WHAT IS DEPRESSION?
Depression is a term that refers both to a transient mood state and a clinical syndrome or disorder. Depression as a mood state is characterized by feeling sad, discouraged, or unhappy, while depression as a clinical condition is a psychiatric disorder in which diagnostic criteria require five or more depressive symptoms, one of which must include either depressed mood or loss of interest or pleasure along with at least four other depressive symptoms including significant weight loss, sleep disturbance, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, diminished ability to think or concentrate, and recurrent thoughts of death. Major depressive disorder (MDD) is distinguished from transient feelings of depression by both the severity and duration of symptoms: symptoms of depression must be present for all or most days of the week for at least 2 weeks, represent a change from a previous level of functioning, and be accompanied by somatic, cognitive, or affective symptoms (Figure 1) (1).
EPIDEMIOLOGY OF MDD
It has been estimated that more than one in five adults experience MDD at some point in their lifetimes, and depression may be twice as likely to occur in women compared with men. As many as one in four adolescents may experience depression, and young adults who experience depression in adolescence are at twice the risk of experiencing another depressive episode as adults compared with adolescents who do not experience MDD.
Depression also is commonly observed to co-occur with many medical conditions, including obesity, diabetes, and cardiovascular disease. Indeed, approximately 20% of patients with coronary heart disease (CHD) experience depression, and an additional 20% may experience elevated depressive symptoms without meeting diagnostic criteria for MDD.
ASSESSMENT OF DEPRESSION
MDD is diagnosed by psychiatric interview, of which, several validated versions are available. In addition to interviews, a number of self-report questionnaires have been used to assess the severity of depressive symptoms (Table 1). It should be noted that, although questionnaires may have established “cut-points” to identify persons who clinically may be depressed, such instruments are not diagnostic tools but rather measures of the presence and severity of depressive symptoms. Two of the most widely used self-report instruments are the Beck Depression Inventory (BDI) and the Patient Health Questionnaire-9 (PHQ-9). A recent scientific advisory panel commissioned by the American Heart Association (11) suggested that the PHQ-9 be considered as a potential instrument for identifying persons who clinically may be depressed. The two-item PHQ-2 was suggested as possible brief screen, followed by the full PHQ-9 for patients who screen “positive” on the PHQ-2 (Table 2). An algorithm for screening for depression that could be used in clinical practice is displayed in Figure 2.
CLINICAL SIGNIFICANCE OF DEPRESSION
MDD is associated with poorer quality of life and increased medical expenditures and health care utilization. In addition, depression is one of the leading sources of disability in the United States and is associated with significantly increased missed time at work. According to the World Health Organization, depression is the second leading cause of disability adjusted life years after CHD.
There also is a mounting literature that has documented the association of depression with adverse health outcomes in both healthy individuals and patients with CHD. Many studies of patients with a variety of cardiac conditions have reported that depression is associated with a two- to four-fold increase in risk of adverse health outcomes, including patients’ postmyocardial infarction, coronary bypass surgery, stable and unstable angina, and chronic heart failure (4,16). In addition, many studies have shown that CHD patients who have elevated depressive symptoms, that is, who obtain BDI scores of 10 or higher without necessarily meeting criteria for MDD, are at increased risk for death or other adverse cardiac events, suggesting that increased depressive symptoms may worsen prognosis, even if patients are not clinically depressed.
CONVENTIONAL TREATMENTS FOR DEPRESSION
Pharmacotherapy. MDD is most commonly treated with antidepressant medication (14). Many randomized clinical trials (RCTs) have examined the effectiveness of various pharmacological compounds on depression outcomes. The current recommendations for depression treatment typically involve pharmacological treatment, usually with a selective serotonin release inhibitor, although treatments with tricyclic antidepressants, benzodiazepines, and combined therapies also are common (for most frequently prescribed antidepressant, see Table 3). It has been estimated that approximately 50% of patients will have a clinical “response” to treatment (i.e., a 50% reduction in symptoms), whereas many individuals will require augmented treatment with more than one antidepressant agent. However, many patients do not respond to antidepressant medications or experience untoward side effects. In addition, results of placebo-controlled trials in which research participants receive either a placebo (i.e., sugar) pill or active antidepressant medication yield mixed results, and evidence generally suggests that antidepressants may be especially effective for patients with more severe depression (8) (Figure 3).
