Context: Stress is suggested to lead to metabolic dysregulations as clustered in the metabolic syndrome, but the underlying biological mechanisms are not yet well understood.Objective: We examined the relationship between two main str systems, the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis, with the metabolic syndrome and its components.Design: The design was baseline data (yr 2004–2007) of a prospective cohort: the Netherlands Study of Depression and Anxiety (NESDA).Setting: The study comprised general community, primary care, and specialized mental health care.Participants: This study included 1883 participants aged 18–65 yr.Main Outcome Measures: Autonomic nervous system measures included heart rate, respiratory sinus arrhythmia (RSA; high RSA reflecting high parasympathetic activity), and preejection period (PEP; high PEP reflecting low sympathetic activity). HPA axis measures included the cortisol awakening response, evening cortisol, and a 0.5 mg dexamethasone suppression test as measured in saliva. Metabolic syndrome was based on the updated Adult Treatment Panel III criteria and included high waist circumference, serum triglycerides, blood pressure, serum glucose, and low high-density lipoprotein cholesterol.Results: RSA and PEP were both independently negatively associated with the presence of the metabolic syndrome, the number of metabolic dysregulations as well as all individual components except high-density lipoprotein cholesterol (all P < 0.02). Heart rate was positively related to the metabolic syndrome, the number of metabolic dysregulations, and all individual components (all P < 0.001). HPA axis measures were not related to metabolic syndrome or its components.Conclusion: Our findings suggest that increased sympathetic and decreased parasympathetic nervous system activity is associated with metabolic syndrome, whereas HPA axis activity is not.

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.

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.

Background
Dyslipidemia and obesity have been observed in persons with severe anxiety or depression, and in tricyclic antidepressant (TCA) users. This likely contributes to the higher risk of cardiovascular disease (CVD) in anxiety and depressive disorders. We aimed to elucidate whether biological stress systems or lifestyle factors underlie these associations. If so, they may be useful targets for CVD prevention and intervention.
Methods
Within 2850 Netherlands Study of Depression and Anxiety (NESDA) participants, we evaluated the explaining impact of biological stress systems (i.e., the hypothalamic–pituitary–adrenal [HPA] axis, autonomic nervous system [ANS] and inflammation) and lifestyle factors (i.e., tobacco and alcohol use, and physical activity) on adverse associations of anxiety and depression severity and TCA use with high and low-density lipoprotein cholesterol, triglycerides, body mass index and waist circumference. Through linear regression analyses, percentual change (%Δ) in β was determined and considered significant when %Δ>10.
Results
The inflammatory marker C-reactive protein had the most consistent impact (explaining 14–53% of the associations of anxiety and depression severity and TCA use with lipid and obesity levels), followed by tobacco use (explaining 34–43% of the associations with lipids). The ANS mediated all associations with TCA use (explaining 32–61%). The HPA axis measures did not explain any of the associations.
Conclusions
Increased dyslipidemia and (abdominal) obesity risk in patients with more severe anxiety disorders and depression may be partly explained by chronic low-grade inflammation and smoking. TCAs may increase metabolic risk through enhanced sympathetic and decreased parasympathetic ANS activity. That the HPA axis had no impact in our sample may reflect the possibility that the HPA axis only plays a role in acute stress situations rather than under basal conditions.

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.