Controlled Clinical Trials 23 (2002) 584–603 0197-2456/02/$—see front matter © 2002 Elsevier Science Inc. All rights reserved.PII: S0197-2456(02)00226-X Design paperARTICLE IN PRESS The DOSE study: a clinical trial to examine efficacy and dose response of exercise as treatment for depression Andrea L. Dunn, Ph.D. a, *, Madhukar H. Trivedi, M.D. b ,James B. Kampert, Ph.D. a , Camillia G. Clark, Ph.D. c , Heather O. Chambliss, Ph.D. a a The Cooper Institute, Dallas, Texas, USA b The University of Texas Southwestern Medical Center, Dallas, Texas, USA c Alberta Children’s Hospital, Calgary, Alberta, Canada Manuscript received October 22, 2001; manuscript accepted May 28, 2002 Abstract The Depression Outcomes Study of Exercise (DOSE) was a randomized clinical trial to determinewhether exercise is an efficacious treatment for mild to moderate major depressive disorder (MDD) inadults ages 20 to 45 years. The specific hypotheses under investigation were (1) active exercise is anefficacious monotherapy for mild to moderate levels of MDD, and (2) there is a dose-response relationbetween the exercise amount and reduction in depressive symptoms. The primary outcome measurewas the Hamilton Rating Scale for Depression (HRSD) collected weekly over 12 weeks. Secondaryoutcome measures were the Inventory of Depressive Symptoms (clinician and self-report), HRSDscores at 24 weeks, cardiorespiratory fitness, self-efficacy, and quality of life. Eighty men and womenwho were diagnosed with a Structured Clinical Interview for Depression and who had mild (HRSD12–16) to moderate (HRSD 17–25) MDD were randomized to one of five doses of exercise: 7.0 kcal/kg/week in 3 days/week; 7.0 kcal/kg/week in 5 days/week; 17.5 kcal/kg/week in 3 days/week; 17.5kcal/kg/week in 5 days/week; or 3 days/week of stretching and flexibility exercises for 15 to 20 min/session. Participants exercised under supervision in our laboratory over the course of 12 weeks. Symp-toms of depression were measured weekly by trained clinical raters blinded to the participant’s treat-ment assignment. The design of the study restricted participant characteristics to mild to moderateMDD and controlled exercise features to permit the evaluation of exercise as a sole treatment for de-pression. This study is the first to examine dose-response effects of exercise in participants diagnosedwith MDD. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Major depressive disorder; Exercise; Dose response; Randomized clinical trial * Corresponding author: Andrea L. Dunn, Ph.D., Senior Associate Director, Division of Research, The Coo-per Institute, 12330 Preston Road, Dallas, TX 75230. Tel.:  1-972-341-3242; Fax:  1-972-341-3225.E-mail address: [email protected]. Dunn et al./Controlled Clinical Trials 23 (2002) 584–603 585ARTICLE IN PRESS Background and aims Depression is a prevalent illness (17% lifetime prevalence) [1] with a high cost to society (es-timated $44 billion/year) [2] and to the quality of life of the individual [3,4]. The Global Burdenof Disease study [5] found that in developed nations unipolar major depression ranks second be-hind ischemic heart disease in lost years of healthy life due to premature death or disability. Cur-rent estimates indicate that only 25% of adults suffering from depression seek treatment despitemajor advances in effective pharmacological and psychotherapeutic treatments. The goal forpersons seeking depression treatment set by Healthy People 2000 was 35% [6] and 50% for2010 [7]. Social stigma and distrust of the medical regimens used to treat depression are majorreasons that individuals will not seek treatment even when these individuals acknowledge psy-chological symptoms [8]. The lack of use of effective pharmacological or cognitive-behavioraltherapies demonstrates the need for acceptable treatments for individuals with depression.Engaging in regular exercise does not carry a stigma, is relatively low cost, and can bedone outside standard medical settings. In addition, exercise may be a more acceptable treat-ment for some (e.g., pregnant women or adolescents) because of its relative safety and lackof side effects compared to antidepressant drug treatments. Exercise can be safely prescribedand monitored in many of these individuals. Although risks are associated with exercise,these are low, especially in younger people where the prevalence of depression is high. Thecost-benefit ratio clearly favors an exercise alternative [9].One major limitation is that exercise has not met established efficacy standards [10] despitea number of epidemiological and experimental studies demonstrating a reduction in depressivesymptoms with exercise. Several clinical studies [11–14] and a recent meta-analysis [15] haveshown exercise to be comparable to psychotherapy. More recently Blumenthal et al. [16] con-ducted a randomized clinical trial comparing the effects of group exercise, antidepressant med-ication, and group exercise in combination with antidepressant medication in older adults withmild to moderate major depressive disorder (MDD) over a 16-week acute phase study. The ma-jor finding from this study was that all treatments were efficacious in reducing symptoms of de-pression. While this study adequately diagnosed depression and measured treatment effects, thefact that the exercise was done in a group rather than an individual setting still leaves a questionof whether social support could influence outcomes. Moreover, the study was conducted inonly older subjects, limiting the generalizability of results. Therefore, it is important to furtherexamine the effects of exercise in depressed subjects of different age groups and to isolate exer-cise effects from social support. It is also important to quantify the amount of exercise neededto reduce depressive symptoms so that recommendations for exercise prescription can be de-veloped for the purpose of treating depression. The Depression Outcomes Study of Exercise(DOSE) is the first dose-response study of exercise as a monotherapy for the treatment of mildto moderate MDD in young to middle-aged adults. Specific objectives There were two major objectives of the DOSE study. The first was to determine the effi-cacy of aerobic exercise as a sole treatment of mild to moderate MDD in participants ran-domized to exercise compared with an “equal contact” exercise placebo control group over a586 A.L. Dunn et al./Controlled Clinical Trials 23