Psychotherapy. There are many varieties of psychotherapy (i.e., “talk” therapy). Psychotherapy involves individual or group counseling of more than 4 to 6 months or longer. The American Psychological Association recognizes several “empirically validated” treatments, that is, therapies that have been demonstrated to be effective compared with a control group by two or more investigative teams. The most effective treatments for MDD include cognitive behavioral therapy (CBT), behavior therapy (BT), and interpersonal psychotherapy (IPT). CBT focuses on identifying and modifying maladaptive thought patterns, whereas IPT emphasizes the social context in which depression occurs and focuses on improving communication skills. BT emphasizes increasing engagement in positive daily activities, decreasing negative life experiences, and improving social skills and adaptive behaviors (Table 4). Psychotherapy has been shown to be one of the most effective long-term treatments of depression and often is used in conjunction with pharmacotherapy among individuals with more severe depression.
EXERCISE AS A TREATMENT FOR DEPRESSION
The effects of exercise on individuals with elevated depressive symptoms have been examined in more than two dozen RCTs and have been the topic of several meta-analyses and systematic reviews, including one Cochrane review (12). Existing studies have varied substantially in size, type of control group, methodological rigor, length of follow-up, and even the type of exercise modality. Randomized trials of exercise have ranged generally in length from 6 weeks to 4 months and typically emphasize aerobic exercise, although some studies of resistance training also have been reported. Although multiple trials have been conducted among adults with MDD, few studies have used high-quality methodologies in which treatment allocation is concealed, intention-to-treat analyses are used, a control group is included in the design, and depression is assessed by clinical interview in which the assessor is blinded to the treatment group.
In a landmark review, Lawlor and Hopker (10) conducted a meta-regression of randomized trials of aerobic exercise and depression among published, randomized trials conducted among adults. Their literature search yielded 14 studies for inclusion, incorporating data from approximately 850 individuals. Using the BDI as their outcome measure, the authors reported that exercise reduced depressive symptoms by −7.3 points (95% confidence interval [CI], −10.0 to −4.6) and that this effect was greater in trials with shorter follow-up periods. Despite the findings of improved depressive symptoms, the authors concluded that the effectiveness of exercise in treating depression could not be determined because of a lack of good quality research in clinical populations and a lack of appropriate follow-up assessments.
In a subsequent review, Mead and colleagues (12) conducted a comprehensive literature search of randomized controlled trials in adults in which exercise was compared with a standard treatment, no treatment, or a placebo control. Their search yielded 28 studies that met their inclusion criteria. Methodological quality varied substantially across studies, with a minority of studies adequately concealing treatment, using intention to treat analyses, and using objective measures of depressive symptoms. Approximately half of the studies included used a two-arm design, comparing exercise with controls only. Other studies used a three-arm design, comparing exercise with one other treatment modality (e.g., pharmacotherapy, cognitive therapy, or a different intensity exercise group) and a control group. Most studies used jogging/running as their treatment modality, but some used walking, aerobic training with an instructor, stationary cycling, or mixed exercise (e.g., resistance training and stretching).
In the Cochrane review, the primary analyses were limited to those trials comparing exercise treatment with no treatment or a control intervention (n = 25) and found large, clinically meaningful improvements associated with exercise in comparison with controls (standardized mean difference [SMD], −0.82 [95% CI, −1.12 to −0.51]). However, when the analyses were further limited to those trials using intention-to-treat analyses and blinded outcome assessment, the effect was slightly weaker, suggesting only a moderate antidepressant effect associated with exercise. In addition, when analyses were conducted among the five trials that collected long-term follow-up data, the effects of treatment were again slightly weaker, consistent with a moderate clinical improvement (SMD, −0.44 [95% CI, −0.71 to −0.18]).
