Antidepressant Efficacy of Adjunctive Aerobic Activity and Associated Biomarkers in Major Depression: A 4-Week, Randomized, Single-Blind, Controlled Clinical Trial

RESEARCH ARTICLE Antidepressant Efficacy of Adjunctive Aerobic Activity and Associated Biomarkers in Major Depression: A 4-Week, Randomized, SingleBlind, Controlled Clinical Trial Cristiana Carvalho Siqueira1, Leandro L. Valiengo1, André F. Carvalho6, Paulo Roberto Santos-Silva3, Giovani Missio5, Rafael T. de Sousa1,2, Georgia Di Natale1, Wagner F. Gattaz1,4, Ricardo Alberto Moreno5, Rodrigo Machado-Vieira1,2,4* a11111 OPEN ACCESS Citation: Siqueira CC, Valiengo LL, Carvalho AF, Santos-Silva PR, Missio G, de Sousa RT, et al. (2016) Antidepressant Efficacy of Adjunctive Aerobic Activity and Associated Biomarkers in Major Depression: A 4-Week, Randomized, Single-Blind, Controlled Clinical Trial. PLoS ONE 11(5): e0154195. doi:10.1371/journal.pone.0154195 Editor: Maciej Buchowski, Vanderbilt University, UNITED STATES Received: July 15, 2015 Accepted: April 8, 2016 Published: May 6, 2016 Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Data Availability Statement: Data contain potentially identifying information and may not be publicly shared. Data requests may be sent to the corresponding author. Funding: Support for this work was provided by grant 2012/20002-5, São Paulo Research Foundation (FAPESP). The grant was used to create the Physical Training Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 1 Laboratory of Neuroscience LIM-27, Institute and Department of Psychiatry, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil, 2 Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health (NIMH), Bethesda, Maryland, United States of America, 3 Laboratory of Movement Studies, University of Sao Paulo School of Medicine Hospital das Clínicas, Sao Paulo, Sao Paulo, Brazil, 4 Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil, 5 Mood Disorders Unit (GRUDA), Institute and Department of Psychiatry, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil, 6 Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil * ; Abstract Background Major depressive disorder (MDD) is a highly prevalent, heterogeneous and systemic medical condition. Treatment options are limited, and recent studies have suggested that physical exercise can play an important role in the therapeutics of MDD. The aim of this study was to evaluate the antidepressant efficacy of adjunctive aerobic activity in association with pharmacotherapy (selective serotonin reuptake inhibitor) in symptomatic MDD as well as its association with physiological biomarkers. Methods In this randomized, single-blind, add-on, controlled clinical trial, 57 patients (18–55 years of age) were followed-up for 28 days. All patients were drug-free, had been diagnosed with symptomatic MDD and received flexible dose of sertraline during the trial. Patients were randomized to either a 4-week program (4x/week) of add-on aerobic exercise (exercise group, N = 29) or no activity (control group, N = 28). Depression severity was assessed using the Hamilton Rating Scale for Depression (HAM-D) as the primary outcome. At baseline and endpoint, all patients underwent a comprehensive metabolic/cardiopulmonary exercise testing—including determination of maximal oxygen uptake (VO2max), VO2 at the second ventilatory threshold (VO2-VT2), and oxygen pulse (O2 pulse). PLOS ONE | DOI:10.1371/journal.pone.0154195 May 6, 2016 1 / 11 Short-Term Exercise in Depression Competing Interests: The authors have declared that no competing interests exist. Results Depression scores significantly decreased in both groups after intervention. Importantly, patients in the aerobic exercise group required lower sertraline dose compared to the control group (sertraline monotherapy). The VO2max and O2 pulse parameters increased over time only in the exercise group and remained unchanged in the control group. Conclusions The present findings suggest that a 4-week training of aerobic exercise significantly improves functional capacity in patients with MDD and may be associated with antidepressant efficacy. This approach may also decrease the need for higher doses of antidepressants to achieve response. Further studies in unmedicated and treatment-resistant MDD patients are needed in order to confirm the utility of short-term aerobic exercise as an alternative therapeutic approach in MDD. Trial Registration ClinicalTrials.gov NCT02427789 Introduction Patients with Major Depressive Disorder (MDD) experience metabolic dysfunction associated with reduction in physical capacity and higher risk of death [1]. According to the World Health Organization [2], MDD is currently the fourth leading cause of disability worldwide and are projected to become the second leading cause by 2020. Current treatments only improve partially or do not induce response in a significant percentage of patients. As alternative, non-pharmacological treatments for MDD have been studied and one important approach is physical exercise [3]. Initial studies have suggested that systematic physical exercise is associated with the prevention and improvement of depressive symptoms [4, 5]. Thus it represents a viable option for treatment as an add-on approach to pharmacotherapy. Physical exercise has a favorable side effect profile, low-cost and is widely accessible. It can be also tailored to the individual needs, depending on age, medical comorbidities, lifestyle and functional status [6, 7]. However, there is uncertainty regarding the physiological effects of physical exercise (e.g. duration and intensity necessary to bring about positive changes in mood and well-being) [3] underlying its potential antidepressant effects [8–13]. Studies have shown that exercise programs (4–12 weeks) are effective in reducing depressive symptoms [14] and at least two weeks are required to alter key neural cicuits in mood regulation [15, 16]. Physical exercise have been proposed as an alternative therapy to improve depression [8,11,15]. Cardiopulmonary exercise testing (CPET), which combines exercise testing and spirometry, is a key method to evaluate the physiological responses, ensuring greater safety and more accurate results [17]. This approach has never been applied systematically in clinical trials in depression. Previously, Sui et al. demonstrated an association between high cardiorespiratory fitness and a lower prevalence of depressive symptoms, independent of risk factors [18]. Similarly, Tolmunen et al. found that low maximal oxygen uptake (VO2max) were associated with greater severity of depressive symptoms in (...truncated)