Augmentation strategies for treatment of major depression have received increased attention in recent years because initial treatment strategies often fail to fully relieve depressive symptoms.1 Of patients receiving initial treatment with a standard antidepressant medication, 65%-75% will not achieve remission.2-4 Incomplete remission results in lingering depressive symptoms such as sadness, irritability, insomnia, and difficulty concentrating.5 Residual depressive symptoms contribute to continued medical costs and disability, and the prognosis for patients who exhibit partial response is inferior to those who attain remission.6-8
Currently, the most common augmentation strategies use pharmacological agents. Lithium and thyroid supplementation have the most robust evidence for efficacy.9,10 However, neither lithium nor thyroid supplementation has become widely used for a number of reasons, including difficulty of monitoring and complexity of use. Other pharmacological augmentation strategies have been suggested, but few have been evaluated by randomized placebo-controlled trials.10 Most important, pharmacological augmentation strategies have the potential to cause adverse effects due to the interaction of multiple agents. Thus, there is a need for nonpharmacological strategies that have a more favorable side effect profile.
The use of exercise as an augmenting strategy is a novel approach to the treatment of depression, and one with a low risk of negative interactions with existing treatments. Moreover, exercise has additional long-term benefits both for the treatment of depression as well as general health.11-14
While there is no extensive research on the use of exercise as an augmenting strategy, exercise does appear promising based on studies examining its use as monotherapy.15,16 In addition, studies in which exercise has been used in combination with other treatments suggest that the combined use of exercise with other antidepressant treatments also reduces depressive symptoms and therefore may be an effective approach to treating depression.17-21 However, a true test of exercise as an augmenting strategy must assess the addition of exercise following an adequate trial of antidepressant treatment.
This study represents a first step in testing the potential of exercise as an augmenting strategy for the treatment of depression. The primary goal was to assess changes in depressive symptoms in participants who added an individual exercise program to their existing antidepressant treatment. It is important to note that this study used an exercise program that is readily generalizable and can be applied in a clinical practice setting.
Participants were recruited from community volunteers and physician referrals. After a complete description of the study, informed consent (approved by UT Southwestern and The Cooper Institute Institutional Review Boards) was obtained from participants who met the following preliminary screening criteria: 1) 20-45 years of age, 2) primary diagnosis of unipolar, nonpsychotic major depressive disorder, 3) treatment with a selective serotonin reuptake inhibitor or venlafaxine for 6 or more weeks at a therapeutic dose (at least 10 mg/day escitalopram; 20 mg/day paroxetine, citalopram, or fluoxetine; 50 mg/day sertraline; or 150 mg/day venlafaxine), 4) Hamilton Rating Scale for Depression22,23 (17-item; HRSD17) score ≥ 14, and 5) physically inactive at time of study (i.e., exercising < 3 days/week and ≤ 20 minutes each time). Persons with significant general medical conditions or concurrent primary DSM-IV Axis I diagnoses or those who were using other psychotropic medications were excluded. Participants continued to receive antidepressant treatment (unchanged in dose and type) from their treating physician during the study. Participants' physical readiness for exercise was determined by the Physical Activity Readiness Questionnaire24 (PAR-Q) (www.csep.ca/forms.asp) and a physical examination. Note four eligible subjects declined participation (i.e., unspecified withdrawal) after completing the baseline visit.
The Structured Clinical Interview for DSM-IV Axis I Disorders-Clinician Version25 (SCID-CV) was used to obtain diagnoses. The 17-item Hamilton Rating Scale for Depression22,23 (HRSD17; primary outcome) and the 30-item Inventory of Depressive Symptomatology-Self-Report26-28 (IDS-SR30; secondary outcome) were both administered each week before the participants' first exercise session for the week. The General Activities form of the Quality of Life Enjoyment and Satisfaction Scale29 (Q-LES-Qgeneral) was administered at pre- and post-treatment to assess psychosocial function. The Q-LES-Qgeneral measures patients' perception of their functioning in many areas of life, including work, school, and relationships.
The 12-week intervention consisted of both supervised (The Cooper Institute, Dallas, TX) and home-based exercise sessions. In the exercise laboratory, participants had the choice of using treadmills or stationary cycles (Life Fitness, Franklin Park, IL), or a combination of the two. For home-based sessions, participants could choose to use a treadmill, stationary cycles, a combination of both, or overground walking. These modes of exercise were chosen to allow precise estimation of total calories expended for each session. Exercise intensity was self-selected and held constant throughout an entire exercise session but could be changed between sessions according to participant preference.