COMPARATIVE EFFECTIVENESS OF EXERCISE WITH CONVENTIONAL TREATMENTS
The Mead meta-analysis examined several of these comparative effectiveness analyses, conducting sensitivity analyses of those trials comparing established treatments with exercise. Comparison with exercise and CBT showed no difference between exercise and cognitive therapy (SMD, −0.17 [95% CI, −0.51 to 0.18]). An additional sensitivity analysis was conducted comparing the results of exercise compared with antidepressant medication. Only two studies, both from researchers at Duke University, compared the effectiveness of exercise with pharmacotherapy. No differences between exercise and antidepressant medication were noted (SMD, −0.04 [95% CI, −0.31 to 0.24]).
THE DUKE SMILE STUDIES
Blumenthal and colleagues conducted several RCTs comparing the effects of aerobic exercise to antidepressant medication. In the first Standard Medical Intervention versus Long-term Exercise (SMILE) study (3), 156 older adults with MDD were randomized to 4 months of either aerobic exercise, sertraline, or a combined exercise and sertraline group. Participants in the exercise conditions exercised in a group setting three times per week at 70% to 85% of their heart rate reserve. Participants in the sertraline condition were titrated for therapeutic response on sertraline by a study psychiatrist (50–200 mg), consistent with standard clinical treatment of depression. After 16 weeks of treatment, groups did not differ in their level of depressive symptoms, suggesting that exercise and standard antidepressant treatments were equally effective. Interestingly, a follow-up examination of these participants conducted 10 months after the completion of the treatment period showed that participants in the exercise group showed lower rates of depression relapse in comparison with both the sertraline and combined groups. Moreover, participants who reported engaging in regular exercise during the follow-up period were more than 50% less likely to be depressed at their 10-month assessment compared with nonexercisers.
The Duke group (5) later extended these findings by including a placebo control group and by adding a group that exercised at home on their own, without the social interaction facilitated by group exercise that could contribute to the antidepressant effects of exercise. Participants were randomized to either home-based or supervised aerobic exercise, sertraline, or placebo for a 4-month period. Home-based exercisers were provided with the same exercise prescription as supervised participants and received an initial home visit to establish their exercise training routine, as well as instructions on how to monitor their heart rates accurately. Results revealed that participants in either exercise or sertraline groups tended to show greater improvement in comparison with placebo participants, and these results became statistically significant when “early responders” (i.e., participants who experienced a self-reported improvement in depressive symptoms of >50% within the first week of treatment), were eliminated from analyses.
In a recent follow-up analysis (2), participants’ depression was reassessed 1 year after their enrollment in the trial. Interestingly, neither group assignment nor antidepressant medication usage during the follow-up period was significant predictors of depression at this follow-up time point. Instead, the only significant predictor was regular exercise during the follow-up period. In other words, regardless of initial treatment group assignment or background characteristics, those individuals who reported regular exercise after completion of the intervention were the least likely to be depressed at follow-up. Taken together, these data suggest that exercise is effective in reducing depression in patients with MDD, and exercise may reduce the risk of relapse.
