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Physical activity dose-response effects on outcomes of depression and anxiety

DUNN, ANDREA L.; TRIVEDI, MADHUKAR H.; O’NEAL, HEATHER A.

Medicine and Science in Sports and Exercise: June 2001 - Volume 33 - Issue 6 - p S587-S597
Article

DUNN, A. L., M. H. TRIVEDI, and H. A. O’NEAL. Physical activity dose-response effects on outcomes of depression and anxiety. Med. Sci. Sports Exerc., Vol. 33, No. 6, Suppl., 2001, pp. S587–S597.

Purpose: The purpose of this study was to examine the scientific evidence for a dose-response relation of physical activity with depressive and anxiety disorders.

Methods: Computer database searches of MEDLINE, PsychLit, and Internet and personal retrieval systems to locate population studies, randomized controlled trials (RCTs), observational studies, and consensus panel judgments were conducted.

Results: Observational studies demonstrate that greater amounts of occupational and leisure time physical activity are generally associated with reduced symptoms of depression. Quasi-experimental studies show that light-, moderate-, and vigorous-intensity exercise can reduce symptoms of depression. However, no RCTs have varied frequency or duration of exercise and controlled for total energy expenditure in studies of depression or anxiety. Quasi-experimental and RCTs demonstrate that both resistance training and aerobic exercise can reduce symptoms of depression. Finally, the relation of exercise dose to changes in cardiorespiratory fitness is equivocal with some studies showing that fitness is associated with reduction of symptoms and others that have demonstrated reduction in symptoms without increases in fitness.

Conclusion: All evidence for dose-response effects of physical activity and exercise come from B and C levels of evidence. There is little evidence for dose-response effects, though this is largely because of a lack of studies rather than a lack of evidence. A dose-response relation does, however, remain plausible.

The Cooper Institute, Dallas, TX; and University of Texas Southwestern Medical Center, Dallas, TX

Submitted for publication January 2001.

Accepted for publication March 2001.

Proceedings for this symposium held October 11–15, 2000, Ontario, Canada.

Understanding the dose-response relation of physical activity to depression and anxiety requires consideration of several conceptual issues. Haskell concisely summarized these issues for the 1992 Second International Consensus Conference on Physical Activity, Fitness, and Health (22), and they are of considerable importance to the topic of depression and anxiety. Their consideration, described below, provides a framework to focus the content of this review and to identify future research directions.

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ISSUES RELATED TO THE SPECIFICITY OF THE RESPONSE

Defining depression and anxiety.

The first issue that should be considered before undertaking a review of depression and anxiety is specifically defining the response. Just as the dose-response varies for different health outcomes, it is also likely to differ depending on how one defines the desired outcomes, in this case, depression and anxiety. Experimental and quasi-experimental studies have examined effects of exercise training using various outcome measures. The participants studied have ranged from healthy individuals with few or no symptoms of depression or anxiety to individuals experiencing a clinically diagnosed disorder that could be classified as severe. Furthermore, many studies have examined the acute effects of exercise on symptoms, but such effects do not reflect the true nature of these disorders, as these illnesses are considered to be chronic and not responsive to acute treatment. Not surprisingly, this wide variation in disease severity or diagnostic criteria leads to a wide variation in responses. Consequently, for the purpose of this review, we have chosen to use standardized and specific diagnoses of depressive and anxiety disorders as outlined by Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) (1). Furthermore, we have chosen to specify depression and anxiety outcomes that are likely to be ameliorated by exercise or physical activity. For example, Bipolar Disorder is thought to have a particularly strong genetic linkage that increases susceptibility to the disorder compared with other depression subtypes (20). Because of this stronger genetic link, it is unlikely that exercise alone could be an effective treatment for this disorder. Similarly, many anxiety disorders such as phobias and Posttraumatic Stress Disorder are linked to specific situations or cues (1). These disorders can be effectively treated with psychotherapy alone, and it seems unlikely that exercise could be a plausible single treatment modality. The specific definitions of depression and anxiety that have been chosen for evaluating dose-response effects should be limited to those disorders where exercise is biologically plausible.

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Criteria for diagnoses.

