Choi K, Zheutlin A, Karlson R, et al. Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study [published online November 5, 2019]. Depress Anxiety. doi:10.1002/da.22967
To determine whether physical activity is associated with genetic risk for depression and assess levels of physical activity that associate with risk
Cohort study—observational noninterventional study
Participants were patients in the Partners Biobank, which is an ongoing virtual cohort study of patients across the Partners HealthCare hospital system. Survey data on self-reported physical activity and the necessary genomic data were available for a total of 11,615 participants.
The final study included 7,968 participants of European ancestry with an average age of 59.9 years and a 57% female distribution. All participants had no diagnoses of depression (based on billing codes) in the 1 year prior to completing the survey.
Case-versus-control status was defined as 2 or more depression-related billing codes in the 2-year study period following initial self-report surveys versus those with none. Those with just 1 code were removed from the study.
Study Parameters Assessed
Polygenic risk was determined using a large genomic-wide association studies meta-analysis. Participants were stratified into 3 groups: low risk, intermediate risk, and high risk.
Physical activity levels were based on self-report surveys of different types of activities performed weekly, as well as the average number of hours spent performing physical activities. Levels of physical activity were separated into quintiles based on the average number of hours of activity: 0.1 hour, 1.1 hours, 3.2 hours, 6 hours, and 11.6 hours. Calculated metabolic equivalent of task (MET) hours were highly correlated with total hours of physical activity, so with consideration of actionable recommendations, the researchers used total hours as the primary analytic variable.
Jogging and running showed the strongest associations with effects on depression incidence.
The researchers compared the incidence of depression (based on billing codes) across polygenic risk groups for 2 years after the survey was taken.
In general, the 2-year prevalence of incident depression was higher among those in the lowest physical activity groups and lower among those engaging in the most physical activity. Overall, about 8% of the total cohort (n=7,968) met the criteria for incident depression in the 2 years after the exercise survey. The 2 bottom quintiles of physical activity (0.1 hour and 1.1 hours) demonstrated higher than average incident depression (10% and 9.5%, respectively), whereas the 3 top quintiles of physical activity (3.2 hours, 6 hours, and 11.6 hours) exhibited lower than average incident depression (6.5%, 7.2%, and 6.2%, respectively).
Similarly, the prevalence of depression was lower among more physically active individuals (those reporting at least 3.2 hours per week) within each polygenic risk group. The following is a comparison of percentage incidence of depression per polygenic risk category for quintiles 1 to 2 (0 to 1.1 hours per week) versus quintiles 3 to 5 (≥3.2 hours per week):
- Low-risk group 8.7% vs 5.6%
- Intermediate-risk group 9.1% vs 6.5%
- High-risk group 12.7% vs 8.1%
Ultimately, those with the highest polygenic risk of depression who exercised had a lower incidence of depression than their inactive, low-risk counterparts. Not surprisingly, those who were highly physically active and in the lowest polygenic risk group fared the best, with the lowest incidence of depression (5.6%).
These results persisted even after adjusting for potential confounders such as body mass index (BMI), educational attainment, employment status, and prior depression. Both low-intensity and high-intensity exercise subgroups showed positive effects on depression incidence. Jogging and running showed the strongest associations with effects on depression incidence.
The effects of exercise on preventing or treating depression have been extensively studied and are well established.1-3 However, this study appears to be one of the first to prospectively assess whether physical activity can have a protective effect on the incidence of depression in those with increased genetic risk for the condition. The most significant finding of this study remains that even in the presence of increased polygenic risk, exercise—a modifiable behavioral factor—can have a dose-dependent inverse effect on the risk of depression.
