Key PointsQuestion  Does physical activity have a potential causal role in reducing risk for depression?

Findings  In this 2-sample mendelian randomization study using genetic instruments from large-scale genome-wide association studies to support potential causal inference, higher levels of physical activity (indexed by objective accelerometer data) were linked to reduced odds for major depression.

Meaning  Findings strengthen empirical support for physical activity as an effective prevention strategy for depression.

Importance  Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.

Objective  To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.

Design, Setting, and Participants  This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes—self-reported (n = 377 234) and objective accelerometer-based (n = 91 084)—and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR–Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.

Main Outcomes and Measures  MDD and physical activity.

Results  GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (β = −0.08 in mean acceleration per MDD vs control status; 95% CI, −0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (β = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, −0.008 to 0.05; P = .15).

Conclusions and Relevance  Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed—but not self-reported—physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression.

Depression is a common psychiatric condition that represents a leading cause of disability worldwide.¹ Despite this, efforts to prevent depression have been challenging, with few established protective factors, particularly modifiable targets for prevention. One promising target is physical activity, defined broadly as musculoskeletal movement resulting in energy expenditure.² The relationship between physical activity and depression has received much attention in recent years. For example, meta-analytic data from randomized clinical trials³ have suggested that physical activity is linked to reduced depressive symptoms in at-risk populations, and prospective studies^4,5 have demonstrated associations between higher levels of physical activity and decreased risk for later depression.

Although such findings point to a potential protective role of physical activity for depression, several questions remain. First, does physical activity causally influence risk for depression—or is this better explained by reverse causation? Some studies^6,7 show that depression may also lead to reduced physical activity, but few studies have simultaneously tested both directional relationships. Second, does measurement of physical activity matter? Literature to date has relied mostly on self-reported measures of activity,⁵ which may be subject to confounding by participant mood, memory inaccuracy, and social desirability bias.⁸ Third, does the relationship between physical activity and depression persist when potential confounding is minimized? Although randomized clinical trials minimize confounding from unaccounted variables by design, they are intensive to conduct and have been of relatively limited size, with a mean of fewer than 60 participants per trial.^3,9,10 More critically, randomized clinical trials have focused on treating symptoms in depressed individuals rather than testing preventive effects of physical activity on depression, which has population-wide implications but requires large samples unselected for depression. The most convincing evidence to date that physical activity is associated with a reduced risk for depression comes from meta-analyses of prospective studies,⁵which are high quality yet still limited by the breadth of behavioral, social, and genetic confounders that cannot be fully ruled out in observational designs.

Mendelian randomization (MR) is an alternative method for potential causal inference that treats genetic variation as a natural experiment in which individuals are essentially assigned to higher vs lower mean levels of a nongenetic exposure during their lifetime.¹¹ Because genetic variants are considered to be allocated randomly before birth, they are relatively independent of environmental factors and established well before onset of disease, thereby minimizing issues of residual confounding and reverse causation that limit typical observational studies. If an exposure such as physical activity causally influences an outcome such as depression, then a variant that affects physical activity should be expected to influence depression to a proportional degree, provided no separate pathway exists by which this variant can affect depression, a phenomenon known as horizontal pleiotropy. Under these conditions, variants strongly associated with an exposure of interest may serve as proxies, or instruments, for estimating potential causal relationship with an outcome (Figure 1). In a 2-sample MR design, instruments can be extracted from summary statistics of large-scale, nonoverlapping genome-wide association studies (GWAS), which have recently become available for physical activity¹² and major depressive disorder (MDD).¹³ Herein, we apply bidirectional MR to assess the potential causal relationship of physical activity with the risk for depression, and vice versa. Furthermore, we examine genetic instruments for physical activity assessed subjectively via self-report and objectively using wearable accelerometers.

Key PointsQuestion  Who is at greatest risk for developing mental health problems such as posttraumatic stress disorder (PTSD) or major depression after sustaining a mild traumatic brain injury (mTBI)?

Findings  In this cohort study of 1155 patients with mTBI and 230 patients with orthopedic injuries not involving the head, patients with mTBI were more likely to report PTSD and/or major depressive symptoms 3 and 6 months after injury. Among patients with mTBI, a number of preinjury (eg, prior mental health problems) and injury-related (eg, assault or other violent cause of injury in the case of PTSD) characteristics were associated with increased risk of mental health problems.

Meaning  Injury to the brain is associated with new onset or exacerbation of preexisting mental health problems in a substantial minority of patients; knowledge of risk factors can inform efforts at prevention, screening, diagnosis, and improved treatment.

Importance  Traumatic brain injury (TBI) has been associated with adverse mental health outcomes, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), but little is known about factors that modify risk for these psychiatric sequelae, particularly in the civilian sector.

Objective  To ascertain prevalence of and risk factors for PTSD and MDD among patients evaluated in the emergency department for mild TBI (mTBI).

Design, Setting, and Participants  Prospective longitudinal cohort study (February 2014 to May 2018). Posttraumatic stress disorder and MDD symptoms were assessed using the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9 Item. Risk factors evaluated included preinjury and injury characteristics. Propensity score weights-adjusted multivariable logistic regression models were performed to assess associations with PTSD and MDD. A total of 1155 patients with mTBI (Glasgow Coma Scale score, 13-15) and 230 patients with nonhead orthopedic trauma injuries 17 years and older seen in 11 US hospitals with level 1 trauma centers were included in this study.

