Physical activity, alcohol use and smoking might affect cardiovascular disease through modifying autonomic nervous system (ANS) activity. We investigated: 1) whether there are consistent relationships between lifestyle factors and cardiac ANS activity over time, and 2) whether 2-year changes in lifestyle factors relate to 2-year changes in cardiac activity. Baseline (n=2618) and 2-year follow-up (n=2010) data of the Netherlands Study of Depression and Anxiety was combined. Baseline data was collected in the Netherlands from 2004–2007. Lifestyle factors were habitual physical activity, frequency of sport activities, alcohol use, and smoking. Indicators of cardiac activity were heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP) (100min of registration). The results showed that high physical activity (−1.8beats/min compared to low activity), high frequency of sport activities (‘couple of times/week’: −2.5beats/min compared to ‘almost never’) and mild/moderate alcohol use (−1.2beats/min compared to non-drinking) were related to low HR. Heavy smoking was related to high HR (>30cigarettes/day: +5.1beats/min compared to non-smoking). High frequency of sport activities was associated with high RSA (‘couple of times/week’:+1.7ms compared to ‘almost never’) and moderate smoking with longer PEP (11–20cigarettes/day: +2.8ms compared to non-smoking). Associations were consistent across waves. Furthermore, 2-year change in frequency of sport activities and number of smoked cigarettes/day was accompanied by 2-year change in HR (β=−0.076 and β=0.101, respectively) and RSA (β=0.046 and β=−0.040, respectively). Our findings support consistent effects of lifestyle on HR and parasympathetic activity in the expected direction. Cardiac autonomic dysregulation may be partly mediating the relationship between lifestyle and subsequent cardiovascular health.

Context
Basal autonomic nervous system (ANS) functioning has been linked to the metabolic syndrome (MetS), but the role of ANS reactivity in response to stress remains unclear.
Objective
To examine cross-sectionally and longitudinally to what extent ANS basal level and stress reactivity are related to MetS.
Design
2-year and 6-year data from a prospective cohort: the Netherlands Study of Depression and Anxiety.
Setting
Participants were recruited from the general community, primary care, and mental health care organizations.
Participants
1922 respondents (mean age=43.7years).
Main outcome measures
Indicators of ANS functioning were heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP). ANS stress reactivity was measured during a cognitively challenging stressor and a personal-emotional stressor. MetS components included triglycerides, high-density lipoprotein cholesterol, blood pressure, glucose and waist circumference.
Results
Cross-sectional analyses indicated that higher basal HR, lower basal values of RSA and PEP, and higher RSA reactivity during cognitive challenge were related to less favorable values of almost all individual MetS components. Longitudinal analyses showed that higher basal HR and shorter basal PEP predicted 4-year increase in many MetS abnormalities. Higher RSA stress reactivity during cognitive challenge predicted 4-year increase in number of MetS components.
Conclusion
Higher basal sympathetic, lower basal parasympathetic activity, and increased parasympathetic withdrawal during stress are associated with multiple MetS components, and higher basal sympathetic activity predicts an increase in metabolic abnormalities over time. These findings support a role for ANS dysregulation in the risk for MetS and, consequently, the development of cardiovascular disease.