Though this particular research group did not explore the mechanism by which exercise exerts its effect, several potential mechanisms have been proposed in the literature. Studies suggest that the effects of exercise on depression may be due to the increased hippocampal neurogenesis seen with exercise, as well as the anti-inflammatory effects.4,5 Evidence demonstrates that the acute inflammation that results from a bout of exercise can kickstart the body’s natural anti-inflammatory release of cytokines that lead to the inhibition of pro-inflammatory cytokines associated with depression.6 This neuroinflammatory hypothesis is corroborated by the literature supporting the use of omega-3 fatty acid supplementation in the treatment and prevention of depression.7 The International Society for Nutritional Psychiatry Research now recognizes the evidence base for the use of omega-3 fatty acids, having released official practice guidelines on how to safely and effectively use omega-3 supplementation in the treatment and prevention of major depressive disorder.7
The authors of the current study reached a general conclusion that individuals engaging in 3 or more hours of physical activity per week exhibited a reduced prevalence of depression incidence. With incremental increases in weekly physical activity, the results further improved, leading to a broad recommendation of 45 minutes of additional activity daily to achieve meaningful reductions in depression risk. These results were consistent for individuals within each polygenic risk group, so no matter what the baseline risk was, physical activity appeared to be associated with decreased depression incidence. Both higher- and lower-intensity exercise were associated with these benefits; the most important marker seems to be the amount of time spent being physically active. Combining this data with previously established evidence, we see that the most efficacious recommendation for depression is moderate-to-vigorous-intensity aerobic exercise performed 3 to 5 days per week for at least 6 months.6,8
Depression is the leading cause of disability in the world and is associated with significant morbidity and mortality as a cause or result of many other conditions.1 Having an elevated genetic risk for the condition can create a sense of helplessness for those with family history. This is one of the major areas where research into preventative and protective interventions can be incredibly helpful. At the very least, literature such as this study can help combat the misperception that genetic risk and disease outcomes are nonmodifiable. Beyond that, exercise and physical activity are well known to help prevent and treat an endless list of other health conditions, so the positive benefits of supporting the use of exercise as a medical recommendation are plentiful.
Perhaps the most important outcome of this study will be to help push medical providers and healthcare professionals to not shy away from using physical activity as a foundational treatment recommendation. It is a well-established phenomenon that healthcare providers have an inherent bias not to see exercise as a viable treatment option for depression, despite the evidence showing its efficacy being equal to antidepressants.2 As more studies continue to be published, it is only a matter of time before the official recommendations recognize exercise as what it is—a natural antidepressant.
Though promising and exciting, the work of Choi et al does have some limitations in generalizing the conclusions that they reached. Namely, the observational and noninterventional design allows only for an associative relationship to be assumed, although there are previous interventional studies showing the positive effects of exercise on depression. Further, data collection based on electronic health record (EHR) codes and self-reported surveys from a relatively homogenous group of highly educated individuals of European ancestry also limits the ability to generalize these findings to other socioeconomic or genetically varied populations. The collected data and conclusions formed do, however, create a study design for future researchers to explore.
- Choi K, Zheutlin A, Karlson R, et al. Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study [published online November 5, 2019]. Depress Anxiety. doi:10.1002/da.22967
- Netz Y. Is the comparison between exercise and pharmacologic treatment of depression in the clinical practice guideline of the American College of Physicians evidence-based? Front Pharmacol. 2017;8:257.
- Klenger F. Exercise as a treatment for depression: a meta-analysis adjusting for publication bias. Physioscience. 2016;12(03):122-123.
- Yau S, Li A, Hoo R, et al. Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc Natl Acad Sci USA. 2014;111(44):15810-15815.
- Miller A, Maletic V, Raison C. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732-741.
- Medina JL, Jacquart J, Smits J. Optimizing the exercise prescription for depression: the search for biomarkers of response. Curr Opin Psychol. 2015;4:43-47.
- Guu T, Mischoulon D, Sarris J, et al. International Society for Nutritional Psychiatry research practice guidelines for omega-3 fatty acids in the treatment of major depressive disorder. Psychother Psychosom. 2019;88(5):263-273.
- Machado S. Exercise is medicine: is there a dose-response for major depression? J Psychiatry. 2018;21:e112.