The Role of Exercise in Preventing and Treating Depression

Introduction[edit | edit source]

Depression is a leading cause of the global burden of disability. Depression and anxiety are the most common mental illness worldwide.[1] [2][3] Treatment primarily focuses on pharmacological and psychological interventions. However, these treatments are not effective for all patients, so it is necessary to explore alternative management options.[4] Recent research has found that higher physical activity (PA) levels and exercise can have protective effects on incident depression.[5] And various studies have found that exercise can help to reduce symptoms for people with depression.[6][7][8] However, while exercise can be effective, some individuals may experience more benefit than others. It is, therefore, important to identify potential predictors of response. Dropout from exercise interventions is similar to dropout levels for other depression treatments. It is also comparable to levels of dropout for other clinical conditions. Strategies designed to improve adherence should be considered.[4]

Major depressive disorder (MDD), also known simply as depression,[9]:

  • A highly prevalent disorder in most cultures across the world with a point prevalence ranging from 6% to 18% across different countries.
  • The prevalence of people with subsyndromal/subthreshold depression, or those that have significant depressive symptoms but do not meet the criteria for a formal diagnosis of MDD, prevalence rate is approximately 15% to 20%.
  • One of the top 10 causes of years lived with disability across the world and a leading global cause of burden, and the economic costs are considerable. For instance, the costs associated with the days lost of work due to depression and anxiety is estimated in the US $ 1.15 trillion per year worldwide, and this amount is expected to increase twofold by 2030.

The core features of depression symptoms include low mood, decreased interest or pleasure in most or all activities of the day, decreased motivation, increases or decreases in appetite and weight, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue, cognitive impairments, such as memory deficit, and suicidal thoughts with or without suicidal plans or attempts.

In addition to the profound burden on mental health and well-being, there is a growing body of evidence to suggest that people with MDD experience substantially poorer physical health. eg people with depression present increased prevalence of cardiometabolic disease, diabetes, and cardiovascular disease, and experience premature mortality by 10 yr compared with the general population. While suicide accounts for a part of the premature deaths among people with depression, it is well established that the higher levels of cardiovascular and metabolic disease when compared with the general population play a significant role to the premature mortality gap. 

The current focus of treatment for people with confirmed MDD consists of antidepressants and psychotherapies. While antidepressants are typically more efficacious than placebo, some evidence suggests that only about half of the people taking antidepressants achieve a clinically significant response (a decrease of 50% or more on depressive symptoms). [10]Also, dropout rates are considerable, ranging from 15% to 132% higher than placebo. Another factor that influences adherence is the side effects of antidepressant medication which can include weight gain, increased diabetes risk, and sexual dysfunction among others. Psychological therapies, such as cognitive behavioral therapy, have a small-to-moderate effect for people with depression, the impact of psychotherapies on the poor physical health and premature-associated mortality is unclear. 

Given the considerable individual and societal burden of depression, there is a pressing need to identify modifiable risk factors which may be amenable to change. To this end, there is growing recognition that lifestyle behaviors, such as physical activity (PA) and exercise partially contribute to the risk of developing depression and can be useful strategies for treating depression, reducing depressive symptoms, improving quality of life, and improving physical health outcomes.[4]

Acute Management of Symptoms (Effects of a Single-exercise Bout)[edit | edit source]

People with MDD can benefit from a single bout of exercise. A study by Meyer and colleagues compared the effects of a 20-min cycling bout at three different intensities: light (RPE, 11), moderate (RPE, 13), or hard (RPE, 15) on 24 women with MDD versus a control group (sitting quietly). The comparative analyses showed that all intensities were equally effective and better than the control in promoting well-being at 10 and 30 min after the exercise. Also, in following analysis of the same trial, Meyer and colleagues investigated the role of self-selected or preferred intensity on acute well-being. For this, the patients exercised at light (RPE, 11), moderate (RPE, 13), or hard (RPE, 15) intensities, or chose the workload themselves across a 20-min cycling session. Interestingly, no differences were found between the self-selected/preferred intensity and the closest intensity, suggesting that all intensities can equally promote acute well-being in people with MDD, regardless if it is self-selected or determined.[4]

Moderators of Response[edit | edit source]

Exercise can improve depressive symptoms in people with depression. However, similar to other treatments, exercise is not a panacea and may not work equally for all. A seminal study by Dunn et al., the Depression Outcomes Study of Exercise, found a response rate of about 40% in depressed people free from other treatments. These results are comparable with more recent data found in the REGASSA trial, the largest study with exercise and depression, which found a response rate of about 50%. The remission rate (people who no longer meet criteria for MDD diagnosis) was evaluated in the Treatment with Exercise Augmentation for Depression (TREAD) study using and adapting (16 kilocalories per kilogram of weight spent in exercise per week) the pioneering idea of Andrea Dunn in determining the exercise dose based on the energetic expenditure did find a remission rate of about 28%. To maximize the benefits to the patients and to deal with patients’ and health professionals’ expectations, matching the “right patient for the right treatment,” or understanding who are the patients that are more likely to benefit the most regarding depressive symptoms reduction, is necessary. For doing that, understanding the potential predictors and moderators of the antidepressant effects of exercise is required.

