Table 5.

Assessing the Evidence Against Causal Criteria

Criterion	Findings for physical activity and depression	Findings for physical activity and anxiety
(1) Temporality criterion: exposure preceded outcome in the included cohort studies. Inclusion of prospective based studies allowed for the examination of the temporal sequence between baseline levels of physical activity and primary prevention of depression, anxiety at follow-up.	Mammen and Faulkner34 and Schuch et al.19 included primary results from prospective cohort studies. We considered that the evidence from these 2 reviews meets the temporality criteria where the exposure (physical activity) is seen to precede the effect (depression).	Both reviews by Schuch, Stubbs36 and McDowell and Dishman35 included only prospective cohort studies with a follow-up period of >1 year. These 2 reviews assess prospective evidence where exposure (physical activity) preceded the effect (anxiety) in time. This evidence meets the temporality criterion.
(2) Strength of association We used an adaptation of measures by Webb, Bain27 to guide our classification where relative risk (RR) >3.0 (<0.33) are classified as moderately strong, >5.0 (<0.2), strong. Additional measures: RR=1.5–2.9 (0.34–0.67) classified as modest and RR<1.5 (>0.67), weak association (Appendix 1, available online, and Appendix Table 2, available online). Though the strength of association facilitates assessment for possible causal relationship, a strong association is neither necessary nor sufficient for causality, and weakness is neither necessary nor sufficient for concluding absence of causality.	The relative effects reported in the included reviews were considered weak. Weakness of an association makes the risk of alternative explanations greater but does not preclude causality. Measures of association: Mammen and Faulkner34 Out of 30 included primary studies, 25 reported a significant inverse relationship between PA and incident depression while 5 found no relationship. The point estimates for all studies are not reported. Below is a summary of estimates reported. engaging in <150 minutes/week and >150 minutes/week were associated with an 8%–63% (n=3) and 19%–27% (n=3) decreased risk of future depression, respectively. Being physically active for >240 minutes/week (n=2) and 420 minutes/week (n=1) were protective against subsequent depression. As little as 10–29 minutes (RR=0.90) of daily PA was preventive in the onset of depression and, higher levels of daily PA (60–90 minutes/day, RR=0.84; >90 minutes/day, RR=0.80) were significantly associated with decreased risk of developing depression (n=1). Engaging in PA for >30 minutes/day reduced the odds of subsequent depression by 48% (n=1). Even “low” walking levels were associated with a decreased risk of depression of up to nearly 60% (n=2). Even walking at an average pace of <20 minutes/day and >40 minutes/day was protective against depression of up to 6% and 17%, respectively (n=1). Being physically active less than twice per week was associated with an increased risk (OR=1.34) of developing depression (n=1). Being active one to 2 times/week or more than once per week was associated with a decreased risk of depression of up to 40% (n=2). Schuch et al.19 Authors reported adjusted odds ratios for 36 cohorts from the 34 unique primary studies that provided this data. Of these, a total of 32 cohorts reported point estimates <1 and 4 reported point estimates >1. Below are the estimates from the meta-analysis: Compared with people with low levels of physical activity, those with high levels had lower odds of developing depression (AOR=0.83,95% CI=0.79,0.88, I2=0.00, (n=36); OR=0.59, 95% CI=0.51, 0.68, I2=52.38, (n=19) and had decreased risks on adjusted and crude relative risk analyses (adjusted RR=0.83, 95% CI=0.76, 0.90, I2=0.00, [n=18]; RR=0.68, 95% CI=0.60, 0.78, I2=33.40 [n=17]). Physical activity had a protective effect against the emergence of depression in youths (AOR=0.90, 95% CI=0.83, 0.98, I2=0.00), in adults (AOR=0.78, 95% CI=0.70, 0.87, I2=0.00), and in elderly persons (AOR=0.79, 95% CI=0.72, 0.86, I2=0.00). Protective effects against depression were found across geographic regions, with adjusted odds ratios ranging from 0.65 to 0.84 in Asia, Europe, North America, and Oceania, and against increased incidence of positive screen for depressive symptoms (AOR=0.84, 95% CI=0.79, 0.89, I2=0.00) or major depression diagnosis (AOR=0.86, 95% CI=0.75, 0.98, I2=0.00).	The strength of association between physical activity and anxiety was considered weak. The mean odds ratio was considered modest in strength though with a very wide CI. OR values >0.67 were classified as weak associations. Measures of association: McDowell, Dishman35 Self-reported anxiety symptoms: mean crude OR= 0.84 (95% CI=0.76, 0.93, I2=47.31%), mean AOR= 0.87 (95% CI=0.77, 0.99, I2=48.67%). All AORs (n=9) were <1.00. Diagnosis of Any Anxiety Disorder: mean OR was 0.66 (95% CI=0.53, 0.82, I2=62.26%). All AORs (n=3) were <1.00. Diagnosis of Generalized Anxiety Disorder: mean OR was 0.54 (95% CI=0.32, 0.92, I2=0.00%). All AORs (n=3) were <1.00. Schuch and Stubbs36 Authors reported AORs from 11 primary stuies that provided this data. All 11 reported point estimates < 1. Below are the estimates from the meta-analysis across 14 cohorts of 13 unique prospective studies People with high self- reported physical activity (versus low physical activity) were at reduced odds of developing anxiety (AOR=0.74, 95% CI=0.62, 0.88, I2=23.96; crude OR=0.80, 95% CI=0.69, 0.92, I2=0.00). Protective effects for anxiety were evident in Asia (AOR =0.31, 95% CI= 0.10, 0.96, I2=0.00) and Europe (AOR=0.82, 95% CI=0.69, 0.97, I2=11.36); for children/adolescents (AOR=0.52, 95% CI=0.29, 0.90, I2=0.00) and adults (AOR=0.81, 95% C =0.69, 0.95, I2=12.18).
