Research protocol

The role of the autonomic nervous system in the association between depressive/anxiety disorders and cardiovascular disease Xian Hu

Introduction

Depressive and anxiety disorders have been associated with an increased risk of cardiovascular disease (CVD).1-4 It has been suggested that dysregulation of the autonomic nervous system (ANS) may be one of the underlying physiological mechanisms linking these psychiatric disorders to unfavourable health outcomes.3,5 The ANS is specifically involved in the human stress response and can be divided into two divisions: 1) the sympathetic nervous system (SNS), activated by stressful and dangerous situations to prepare the body for action, and 2) the parasympathetic nervous system (PNS), regulating the body’s resting state.6 Since depression/anxiety induces chronic or recurrent stress, it is hypothesized that these psychiatric disorders are associated with increases in SNS and decreases in PNS activity.7 Licht et al. investigated sympathetic and parasympathetic activity in patients with depression8,10,11 and anxiety disorders9-11 in the large depression and anxiety cohort of NESDA (the Netherlands Study of Depression and Anxiety, n=2981) and did not find association between these disorders and autonomic dysregulation independent from a robust association with use of antidepressants. Where adjustment for lifestyle had little impact on the initially found correlation between depression/anxiety and dysregulated ANS,

adjustment for antidepressant rendered all significant associations nonsignificant.8,9 Moreover, in a 2-year longitudinal study it was shown that use of antidepressants likely has a causal role in dysregulating ANS functioning, whereas discontinuation of antidepressants led to recovery of autonomic function.10,11 Since the studies of Licht et al., NESDA has gathered more longitudinal data on depressive and anxiety disorders. This PhD project will use these data to shed more light on the role of the autonomic nervous system in the association between depressive/anxiety disorders and cardiovascular disease. The next sections will briefly introduce the questions that will be addressed during this project. Finally, a description will be given of NESDA and MOTAR and we will conclude with an overview of the predictor and outcome variables.

Research question 1: Longitudinal association of psychopathology/antidepressants with ANS functioning

At the moment of their research, Licht et al. only had baseline data and 2-year follow-up data available for analyses. Therefore, they were only able to assess relatively short-term effects of depressive and anxiety disorders on ANS activity. Not much is known about the time frame of the physiological mechanisms underlying ANS dysregulation in depression/anxiety.3,5 The possibility exists that changes in ANS functioning only manifest themselves after a longer time-period of disorder chronicity. Furthermore, Licht et al. found that, on top of an altered ANS functioning at baseline for antidepressant users, 2-year continuous use of antidepressants further altered ANS activity.11 It would be valuable to find out whether prolonged persistent use of antidepressants enhances or even deteriorates ANS dysregulation. In addition, normalization of ANS activity was seen in subjects who stopped

using antidepressants.10,11 In concordance, it would be useful to investigate whether a prolonged non-use period of antidepressants will further improve ANS function. Since the studies of Licht et al., NESDA has gathered 6- (and 9-) year follow-up data. With these data we will be able to replicate the research of Licht et al.10,11 over a longer time-period. This longitudinal study will examine the 6- (and 9-) year-term effect of depressive/anxiety disorders and antidepressant use on changes in ANS activity. In addition, since clinical heterogeneity of disorder is thought to be associated with different biological dysregulations,3 we will investigate the role of symptom profiles in ANS functioning.

Research question 2: Autonomic nervous system reactivity to stressors in depressive/anxiety disorders

Several studies have implied a different ANS reactivity to stressors among depressed/anxious patients rather than ANS dysregulation during baseline conditions. 12,13 Licht et al. did not include a true stress condition which, besides short time-period of disorder chronicity, might be an explanation for the lack of evidence for an altered ANS in depressed and anxious subjects.8-11 In order to investigate this, we will measure stressorinduced sympathetic and parasympathetic reactivity in the 2-year follow up assessment of the NESDA cohort. We will compare stressor-induced ANS reactivity (during several levels of the N-back task) between depressed/anxious subjects and healthy controls, taking into account that subjects have adequate task performance. In addition, we will specifically examine the confounding effects of antidepressants on stressor-induced ANS reactivity.