A previous systematic review identified some potential biological, clinical, psychological, social factors, as well as the interaction between two or more factors (composed) that were associated with greater response/remission rates. Since the publication of this study, some studies have improved the state of the art in the field. 

  1. Biological: higher levels of brain-derived neurotrophic factor (BDNF), interleukin (IL)-1B, and of tumor necrosis factor-alpha are associated with greater response to exercise. A further study analyzing data from the REGASSA trial identified that higher levels of IL-6 predict greater response rates. 
  2. Clinical: better global functioning, as well as more severe physical symptoms, predict response to exercise. Later, data from the TREAD study revealed that atypical depression benefits more from exercise than other subtypes. Also, lower cardiorespiratory fitness is linked to a greater chance of non-response. 
  3. Psychological: higher self-esteem and life satisfaction predict better outcomes. 
  4. Social: social support was the only moderator/predictor that was consistently associated with better outcomes.
  5. Composed: it is reasonable to expect that a better-described group and limited group, including a greater number of identifiable traits or characteristics, may present a greater chance of response. For example, when we say that men respond more to exercise, in this group of men, there will be subgroups that may respond more while others will respond less, or some won’t respond at all. Therefore, it is expected that models including more variables will have a better predictive value.[4]

Neurobiological Mediators of the Antidepressant Response[edit | edit source]

The neurobiological mechanisms underpinning the antidepressant effects of exercise are largely unclear. However, some hypotheses involving inflammation, oxidative stress, and neuronal regeneration are speculated.

Inflammation and oxidative stress markers are altered in people with depression. For example, IL-6 and IL-1B, inflammation markers, and thiobarbituric acid reactive species are increased in people with depression. Exercise training, however, is able to promote increases in anti-inflammatory and antioxidant enzymes, referred to as a hormesis response, and subsequently, decrease IL-6 levels. This effect was demonstrated in the REGASSA trial, where decreases in IL-6 serum levels were associated with reductions in depressive symptoms.

Substantial evidence demonstrates that people with depression have decreased levels of BDNF, a marker of neuronal growth and plasticity. Potentially, these reduced levels of neuronal regeneration are linked to a decreased volume and activity of certain brain regions, including hippocampus, orbitofrontal cortex, anterior and posterior cingulate, insula, and temporal lobes observed in people with depression.

Exercise, inversely, can promote brain plasticity, increasing hippocampus volume. However, there is not enough evidence on changes in brain volume due to regular exercise in people with depression.[4]

Prescription, Adherence, and Dropout to Exercise Interventions[edit | edit source]

Starting and sustaining an exercise program is a challenge for any clinical population, and naturally, this also is true for people with depression. For example, the dropout rates to exercise interventions is about 20% for people with type II diabetes mellitus, 29% for people with HIV, 26% for people with schizophrenia, and 17% for children with attention deficit hyperactivity disorder. The dropout rate in exercise trials for people with depression is not greater than that for other clinical populations, being of about 18%. Also, it is important to note that adherence to other treatments for depression is equally challenging. For example, the dropout rate from psychotherapies, in general, is about 19% while the dropout rate from selective serotonin reuptake inhibitors is 26% and tricyclics about 28%. Some strategies may be useful for clinicians and exercise professionals to help people with depression to engage in PA and to prevent dropout.

First, Vancampfort et al. suggest that autonomous motivation may “hold the key” to keep people with mental illness active. Autonomous motivation is the motivation that leads someone to do something for its own sake, for example, finding exercise enjoyable or challenging. Therefore, adapting exercise prescription for people with depression should account for personal preferences and previous experiences in terms of making it the most enjoyable experience possible. In this line, Brand and Ekkekakis have suggested that self-selected intensities or intensities above the ventilatory threshold can be used as an appropriate option for public health promotion. Self-selected intensities and intensities above the ventilatory threshold are linked to positive core affective valence, whereas higher intensities are usually linked to a negative core affective valence in sedentary and low-active groups, which is the case for people with depression. It should be noted, however, that higher intensities have demonstrated greater effects on reducing depressive symptoms; therefore, a progression of the exercise intensity should be considered.

