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Original Investigation
July 2018

Association of Depressive Symptoms and Heart Rate Variability in Vietnam War–Era Twins: A Longitudinal Twin Difference Study

Author Affiliations
  • 1Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia
  • 2Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
  • 3Department of Pediatrics, Georgia Prevention Institute, Augusta University, Augusta, Georgia
  • 4Vietnam Era Twin Registry, Seattle Epidemiologic Research and Information Center, US Department of Veterans Affairs, Seattle, Washington
  • 5Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington
  • 6Division of Cardiology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
  • 7Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
  • 8Atlanta Veterans Affairs Medical Center, Atlanta, Georgia
JAMA Psychiatry. 2018;75(7):705-712. doi:10.1001/jamapsychiatry.2018.0747
Key Points

Question  What is the direction of the association between heart rate variability, an index of autonomic regulation, and depressive symptoms?

Findings  In this longitudinal twin difference study that included 146 veteran twins (73 pairs), lower heart rate variability at baseline was independently associated with increasing depressive symptoms at follow-up. The opposite longitudinal association between depressive symptoms at baseline and lower heart rate variability at follow-up was less robust and mostly explained by antidepressant medication use.

Meaning  Autonomic dysregulation is likely to be a risk factor for depression, rather than a consequence.


Importance  Depressive symptoms are associated with lower heart rate variability (HRV), an index of autonomic dysregulation, but the direction of the association remains unclear.

Objective  To investigate the temporal association between depression and HRV.

Design, Settings, and Participants  A longitudinal, cross-lagged twin difference study, with baseline assessments from March 2002 to March 2006 (visit 1) and a 7-year follow-up (visit 2) at an academic research center with participants recruited from a national twin registry. Twins (n = 166) from the Vietnam Era Twin Registry, who served in the US military during the Vietnam War, and were discordant for depression at baseline were recruited.

Main Outcomes and Measures  At both visits, depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II), and HRV was measured through 24-hour electrocardiogram monitoring. To assess the direction of the association, within-pair differences in multivariable mixed-effects regression models were examined, and standardized β coefficients for both pathways were calculated. The associations were evaluated separately in monozygotic and dizygotic twins.

Results  In the final analytic sample (N = 146), all participants were men, 138 (95%) were white, and the mean (SD) age was 54 (3) years at baseline. Results showed consistent associations between visit 1 HRV and visit 2 BDI score across all HRV domains and models (β coefficients ranging from −0.14 to −0.29), which were not explained by antidepressants or other participant characteristics. The magnitude of the association was similar in the opposite pathway linking visit 1 BDI score to visit 2 HRV, with β coefficients ranging from 0.05 to −0.30, but it was largely explained by antidepressant use. In stratified analysis by zygosity, significant associations were observed in monozygotic and dizygotic twins for the path linking visit 1 HRV to visit 2 BDI score, although the associations were slightly stronger in dizygotic twins.

Conclusions and Relevance  The association between depression and autonomic dysregulation, indexed by HRV, is bidirectional, with stronger evidence suggesting that autonomic function affects depression risk rather than vice versa. The opposite causal pathway from depression to lower HRV is mostly driven by antidepressant use. These findings highlight an important role of autonomic nervous system in the risk of depression and contribute new understanding of the mechanisms underlying the comorbidity of depression and cardiovascular disease.