Psychiatric–Medical Comorbidity1Moderators of the relationship between depression and cardiovascular disorders: a systematic review☆,☆☆,
Introduction
The association between cardiovascular diseases (CVDs) and depression has long been recognized. Reports as early as 1937 suggested that institutionalized psychiatric patients had an eight times higher mortality rate than the general population, with “diseases of the heart” accounting for almost 40% of these deaths [1].
In the following decades, the comorbidity of depression and CVDs has been rigorously investigated in many cross-sectional and longitudinal studies. Current literature suggests that the relationship between CVD and depression is bidirectional. Numerous clinical and epidemiological studies investigating the association between depression and cardiovascular disease have suggested that depression increases the risk of subsequent CVD 1.5-fold on average [2], [3], [4], [5] and that patients with coronary artery disease and depression have a two- to threefold increased risk of future nonfatal and fatal cardiac events compared to those cardiac patients without depression [6], [7], [8], [9]. Moreover, depression has been found to be an independent predictor of a poorer outcome after an ischemic event [5], [10], [11].
Research addressing the etiology and pathophysiology of the relationship between depression and CVD has primarily focused on biological mechanisms. Plausible models that might link these two conditions include the hypothalamic-pituitary-adrenal (HPA) axis, pro-inflammatory cytokines, increased sympathetic tone, platelet dysfunction, changes in arterial vessel elasticity and endothelial function (for reviews see Refs. [2], [4], [6], [12], [13], [14], [15], [16], [17], [18], [19], [20]). These complex and interrelated biological mechanisms have been implicated in the pathogenesis and pathophysiology of both depression and CVD as recently reviewed by our group [21]. In brief, dysregulation of the immune system including inflammatory activation and increased oxidative and nitrosative stress has been implicated in the pathogenesis and pathophysiology of depression and its medical comorbidities including obesity and diabetes [22]. These inflammatory mediators in juxtaposition with the dyslipidemia associated with the comorbidities may contribute to accelerated atherosclerosis (for review see Ref. [23]). The inflammatory mediators may also have additional effects which predispose to thrombosis [24]. Dysregulation of the HPA axis may act to provide positive feedback to the already disturbed neuroimmune axis [6], [25], in addition to contributing to sympathoadrenal hyperactivity via central pathways [14], [26], [27]. The sequelae of this increase in sympathetic tone include vasoconstriction, heart rate elevation with reduced variability, and platelet activation contributing to accelerated atherosclerosis, arrhythmia and thrombosis, respectively [14], [26], [28]. Finally, endothelial dysfunction, including attenuated arterial dilation in response to flow or other stimuli, as well as increases in endothelial adhesion molecules and chemokines, may contribute to atherosclerosis, thrombosis and vasospasm [29], [30], [31], [32], [33], [34]. These biological mechanisms may be differentially associated with the illness characteristics and sociodemographic moderators reviewed below.
Clinical depression characteristics such as disease duration, age at first onset, symptom severity and number of depressive episodes are generally regarded as important determinants of treatment and long-term disease outcome. However, previous studies on the depression–CVD association have rarely considered these clinical characteristics in their analyses. Thus, it remains unclear if the increased risk for CVD in cases with depression varies in magnitude according to symptom severity, number of depressive episodes or other characteristics of depression [5], [11]. This question is even more important since it has been suggested that these clinical characteristics may influence causal biological mechanisms of the association between CVD and depression [35].
The aim of this literature review was to summarize the evidence if and how clinical depression characteristics influence the bidirectional relationship between depression and CVD. If characteristics such as duration of illness, severity of depressive symptoms, number of depressive episodes and age of first onset of depression have an impact on the strength of the association between depression and CVDs, future studies should include the assessment of these clinical variables. A second and related aim of this review was to summarize the literature on the influence of sociodemographic factors (age, gender, education) on the depression–CVD relationship as these factors may also influence the strength of the observed association.
Section snippets
Methods
The literature search for this review was carried out according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines as they apply to systematic reviews [36]. A systematic literature search was performed using MEDLINE, the Cochrane Library and PsycINFO databases covering publications from 1969 to 2011. The following search terms were used: (depression OR dysthymia OR depressive ORdepressi* (truncated) OR bipolar disorder OR major depression) AND
Impact of the duration of depressive episodes on the depression–CVD association
The total duration of depressive episodes is a potential marker for the cumulative exposure to biological correlates of the depressive illness and may therefore moderate the relationship between depression and CVDs. This hypothesis has rarely been addressed in the recent literature.
One study found that depressive episodes with a length of ≥ 30 days had a stronger association with CVDs than those with shorter duration, but this was not indicative of a dose–response relationship since episodes of ≥
Discussion
A meta-analysis in the year 2006 described significant deficiencies in the quality of prospective studies addressing the interrelationship between depression and CVDs. Although the meta-analysis overall found support for an association between the two conditions, it was stated that the majority of published studies did not adequately control for covariates of depression and CVDs [5]. In our review, we describe the available evidence for a moderating effect of clinical characteristics of
Conclusion
In this article, we have reviewed the evidence for a moderating effect of clinical characteristics of depression and sociodemographic variables on the bidirectional relationship between cardiovascular disease and depression. A complete model of the depression–CVD relationship should consider these variables in conjunction with subtypes of depression and biological characteristics (see Fig. 2). Such a comprehensive model is advantageous for future research in that it may inform the design and
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Support: The study was supported in part by a research grant from the German Ministry of Education and Research (BMBF, FKZ01ERo816).
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Conflict of interest: All authors declare no conflict of interest.
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The Psychiatric–Medical Comorbidity section will focus on the prevalence and impact of psychiatric disorders in patients with chronic medical illness as well as the prevalence and impact of medical disorders in patients with chronic psychiatric illness.