(3) Consistency	Consistent findings were observed across the 2 included reviews. In their discussions, the authors of the 2 reviews indicated that consistency had been witnessed in the various primary studies that had been carried out in different populations.	In the review by McDowell and Dishman35 all crude and adjusted associations included in their meta-analyses indicated inverse associations between physical activity and subsequent anxiety. Similarly, Schuch and Stubbs36 provide evidence of the protective effects of self‐reported physical activity on anxiety development referencing previous cross‐sectional studies. We found that there is evidence for repeated observation of an association between physical activity and anxiety from other studies in different populations under different circumstances. These findings support the criterion of consistency.
(4) Dose–response relationship A dose–response relationship supports a causal interpretation.27,29	A dose–response relationship was reported in several primary studies included in the review by Mammen and Faulkner.34 Schuch and Vancampfort19 did not investigate a dose–response relationship owing to the varied definitions of low or high physical activity in their included primary studies.	Schuch and Stubbs36 did not investigate a dose response relationship between physical activity exposure and anxiety. In the review by McDowell and Dishman35 a total of 11 primary studies assessed for a dose response relationship between physical activity and various anxiety outcomes. All of which reported lower odds of anxiety outcomes for increased amounts of physical activity. In all, there is modest evidence of a dose–response relationship.
(5) Biological plausibility	Mammen and Faulkner34 and Schuch, Vancampfort19 highlight that it is likely that no single mechanism can explain the protective effect of physical activity in the development of depression. They discuss that a range of biochemical and psychosocial factors are likely responsible, including biological mechanisms through, which exercise increases neurogenesis and reduces inflammatory and oxidant markers and activates the endocannabinoid system; a neuromodulatory system involved in several mental disorders. Moreover, they report that people with depression have decreased hippocampal volumes and levels of markers of neurogenesis, and increased levels of inflammatory and oxidant markers. There is evidence that physical activity may regulate these abnormalities, increasing hippocampal volume and neurogenesis levels, as well as adjusting the imbalance between antiinflammatory and proinflammatory and oxidant markers. Also, physical activity may directly increase psychological factors such as self-esteem or perceptions of physical competence. Improved levels of fitness lead to both subjective and objective improvements in physical health status. In both reviews, the authors recommend that future research should investigate these underlying biological and psychological mechanisms.19,34 We concluded that the available evidence meets the biological plausibility criterion.	Though the mechanisms are largely unclear, Schuch and Stubbs36 and McDowell and Dishman35 presented evidence of potential biological processes that may underlie the protective effect of physical activity on incident anxiety. Physical activity is known to influence similar pathways as those seen to play a role in the pathogenesis of anxiety disorders. Some of these biological processes include inflammation, oxidative and nitrogen stress, and subsequent alteration of neurotrophins, neurogenesis, and neuroplasticity. For instance, physical activity may promote neuroregeneration, or the balance between inflammatory/anti‐inflammatory and oxidative/antioxidative markers. This may protect against anxiety. From a psychological perspective, physical activity may reduce the risk of developing anxiety through reduced anxiety sensitivity or improved psychological factors such as increased self-efficacy regarding the ability to exert control over potential threats.
(6) Specificity	This criterion is not met—physical inactivity does not invariably lead to depression, and depression is not the only health condition associated with inactivity. However, this criterion was thought of in relationship to infectious agents, and seldom applies.	As with depression, this criterion is not met but of questionable relevance.
(7) Coherence	We considered that the interpretation of the association between physical activity and depression does not conflict with what is known of the natural history and biology of depression.	The interpretation for the association of physical activity and anxiety does not conflict with what is known of the natural history and biology of anxiety.
Assessed against Bradford Hill's criteria for causality.27,29 Assessment of grade of evidence: Convincing (strong)/probable/possible (suggestive)/insufficient	We graded the evidence as strong enough to support a judgment of a probable causal relationship, with higher levels of physical activity probably leading to a lower risk of depression.	We considered that the evidence supports a judgment of a probable causal relationship.

I², I-squared statistic; PA, physical activity.