression in Older Adults (Doctoral Thesis)

2013-04-24T00:00:00Z

Anxiety disorders and depression are common and complex disorders. Despite decades of research, their etiology is largely unknown. Study of the occurrence and determinants, i.e. the epidemiology of anxiety disorders and depression, helps unravel their etiology. This thesis examines the epidemiology of anxiety disorders and depression in older adults. In particular, comorbidity, health care use, cortisol and atherosclerosis and genetic factors are studied in relation to anxiety and, or depression.

The prevalence and characteristics of complicated grief in older adults (Article)

2011-07-01T00:00:00Z

Background: Complicated grief is a prolongation of the normal grieving process with distinct characteristics. It impairs mental and physical health and can potentially greatly impact the quality of life of sufferers and their families. The prevalence and characteristics of complicated grief in the general population are currently unclear. The aims of the present study were therefore to evaluate the prevalence of complicated grief in a population-based cohort, examine the overlap between anxiety and depression and identify common bereavement-related and socio-demographic characteristics. Methods: Based within the Rotterdam Study, 5741 older adults were evaluated. Complicated grief was assessed with a 17-item Inventory of Complicated Grief. Results: Prevalence within the general population was 4.8%. Current grief was reported by 1089 participants, and of these 277 (25.4%) were diagnosed with complicated grief. Inflated anxiety and depression rates were documented in people with complicated grief, but the vast majority remained free from co-morbidity. Time since bereavement and relationship to deceased, particularly when the source was a spouse or child, were predictive of complicated grief. People with complicated grief were older, had a lower level of education, and more cognitive impairment. Conclusions: The prevalence of complicated grief in older adults in the general population was noteworthy. Several factors were predictive of complicated grief and it was demonstrated as a separate condition to anxiety and depression. These findings highlight the need for prevention, diagnosis and treatment options for older adults with complicated grief and for recognition of complicated grief as a distinct diagnosis.

The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression (Article)

2011-04-28T00:00:00Z

Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.

The Neuronal Transporter Gene SLC6A15 Confers Risk to Major Depression (Article)

2011-04-01T00:00:00Z

SUMMARY: Major depression (MD) is one of the most prevalent psychiatric disorders and a leading cause of loss in work productivity. A combination of genetic and environmental risk factors probably contributes to MD. We present data from a genome-wide association study revealing a neuron-specific neutral amino acid transporter (SLC6A15) as a susceptibility gene for MD. Risk allele carrier status in humans and chronic stress in mice were associated with a downregulation of the expression of this gene in the hippocampus, a brain region implicated in the pathophysiology of MD. The same polymorphisms also showed associations with alterations in hippocampal volume and neuronal integrity. Thus, decreased SLC6A15 expression, due to genetic or environmental factors, might alter neuronal circuits related to the susceptibility for MD. Our convergent data from human genetics, expression studies, brain imaging, and animal models suggest a pathophysiological mechanism for MD that may be accessible to drug targeting.

Genetics of cortisol secretion and depressive symptoms: A candidate gene and genome wide association approach (Article)

2011-02-14T00:00:00Z

Background: Depressive patients often have altered cortisol secretion, but few studies have investigated genetic variants in relation to both cortisol secretion and depression. To identify genes related to both these conditions, we: (1) tested the association of single nucleotide polymorphisms (SNPs) in hypothalamic-pituitary-adrenal-axis (HPA-axis) candidate genes with a summary measure of total cortisol secretion during the day (cortisolAUC), (2) performed a genome wide association study (GWAS) of cortisolAUC, and (3) tested the association of identified cortisol-related SNPs with depressive symptoms. Methods: We analyzed data on candidate SNPs for the HPA-axis, genome-wide scans, cortisol secretion (n = 1711) and depressive symptoms (the Centre for Epidemiology Studies Depression Scale, CES-D) (n = 2928) in elderly persons of the Rotterdam Study. We used data from the Whitehall II study (n = 2836) to replicate the GWAS findings. Results: Of the 1456 SNPs in 33 candidate genes, minor alleles of 4 SNPs (rs9470080, rs9394309, rs7748266 and rs1360780) in the FKBP5 gene were associated with a decreased cortisolAUC (p < 1 × 10(-4) after correction for multiple testing using permutations). These SNPs were also associated with an increased risk of depressive symptoms (rs9470080: OR 1.19 (95%CI 1.0; 1.4)). The GWAS for cortisol yielded 2 SNPs with p-values of 1 × 10(-06) (rs8062512, rs2252459), but these associations could not be replicated. Conclusions: These results suggest that variation in the FKBP5 gene is associated with both cortisolAUC and the likelihood of depressive symptoms.