Current public health recommendations state that all adults should perform 30 minutes or more of moderate intensity physical activity on most days of the week or expend at least 1,000 kilocalories (kcal) weekly.30 Thus, the exercise dose for energy expenditure was 16 kcal/kg/wk (KKW) to approximate the public health dose. Participants were weighed during the first visit each week to calculate weekly energy expenditure, and a total of 3-5 exercise sessions/week were recommended to achieve the prescribed exercise dose (Table 1). Previous research has shown no effect of exercise frequency on depressive symptom reduction16; thus, participants were allowed to choose frequency based on scheduling and preference.
A combined supervised and home-based program was utilized. Participants reported to The Cooper Institute 3 days during the first week, 2 days during the second week, and 1 day during the third week. Remaining sessions were performed using a home-based program in weeks 4 through 12. This tapered exercise program was used to familiarize participants with the study protocol, demonstrate proper documentation of their exercise sessions, and assure staff that the participants could meet their exercise dose. If participants had difficulty completing their prescribed exercise dose during the first session of week 1, the exercise protocol was ramped to gradually increase intensity and/or duration for the first 3 weeks (with the target dose achieved by the end of the third week) to prevent soreness, fatigue, and injuries, and to promote adherence.
Weekly exercise log forms (Appendix 1) were given to participants, which included the prescription for the amount of weekly exercise and a plan for how the exercise was to be performed (number of sessions, duration, and type of exercise). This tailored exercise prescription was based on the exercise information (treadmill speed, grade, bike watts, cadence, and outside walking pace) collected during the supervised sessions in the initial 3 weeks. Weekly exercise logs were reviewed by a member of The Cooper Institute staff, and energy expenditure (kcal) was calculated for each logged home-based exercise session. This same staff member maintained phone contact with participants on a regular basis to verify logs and troubleshoot adherence issues with participants as needed.
The intent-to-treat sample (N = 17), analyzed by two-tailed paired t-tests and last observation carried forward (LOCF) methods, provided a conservative estimate of the true effect of the exercise intervention. LOCF analyses served as the primary analyses and provided estimates of efficacy that would be comparable to other studies of antidepressant treatments. In order to provide results that are comparable to studies that examine treatment completers, secondary analyses were conducted for those individuals who completed all 12 weeks of exercise (N = 8).
Patient demographic and clinical characteristics. Seventeen participants met entrance criteria and had at least one post-baseline measure. Characteristics of participants are presented in Table 2. The sample was predominantly female (82%) with a mean age of 39 years. Citalopram was the most common antidepressant medication used by this sample.
Characteristics of exercise. Walking was the most common mode of exercise, with over 50% of all sessions conducted on the treadmill and over 30% of all sessions conducted by overground walking. On average, participants exercised three times/week, with a mean session length of 55.3 minutes during Week 1 and 50.6 minutes during Week 12. Energy expenditure (kcal/session) remained statistically constant from the beginning to the end of the study, with a mean kcal/session of 336.2 during Week 1 and 363.1 during Week 12. Intensity was self-selected and remained statistically constant when measured by post-exercise heart rate (mean = 118.5 beats/minute [bpm] during Week 1 and 133.5 bpm during Week 12). Rating of perceived exertion (RPE, as defined by the Borg scale31) also remained constant throughout the study, with a mean of 12.9 during Week 1 and 12.0 during Week 12. The Borg scale rates exertion on a scale from "6 = no exertion at all" to "20 = maximal exertion," with a score of 11 on the Borg scale corresponding to "fairly light", while 13 corresponds to "somewhat hard." Thus, on average, the level of perceived exertion in our sample fell between these values, which is consistent with previous research on preferred exercise intensity.32Table 3 presents a summary of these data.
Symptom severity. Baseline depression scores were 17.4 (HRSD17) and 34.8 (IDS-SR30). Based on LOCF analyses, HRSD17 scores decreased 5.8 (±7.7) points [t(16) = 3.1, p < 0.008]. IDS-SR30 scores decreased by 13.9 (±12.7) points [t(13) = 4.1, p < 0.002]. Baseline IDS-SR30 scores were missing for three participants; therefore, these individuals were not included in the analysis for IDS-SR30. Mean scores at pre- and post-treatment are provided for both depression measures in Table 4.
Weekly mean HRSD17 and IDS-SR30 scores for both the intent-to-treat sample and all available weekly data (i.e., actual data from patients who were still participating at each time period) are provided in Figure 1. Mean scores generally decreased each week, with some fluctuations, particularly after week 6.