DOSING OF EXERCISE
To our knowledge, only one RCT has systematically examined the optimal “dose” of exercise needed to improve depression. Dunn and colleagues (7) randomized 80 sedentary adults diagnosed with MDD to 12 weeks of one of five aerobic exercise-training treatment conditions: low energy expenditure and 3 days of exercise training per week, high energy expenditure and 3 days of exercise training per week, low energy expenditure and 5 days of exercise training per week, high energy expenditure and 5 days of exercise training per week, or stretching and flexibility control. Results of the trial showed that exercise conducted at the high energy expenditure dose (consistent with public health recommendations) was effective in reducing depressive symptoms (47% from baseline measurement) over the 12-week treatment period. In contrast, although participants randomized to the low energy expenditure dose experienced some reduction in depression over the treatment period (30% decline from baseline), those participants did not respond any better than participants in the control condition did (29% decline from baseline). Regarding frequency of training, no significant difference in treatment response was found between those participants who exercised 3 days per week relative to those who exercised 5 days per week. The authors concluded that a higher energy expenditure was critical to remission of MDD.
In contrast, other studies, including the two SMILE studies described previously, reported that three sessions per week of 30 to 45 minutes per session was sufficient to reduce depression, and the follow-up of study participants suggested that 90 minutes per week was sufficient to reduce the risk of relapse. Similarly, in an observational study of 522 cardiac patients, Milani and Lavie (13) reported that aerobic exercise in the context of a comprehensive cardiac rehabilitation program (i.e., three times per week for 30 minutes for 3 months) was associated with significant reductions in depressive symptoms. Patients who showed no gain or a loss in aerobic capacity were less likely to benefit compared with those patients who showed improvement in aerobic capacity. However, patients were not randomized to different levels of exercise, and the relation of exercise dose and improved depression and aerobic capacity was not examined. Therefore, there remains uncertainty about the optimal dose of exercise to improve depression, but clearly, some exercise is better than no exercise.
Patients with MDD may find it difficult to initiate and sustain an exercise routine. Motivation for exercise may be affected by depressive symptoms such as fatigue, indecisiveness, low self-esteem, loss of interest and pleasure, and poor sleep. Depressed patients with higher levels of anxiety and lower levels of fitness may be at particular risk for exercise nonadherence (6). Because the antidepressant affects of exercise are experienced by participants who maintain the exercise habit over time, strategies to sustain exercise are essential for patients to achieve the mental health benefits of exercise.
Exercise professionals who work with depressed patients may benefit from becoming familiar with the principles of motivational interviewing (MI), a well-researched approach to promoting behavioral change (15). MI is a collaborate approach in which the health professional functions not as an expert who offers directions and prescriptions but as a consultant who tries to understand a patient’s goals and helps the patient to achieve his or her goals. The MI approach relies heavily on open-ended questions (e.g., “when if ever have you tried to start an exercise program?”) and reflections (e.g., “you worry that you won’t be able to stick with an exercise program, but you think it may be beneficial for you”) to highlight discrepancy, elicit change talk, and enhance self-efficacy. Discrepancy refers to differences between where the patient hopes to be and where they are now. Change talk is any expression of desire, reason, need, or commitment to exercise. Self-efficacy is the patient’s belief that he or she has the ability to successfully implement an exercise program. An exercise professional who is using MI will help patients negotiate exercise goals that patients feel confident about and will help patients to identify and overcome barriers. When problems arise, lapses are viewed as learning opportunities.
Exercise professionals would do well to remember that depression often is a cyclical disorder. Patients with an established exercise regimen can still be susceptible to future depressive episodes, which, in turn, can disrupt their exercise regimen. Helping patients anticipate barriers to maintenance of exercise, including recurrence of depression, can increase the likelihood of success (Table 5).
CONDENSED VERSION AND BOTTOM LINE
In summary, exercise seems to be an effective treatment for depression, improving depressive symptoms to a comparable extent as pharmacotherapy and psychotherapy. Observational studies suggest that active people are less likely to be depressed, and interventional studies suggest that exercise is beneficial in reducing depression. It seems that even modest levels of exercise are associated with improvements in depression, and although most studies to date have focused on aerobic exercise, several studies also have found evidence that resistance training also may be effective. While the optimal “dose” of exercise is unknown, clearly, any exercise is better than no exercise. Getting patients to initiate exercise — and sustain it — is critical.
This study was supported in part by a grant (HL080664) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD.
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