Depression and anxiety will be defined according to the DSM-IV and the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and ICD-10 criteria (1). Depression will include Major Depressive Disorder (MDD) (Code 296.2 or 296.3) (0–6), Dysthymic Disorder (300.4), and Depressive Disorder Not Otherwise Specified (311), but will not include Bipolar Disorder, Cyclothymia, Mood Disorder Due to a General Medical Condition, or Substance-Induced Mood Disorder. Anxiety will include Panic Disorder without Agoraphobia (300.01), Generalized Anxiety Disorder (300.02), or Anxiety Disorder Not Otherwise Specified (300.00). Other anxiety disorders such as Posttraumatic Stress Disorder, Social Phobia, Acute Stress Disorder, Agoraphobia, Obsessive Compulsive Disorder, Specific Phobias, Anxiety Disorder Due to a General Medical Condition, or Substance-Induced Anxiety Disorder will not be included.

Only studies that have evaluated the specific symptoms linked to these illnesses and include gradations of symptoms that would include at least mild to moderate levels of depression or anxiety disorders will be included in this review. Furthermore, randomized control trials (RCTs) and quasi-experimental studies will only be included if the study population has been diagnosed with the depression or anxiety disorders specified above. Depression also can be secondary to other illnesses such as cardiovascular disease, stroke, cancer, and diabetes. Similarly, other complications can arise from untreated depression such as substance abuse and alcoholism (24). These associations with other illnesses are likely to involve different or additional mechanisms that further complicate the dose-response question. To clarify issues of dose-response, it will be judicious to only review studies where depression and anxiety are the primary disorder and are not secondary to other illnesses or psychopathology.

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Criteria for clinical outcomes.

Another issue that is related to the specificity of the response is the way one defines the treatment response. A dose-response study of exercise as a treatment for depression or anxiety should use similar criteria to those used for established treatments of pharmacotherapy and psychotherapy. In this literature, treatment plans are linked to five key clinical outcomes. They are: 1) response and 2) remission, goals of acute phase treatment; 3) prevention of relapse and 4) recovery, goals of continuation phase treatment; and 5) prevention of recurrence, the goal during maintenance phase treatment (28,43). Response is generally operationalized and defined by clinical practice guidelines as a 50% reduction in symptoms during the acute phase of treatment. Often this acute phase of treatment lasts from 6–12 wk. There are two key points in this particular guideline that are related to dose-response. First, studies that demonstrate a statistical improvement in depressive or anxious symptoms may not always meet the accepted criterion for a treatment response. We believe this stricter criterion of a 50% reduction in symptoms should be used in establishing dose-response effects, since an improvement that is less than 50%, although statistically significant, is unlikely to be clinically relevant. Second, it is clear that amelioration of symptoms takes 6–12 wk and may not be well sustained when it occurs after a short bout of medication, psychotherapy, or exercise.

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Potential etiological mechanisms.

Depression and anxiety have been linked to multiple etiologies including psychological trauma and chronic stress, faulty neurotransmitter systems such as norepinephrine (NE) and serotonin (5-HT), and hypothalamic-pituitary-adrenocortical (HPA) dysfunction (11,14,34). It is highly likely that depression, like high blood pressure, has multiple etiologies, and that exercise, acting on multiple biological and psychological systems, could lead to synergistic adaptations that effectively reduce symptoms of these disorders. At the present time, the exact etiology of depression and anxiety is unknown. However, the recently released Surgeon General’s Report on Mental Health documents an evolving understanding that both depression and anxiety have a biochemical basis that is found in the brain (52). For this reason, dose-response effects of exercise are biologically plausible. In fact, well-designed RCTs of nonpharmacological treatments such as psychotherapy have been shown to relieve symptoms of depression, and symptom relief is associated with neurobiological changes among treatment responders (52).

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METHODS

Selection of articles for this review.