Remission rates were also computed. Remission was defined as an HRSD17 score ≤ 7 achieved during the course of treatment. Twenty-nine percent (5 out of 17) of the intent-to-treat group met this criterion.
Adherence. The average length of participation in the trial was 6.2 weeks for the intent-to-treat sample (N = 17). Adherence was based on the percentage of weekly energy expenditure (kcal) actually completed from the prescribed exercise dose, as reported on the log forms (expended kcal/prescribed kcal). Mean percent adherence for individuals who exercised at least once (n = 13) was 76.8% when calculated up to the point of participant dropout.
Patient demographic and clinical characteristics. A total of 8 participants completed the full 12-week study, and 10 participants completed at least 4 weeks of exercise. Reasons for drop out included unspecified withdrawal (n = 4), illness or injury unrelated to the study (n = 3), move (n = 1), and schedule conflicts (n = 1).
Outcome measures. When data for those who completed the study were analyzed (n = 8), HRSD17 scores decreased by 10.4 (± 7.2) [t(7) = 4.1 p < 0.005] points, and IDS-SR30 scores decreased by 18.8 (±10.3) [t(7) = 5.1 p < 0.002] points (see Table 4). Sixty-three percent (5 out of 8) of participants who completed the study met the criterion for remission (HRSD17 score ≤ 7). Eighty-eight percent (7 out of 8) of the completers had an HRSD17 score of 10 or less at the end of the study.
Because quality of life was only evaluated at baseline and study completion, quality of life data are only available for individuals who completed the study. A two-tailed paired t-test was used to measure the pre- and post-treatment quality of life and functioning on the 8 subjects who completed both measurements. Q-LES-Qgeneral scores significantly improved after 12 weeks of exercise augmentation treatment, as indicated by a mean change of 14.3 (±9.8) points [t(7) = 4.1, p < 0.005] (see Table 4).
The purpose of this pilot study was to make a preliminary assessment of the use of exercise as an augmentation strategy in individuals with major depression. This study included patients with a partial response to an adequate dose and duration of an antidepressant medication, an individualized exercise program with a specific energy expenditure dose, and standardized diagnosis and assessment of depressive symptoms. The results of this study suggest that exercise can be used as an augmenting strategy in the treatment of depressed patients who were previously sedentary. Both clinician-rated and self-reported depressive symptoms improved during the course of the exercise intervention. Quality and satisfaction with life also improved. These data are consistent with previous reports on combining exercise with antidepressant treatment.17-21 The results are also consistent with studies of second-step antidepressant treatments, in which the first-step monotherapy treatment was implemented for a well-defined dose and duration.1,33
It is important to note that a clinically significant mean change of 5.8 points was observed on the HRSD17 using a conservative intent-to-treat analysis, which included participants who dropped out of the study while they were still symptomatic. The completer group yielded a mean change greater than 10 points on the HRSD17. This is particularly notable, because patients were receiving treatment prior to study entry and had had an average of 4 months of antidepressant medication prior to the addition of the exercise intervention. A major concern with most augmentation trials that use a shorter duration of initial monotherapeutic medication (≤ 12-16 weeks) is that observed effects may be explained simply by a longer duration of treatment with the initial medication.34 Thus, this design was conservative since it involved a relatively long course of initial treatment, yielding patients who were true partial responders to the medication with which they were initially treated.
The goal of this study was not only to assess the effect of exercise on depressive symptoms, but also to learn how to develop and evaluate a home-based exercise program for depressed individuals, with the goal of having a program that would be appropriate for use in the course of routine clinical care. Depression is associated with reduced energy, fatigue, and decreased motivation, all of which present challenges to the implementation and long-term use of exercise as a treatment modality. Because exercise requires continued and frequent practice, a home-based approach is essential so that patients with depression can easily make exercise a routine part of their daily lives. Previous studies of exercise in depression have not adequately evaluated the use of exercise as a treatment approach outside a supervised setting. Therefore, the generalizability of such an intervention has not previously been assessed. This study provides preliminary support for an approach designed to assist previously sedentary individuals in adopting structured exercise with the goal of achieving mental health benefits. An exercise program using supervised exercise during the initial weeks of treatment and then tapering to self-directed exercise provides patients with the needed information and support to adopt exercise. Ongoing phone support provides opportunities for symptom monitoring, addressing adherence concerns, and adjusting the exercise treatment plan.
