These results confirm and extend previous findings that exercise is comparable to antidepressant medication in the treatment of patients with MDD. In our previous study (13
), 56% of patients receiving sertraline and 47% assigned to supervised exercise were in remission after 4 months of treatment and all patients achieved significant and comparable reductions in depressive symptoms. That study, however, did not include a placebo control group, in the absence of which it could not be affirmed that the observed improvement was due to exercise or medication and not to nonspecific factors such as time, staff attention, or positive expectations. Klein (40
) argued cogently that when comparing nonpharmacologic interventions to antidepressant medications, investigators must include a pill-placebo to assure that the patient sample studied is one that is responsive to medication beyond the effects of a placebo. This perspective maintains that it is not adequate merely to compare a new intervention to a Food and Drug Administration-approved and widely utilized antidepressant (e.g., sertraline), but that all such trials must include a pill-placebo condition. Walsh and Sysko (41
) made similar arguments and concluded that studies evaluating new treatments lack scientific credibility if there is no placebo and the only evidence for treatment efficacy is a response that is statistically indistinguishable from the response to an established medication. Therefore, we considered it essential to include a placebo condition in our study design.
In the current study, both exercise and medication achieved higher remission rates compared with placebo; 45% of MDD patients undergoing supervised exercise, 40% undergoing home-based exercise, and 47% receiving medication were in remission after 16 weeks of treatment, compared with only 31% receiving placebo. These remission rates are considered to be clinically meaningful, especially because HAM-D scores of <8 are associated with low relapse rates (42
). The odds ratio for patients receiving either medication or exercise compared with placebo was 0.50, which represents a 50% reduction in the odds of remaining depressed after 16 weeks. The remission rates that were observed in the present study compare favorably with other randomized placebo controlled psychopharmacology trials in patients with MDD, which are typically 35% to 40% (43
). Fourteen (7%) patients exhibited an “early response” defined as a ≥50% reduction in self-reported (BDI) depressive symptoms after only the first week of treatment. When these early responders were removed from the analysis, the differences between active treatments and placebo became more pronounced: 46% of patients in supervised exercise, 38% in home-based exercise, and 44% receiving sertraline were in remission after 4 months, compared with only 26% of the placebo controls.
Although placebo response rates in treatment studies of MDD are highly variable, the 31% placebo response rate observed in the present study is consistent with previous studies that have reported placebo response rates ranging from 30% to 50% (46
). Our finding of no difference in HAM-D scores in patients receiving sertraline and placebo also is consistent with results of other randomized control trials such as the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART) (49
) and the St. John’s Wort trial (50
), which found that reductions in depressive symptoms were comparable when analyzing data from all patients randomized to placebo and sertraline conditions.
Our overall findings are generally consistent with several meta-analytic reviews that suggested that exercise may be an effective treatment for depression (22
). However, as noted by Lawlor and Hopker (21
), the methodological limitations of prior studies have made it impossible to definitively conclude that exercise is efficacious for treating MDD. Our findings also do not provide conclusive evidence for the value of exercise. To our knowledge, the present study is the first to compare the independent effects of exercise and medication to a placebo control group. However, the effect size (defined as the mean group difference divided by the pooled sample SD before treatment) for the HAM-D outcome was rather modest—comparing all active treatment versus placebo, the treatment effect was about 0.20 using ITT and 0.30 after eliminating early responders. One reason for the low effect size relative to other studies may be due to the fact that we used a placebo group rather than a wait list control group. Because expectations for improvement are greater among patients receiving placebo compared with wait list controls, the difference between active treatments and control conditions is likely to be smaller in studies in which there are credible no-treatment control conditions. In addition, the close surveillance and support of placebo participants may have provided additional therapeutic benefit, further reducing differences between the active treatments and placebo controls.
Another factor contributing to the modest effect size in the present study was our use of ITT as our primary analytic approach. We used the last observation carried forward method to derive outcome effects from patients who drop out prematurely and do not undergo follow-up assessments. Although this approach is a widely used method of analysis, differential dropout rates can affect the results. Assuming that there is a general tendency for depressed patients to feel progressively better over the course of treatment, this improvement would be minimized when posttreatment levels of depressive symptoms are represented by observations taken at earlier points (51
). The fact that the dropout rate for supervised exercise (20%) was greater than that for home-based exercise (6%) or sertraline (7%) makes it more difficult to compare the relative effectiveness of the treatment groups in this study.