A computer search of MEDLINE, PsychLit, and the Internet was conducted using combinations of the following keywords: depressive disorder, depression, anxiety, anxiety disorder, physical activity, and exercise. Next we reviewed reference lists from review articles, book chapters, and meta-analyses on exercise and depression, exercise and anxiety, and exercise and mental health. In addition, we searched our personal files and identified more than 1000 potential articles for inclusion. Articles that did not specify methods of measurement of depression or anxiety for study outcomes and that did not measure effects of exercise in depressed and/or anxious participants were excluded. Also, studies that only measured acute effects of exercise on symptoms of depression or anxiety or that measured depression secondary to other comorbid conditions and review articles were excluded. We also excluded all current meta-analyses on depression and anxiety, because the overwhelming number of studies included in the analyses of effect sizes have been performed in populations that are asymptomatic. For example, one of the most complete meta-analyses on the acute and chronic effects of exercise on anxiety included more than 100 studies. Out of these 100-plus studies, 7 were conducted in patient populations with broadly defined psychopathology, and the remainder were conducted in asymptomatic, normal populations (41). After all exclusions, the final yield was 37 articles.

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RESULTS

Dose-response effects of total amount of leisure-time and occupational physical activity effects on symptoms of depression and anxiety (Evidence Category C).

There are nine cross-sectional and nine prospective studies (Tables 1 and 2) that examined the relation of varying amounts of leisure-time and occupational physical activity on levels of depression and anxiety, and these yield similar results across cultures. In a North American sample, Stephens (49) conducted cross-sectional analyses of data combined from surveys conducted in the United States and Canada and found that higher levels of physical activity were associated with little or no symptoms of anxiety and depression. In individuals performing moderate amounts of physical activity, there was a decrease in depressive symptoms, and this was particularly true for women and older populations. Similarly, cross-sectional analyses in a German sample (54) of 1536 men and women found those who reported no physical exercise were 3.15 times more likely to have moderate to severe depression. The odds ratio (OR) for those who reported occasional exercise was also elevated (1.55), but this was not statistically significant. Kivelä and Pahkala (25) and more recently Ruuskanen and Ruoppila (44) found similar results in a population of older adults in Finland. Even though the results of cross-sectional studies are generally consistent, the findings for men and women sometimes differ. Also, it is not clear from these analyses whether physical inactivity leads to depressive symptoms, whether depressive symptoms lead to inactivity, or whether it is a third factor such as social support that might mediate this relation. Prospective studies can help determine the direction of this relation by examining whether low levels of physical activity predict development of depressive symptoms or whether increasing physical activity can reduce depressive symptoms.

Table 1

Table 1

Table 2

Table 2

Table 2

Table 2

Several prospective studies have examined the temporal relation between physical activity and depression to determine if low levels of activity predict future depression. Farmer et al. (16), using survey data from the National Health and Nutrition Examination Survey (NHANES I), found low levels of leisure activity at baseline did predict depression 8 yr later in white women despite depressive symptoms being low at the time of the baseline examination. These findings remained after adjusting for age, other chronic illness, education, employment, and income. The same relation did not hold for men with few symptoms of depression at baseline; however, low levels of physical activity did predict depression in men who had depressive symptoms at the baseline examination. The Alameda County study (8) showed a similar inverse relation. Comparing active to inactive respondents at follow-up and adjusting for sex, health, and age, the ORs for depression were 1.8 for men and 1.7 for women. However, a German study did not find low baseline physical activity to be a risk factor for developing depression at 2 yr (54). A later study of male and female medical students also did not find an increased risk of depression attributable to being inactive at baseline or becoming inactive at a 15-yr follow-up (10).

Five prospective analyses also report whether increases in physical activity lead to reductions in depression. For example, improvements in depression scores come from observations of the Iowa 65+ Rural Health Study (36). A logistic regression analysis of 2084 men and women found those who reported more depressive symptoms at baseline and who walked every day were one third (OR, 0.38) as likely to report high a number of depressive symptoms at follow-up compared with those who did not walk. In the group who reported no depressive symptoms at baseline and who walked every day, there was no change in depressive symptoms (e.g., their depressive symptoms remained low). Paffenbarger et al. (39) also found an inverse relation between physical activity and subsequent risk of depression in the Harvard Alumni study. Men who expended 1000–2499 kcal·wk-1 in walking, stair climbing, and sports play were at 17% less risk of developing clinical depression than their less active peers. Men who expended 2500 or more kcal·wk-1 were 28% less likely to develop clinical depression. This is the only prospective study that demonstrates a dose-response gradient between amounts of physical activity and reduction in diagnosed depression. Other prospective studies examining effects of increasing physical activity on symptom reduction did not analyze any dose-response relation.

