By Ellen Feldman, MD

Altru Health System, Grand Forks, ND

Dr. Feldman reports no financial relationships relevant to this field of study.

SYNOPSIS: The authors of this large-scale, observational study found that three or more hours weekly of physical activity was associated with a decreased incidence of depression, even in patients with a high genetic risk of depression.

SOURCE: Choi KW, et al. Physical activity offsets genetic risk for incident depression assessed via electronic health records in a biobank cohort study. Depress Anxiety 2019; Nov 5. doi: 10.1002/da.22967. [Epub ahead of print].

Does exercise help mitigate the risk of depression? Studies since the early 1900s point to a clear role for exercise in the treatment of depression.1,2 Choi et al bring new and vital information to the field. Specifically, they were interested to know if physical activity was associated with a decreased risk of depression in those with the highest genetic risk of depression, or if this relationship would fade amid the power of genetic loading.

Depression is the leading cause of disability worldwide. Depressive disorders are not only debilitating, but also are highly prevalent; it is estimated that 350 million people worldwide suffer from this disorder. Common treatments involve antidepressant medication and talk therapy. However, medications are not reliably effective for all patients and may produce adverse effects. Specific types of psychotherapy also may not be effective for every patient. Stigma, combined with other factors such as availability, cost, and language barriers, may make this service difficult to access.3,4 Research and public health efforts have pointed toward identifying modifiable risk factors for depression, and physical activity has been a top choice in this area. Although physical activity is associated with a reduced risk of depression, the specifics of this relationship are unknown.5 In a separate study, Choi et al defined the etiology of this connection.6 They followed up with this investigation of the relationship in the genetically prone.

Researchers have noted that depression often exists within families. The heritability rate for depression is 37%, but the inheritance pattern is complex and determined by polygenic factors.7 By comparing genomes of patients with depression to those without, researchers have been able to generate what is known as a polygenic score, which is used to determine the risk of disease inheritance.8

For this study, Choi et al accessed data from the Partners Biobank, a longitudinal, large-scale research project linking genetic information, electronic health records (EHR), and other relevant information, including a self-reported lifestyle survey regarding activity level, frequency, and type of activity. The survey specified time spent in any of eight types of exercise: high-intensity (e.g., dance and aerobics), low-intensity (e.g., yoga), walking/hiking, jogging, running, racquet sports, biking, and swimming. Incident depression was determined by the occurrence of two or more EHR depression-related diagnostic codes within the two years following completion of the lifestyle survey.

To exclude patients with depression at the onset of the study, patients with evidence of such billing codes in the year prior to completion of the survey were excluded. Eligibility for this study included individuals with available polygenic risk scores and physical activity data. In addition, Choi et al looked for patient activity in the medical system. In all, a sample size of 7,968 individuals emerged as appropriate for this study. The prevalence of incident depression in the entire sample group was 628 individuals.

Physical activity was divided into quintiles. Those in the two lowest quintiles of physical activity (0.1-1.1 hours/week of exercise) showed an average 9.5-10% rate of incident depression. Conversely, those in the highest physical activity quintiles (3.2-11.6 hours/week of exercise) exhibited incident depression rates of 6.2-7.2%. Participant data were grouped by genetic risk for depression and activity level.

The researchers discovered a 20% increase in odds of incident depression for each standard deviation (SD) up the polygenic risk score (odds ratio [OR], 1.20; 95% confidence interval [CI], 1.11-1.31; P = 1.04 × 10-5). They also found a 17% decrease in odds of incident depression for each SD increase in physical activity (4.6 hours/week) (OR, 0.83; 95% CI, 0.75-0.90; P = 3.97 × 10-5). When polygenic risk and activity levels were combined, the researchers examined the odds for incident depression when increasing physical activity by one SD (4.6 hours/week). For individuals at low genetic risk, the OR was 0.62 (95% CI, 0.47-0.80; P = 0.0004); for individuals at intermediate genetic risk, the OR was 0.89 (95% CI, 0.79-0.99; P = 0.38); and for individuals with high genetic risk, the OR was 0.82 (95% CI, 0.68-0.98; P = 0.34).

When results were adjusted for body mass index, education level, employment status, and prior depressive episodes, there were no substantial changes in results. Notably, results were not adjusted for medication use and/or involvement in therapy or any other treatment for depression. Because different forms of physical activity involve different levels of energy, all recorded types of physical activity were converted to metabolic equivalent (MET) hours. MET hours were observed to correlate with total hours of physical activity.

