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.

OBJECTIVE: To test the hypotheses that dysregulation of the autonomic nervous system (ANS) is associated with the presence of chronic widespread pain (CWP), and that dysregulation of the ANS is associated with higher pain intensity in CWP.
METHODS: Cross-sectional data were obtained from 1,574 subjects (healthy controls as well as persons with depressive and anxiety disorders) participating in The Netherlands Study of Depression and Anxiety. The Chronic Pain Grade was used to assess pain intensity and pain-related disability. Heart rate (HR), SD of the normal-to-normal interval (SDNN), the preejection period (PEP), and respiratory sinus arrhythmia (RSA) were used to assess the ANS. Logistic regression analyses and linear regression analyses were conducted with adjustment for potential confounders.
RESULTS: No differences in HR, PEP, SDNN, or RSA values were found between CWP subjects and controls after adjustment for confounders. However, lower SDNN and lower RSA were associated with higher pain intensity in subjects with CWP.
CONCLUSION: Lower parasympathetic activity, as assessed with SDNN and RSA, is associated with higher pain intensity in subjects with CWP. This large and well-controlled study does not provide evidence for an association between dysregulation of the ANS and the presence of CWP.

To study late-life depression and its unfavourable course and co morbidities in The Netherlands.

Background
Heavy alcohol use as well as alcohol dependence (AD) have been associated with dysregulation of the hypothalamic–pituitary–adrenal (HPA)-axis and the autonomic nervous system (ANS). However, the relative contribution of alcohol use and AD is unclear.
Methods
Baseline data were derived from 2947 persons of the Netherlands Study of Depression and Anxiety (NESDA), including non-drinkers (n=498), moderate drinkers (n=2112) and heavy drinkers (n=337). We also distinguished between persons with no lifetime DSM-IV AD (n=2496), remitted AD (>1 year; n=243), and current AD (≤1 year; n=208). ANS measures included ECG-based heart rate (HR), respiratory sinus arrhythmia (RSA, high RSA reflecting high cardiac parasympathetic control) and pre-ejection period (PEP, high PEP reflecting low cardiac sympathetic control). HPA-axis measures included the cortisol awakening response (area under the curve with respect to the ground [AUCg] and increase [AUCi]), evening cortisol and a 0.5mg dexamethasone suppression test, all measured in saliva.
Results
Heavy drinkers showed higher basal cortisol levels (AUCg: p=.02; evening cortisol: p=.006) and increased cardiac sympathetic control (higher HR: p=.04; lower PEP: p=.04) compared to moderate drinkers. Persons with current or remitted AD did not differ from persons without lifetime AD on any of the HPA-axis or ANS indicators (all p>.33). Similar patterns of HPA-axis and ANS activity across alcohol use groups were found in persons with and without lifetime AD.
Conclusions
Our findings suggest that current heavy alcohol use, rather than current or remitted AD, is associated with hyperactivity of the HPA-axis and increased cardiac sympathetic control.

Objectives Dysregulated biological stress systems and adverse life events, independently and in interaction, have been hypothesised to initiate chronic pain. We examine whether (1) function of biological stress systems, (2) adverse life events, and (3) their combination predict the onset of chronic multisite musculoskeletal pain.
Methods Subjects (n=2039) of the Netherlands Study of Depression and Anxiety, free from chronic multisite musculoskeletal pain at baseline, were identified using the Chronic Pain Grade Questionnaire and followed up for the onset of chronic multisite musculoskeletal pain over 6 years. Baseline assessment of biological stress systems comprised function of the hypothalamic-pituitary-adrenal axis (1-h cortisol awakening response, evening levels, postdexamethasone levels), the immune system (basal and lipopolysaccharide-stimulated inflammation) and the autonomic nervous system (heart rate, pre-ejection period, SD of the normal-to-normal interval, respiratory sinus arrhythmia). The number of recent adverse life events was assessed at baseline using the List of Threatening Events Questionnaire.
Results Hypothalamic-pituitary-adrenal axis, immune system and autonomic nervous system functioning was not associated with onset of chronic multisite musculoskeletal pain, either by itself or in interaction with adverse life events. Adverse life events did predict onset of chronic multisite musculoskeletal pain (HR per event=1.14, 95% CI 1.04 to 1.24, p=0.005).
Conclusions This longitudinal study could not confirm that dysregulated biological stress systems increase the risk of developing chronic multisite musculoskeletal pain. Adverse life events were a risk factor for the onset of chronic multisite musculoskeletal pain, suggesting that psychosocial factors play a role in triggering the development of this condition.

Objective
The observed poorer physical function in persons with mental disorders could partly be due to dysregulation in physiological stress systems. However, an integrated picture of the role of physiological stress systems on objective physical function is lacking. This study examined the association of multiple physiological stress systems with objective physical function, and explored whether these stress systems contribute to the relationship between depression/anxiety and poorer physical function.
Methods
Data of 2860 persons of the Netherlands Study of Depression and Anxiety was used. Physical function was indicated by hand grip strength assessed using a hand-held dynamometer and lung function assessed using a peak flow meter. Inflammatory markers (CRP, IL-6, TNF-α), salivary cortisol (cortisol awakening response (AUCg, AUCi), evening cortisol) and ANS markers (heartrate, PEP, RSA) were determined. Depression/anxiety disorders were determined using psychiatric interviews. Linear regression analyses were adjusted for sociodemographics, health and lifestyle factors.
Results
Higher inflammation levels were associated with lower hand grip strength (BCRP = -0.21(SE = 0.06), p < .001) and lower lung function (BCRP = -2.07(SE = 0.66), p = .002), BTNF-α = −3.35(SE = 1.42), p = .022). Higher salivary cortisol levels were associated with lower lung function (Bevening cortisol = −2.22(SE = 0.59), p < .001). The association, in women, between depression/anxiety disorders and poorer physical function did not significantly diminish after adjustment for physiological stress markers. Conclusion This large cohort study showed that stress system dysfunction (especially the immune-inflammatory system and HPA-axis) contributes to poorer objective physical function. Stress system dysfunction did not explain the poorer physical function observed in persons with depression/anxiety disorders, suggesting that other pathways are involved to explain that association.