CONTEXT: It has been hypothesized that depression is associated with lower heart rate variability and decreased cardiac vagal control. This may play an important role in the risk of cardiovascular disease among depressed individuals.
OBJECTIVE: To determine whether heart rate variability was lower in depressed individuals than in healthy controls in a large adult sample.
DESIGN: Cross-sectional analyses from a large depression cohort study.
SETTING: The Netherlands Study of Depression and Anxiety.
PARTICIPANTS: Two thousand three hundred seventy-three individuals (mean age, 41.8 years; 66.8% female) who participated in the Netherlands Study of Depression and Anxiety. Included were 524 controls, 774 individuals with a diagnosis of major depressive disorder (MDD) earlier in life (remitted MDD), and 1075 individuals with current MDD based on the Composite International Diagnostic Interview. This sample was sufficiently powered to examine the confounding effects of lifestyle, comorbid anxiety, and antidepressants.
MAIN OUTCOME MEASURES: The standard deviation of normal-to-normal beats (SDNN) and cardiac vagal control, as indexed by respiratory sinus arrhythmia (RSA), were measured during 1(1/2) hours of ambulatory recording of electrocardiograms and thorax impedance. Multivariate analyses were conducted to compare SDNN and RSA across depression groups after adjustment for demographics, health, lifestyle, comorbid anxiety, and psychoactive medication.
RESULTS: Individuals with remitted and current MDD had a lower mean SDNN and RSA compared with controls (SDNN, 3.1-5.7 milliseconds shorter, P < or = .02; RSA, 5.1-7.1 milliseconds shorter, P < .001; effect size, 0.125-0.269). Comorbid anxiety and lifestyle did not reduce these associations. However, accounting for psychoactive medication removed the association with SDNN and strongly attenuated the association with RSA. Depressed individuals who were using selective serotonin reuptake inhibitors, tricyclic antidepressants, or other antidepressants had significantly shorter SDNNs and RSAs (effect size, 0.207-0.862) compared with controls and depressed individuals not taking medication. CONCLUSIONS: This study shows that depression is associated with significantly lowered heart rate variability. However, this association appears to be mainly driven by the effect of antidepressants.

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 determine whether patients with different types of anxiety disorder (panic disorder, social phobia, generalized anxiety disorder) have higher heart rate and lower heart rate variability compared with healthy controls in a sample that was sufficiently powered to examine the confounding effects of lifestyle and antidepressants.
Methods: 
The standard deviation of the normal-to-normal intervals (SDNN), heart rate (HR), and respiratory sinus arrhythmia (RSA) were measured in 2059 subjects (mean age = 41.7 years, 66.8% female) participating in The Netherlands Study of Depression and Anxiety (NESDA). Based on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) and Composite International Diagnostic Interview (CIDI), NESDA participants were classified as healthy controls (n = 616), subjects with an anxiety diagnosis earlier in life (n = 420), and subjects with current anxiety diagnosis (n = 1059).
Results: 
Current anxious subjects had a significantly lower SDNN and RSA compared with controls. RSA was also significantly lower in remitted anxious subjects compared with controls. These associations were similar across the three different types of anxiety disorders. Adjustment for lifestyle had little impact. However, additional adjustment for antidepressant use reduced all significant associations between anxiety and HRV to nonsignificant. Anxious subjects who used a tricyclic antidepressant, a selective serotonin reuptake inhibitor, or another antidepressant showed significantly lower mean SDNN and RSA compared with controls (effect sizes = 0.20–0.80 for SDNN and 0.42–0.79 for RSA). Nonmedicated anxious subjects did not differ from controls in mean SDNN and RSA.
Conclusion: 
This study shows that anxiety disorders are associated with significantly lower HR variability, but the association seems to be driven by the effects of antidepressants.
ANOVA = analysis of variance;
ANS = autonomic nervous system;
ATC = anatomical therapeutic chemical;
BAI = Beck Anxiety Inventory;
BMI = body mass index;
CIDI = Composite International Diagnostic Interview;
CVD = cardiovascular disease;
dZ = changes in thorax impedance;
ECG = electrocardiogram;
GAD = generalized anxiety disorder;
HR = heart rate;
HRV = heart rate variability;
IBI = inter-beat-interval;
MDD = major depressive disorder;
MET = multiple of one’s resting metabolic rate times minutes of physical activity;
NESDA = The Netherlands Study of Depression and Anxiety;
PD = panic disorder;
pv = peak-valley;
PNS = parasympathetic nervous system;
RR = respiratory rate;
RSA = respiratory sinus arrhythmia;
SDNN = standard deviation of the normal-to-normal interval;
SNS = sympathetic nervous system;
SP = social phobia;
VU-AMS = Vrije Universiteit Ambulatory Monitoring System;
SSRI = selective serotonin reuptake inhibitor;
TCA = tricyclic antidepressant.