COMMENTARY

Hopelessness often is a subtle manifestation of depression. This hopelessness can present as skepticism of any intervention, especially when an individual believes unstoppable genetic factors predetermine the development of depression. Choi et al bring the potential of hope to these patients by giving front-line providers real-world data indicating that physical activity may overcome the inevitability of genetic loading.

A close look at the results shows genetics play a significant role in depression and that physical activity can mitigate this only to some extent. Specifically, the association of reduced incident depression in the highest genetic risk group with the highest activity level was similar to the inactive, lowest genetic risk group. The lowest overall rate of incident depression was found in the group with a high activity level and low genetic risk. Thus, it is essential for providers treating these high-risk patients to keep in mind that physical activity is likely only part of the answer.

On the other hand, the message that physical activity may be part of an answer can be powerful. It is no secret to depression-prone families that genetics play a role in this disorder. Informing these patients that physical activity may help prevent new episodes can propel lifestyle changes. Interestingly, Choi et al did not control the results of the study for age. A future direction for research could include identifying the optimal age to implement physical activity as a preventive measure for depression to determine if the effects of such interventions become attenuated with age and examining the effects of starting physical activity as a preventive measure in childhood.

It is important to note Choi et al did not investigate the use of physical activity as a treatment for depression; instead, this study concerned the association between physical activity and prevention of incident depression. As a nonintervention, observational study, all relationships are associations, and causality cannot be attributed. Certainly, the message from this study is aimed at depression prevention. This carries potential significant public health implications because there are few other known measures that can be used to prevent depression.

The two-year follow-up for this study is both a strength and limitation. Although this time frame seems sufficient regarding identifying new episodes of depression, future studies should extend further to provide data about the power of physical activity over time. Choi et al used the results of only a single lifestyle survey, but there was no information regarding physical activity habits following the completion of the survey. Thus, unanswered questions include determining if changes in the type or rate of exercise affect depressive episodes differently over time.

The diversity of the individuals involved in the data pool was not well documented, making efforts to generalize the results difficult. Another aspect that could limit implications of this study involves verifying the diagnosis of depressive episodes. There appeared to be no overall verification process, but instead a reliance on billing codes. These may be subject to provider bias and may not encompass the full degree of depression nor the course. Other researchers may want to examine this aspect more closely, and consider more nuanced methodologies, including controlling for the use of concurrent interventions, such as medication and/or therapy. There was little differentiation in impact noted when investigating the specific type of physical activity, while time spent in a physical activity did seem to have an effect. Other researchers could look at this relationship more closely, and perhaps incorporate other types of physical activity, such as physical labor, as well as attempt to gain a more in-depth understanding of the role of exercise intensity in depression prevention.

Overall, these results represent an exciting direction in the field of genetics and medicine. Although the potential for public health is important, it does not and should not overshadow the effect of this news for an individual. The primary care provider is well-positioned to inform patients that even when there is a strong family history of depression, adding physical activity to an overall prevention plan may decrease the risk of future episodes significantly. Given that the positive potential of physical activity on health is far-reaching, this intervention can be efficacious on multiple levels.

REFERENCES

  1. Chekroud SR, et al. Association between physical exercise and mental health in 1.2 million individuals in the USA between 2011 and 2015: A cross-sectional study. Lancet Psychiatry 2018;5:739-746.
  2. Pinto Pereira SM, et al. Depressive symptoms and physical activity during 3 decades in adult life: Bidirectional associations in a prospective cohort study. JAMA Psychiatry 2014;71:1373-1380.
  3. Wang J, et al. Prevalence of depression and depressive symptoms among outpatients: A systematic review and meta-analysis. BMJ Open 2017;7:e017173.
  4. Kok RM, Reynolds CF 3rd. Management of depression in older adults: A review. JAMA 2017;317:2114-2122.
  5. Harvey SB, et al. Exercise and the prevention of depression: Results of the HUNT cohort study. Am J Psychiatry 2018;175:28-36.
  6. Choi KW, et al. Assessment of bidirectional relationships between physical activity and depression among adults: A 2-sample Mendelian randomization study. JAMA Psychiatry 2019;76:399-408.
  7. Shadrina M, et al. Genetics factors in major depression disease. Front Psychiatry 2018;9:334.
  8. National Human Genome Research Institute. Polygenic risk scores. 2019. Available at: http://bit.ly/38GcB3h.