Exercise is medicine for patients with major depressive disorders : but only if the “pill” is taken!

Discussion

Major depressive disorders (MDDs) are a widespread and burdensome mental illness.^1,2 According to the WHO Global Burden of Disease study, MDDs are the condition with the second greatest number of life years lost due to premature death or disability³ and are projected to be the leading cause in 2030.⁴ Moreover, MDDs are the leading cause of years of life lived with disability in men and women.⁵

MDDs are closely linked with poor quality of life, increased medical expenditures, and elevated utilization of health care services.⁶ Moreover, they are characterized by a high comorbidity with other mental and physical conditions. For instance, people with depression have a two- to fourfold risk for developing metabolic conditions and cardiovascular diseases.^7–10 Several putative mechanisms have been proposed to link MDDs and other medical conditions, including the hypothalamic–pituitary–adrenal axis and sympathomedullary hyperactivity, increased platelet reactivity, reduced heart rate variability, vascular inflammation, oxidative stress, and endothelial dysfunction.^10,11 Other possible factors are lower receipt of high-quality physical health care, reduced compliance with medical recommendations, adverse medication treatment effects, or the presence of modifiable behavioral risk factors such as physical inactivity.⁷

As a consequence, people with MDDs have an increased risk for premature mortality if compared with the general population,^12,13 resulting in a life expectancy of ~10–15 years shorter than that of the general population.¹³ Although these disparities have been recognized since the mid-1980s, this life expectancy gap has widened during the last 30 years.¹⁴ Targeted actions are therefore needed to improve physical health in people with MDDs, in addition to ongoing efforts to enhance psychological well-being.

While the standard treatment of MDDs is medication, psychotherapy, or a combination of both, the effectiveness of these treatments is mixed. With regard to medication-oriented approaches, it has been estimated that only ~30%–50% of all patients show a response to treatment with single-action or dual-action antidepressant monotherapy,^15,16 whereas remission is found in an even smaller portion of participants (15%–40%).^16,17 Hence, >50% of all patients do not respond adequately. Therefore, a switch or augmentation in medication is necessary for many patients.⁶ However, even these additional treatments often do not result in remission.¹⁸ As a consequence, complementary nonpharmacological treatment options are highly warranted from a public health perspective.¹⁹

In several countries, health foundations have encouraged general practitioners to prescribe exercise as a frontline strategy in the treatment of MDDs.^20,21 Meanwhile, several meta-analyses have supported that exercise interventions are able to increase response/remission compared with no treatment or placebo conditions in clinically depressed patients.^20–28 For instance, Josefsson et al²⁸ found a relatively strong effect (Hedges g =−0.77) in favor of exercise treatment, which, however, decreased to a moderate effect if only studies with high methodological standards were considered (eg, allocation concealment, blinded outcome assessment, and intention-to-treat analysis). Nevertheless, Schuch et al²⁶ recently concluded that the effects of exercise might have been underestimated due to publication bias.

Beyond these meta-analyses, studies have shown that exercise therapy might be a worthwhile add-on to standard care,²⁹ that exercise is successful in reducing even treatment-resistant depression,³⁰ and that single bouts of exercise have favorable neurobiological effects.³¹ Importantly, a meta-analysis showed that exercise interventions have the capacity to improve cardiorespiratory fitness in people with MDDs in clinically meaningful ways.³² Based on seven randomized controlled trials, Stubbs et al³² reported an overall effect size of 0.64 (corresponding to a mean increase of 3.05 mL/kg/min of oxygen uptake). This is relevant because improvements of 3.5 mL/kg/min in VO₂ max are related to a 13% and 15% decrease in cardiovascular disease and all-cause mortality, respectively, in the general population.³³

In two further studies, Blumenthal et al^34,35 compared the effectiveness of 4-month aerobic exercise program with pharmacotherapy in 156 older patients and 202 adults with MDDs. Both studies showed that exercise is equally effective in reducing depressive symptoms similar to antidepressant medication. Furthermore, the latter study demonstrated that remission rates are higher with antidepressants or exercise compared with a placebo control condition.³⁵