Objectives 
It remains unclear whether depressive and anxiety disorders are associated with hyporeactivity or hyperreactivity of the autonomic nervous system (ANS) and whether deviant reactivity occurs in all types of stressors. This study compared ANS reactivity in people with current or remitted depression/anxiety with reactivity in healthy controls during two stress conditions.
Methods 
From the Netherlands Study of Depression and Anxiety, data of 804 individuals with current depression/anxiety, 913 individuals with remitted depression/anxiety, and 466 healthy controls (mean age = 44.1 years; 66.4% female) were available. Two conditions were used to evoke stress: a) an n-back task, a cognitively challenging stressor, and 2) a psychiatric interview, evoking personal-emotional stress related to the occurrence of symptoms of depression/anxiety. Indicators of ANS activity were heart rate (HR), root mean square of differences between successive interbeat intervals (RMSSD), respiratory sinus arrhythmia (RSA), and preejection period.
Results 
As compared with controls, participants with psychopathology had significant hyporeactivity of HR (controls = 4.1 ± 4.2 beats/min; remitted = 3.5 ± 3.5 beats/min; current psychopathology = 3.1 ± 3.4 beats/min), RMSSD (controls = −6.2 ± 14.5 milliseconds; remitted = −5.4 ± 17.8 milliseconds; current psychopathology = −3.5 ± 15.4 milliseconds), and RSA (controls = −9.3 ± 17.0 milliseconds; remitted = −7.4 ± 16.5 milliseconds; current psychopathology = −6.9 ± 15.0 milliseconds) during the n-back task. In contrast, during the psychiatric interview, they showed significant hyperreactivity of HR (controls = 2.7 ± 3.4 beats/min; remitted = 3.5 ± 3.4 beats/min; current psychopathology = 4.0 ± 3.3 beats/min), RMSSD (controls = −3.4 ± 12.2 milliseconds; remitted = −4.1 ± 12.1 milliseconds; current psychopathology = −5.6 ± 11.8 milliseconds), and RSA (controls = −3.8 ± 8.1 milliseconds; remitted = −4.3 ± 7.9 milliseconds; current psychopathology = −5.0 ± 7.9 milliseconds). The lack of group differences in preejection period reactivity suggests that the found effects were driven by altered cardiac vagal reactivity in depression/anxiety.
Conclusions 
The direction of altered ANS reactivity in depressed/anxious patients is dependent on the type of stressor, and only the more ecologically valid stressors may evoke hyperreactivity in these patients.

Objective 
Autonomic nervous system (ANS) imbalance has been cross-sectionally associated with inflammatory processes. Longitudinal studies are needed to shed light on the nature of this relationship. We examined cross-sectional and bidirectional prospective associations between cardiac autonomic measures and inflammatory markers.
Methods 
Analyses were conducted with baseline (n = 2823), 2-year (n = 2099), and 6-year (n = 1774) data from the Netherlands Study of Depression and Anxiety. To compare the pattern of results, prospective analyses with ANS (during sleep, leisure time, and work) and inflammation were conducted in two data sets from the Netherlands Twin Register measured for 4.9 years (n = 356) and 5.4 years (n = 472). Autonomic nervous system measures were heart rate (HR) and respiratory sinus arrhythmia (RSA). Inflammatory markers were C-reactive protein (CRP) and interleukin (IL)-6.
Results 
The Netherlands Study of Depression and Anxiety results showed that higher HR and lower RSA were cross-sectionally significantly associated with higher inflammatory levels. Higher HR predicted higher levels of CRP (B = .065, p < .001) and IL-6 (B = .036, p = .014) at follow-up. Higher CRP levels predicted lower RSA (B = −.024, p = .048) at follow-up. The Netherlands Twin Register results confirmed that higher HR was associated with higher CRP and IL-6 levels 4.9 years later. Higher IL-6 levels predicted higher HR and lower RSA at follow-up. Conclusions  Autonomic imbalance is associated with higher levels of inflammation. Independent data from two studies converge in evidence that higher HR predicts subsequent higher levels of CRP and IL-6. Inflammatory markers may also predict future ANS activity, but evidence for this was less consistent.