Main Outcomes and Measures  Probable PTSD (PTSD Checklist for DSM-5score, ≥33) and MDD (Patient Health Questionnaire-9 Item score, ≥15) at 3, 6, and 12 months postinjury.

Results  Participants were 1155 patients (752 men [65.1%]; mean [SD] age, 40.5 [17.2] years) with mTBI and 230 patients (155 men [67.4%]; mean [SD] age, 40.4 [15.6] years) with nonhead orthopedic trauma injuries. Weights-adjusted prevalence of PTSD and/or MDD in the mTBI vs orthopedic trauma comparison groups at 3 months was 20.0% (SE, 1.4%) vs 8.7% (SE, 2.2%) (P < .001) and at 6 months was 21.2% (SE, 1.5%) vs 12.1% (SE, 3.2%) (P = .03). Risk factors for probable PTSD at 6 months after mTBI included less education (adjusted odds ratio, 0.89; 95% CI, 0.82-0.97 per year), being black (adjusted odds ratio, 5.11; 95% CI, 2.89-9.05), self-reported psychiatric history (adjusted odds ratio, 3.57; 95% CI, 2.09-6.09), and injury resulting from assault or other violence (adjusted odds ratio, 3.43; 95% CI, 1.56-7.54). Risk factors for probable MDD after mTBI were similar with the exception that cause of injury was not associated with increased risk.

Conclusions and Relevance  After mTBI, some individuals, on the basis of education, race/ethnicity, history of mental health problems, and cause of injury were at substantially increased risk of PTSD and/or MDD. These findings should influence recognition of at-risk individuals and inform efforts at surveillance, follow-up, and intervention.

It has been commonly assumed, even among many health care professionals, that mild traumatic brain injuries (mTBIs) virtually always resolve without sequelae.¹ This assumption may contribute to these patients not receiving education about their injury at the time of injury and not receiving appropriate follow-up care after the acute injury.^2–4 Whereas it is the case that symptoms in most patients with initial Glasgow Coma Scale (GCS) scores of 13 to 15 and negative computed tomography (CT) scan results do resolve in 1 to 3 months,³studies show that some patients have symptoms that persist for months beyond the acute injury.^5,6 In nearly 25 000 nonmedically evacuated US soldiers returning from Afghanistan or Iraq between 2009 and 2014 and screened for mTBI, a substantial proportion (10%-30%) of those who screened positive had symptoms that persisted for at least 3 months postinjury.⁷ These and other data in civilians indicate that for many patients with mTBI, their course is not inevitably one of improvement.^8,9

Mental health problems may be particularly salient features of nonrecovery from mTBI.^1,10 In civilian patients hospitalized for an orthopedic injury, presence of comorbid mTBI was associated with an increased risk for posttraumatic stress disorder (PTSD) and depression 3 to 6 months postinjury.¹¹ Even among healthy young athletes, premorbid psychological factors have been found to be highly relevant to postconcussive recovery.¹² Among 50 US soldiers with concussive blast traumatic brain injuries (TBIs) followed up for 1 to 5 years, many had posttraumatic stress (PTS) and depressive symptoms that worsened over time.¹³ Preexisting mental disorder¹⁴ and mental health sequelae have been shown to be important determinants of overall functioning and quality of life after mTBI.^15–18 In US Army soldiers, deployment-related mTBI was associated with an increased risk for subsequent PTSD, as well as for major depressive disorder (MDD).¹⁹

Although MDD and PTSD are prevalent after TBI, little is known about which patients are at risk for developing them. In a study of 559 civilians consecutively admitted to a level 1 trauma center with TBI, preinjury history of MDD was associated with an increased risk for MDD.²⁰ A retrospective review of medical records from 276 service members assigned to the United States Army Special Operations Command referred for mTBI evaluation found that premorbid PTS symptoms were associated with an increased risk for PTSD following a subsequent mTBI.²¹ In a 2017 systematic review of 26 observational studies of TBI, the authors found that female sex and preinjury depressive symptoms were predictive of MDD, whereas memory of the traumatic events and early PTS symptoms were predictive of PTSD.²²

Taken together, these observations strongly suggest that mental health problems are common following a “mild” TBI and that there may be individual-specific and injury-specific factors that influence risk for these disorders. We hypothesized that factors (eg, antecedent mental disorder, prior TBI, cause of injury)^23,24 observed in prior studies to increase risk for mental health and/or postconcussive symptoms, which are known to overlap with depressive and PTS symptoms,^25,26 in patients with TBI would be predictive of PTSD and MDD status at 6 months postinjury, with similar risk factors observed at 3 and 12 months. To our knowledge, few studies have been designed and powered to ascertain prevalence of PTSD and MDD and examine hypothesized risk factors in a large, prospective longitudinal study of nonmilitary personnel. Given substantial differences in the nature and context of the injuries and postinjury circumstances of military and civilian personnel sustaining mTBIs,²⁷ additional focus on these factors in a civilian cohort is needed.