Second, some strategies have been shown useful in other clinical samples and can be used by physicians and health professionals to help people with depression to engage in regular PA. For example, Green prescriptions constituted by written exercise prescription by health professionals, defined according to patients’ state of change and individual goals and supported by exercise professionals’ calls and face-to-face meetings have resulted in an increase in 34 min·wk−1 of leisure exercise over 12 months in patients consulting general practitioners. Lastly, supervision provided by trained exercise professionals, as such as physiotherapists, exercise physiologists, physical educators, and others are a protective factor for dropout in people with depression, showing the clear relevance of these professionals in the field. Social support is a potential moderator for symptom improvements from exercising, thus encouraging patients to exercise with friends or family may increase the chance of success of treatment and the subsequent adoption and maintenance of exercise.[4]

Exercise for Improving Physical Health of People with Depression[edit | edit source]

People with mental illness have a reduced life expectancy of about 10 yr when compared with the general population. Much of this reduction is attributable to an increased rate of cardiometabolic diseases in this population. For example, people with MDD have a higher risk (relative risk [RR], 1.36; 95% CI, 1.29–1.72) of having type II diabetes, metabolic syndrome (RR, 1.54; 95% CI, 1.21–1.97), and of cardiovascular disease (OR, 2.08; 95% CI, 1.51–2.88) than age and sex-matched controls.

Exercise and PA are key factors for preventing and managing cardiovascular disease and associated mortality in the general population, and this is no different for people with MDD. Evidence has shown that PA and exercise should be prescribed to people with MDD to promote cardiometabolic health, as shown in improvements in cardiovascular and metabolic markers as fitness, high-density lipoprotein, and weight, epicardial and subcutaneous adipose tissue. For example, exercise can increase aerobic capacity of about 3.05 mL·kg−1·min−1 from baseline to post-intervention in people with MDD. This increase is associated with a significant reduction in the risk of premature mortality and can help to reduce the mortality gap.[4]

Treatment Guidelines for Depression[edit | edit source]

The evidence of the use of exercise is substantial and growing fast. Despite this substantial evidence, the incorporation of exercise as a key component in treatment is inconstant. Some guidelines have incorporated PA and exercise as recommended therapeutic strategies for depression while others have not. Despite this acknowledgement, PA still appears to not receive the deserved attention and its use in clinical practice is not of equitable value to the more dominant strategies such as pharmacotherapy and psychotherapies. According to Ekkekakis and Muri, this can be potentially attributable to the lack of awareness, incredulity, scepticism, or even a reluctance to the existent evidence. Addressing this issue and the current reliance on the two-pronged approach of talking therapies and medication is important in going forward.[4]

References[edit | edit source]

  1. Liu Q, He H, Yang J, Feng X, Zhao F, Lyu J. Changes in the global burden of depression from 1990 to 2017: Findings from the Global Burden of Disease study. Journal of Psychiatric Research. 2020;126:134-40.
  2. Hu S, Tucker L, Wu C, Yang L. Beneficial effects of exercise on depression and anxiety during the covid-19 pandemic: a narrative review. Frontiers in psychiatry. 2020 Nov 4;11:587557.
  3. Tasci G, Baykara S, Gurok MG, Atmaca M. Effect of exercise on therapeutic response in depression treatment. Psychiatry and clinical psychopharmacology. 2019 Apr 3;29(2):137-43.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Schuch FB, Stubbs B. The Role of Exercise in Preventing and Treating Depression. Curr Sports Med Rep. 2019;18(8):299-304.
  5. Schuch et al. Physical Activity and Incident Depression: A Meta-Analysis of Prospective Cohort Studies, American Journal of Psychiatry, May 2018. Dr. Rhonda Patrick ‘Exercise as a Treatment for Depression’ 
  6. Helgadóttir B, Forsell Y, Hallgren M, Möller J, Ekblom O. Long-term effects of exercise at different intensity levels on depression: A randomized controlled trial. Preventive Medicine. 2017;105:37-46.
  7. Paolucci EM, Loukov D, Bowdish DME, Heisz JJ. Exercise reduces depression and inflammation but intensity matters. Biol Psychol. 2018;133:79-84.
  8. Zanetidou S, Belvederi Murri M, Menchetti M, Toni G, Asioli F et al. Physical Exercise for Late-Life Depression: Customizing an Intervention for Primary Care. J Am Geriatr Soc. 2017;65(2):348-55.
  9. Mayo clinic Depression Available: (accessed 13.9.2021)
  10. Xie Y, Wu Z, Sun L, Zhou L, Wang G, Xiao L, Wang H. The effects and mechanisms of exercise on the treatment of depression. Frontiers in Psychiatry. 2021:1904.