Objectives
This study determined temporal stability of ambulatory measured cardiac autonomic activity for different time periods and investigated potential drivers of changes in this activity.
Methods
Data was drawn from baseline (n=2379), 2-year (n=2245), and 6-year (n=1876) follow-up from the Netherlands Study of Depression and Anxiety. Cardiac autonomic activity was measured with heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP). Autonomic temporal stability was determined across 2, 4, and 6year intervals. We subsequently examined the association between sociodemographics, lifestyle, mental health, cardiometabolic health, and the use of antidepressant and cardiac medication with change in cardiac autonomic activity.
Results
Over 2years, stability was good for HR (ICC=0.703), excellent for RSA (ICC=0.792) and moderate for PEP (ICC=0.576). Stability decreased for a 4- (HR ICC=0.688, RSA ICC=0.652 and PEP ICC=0.387) and 6-year interval (HR ICC=0.633, RSA ICC=0.654 and PEP ICC=0.355). The most important determinants for increase in HR were (increase in) smoking, increase in body mass index (BMI) and (starting) the use of antidepressants. Beta-blocking/antiarrhythmic drug use led to a decrease in HR. Decrease in RSA was associated with age, smoking and (starting) antidepressant use. Decrease in PEP was associated with age and (increase in) BMI.
Conclusions
Cardiac autonomic measures were rather stable over 2years, but stability decreased with increasing time span. Determinants contributing to cardiac autonomic deterioration were older age, (increase in) smoking and BMI, and (starting) the use of antidepressants. (Starting) the use of cardiac medication improved autonomic function.

BackgroundEtiological research of depression and anxiety disorders has been hampered by diagnostic heterogeneity. In order to address this, researchers have tried to identify more homogeneous patient subgroups. This work has predominantly focused on explaining interpersonal heterogeneity based on clinical features (i.e. symptom profiles). However, to explain interpersonal variations in underlying pathophysiological mechanisms, it might be more effective to take biological heterogeneity as the point of departure when trying to identify subgroups. Therefore, this study aimed to identify data-driven subgroups of patients based on biomarker profiles.MethodsData of patients with a current depressive and/or anxiety disorder came from the Netherlands Study of Depression and Anxiety, a large, multi-site naturalistic cohort study (n = 1460). Thirty-six biomarkers (e.g. leptin, brain-derived neurotrophic factor, tryptophan) were measured, as well as sociodemographic and clinical characteristics. Latent class analysis of the discretized (lower 10%, middle, upper 10%) biomarkers were used to identify different patient clusters.ResultsThe analyses resulted in three classes, which were primarily characterized by different levels of metabolic health: ‘lean’ (21.6%), ‘average’ (62.2%) and ‘overweight’ (16.2%). Inspection of the classes’ clinical features showed the highest levels of psychopathology, severity and medication use in the overweight class.ConclusionsThe identified classes were strongly tied to general (metabolic) health, and did not reflect any natural cutoffs along the lines of the traditional diagnostic classifications. Our analyses suggested that especially poor metabolic health could be seen as a distal marker for depression and anxiety, suggesting a relationship between the ‘overweight’ subtype and internalizing psychopathology.

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.

Objectives: Cardiac repolarization may be affected by psychiatric disorders and/or antidepressant use, but evidence for this is inconclusive. This study examined the relationship between depressive and anxiety disorder and use of antidepressants with T-wave amplitude (TWA) and QT-interval.Methods: Data was obtained from the Netherlands Study of Depression and Anxiety (n = 1,383). Depression/anxiety was diagnosed with the DSM-IV based Composite International Diagnostic Interview. The use of tricyclic antidepressants (TCAs), selective serotonin and noradrenalin reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs) was established. T-wave amplitude and QT-interval corrected for heart rate (QTc) were obtained from an ECG measured in a type II axis configuration.Results: Compared to controls, persons with depression or anxiety disorders did not show a significantly different TWA (p = 0.58; Cohen’s d = 0.046) or QTc (p = 0.48; Cohen’s d = −0.057). In spite of known sympathomimetic effects, TCA use (p = 0.26; Cohen’s d = −0.162) and SNRI use (p = 0.70; Cohen’s d = −0.055) were not significantly associated with a lower TWA. TCA use (p = 0.12; Cohen’s d = 0.225) and SNRI use (p = 0.11; Cohen’s d = 0.227) were also not significantly associated with a prolonged QTc.Conclusion: We did not find evidence that either depressive/anxiety disorder or antidepressant use is associated with abnormalities in TWA or QTc. Earlier found sympathomimetic effects of TCAs and SNRIs are not evident in these measures of cardiac repolarization.