Biological Determinants of Depression: An epidemiological approach

Understanding the biology behind depression has a long history in research. To date, no unique marker or specific etiological factor was detected. However, we know more about the possible mechanisms that predispose depression or affect clinical presentation and prognosis of depression. In this thesis, we studied various hypotheses to extend our knowledge about biological determinants of depression using an epidemiological approach. The main aims of this thesis were 1) to scrutinize the determinants and the genetic control of different functions of the HPA axis, a well-known neurohormonal correlate of depression, 2) to revisit the vascular depression hypothesis and explored the associations of non-clinical cerebrovascular alterations with depression, and 3) to explore genetic etiology of depression using the genome-wide association approach

Sleep and 24-h activity rhythms in relation to cortisol change after a very low-dose of dexamethasone

The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in sleep. Nevertheless, the association of sleep and its 24-h organization with negative feedback control of the HPA axis has received limited attention in population-based studies. We explored this association in 493 mid

The very low-dose dexamethasone suppression test in the general population: A cross-sectional study

Determinants of the hypothalamic-pituitary-adrenal (HPA) axis functioning are increasingly explored in population-based studies. However, functional tests measuring the negative feedback of the HPA axis cannot easily be implemented into large observational studies. Furthermore, high doses of dexamethasone often completely suppress the HPA axis in healthy persons. This study aimed to detect the effects of the health, lifestyle and sociodemographic factors, psychiatric problems and cognitive functions on the negative feedback of the HPA axis using a very low-dose (0.25 mg) dexamethasone suppression test (DST). We evaluated the associations of several determinants with the saliva cortisol concentrations after dexamethasone intake in a confounder-adjusted model also corrected for baseline saliva cortisol concentrations in the Rotterdam Study, a large population-based study (N = 1822). We found that female sex, low income, lack of exercise, instrumental disability and smoking were all independently associated with stronger suppression of the HPA axis. Even though there were no linear associations between psychiatric measures and cortisol suppression, we found that depressive symptoms and anxiety disorders were more common in persons with non-suppression of cortisol. Conversely, psychotropic medication use was related to enhanced suppression of cortisol after DST. In this large study, we found that female gender, low socioeconomic status and poor health were all related to suppression of the HPA axis. Non-linear associations were detected between the suppression of the HPA axis and common psychiatric disorders in community-dwelling persons

Bivariate genome-wide association analyses of the broad depression phenotype combined with major depressive disorder, bipolar disorder or schizophrenia reveal eight novel genetic loci for depression

Although a genetic basis of depression has been well established in twin studies, identification of genome-wide significant loci has been difficult. We hypothesized that bivariate analyses of findings from a meta-analysis of genome-wide association studies (meta-GWASs) of the broad depression phenotype with those from meta-GWASs of self-reported and recurrent major depressive disorder (MDD), bipolar disorder and schizophrenia would enhance statistical power to identify novel genetic loci for depression. LD score regression analyses were first used to estimate the genetic correlations of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia. Then, we performed four bivariate GWAS analyses. The genetic correlations (rg ± SE) of broad depression with self-reported MDD, recurrent MDD, bipolar disorder and schizophrenia were 0.79 ± 0.07, 0.24 ± 0.08, 0.53

Anxiety disorders and salivary cortisol levels in older adults: A population-based study

Context: The hypothalamic-pituitary-adrenal (HPA) axis is one of the body's main systems that controls response to stress. It acts through the hormone cortisol. While the dysregulation of cortisol has been associated with anxiety disorders, the evidence is inconsistent. Moreover, only a few small studies have assessed this relationship in older adults. Objective: To determine whether in adults aged 65 years and over there is a difference in daily cortisol pattern between those with and without an anxiety disorder. Methods: The study population comprised 1788 older adults from a population-based cohort. The Munich version of the Composite International Diagnostic Interview was used to diagnose anxiety disorders (generalized anxiety disorder, social phobia, specific phobia, agoraphobia and panic disorder). The cortisol awakening response and total cortisol secretion over the day were calculated from cortisol levels in four saliva samples taken over the course of one day (at awakening, 30. min after awakening, at 1700. h, at bedtime). Results: Older adults with an anxiety disorder (n=145, median duration since first symptoms 41 years) had a lower cortisol awakening response (p=0.02) than those without such a disorder (n=1643). This association was most prominent in those with generalized anxiety disorder (p=0.008), but was not associated with the extent of chronicity of anxiety disorders. Conclusion: Older adults from the general population with long-lasting anxiety disorders had a lower cortisol awakening response than those without. This is consistent with the notion that chronic anxiety may result in downregulation of HPA-axis activity. Longitudinal studies are needed to confirm this mechanism

Depressive symptoms predict incident dementia during short- but not long-term follow-up period

Background: Whether depression is a long-term risk factor for dementia or represents a dementia prodrome is unclear. Therefore, we examined the relationship between depressive symptoms and dementia during short and long follow-up in a population-based cohort. Methods: In the Rotterdam Study, 4393 nondemented individuals were followed for incident dementia for 13.7 years by continuous monitoring. Cox proportional hazards models for different time intervals were used to estimate the risk of incident dementia. Results: Five-hundred eighty-two participants developed dementia during 13.7 years. Persons with depressive symptoms had an 8% increased risk of dementia compared with those without depressive symptoms during the overall follow-up. The risk was highest in the short and intermediate follow-up, particularly in men. We did not find an association in the follow-up period beyond 10 years. Conclusion: Our results suggest that late-life depressive symptoms are part of a dementia prodrome rather than an independent risk factor of dementia