While these findings are promising, the long-term effects of exercise therapy are still not well documented, which dampens the notion that “exercise is medicine” in this group of patients (“Exercise is Medicine^® [EIM]” is a campaign managed by the American College of Sports Medicine [ACSM]. With its global health initiative, the ACSM intends to encourage primary care physicians and other health care providers to include physical activity when designing treatment plans for patients. Moreover, EIM emphasizes that physical activity plays an important role in the prevention and treatment of diseases, and therefore, as part of all health care, should be routinely assessed and treated). In this regard, a recent study found that initial improvements in MDD dissipate if regular exercise participation is discontinued after the end of interventions.³⁶ Thus, Hoffman et al³⁶ showed that neither group assignment (exercise vs pharmacotherapy) nor antidepressant medication usage during the follow-up period was associated with response or remission at 12-month follow-up. The only significant predictor was regular exercise during the follow-up period, showing that patients who exercised regularly after completion of the initial treatment had a lower likelihood of depression at follow-up. These results support the findings of a previous study with older adults, in which regular posttreatment exercise was associated with a 50% reduced relapse rate at 6-month follow-up.³⁷

Given these findings, integrating exercise as an add-on to standard care³⁸ and efforts to promote lifestyle physical activity to prevent relapses after the end of in- or out-patient treatment seem necessary. In line with this notion, in a survey among all 55 psychiatric hospitals of the German-speaking part of Switzerland, which was recently published in Neuropsychiatric Disease and Treatment, Brand et al³⁹ showed that all hospitals provided some form of physical activity and exercise program, including sports therapy, activity-related psychotherapeutic interventions, physiotherapy, and body therapies. While this is encouraging and highlights that the potential of physical activity and exercise is increasingly recognized in psychiatric care, the fact that only 25% of patients participated in these programs is critical. Given that across all hospitals, participation in these programs was voluntary and that no particular efforts are undertaken to engage those patients with the lowest physical activity levels, the likelihood to reach the patients who presumably would benefit most from increased physical activity and exercise is limited.

We therefore argue that systematic efforts and concerted actions are needed in order to fully exploit the potential of physical activity and exercise programs in psychiatric care. Moreover, we emphasize that initiating and maintaining regular physical activity among psychiatric patients is a major challenge. For instance, among patients with MDDs, specific dysfunctional cognitive–emotional processes might interfere with their motivation and capacity to self-regulate health-related behaviors. Studies have shown that MDDs are linked with motivational and volitional deficits in all areas of daily life due to feelings of hopelessness, pessimism, and a tendency to postpone tasks.⁴⁰ Not surprisingly, MDDs are associated with decreased exercise-related self-efficacy, increased negative outcome expectations, reduced exercise intentions, and increased perception of situational barriers.⁴¹ Despite these challenges, Mota-Pereira et al³⁰ were able to show that very high compliance to an exercise program (<90%) can be achieved even in patients with treatment-resistant MDDs if behavioral techniques (eg, techniques reminding the participants to exercise) are promoted as an integral part of the exercise intervention.

Given this background, we claim that major therapeutic efforts are required to decrease the unfavorable cognitive–emotional processes experienced by patients with MDDs, in order to support them in overcoming barriers to initiating and maintaining physical activity. Moreover, we suggest that the assessment of physical activity and cardiorespiratory fitness, in close relation to symptom severity, should become routine in psychiatric practice. We further claim that research into the potential of lifestyle physical activity counseling to increase patients’ behavior skills (eg, action planning, coping with exercise-related barriers, social support) should become a top priority in patients with MDDs. Integrating such interventions, which proved to work well among patients suffering from somatic conditions,^42–45 would clearly strengthen the notion of “exercise is medicine” in this specific patient population. Moreover, improved relapse management by emphasizing that exercise is a fluctuating behavior and that alternations between more and less physically active periods are normal for most people can help prevent negative consequences in terms of reduced self-efficacy and hopelessness if patients with MDDs who have participated in structured exercise programs feel unable to continue with their exercise regime. Finally, although it is still difficult to say what kind of physical activity or exercise works best against major depression,⁴⁶ a previous study showed that public health doses seem to be necessary to achieve positive effects.¹⁹ Furthermore, in line with the Dual-Mode Theory of affective responses,⁴⁷ research consistently shows that affective responses during exercise are more positive and homogeneous at moderate intensity levels, whereas more variability occurs at heavier intensities (due to a stronger influence of cognitive factors such as self-efficacy and self-presentational concerns).^48,49 However, fostering favorable emotions during exercise is important because they can facilitate the development of positive implicit attributions that play an important role in the regulation of exercise behavior.^50,51 Thus, while we acknowledge that specific forms of high-intensity exercise training may have positive effects on cardiorespiratory fitness,⁵² we argue that moderate-intensity exercise seems to be more promising to initiate long-term behavior change in patients with MDDs.

Acknowledgment

This correspondence was written without external funding.

Disclosure

The authors report no conflicts of interest in this work.

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