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Exercise training studies: characterizing the dose in terms of intensity, duration, and frequency on depression and anxiety (Evidence Category B).

Table 3 shows consistency across studies in demonstrating a reduction in symptoms of depression and anxiety with aerobic and resistance training protocols. Eight of 18 studies indicate a 50% reduction in symptoms during the acute phase treatment. Furthermore, in the seven studies that also included a follow-up or maintenance phase, this response was maintained for periods of 3–21 months. Although the results of these studies are consistent, there are limitations and design flaws in many of these studies including lack of adequate control groups, mixing of treatments (e.g., exercise is combined with pharmacotherapy or psychotherapy), and small sample sizes. Also, we were able to locate only two studies examining these effects in patients diagnosed with anxiety disorders.

Table 3

Table 3

Table 3

Table 3

We were not able to locate a single published study that has examined the combined effect of varying intensity, duration, and frequency of exercise, although some studies have compared different intensities or different frequencies. With regard to intensity, Sexton et al. (45) examined reductions in depressive symptoms and anxiety in “neurotic” inpatients assigned to either a walking treatment or a more vigorous jogging treatment. Both groups showed equal reduction in their symptoms of anxiety and depression, but the jogging group had significantly more dropouts. Veale et al. (53), who compared aerobic exercise of low intensity with higher intensity, found similar results. Both groups decreased their depressive symptoms, but there was no significant difference between groups.

In addition to the issue of exercise intensity, one study has examined the effects of two different frequencies of aerobic training on depressive symptoms. Conroy and colleagues (9) examined the effects of exercise 1 d·wk-1 versus 3 d·wk-1 over a 6-wk period and found the 3-d·wk-1 treatment had greater effects than the 1-d·wk-1 treatment. We were unable to locate any published studies in depressed patients that have examined differing durations of exercise. Future studies that examine the dose of exercise will also need to take into account total energy expenditure, because the intensity, frequency, and duration sum to total energy expenditure.

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Aerobic versus resistance training and reduction of symptoms of depression and anxiety (Evidence Category B).

Sixteen of the 19 studies in Table 3 used only aerobic exercise as the exercise treatment modality. Of the remaining three studies, two compared aerobic exercise with resistance training (13,30), and one examined the effects of resistance training compared with a health education control (47). Each of these three studies examining the effects of resistance training showed significant effects in reducing depressive symptoms among different aged populations.

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Fitness and treatment response (Evidence Category B).

Only 25% of the studies in Table 3 and none of the studies in Tables 1 and 2 measured whether improvements in cardiorespiratory fitness were associated with changes in depression. Studies that did measure changes in fitness are equivocal. For example, the first study by Martinsen et al. (32) indicated the decrease in depression was significantly correlated with the increase in cardiorespiratory fitness, whereas the later study comparing aerobic fitness and weight training exercise did not replicate this finding (30).

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SUMMARY

First, with regard to the question of whether the amounts of occupational and leisure time physical activity are linked to reductions in symptoms of depression and anxiety: This evidence is generally consistent for both cross-sectional and prospective studies and findings are similar across cultures; however, these studies are only observational. Also, only two of these observational studies presented data on anxiety symptoms. Second, with regard to the question of whether varying the intensity, frequency, and duration of the exercise prescription has a dose-response effect on depression and anxiety, there is evidence to suggest that both moderate and vigorous exercise can reduce symptoms of depression. No studies have varied frequency or duration or controlled for total energy expenditure. Third, with respect to resistance and aerobic exercise, there is evidence that both can reduce symptoms of depression. However, in the studies that compared aerobic versus resistance training, it is unknown if total energy expenditure was equivalent. Fourth, it is also not clear from the exercise training studies whether or not increases in cardiorespiratory fitness are necessary to reduce symptoms of depression. Also, with respect to all of these questions, there are more data examining depression disorders compared with anxiety disorders.