Another question we addressed in the present study was whether the beneficial effects of exercise observed in our previous study could have been attributable to the social stimulation and support provided by the group setting of the exercise intervention. Would the same benefit be observed if patients engaged in the exercise regimen individually at home? A small, randomized, controlled trial (14
) recently demonstrated that exercise was associated with reduced depressive symptoms independent of group support. However, this conclusion is weakened by the fact that only 53 of 80 patients actually completed the 12-week trial, including 5 of 13 no-treatment controls. The present sample included 202 patients with MDD, and all randomized patients were included in the primary ITT analyses. Our findings showed that there was no difference in remission rates between patients who exercised in a supervised group setting and those who exercised on their own. Although the two groups showed similar rates of compliance with the exercise prescription, the supervised exercisers tended to push themselves more consistently into the target heart rate range, which probably accounts for why this group performed better than the home exercisers on end-of-study assessments of aerobic fitness. The present findings suggest that, for this patient population, supervised exercise yields better outcomes than home exercise with respect to physical conditioning, but that both seem equally effective in achieving remission of clinical depression. Some studies (52
), but not all (54
), have reported that supervised exercise training results in larger improvements in functional capacity compared with home-based exercise, and that greater energy expenditure is associated with larger reductions in depressive symptoms (14
). It should be noted, however, that our study was not powered to detect the relatively small differences in depressive symptoms that we observed between the two exercise conditions; it is therefore not possible to be certain that home-based exercise is comparable with supervised exercise in reducing depressive symptoms. Even with greater power, however, it is not clear that such differences would be clinically meaningful.
The mechanisms responsible for exercise-related improvements in depression are not known. Although our data suggest that social support was not necessarily critical to the therapeutic benefit of exercise, a number of psychological factors have been proposed to explain the effect that exercise has on depressed mood including increased self-efficacy, a sense of mastery, positive thoughts, distraction from negative thoughts, and enhanced self-concept. A number of biologic pathways also have been suggested including increased central norepinephrine neurotransmission (55
), alterations in the hypothalamo-pituitary-adrenocortical axis (58
), and increased secretion of amine metabolites as well as serotonin synthesis and metabolism (59
It also should be emphasized that the intent of our study was not to determine if exercise is superior to sertraline. It is more difficult to distinguish between active therapies than it is to find a difference between active therapies and placebo. To reliably detect the small differences in depression as measured by the HAM-D or BDI scores, it is estimated that at a minimum of 300 patients per arm is required (63
). Although our sample of 202 patients with MDD is, to our knowledge, the largest single site exercise study of MDD yet conducted, it also is important to recognize that our study was underpowered to detect small differences between the active treatment groups. Our initial power analysis determined that we had enough power to detect just over a half SD (d = 0.55) difference with 50 patients per cell, which translates into about a 4-point difference on the HAM-D (depending on the estimate of the variance of the scores). However, we observed only a little over a 1-point difference between active treatment and placebo on the HAM-D. If we assume that this is a reasonable estimate of the population treatment effect, we would have required 950 patients to detect a statistically significant difference, and a 1-point difference is not clinically meaningful.
Because participants in this study represent patient volunteers, it is difficult to determine the extent to which these findings may generalize to typical outpatients seeking treatment for MDD. Zimmerman et al. (64
) estimated that only one in seven patients seen in an outpatient clinical setting would be eligible to participate in pharmacological clinical trials, suggesting that the response rate could be lower for patients seeking treatment in outpatient psychiatric settings than those observed in clinical trials. Also, patients who are actively suicidal or who have severe MDD are ineligible for most placebo-controlled trials in which a subgroup of individuals essentially receive “no treatment” for several months. Our sample consisted primarily of patients with mild depression; only 39% of our sample had moderate-severe depression (HAM-D scores of ≥18), which may limit the generalizability of our findings. However, the more severely depressed patients in our study showed the same pattern of results as their less depressed counterparts, suggesting that exercise may be beneficial to patients with moderately severe depression as well as mild depression. Finally, we note that most of the participants in the present study enrolled with the hope that they would receive exercise treatment for their depression. It is unknown to what extent this willingness to engage in exercise therapy is shared by the general population of outpatients with MDD. Thus, although these results are promising and suggest that patients receptive to exercise therapy can achieve significant symptomatic relief comparable to established medical therapies, the clinical application of exercise therapy and the long-term benefits of exercise need to be studied further.