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Original Investigation
August 18, 2021

Effect of Exercise, Escitalopram, or Placebo on Anxiety in Patients With Coronary Heart Disease: The Understanding the Benefits of Exercise and Escitalopram in Anxious Patients With Coronary Heart Disease (UNWIND) Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina
  • 2Department of Medicine, University of North Carolina at Chapel Hill
  • 3Department of Medicine, Duke University Medical Center, Durham, North Carolina
JAMA Psychiatry. Published online August 18, 2021. doi:10.1001/jamapsychiatry.2021.2236
Key Points

Question  Do aerobic exercise and escitalopram reduce anxiety and improve coronary heart disease biomarkers more than a placebo?

Findings  In this randomized clinical trial including 128 patients with coronary heart disease and anxiety, escitalopram, but not exercise, resulted in reduced levels of anxiety and depression compared with a placebo control.

Meaning  For patients in this study with coronary heart disease and high anxiety, escitalopram was an effective treatment for reducing anxiety, although the extent to which this benefit may improve clinical outcomes remains uncertain.

Abstract

Importance  Anxiety is common among patients with coronary heart disease (CHD) and is associated with worse health outcomes; however, effective treatment for anxiety in patients with CHD is uncertain.

Objective  To determine whether exercise and escitalopram are better than placebo in reducing symptoms of anxiety as measured by the Hospital Anxiety and Depression-Anxiety Subscale (HADS-A) and in improving CHD risk biomarkers.

Design, Setting, and Participants  This randomized clinical trial was conducted between January 2016 and May 2020 in a tertiary care teaching hospital in the US and included 128 outpatients with stable CHD and a diagnosed anxiety disorder or a HADS-A score of 8 or higher who were older than 40 years, sedentary, and not currently receiving mental health treatment.

Interventions  Twelve weeks of aerobic exercise 3 times per week at an intensity of 70% to 85% heart rate reserve, escitalopram (up to 20 mg per day), or placebo pill equivalent.

Main Outcomes and Measures  The primary outcome was HADS-A score. CHD biomarkers included heart rate variability, baroreflex sensitivity, and flow-mediated dilation, along with 24-hour urinary catecholamines.

Results  The study included 128 participants. The mean (SD) age was 64.6 (9.6) years, and 37 participants (29%) were women. Participants randomized to the exercise group and escitalopram group reported greater reductions in HADS-A (exercise, −4.0; 95% CI, −4.7 to −3.2; escitalopram, −5.7; 95% CI, −6.4 to −5.0) compared with those randomized to placebo (−3.5; 95% CI, −4.5 to −2.4; P = .03); participants randomized to escitalopram reported less anxiety compared with those randomized to exercise (−1.67; 95% CI, −2.68 to −0.66; P = .002). Significant postintervention group differences in 24-hour urinary catecholamines were found (exercise z score = 0.05; 95% CI, −0.2 to 0.3; escitalopram z score = −0.24; 95% CI, −0.4 to 0; placebo z score = 0.36; 95% CI, 0 to 0.7), with greater reductions in the exercise group and escitalopram group compared with the placebo group (F1,127 = 4.93; P = .01) and greater reductions in the escitalopram group compared with the exercise group (F1,127 = 4.37; P = .04). All groups achieved comparable but small changes in CHD biomarkers, with no differences between treatment groups.

Conclusions and Relevance  Treatment of anxiety with escitalopram was safe and effective for reducing anxiety in patients with CHD. However, the beneficial effects of exercise on anxiety symptoms were less consistent. Exercise and escitalopram did not improve CHD biomarkers of risk, which should prompt further investigation of these interventions on clinical outcomes in patients with anxiety and CHD.

Trial Registration  ClinicalTrials.gov Identifier: NCT02516332

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    1 Comment for this article
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    Escitalopram and placebo effect beat exercise
    Johannes Burtscher, PhD | University of Lausanne
    We read with great interest the recent study of Blumenthal et al. 1. The authors report a more pronounced reduction of anxiety in individuals with coronary artery diseases after treatment with Escitalopram as compared with an aerobic exercise intervention. While encouraging especially for people with limited possibilities to perform regular exercise, in our opinion the direct comparison of drug treatment and the exercise condition requires further scrutiny.
    As discussed by the authors, the exercise dose (volume, frequency and intensity) has not been tailored to the individual needs in this study (while the drug dose has been). Further, the duration of
    the 12-week exercise protocol was likely too short to induce optimal exercise effects on anxiety, which have been reported for protocols longer than 16 weeks 2. Indeed, the time course for state anxiety (figure 3 1) suggests increasing benefits of exercise after 8 – 12 weeks of treatment concomitant with a plateauing of the effects of Escitalopram. Variations in exercise modes might additionally improve anxiety-related outcomes. For example, also resistance exercise (strength training as opposed to aerobic / endurance training) can mitigate anxiety 3 and it is possible that group programs or a combination with psychotherapy synergistically increase the positive effects 4.
    Most importantly, however, is the lack of correction for the (expected 5) placebo effect in the Escitalopram versus exercise comparison 1. If the exercise effect were to be directly compared to Escitalopram, an additional group of combined exercise and placebo would be necessary. In fact, the placebo effect demonstrated for the Hospital Anxiety and Depression-Anxiety Subscale (HADS-A) in figure 2 1 suggests that a combined exercise plus placebo treatment might have further reduced anxiety. Also an exercise plus Escitalopram group would have been instructive as to whether Escitalopram indeed increases exercise-induced benefits on anxiety.
    In conclusion, while the demonstrated effect of Escitalopram on anxiety in the studied cohort is impressive, it cannot be directly compared to the exercise effects, which in addition could certainly be further optimized. Based on the general health promoting increases of aerobic capacities, absence of side-effects of bioactive drugs and potentially continuously increasing and long-lasting anxiety benefits of longer exercise protocols, it would be dangerous to consider regular physical exercise as a less effective intervention against anxiety than Escitalopram.

    Authors: Johannes Burtscher, Grégoire P. Millet (both University of Lausanne) and Martin Burtscher (University of Innsbruck)

    Ref:
    1. Blumenthal JA et al. Effect of Exercise, Escitalopram, or Placebo on Anxiety in Patients With Coronary Heart Disease: The Understanding the Benefits of Exercise and Escitalopram in Anxious Patients With Coronary Heart Disease (UNWIND) Randomized Clinical Trial. JAMA Psychiatry. 2021.
    2. Petruzzello SJ et al. A meta-analysis on the anxiety-reducing effects of acute and chronic exercise. Outcomes and mechanisms. Sports Med. 1991;11(3):143-182.
    3. Gordon BR, et al. The Effects of Resistance Exercise Training on Anxiety: A Meta-Analysis and Meta-Regression Analysis of Randomized Controlled Trials. Sports Med. 2017;47(12):2521-2532.
    4. Asmundson GJ et al. Let's get physical: a contemporary review of the anxiolytic effects of exercise for anxiety and its disorders. Depress Anxiety. 2013;30(4):362-373.
    5. Kirsch I. Placebo Effect in the Treatment of Depression and Anxiety. Front Psychiatry. 2019;10:407.
    CONFLICT OF INTEREST: None Reported
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