This pilot study had several limitations. First, it was not a randomized, controlled trial. The lack of placebo control in this open label trial prevents assessment of whether the observed decreases in symptom severity were due to extended antidepressant treatment or the addition of exercise, although the likelihood of a robust placebo response rate is low given the well-documented adequate antidepressant trial prior to entry into the study. Furthermore, while we made every attempt to guard against effects of attention, we could not eliminate or discern the impact of the attentional component (i.e., trainer or physician contact) of the intervention on treatment response. Another limitation of the study was the small sample size and relatively low completion rate of 47%. However, typical augmentation trials last from 6-8 weeks and yield dropout rates that are generally in the range of 30%-40%.35 Dropout rates are much higher for studies of longer duration or those that examine remission rates as an a priori outcome criterion, such as this one.36,37 In addition, implementation of exercise programs in both patient and non-patient samples yields dropout rates as high as 50%, even in short-term trials.38,39 Therefore, the dropout rate in our study is consistent with those observed in previous studies. Regardless, this rate may suggest that exercise augmentation is helpful for only a subset of depressed individuals. An additional limitation was that the exercise dose was quantified and controlled in terms of energy expenditure. Since intensity and exercise modality were self-selected, these variables were not analyzed. A final limitation is that while one might be tempted to use the current study to estimate the potential effect size of an exercise augmentation intervention, the limited sample size and significant design differences in pilot studies preclude this use of these types of data (see Kraemer et al. 200640).
The potential public health impact of exercise augmentation in the treatment of depression is substantial. A concern with current antidepressant augmentation strategies is that they require patients to be on multiple medications for extended periods of time, and many patients may be reluctant to take additional medication. There is clear research evidence suggesting that patients who are not treated until they achieve full remission are at considerably higher risk for relapse and recurrence.41,42 Therefore, it is important to identify acceptable treatment strategies for patients who have had only a partial response to antidepressant monotherapy. If exercise is indeed shown to be an effective augmenting treatment for depression, the impact on clinical practice could be great. Exercise is unlikely to negatively interact with ongoing pharmacotherapy. In addition to the reduction of depressive symptoms, the use of exercise could substantially improve patients' overall health and functional status and reduce the enormous cost burden that is associated with depressive illness.
Although this was a preliminary study, the results indicate a significant effect of exercise augmentation on reducing depressive symptoms in patients who were partial responders to standard antidepressant treatment. A larger randomized, controlled efficacy trial of exercise augmentation for depression is warranted to further evaluate the benefits of exercise augmentation in depression. In addition, future investigations should assess the effects of exercise on longer-term outcomes, as well as ways to facilitate the adoption of exercise as a routine part of clinical care, both by physicians and patients. Despite the limitations discussed in the previous section, the results of this study support the use of exercise in conjunction with antidepressant treatment and suggest that a predominantly home-based intervention can yield clinical benefits.
The exercise program used in this study can be readily implemented in a clinical setting. Some general recommendations for exercise augmentation are given below:
Exercise dose: Most patients can achieve the recommended exercise dose by doing moderate-intensity exercise (e.g., brisk walking at 3-4 miles per hour, stationary cycling at 50-100 watts) for a total of at least 150 minutes per week. Practitioners can ask patients about their physical activity habits and history to match the exercise plan to individual needs and preferences.
Exercise supervision: Ongoing professional support on a weekly or biweekly basis is recommended to ensure adherence and address any issues related to the exercise dose. It may be helpful to collaborate with a fitness professional who can supervise exercise sessions during the initial weeks of the program. Look for fitness professionals certified by national organizations such as the American College of Sports Medicine (ACSM) or the American Council on Exercise (ACE).
Logging exercise sessions: Patients should be instructed to record frequency, duration, and mode of exercise for all exercise sessions on a weekly basis. It may also be helpful for patients to record barriers to exercise to facilitate problem solving during clinical follow-up visits.
Acknowledgements. This work was supported in part by a National Alliance for Research on Schizophrenia and Depression (NARSAD) Independent Investigator Award (PI: MH Trivedi), by a NARSAD Young Investigator Award (PI: TL Greer), and by the National Institute for Mental Health (1-R01-MH067692-01; PI: MH Trivedi). The authors would like to thank Prabha Sunderajan, MD, Tim Church, MD, PhD, Elizabeth Darr, Kim Warren, Elvira Espinoza, and Erin Sinclair for assistance with the conduct of this study; Melissa K. Haldeman for assistance with manuscript preparation; A. John Rush, MD, for comments on the manuscript; and Eric Nestler, MD, PhD, Lou and Ellen McGinley Distinguished Professor and Chairman, Department of Psychiatry, University of Texas Southwestern Medical Center for administrative support.
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