Atherosclerosis and Incident Depression in Late Life (Article)

2010-11-01T00:00:00Z

Abstract CONTEXT: Depression is a prominent concern for older adults; therefore, it is important to identify causal mechanisms so that prevention and treatment strategies can be developed. The vascular depression hypothesis proposes that vascular factors precede the onset of depression in older adults. However, although cross-sectional associations have been established, owing to a lack of objective assessments and longitudinal data, the validity and temporal nature of this relationship is unclear. OBJECTIVE: To examine whether atherosclerosis, an asymptomatic subclinical indicator of vascular burden, increases the risk of developing depression in older adults. DESIGN: Prospective, population-based study. SETTING: Set within the Rotterdam study, participants were assessed on objective measures of generalized atherosclerosis at baseline (1997-1999) and followed up for an average of 6 years for incident depression. PARTICIPANTS: The baseline sample consisted of 3564 participants (56% female) with a mean age of 72 years who initially did not have depression or dementia. MAIN OUTCOME MEASURES: Depression was categorized into symptoms or syndromes and assessed in a multidimensional manner from physician and mental health specialist reports, pharmacy records (antidepressant usage), a clinical interview, and self-report. RESULTS: During 21 083 person-years, 429 incidents of depressive symptoms and 197 incidents of depressive syndromes occurred. Individual atherosclerotic measures and a composite measure were not predictive of incident depressive symptoms (composite measure hazard ratio, 0.93; 95% confidence interval, 0.83-1.05) or incident depressive syndromes (composite measure hazard ratio, 0.97; 95% confidence interval, 0.81-1.16). An a priori power analysis indicated a sufficient sample size (α = .05; 0.95 power). CONCLUSIONS: Atherosclerosis does not appear to increase the risk of incident depression in older adults. These findings do not support the vascular depression hypothesis and, alternatively, taking findings from prior studies into account, suggest either that depression contributes to vascular burden or that both result from an underlying biological substrate.

Genetic risk profiles for depression and anxiety in adult and elderly cohorts (Article)

2010-06-01T00:00:00Z

Abstract 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 approximately 0.7% of the variance in depression in Rotterdam Study and up to approximately 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

The PCLO gene and depressive disorders: replication in a population-based study (Article)

2010-02-01T00:00:00Z

Abstract: Previous genome-wide association analysis revealed a new putative candidate gene for major depression: the PCLO gene. Replication in one population-based cohort did not yield genome-wide significance and further replication efforts in clinical studies were unsuccessful. We aimed to validate the association of single-nucleotide polymorphism (SNP) rs2522833 in the PCLO gene with depression in the Rotterdam Study, a prospective population-based cohort of elderly persons. In the Rotterdam Study, we identified 579 persons with a broad depression phenotype (depressive syndromes) of whom 178 cases with DSM-defined depressive disorder. The control group consisted of 912 persons free of depression during the follow-up period and in their histories. Logistic regression analysis showed an association between rs2522833 and depressive disorders (P = 0.0025). However, no association between the broader depressive syndrome group and this SNP was observed (P = 0.20). A meta-analysis combining all studies from the original publication and our study yielded a P-value of 2.16 x 10(-3) for the association between SNP rs2522833 and depressive disorders. However, as in the previous publication, high heterogeneity between studies was observed. Thus, a meta-analysis with the findings from three population-based studies was performed. This demonstrated a genome-wide significant P-value (P = 1.93 x 10(-9)). In conclusion, this study provides additional evidence for an association between PCLO and depressive disorders in a population-based study; no association with a broader syndromal phenotype was observed.