Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk

Abstract

Context: There is evidence that heart rate variability (HRV) is reduced in major depressive disorder (MDD), although there is debate about whether this effect is caused by medication or the disorder per se. MDD is associated with a two to fourfold increase in the risk of cardiac mortality, and HRV is a robust predictor of cardiac mortality; determining a direct link between HRV and not only MDD, but common comorbid anxiety disorders, will point to psychiatric indicators for cardiovascular risk reduction.

Objective: To determine in physically healthy, unmedicated patients whether (1) HRV is reduced in MDD relative to controls, and (2) HRV reductions are driven by MDD alone, comorbid generalized anxiety disorder (GAD, characterized by anxious anticipation), or comorbid panic and posttraumatic stress disorders (PD/PTSD, characterized by anxious arousal).

Design, setting, and patients: A case-control study in 2006 and 2007 on 73 MDD patients, including 24 without anxiety comorbidity, 24 with GAD, and 14 with PD/PTSD. Seventy-three MDD and 94 healthy age- and sex-matched control participants were recruited from the general community. Participants had no history of drug addiction, alcoholism, brain injury, loss of consciousness, stroke, neurological disorder, or serious medical conditions. There were no significant differences between the four groups in age, gender, BMI, or alcohol use.

Main outcome measures: HRV was calculated from electrocardiography under a standardized short-term resting state condition.

Results: HRV was reduced in MDD relative to controls, an effect associated with a medium effect size. MDD participants with comorbid generalized anxiety disorder displayed the greatest reductions in HRV relative to controls, an effect associated with a large effect size.

Conclusions: Unmedicated, physically healthy MDD patients with and without comorbid anxiety had reduced HRV. Those with comorbid GAD showed the greatest reductions. Implications for cardiovascular risk reduction strategies in otherwise healthy patients with psychiatric illness are discussed.

Conflict of interest statement

Competing Interests: The authors received funding for this study from commercial sources. These included GlaxoSmithKline, Australia, Postgraduate Support Grant (2007–08), which provided support to AHK for conference travel. Brain Resource and Johnson & Johnson Pharmaceutical Research and Development, RED Europe funded the research on which this study is based. AHK was employed on a part-time contractual basis to coordinate the research activities. These funding arrangements do not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. Indeed, the data on which the present study is based is made available by BRAINnet, www.BRAINnet.net, under the governance of the BRAINnet Foundation. BRAINnet is the scientific network that coordinates access to the Brain Resource International Database for independent scientific purposes.

Figures

Figure 1. DASS-42 scale scores (mean ± standard deviation) for MDD vs CTL (1a) and MDD groupings.

Figure 2. Time (row 1), frequency (row 2) and non-linear (row 3) domain measures of HRV in unmedicated patients with major depressive disorder (MDD) relative to controls (CTL).

Figure 3. Time (row 1), frequency (row 2) and non-linear (row 3) domain measures of HRV in controls, MDD without anxiety, MDD with comorbid PD and/or PTSD and MDD patients with GAD.

Figure 4. Proposed model for reduced heart rate variability (HRV) in patients with major depressive disorder (MDD) and comorbid generalised anxiety disorder (GAD).

These patients typically experience worry and hypervigilance to threat, leading to a chronic withdrawal of the parasympathetic nervous system (PNS) and long-term reductions in HRV, placing these patients at an increased risk for cardiovascular disease (CVD) and sudden cardiac death (SCD).