The present study compared blood pressure levels between subjects with clinical anxiety and depressive disorders with healthy controls. Cross-sectional data were obtained in a large cohort study, the Netherlands Study of Depression and Anxiety (N=2981). Participants were classified as controls (N=590) or currently or remittedly depressed or anxious subjects (N=2028), of which 1384 were not and 644 were using antidepressants. Regression analyses calculated the contributions of anxiety and depressive disorders and antidepressant use to diastolic and systolic blood pressures, after controlling for multiple covariates. Heart rate and heart rate variability measures were subsequently added to test whether effects of anxiety/depression or medication were mediated by vagal control over the heart. Higher mean diastolic blood pressure was found among the current anxious subjects (β=0.932; P=0.03), although anxiety was not significantly related to hypertension risk. Remitted and current depressed subjects had a lower mean systolic blood pressure (β=−1.74, P=0.04 and β=−2.35, P=0.004, respectively) and were significantly less likely to have isolated systolic hypertension than controls. Users of tricyclic antidepressants had higher mean systolic and diastolic blood pressures and were more likely to have hypertension stage 1 (odds ratio: 1.90; 95% CI: 0.94 to 3.84; P=0.07) and stage 2 (odds ratio: 3.19; 95% CI: 1.35 to 7.59; P=0.008). Users of noradrenergic and serotonergic working antidepressants were more likely to have hypertension stage 1. This study shows that depressive disorder is associated with low systolic blood pressure and less hypertension, whereas the use of certain antidepressants is associated with both high diastolic and systolic blood pressures and hypertension.

Background
It was previously shown that antidepressants are associated with diminished vagal control over the heart. Longitudinal studies are needed to test the causality of this association further.
Methods
Longitudinal data were obtained in the Netherlands Study of Depression and Anxiety. At baseline and at 2-year follow-up, heart rate and cardiac vagal control as indexed by respiratory sinus arrhythmia were measured in 2114 subjects (mean age = 42.0 years; 66.2% female), who either used antidepressants at one or two time points (n = 603) or did not use antidepressants at any time point (n = 1511). Linear mixed-model analyses were conducted to compare changes in respiratory sinus arrhythmia and heart rate over time across antidepressant-naive subjects, subjects who started using an antidepressant during follow-up, subjects who stopped using an antidepressant, and persistent antidepressant users. Analyses were adjusted for demographics, health, and lifestyle factors.
Results
Compared with continuous nonusers, subjects who started the use of a tricyclic antidepressant or a serotonergic and noradrenergic antidepressant showed a significantly greater increase in heart rate and a decrease of respiratory sinus arrhythmia at 2 years. Subjects who started the use of selective serotonin reuptake inhibitors also showed a decrease in respiratory sinus arrhythmia, but their heart rate did not increase. Discontinuing antidepressants systematically caused opposite effects; levels returned in the direction of those observed among nonusers.
Conclusions
These 2-year longitudinal results indicate that all antidepressants cause a decrease in cardiac vagal control. After discontinuing antidepressants, autonomic function recovers, suggesting that the unfavorable effects are (partly) reversible.