Research question 3: Effect of running therapy compared to antidepressants on ANS functioning

If antidepressants indeed have a detrimental effect on ANS activity, as has been implied by Licht et al.,8-11 it is worthwhile to compare the effect of antidepressants on the autonomic nervous system to other treatments that have proved to be effective in depression/anxiety as well, such as running therapy.14,15 If running therapy is shown to have less unfavourable ANS outcome than antidepressants but similar benefits on mental health, this therapy might more often be opted as a treatment in clinical practice. In order to investigate the difference in ANS functioning associated with both treatments, we will use data from the MOod Treatment with Antidepressants or Running (MOTAR) study.16 We will compare short-term and long-term impact of running therapy compared to antidepressants on ANS functioning, and we will weigh the outcome of both treatments against their beneficial effects on symptoms of depression/anxiety.

Research question 4: The predictive value of ANS functioning in developing the metabolic syndrome/somatic problems/CVD

Assuming that depressive/anxiety disorders and/or antidepressants have a negative effect on ANS activity, the next important step is to determine the association between ANS dysregulation and unfavourable health outcomes. For instance, a cost/benefit analysis may have implications for choice of antidepressant treatment in clinical practice. In a 2-year longitudinal study, Licht et al. concluded that increased SNS activity predicts development of metabolic abnormalities.17 Again, Licht et al. only had access to 2-year follow-up data, which

might have been too short to show robust results considering PNS activity. Since more longitudinal data is available now, a longer term assessment can be made of the predictive value of ANS activity for the metabolic syndrome/somatic problems/CVD. In addition, the predictive value of ANS reactivity to stressors for the long-term development of metabolic abnormalities/somatic problems/CVD can be assessed. We will aim to answer the following research question: Can ANS functioning at baseline and/or during stressors predict 6- (and 9) year development of the metabolic syndrome/somatic problems/CVD?

NESDA

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 longterm course and consequences. Its design is an ongoing 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. During multiple assessments including written questionnaires, interviews, a medical examination, a cognitive computer task and collection of blood and saliva samples, extensive longitudinal information was gathered about key (mental) health outcomes and demographic, psychosocial, clinical, biological and genetic determinants.18

MOTAR

The MOod Treatment with Antidepressants or Running (MOTAR) study is a multi-center randomized clinical trial to examine whether depression and anxiety treatment reduces physiological stress. The study’s design is a 16-week treatment program with either SSRIs or three times per week running. The sample consists of 240 participants with current major depressive disorder and/or current anxiety disorder recruited in the mental health care setting. During multiple assessments (baseline, immediately after treatment and 1-year follow-up) written questionnaires, an interview, medical examination, blood, urine and saliva collection and a cycle ergometer test were taken and information was gathered about demographic, (mental) health outcomes, psychosocial, clinical, biological and genetic determinants. In addition, alterations in brain processes in a subsample of minimal 25 patients per treatment arm were assessed using MRI.16

Variables

To ascertain the presence and severity of depressive and anxiety disorders we will include the following predictor variables: CIDI diagnoses according to DSM-IV criteria, scores on the 30-item Inventory of Depressive Symptomatology, Self-Report (IDS-SR) and Beck Anxiety Inventory (BAI) scores. We will also include the following possible covariates: Respiration rate, sociodemographic characteristics (age, sex, and education in years), health indicators (BMI, physical activity, smoking, alcohol use), the presence of heart disease and other chronic conditions, and the use of medication and specifically the following antidepressants: tricyclic antidepressants (TCAs, ATC code N06AA), selective serotonin reuptake inhibitors

(SSRIs, ATC code N06AB), and serotonergic and noradrenergic working antidepressants (SNRIs, antidepressants classified as N06AX). ANS activity was recorded using the VU University Ambulatory Monitoring System (VU-AMS; Vrije Universiteit, Amsterdam, The Netherlands), a lightweight portable device that records electrocardiograms and changes in thorax impedance. The participants wore the VU-AMS device during a large part of the assessments described under headline ‘NESDA’. From the VU-AMS recordings the following outcome variables were computed: standard deviation of the normal-to-normal intervals (SDNN), heart rate, respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP).