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RESEARCH RECOMMENDATIONS

The questions posed for this review suggest several lines of research to understand dose-response effects of exercise and physical activity on the treatment and management of depression and anxiety disorders. In all of these future research efforts, studies should follow criteria established for treatment studies in terms of adequately diagnosing patients and using outcome measures with appropriately defined treatment standards. Until this becomes the accepted practice, rather than the exception, little progress will be made with regard to understanding exercise as a treatment modality for either depression or anxiety. Furthermore, future studies should carefully document the exercise dose and examine the relation of treatment outcomes with cardiorespiratory and/or muscular fitness.

  • 1. Prospective observational studies should be conducted to determine whether increasing the frequency, intensity, or duration of physical activity is associated with symptom reduction of depression and anxiety. Furthermore, it will be important to compare various subgroups in these analyses (e.g., comparing older with middle-aged and younger persons, comparing men with women, and comparing different ethnicities).
  • 2. Prospective observational studies also are needed to examine the relation between cardiorespiratory fitness and symptoms of depression. Again, it will be important to examine the influence of age, gender, and ethnic subgroups.
  • 3. RCTs are needed to examine the effect of types of exercise as well as frequency, intensity, and duration on various subtypes of depression and anxiety. Future trials also should examine whether different doses of exercise can be a sole treatment or should be implemented as an adjunct treatment depending on depression or anxiety severity and subtype.
  • 4. To clarify issues related to intensity of exercise and physical activity, it will be important to examine effort sense (rating of perceived exertion) for both relative and absolute exercise intensities in patients with different subtypes of depression and anxiety.
  • 5. RCTs examining biological and psychological mechanisms in relation to exercise dose and treatment effects need to be conducted. Examples of mechanisms to be investigated include brain imaging studies similar to those conducted for antidepressant drug studies, effects on HPA axis function, or neurotransmitter regulation.
  • 6. Because both resistance training and aerobic exercise have demonstrated similar effects, it will be important to explore possible mechanisms that these different types of exercise share (e.g., changes in vagal tone or neurotransmitter modulation), and the relation to possible treatment effects.
  • 7. Dose of exercise also needs to be examined with respect to the other phases of the illness, in addition to the acute phase treatment. For example, how many weeks of exercise are needed for a full remission? Can different types of physical activity and/or exercise prevent recurrence?
  • 8. Finally, exercise may have its greatest impact on prevention of depression. Population studies are needed to evaluate this question. Also, RCTs should be conducted to examine the effects of exercise on recurrence of depression or anxiety disorders, particularly during continuation or maintenance phase treatment.
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CONCLUSION

All evidence for dose-response effects of physical activity and exercise comes from Evidence Category B and C levels. Cross-sectional data from observational studies consistently demonstrate that physical activity is associated with reduced symptoms of depression, but there is less evidence for reduced symptoms of anxiety. Data from prospective studies are more equivocal. Furthermore, there is only one prospective study that has examined the dose-response question with respect to depression. Clearly, more observational studies are needed to evaluate the potential for prevention of clinical illness. Evidence from quasi-experimental studies and RCTs also consistently demonstrates a reduction in symptoms of depression attributable to both aerobic and resistance exercise. Again, there are fewer quasi-experimental studies and RCTs in patients diagnosed with anxiety disorder. Additional RCTs are needed to examine dose-response of exercise as both a sole and adjunct treatment in different subtypes of depression and anxiety and in various subgroups. Also, RCTs are needed to explore the possible underlying biological and psychological mechanisms of treatment effects. At this point the evidence is suggestive but not convincing.

We thank Heather Kitzman, Melba Morrow, and Stephanie Parker for their assistance in preparing this manuscript.

Address for correspondence: Andrea L. Dunn, Ph.D., The Cooper Institute, 12330 Preston Road, Dallas, TX 75230; E-mail: adunn@cooperinst.org.

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      Keywords:

      MAJOR DEPRESSIVE DISORDER (MDD); ANXIETY; TREATMENT; EFFICACY; PHYSICAL ACTIVITY; EXERCISE; REVIEW

      © 2001 Lippincott Williams & Wilkins, Inc.