Adolescent Cardiorespiratory Fitness and Future Risk of Depression and Antidepressants: A Nationwide Cohort Study with Sibling Comparators

ObjectiveTo examine the association between adolescent cardiorespiratory fitness and future risk of incident depression and dispensation of antidepressants, while addressing the role of familial confounding. MethodsA nationwide cohort study with registry-linkage and incorporating full sibling comparators, based on Swedish men who participated in mandatory military conscription examinations between 1972 and 1995. Cardiorespiratory fitness was estimated using a maximal ergometer bicycle test. Depression diagnosis in inpatient or specialised outpatient care, and dispensation of antidepressants until 31 December 2023, was ascertained using nationwide registers. ResultsA total of 1 013 885 men (mean age 18.3 years), of which 410 198 were full siblings, were followed until a median age of 56.8 years, during which 47 283 were diagnosed with depression and 237 409 were dispensed antidepressants at least once (18 150 and 93 150 among siblings). In cohort analysis, after controlling for observed confounders, the highest decile of fitness had lower risks of depression (hazard ratio [HR] 0.54; 95% CI 0.52, 0.57) and antidepressants (HR 0.63; 0.62, 0.65) compared to the lowest decile, with a difference in the standardised cumulative incidence at age 65 of -3.9% and -12.3% respectively. In sibling-comparison analyses accounting for unobserved familial confounders, the associations attenuated for both depression (HR 0.67, 0.59 to 0.75; incidence difference -2.4%) and antidepressants (HR 0.76, 0.72 to 0.80; incidence difference -7.2%). Hypothetically shifting everyone to the highest decile of fitness was associated with a preventable fraction of 29.1% for depression and 17.8% for antidepressants in cohort analysis, which attenuated to 17.6% and 10.4% in sibling-comparisons. ConclusionsHigher levels of adolescent cardiorespiratory fitness were associated with a lower risk of future depression diagnosis and dispensation of antidepressants, but the associations may be overstated due to familial confounding. These findings highlight the importance of triangulation to better understand the link between adolescent cardiorespiratory fitness and future risk of depressive disorders. Key pointsO_LIIn this nationwide cohort study of more than 1 million men, of which more than 400,000 were full siblings, higher levels of adolescent cardiorespiratory fitness were associated with lower risks of future depression and dispensation of antidepressants even up to five decades later. C_LIO_LIHowever, after controlling for unobserved confounders shared between full siblings (i.e., behavioural, environmental, and genetic factors), the magnitude of the associations attenuated by up to 40%, suggesting that the benefits associated with fitness may be overstated due to familial confounding. C_LIO_LIMonitoring cardiorespiratory fitness among adolescents could offer insights into their future risk of depression, but the causal relationship may be overestimated in traditional studies, underscoring the need for further causal analyses to triangulate results and yield more robust estimates. C_LI