References 1. Möller-Leimkühler, A. M. (2010). Higher comorbidity of depression and cardiovascular disease in women: a biopsychosocial perspective. World Journal of Biological Psychiatry, 11(8), 922-933. 2. Nicholson, A., Kuper, H., & Hemingway, H. (2006). Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. European Heart Journal, 27(23), 2763-2774. 3. Penninx, B. W., Milaneschi, Y., Lamers, F., & Vogelzangs, N. (2013). Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC medicine, 11(1), 129. 4. Vogelzangs, N., Seldenrijk, A., Beekman, A. T., van Hout, H. P., de Jonge, P., & Penninx, B. W. (2010). Cardiovascular disease in persons with depressive and anxiety disorders. Journal of affective disorders, 125(1), 241-248. 5. Holsen, L. M., Lee, J. H., Spaeth, S. B., Ogden, L. A., Klibanski, A., Whitfield-Gabrieli, S., ... & Goldstein, J. M. (2012). Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: a preliminary study. Neuroscience letters, 514(1), 57-61. 6. Martini, F. H., & Martini, F. (1992). Fundamentals of anatomy and physiology. Prentice Hall. 7. McEwen, B. S. (2008). Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. European journal of pharmacology, 583(2), 174-185. 8. Licht, C. M., de Geus, E. J., Zitman, F. G., Hoogendijk, W. J., van Dyck, R., & Penninx, B. W. (2008). Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). Archives of General Psychiatry, 65(12), 1358-1367.

9. Licht, C. M., de Geus, E. J., van Dyck, R., & Penninx, B. W. (2009). Association between anxiety disorders and heart rate variability in The Netherlands Study of Depression and Anxiety (NESDA). Psychosomatic medicine, 71(5), 508-518. 10. Licht, C. M., de Geus, E. J., van Dyck, R., & Penninx, B. W. (2010). Longitudinal evidence for unfavorable effects of antidepressants on heart rate variability. Biological psychiatry, 68(9), 861-868. 11. Licht, C. M., Penninx, B. W., & de Geus, E. J. (2012). Effects of antidepressants, but not psychopathology, on cardiac sympathetic control: a longitudinal study. Neuropsychopharmacology, 37(11), 2487-2495. 12. Hughes, J. W., & Stoney, C. M. (2000). Depressed mood is related to high-frequency heart rate variability during stressors. Psychosomatic Medicine, 62(6), 796-803. 13. Sheffield, D., Krittayaphong, R., Cascio, W. E., Light, K. C., Golden, R. N., Finkel, J. B., ... & Sheps, D. S. (1998). Heart rate variability at rest and during mental stress in patients with coronary artery disease: differences in patients with high and low depression scores. International journal of behavioral medicine, 5(1), 31-47. 14. Lapmanee, S., Charoenphandhu, J., & Charoenphandhu, N. (2013). Beneficial effects of fluoxetine, reboxetine, venlafaxine, and voluntary running exercise in stressed male rats with anxiety-and depression-like behaviors. Behavioural brain research, 250, 316-325. 15. Kruisdijk, F. R., Hendriksen, I. J., Tak, E. C., Beekman, A. T., & Hopman-Rock, M. (2012). Effect of running therapy on depression (EFFORT-D). Design of a randomised controlled trial in adult patients [ISRCTN 1894]. BMC public health, 12(1), 50. 16. MOTAR study Research protocol. 17. Licht, C. M., de Geus, E. J., & Penninx, B. W. (2013). Dysregulation of the autonomic nervous system predicts the development of the metabolic syndrome. The Journal of Clinical Endocrinology & Metabolism, 98(6), 2484-2493. 18. Penninx, B. W., Beekman, A. T., Smit, J. H., Zitman, F. G., Nolen, W. A., Spinhoven, P., ... & Van Dyck, R. (2008). The Netherlands Study of Depression and Anxiety (NESDA): rationale, objectives and methods. International journal of methods in psychiatric research, 17(3), 121-140.