Depression and Adverse Cardiovascular Disease Outcomes: Cause or Consequence?

It is well established that depression and cardiovascular disease (CVD) commonly accompany each other.[1] In patients with existing CVD, depression is associated with worse disease outcomes.[2] However, the potential existence of a causal relationship has eluded our understanding despite over two decades of research.[3] It remains unclear if depression may contribute to the development and exacerbation of CVD or whether the presence and severity of CVD may favor the development of depression. This question has been studied extensively in the context of coronary heart disease (CHD) and more advanced heart disease, especially heart failure (HF). For example, in patients with HF, elevated depressive symptoms have been shown to predict hospitalization and mortality, independent of established HF biomarkers of adverse outcomes.[4] Moreover, depressive symptoms that worsen over time in patients with HF have also been found to add further to the risk of these adverse outcomes.[5,6] To better understand the nature of the association between depression and CVD, studies of the biological and behavioral pathways that are common to both are likely to play a critical role. Pan and colleagues[7] reported that lower levels of brain-derived neurotrophic factor (BDNF) predicted increased risk of CVD events, independently of depressive symptoms, in a study sample of over 100 hospitalized CHD patients. Their exciting and important study underscores the need for further research focusing on BDNF in the context of depression and CVD. BDNF is a neurotrophin involved in the growth and maintenance of neurons in the central and peripheral nervous systems.[8] Clinical studies have reported lower levels of BDNF in individuals with depression, as well as with the development of depression and worsening depressive symptoms.[8] Moreover, low BDNF levels are also implicated in the pathophysiology of CVD and are associated with an increased risk of adverse CVD events.[9] Whether BDNF is indeed a marker or mechanism by which depression is associated with an increased risk of CVD events is uncertain. Further studies of BDNF levels in patients with CVD hold the promise of unraveling the nature of the link between depression, CVD, and adverse outcomes in patients with existing CVD.[10] BDNF may also explain why health behaviors such as aerobic exercise or healthy eating patterns are beneficial in the context of both depression and CVD.[11] Because depression, CVD, and BDNF are related through both physiological and behavioral mechanisms, understanding their interrelationships holds the potential for the development of novel therapeutic interventions that target pathways common to the development and exacerbation of both depression and CVD. More research is needed to elucidate the precise mechanisms underlying these interrelationships and consequently guide in identifying interventions likely to lower the risk of adverse events and improve the quality of life in patients with CVD. Author contributions Andrew Sherwood wrote the first draft of the commentary. James Blumenthal and Alan Hinderliter provided edits and additional content. All authors have given final approval for the current version to be published. Conflicts of interest Dr. James A. Blumenthal is an Editorial Board Member of Heart and Mind. The article was subject to the journal's standard procedures, with peer review handled independently of Dr. James A. Blumenthal and the research groups. There are no conflicts of interest.