Is There Residual Uncontrolled Confounding?
Although the obvious confounding variables should be controlled for as a requirement for inclusion in a quantitative review, residual uncontrolled confounding cannot be ruled out due to the complex nature of the depression and CHD relationship. For example, a depressive state may be associated with other CVD risks such as smoking and other chronic medical conditions.
Reviews of the literature reporting associations between psychosocial factors and CHD found strength of evidence for depression as a causative factor to be strong compared to anxiety where the effect was less consistent [
2,
15]. A role for anxiety in the development of CHD is biologically plausible. Anxiety, as with depression, affects the autonomic regulation of the heart via the hypothalamic-pituitary-adrenocorticol (HPA) axis [
10,
29]. Chronic over-activation of these systems due to anxiety would help to explain the increased frequency of cardiovascular risk factors in patients with anxiety disorders [
10]. Reduced heart rate variability in those with anxiety disorders could also involve impaired vagal control [
12]. In the hypertensive state a chronic anxiety disorder may trigger increased levels of epinephrine and norephinephrine which could also increase the heart rate, total peripheral resistance and even increase the circulating fatty acids [
10]. There is significant evidence which links anxiety disorders to sudden cardiac death [
30,
31]. However, anxiety has not been associated with myocardial infarction in these studies [
12,
31].
While some reviews have found an association between anxiety and CHD [
32], they included fewer of the primary studies with negative findings than the review by Kuper
et al [
15,
33]. We have concluded there is neither strong nor consistent evidence for a causal association between anxiety disorders and CHD [
33].
However, depression and anxiety are strongly co-morbid [
34,
35]. Hence we need to consider anxiety as a confounder in the relationship between depression and CHD. Given the conclusion above that anxiety disorders (alone) do not have a proven etiological relationship with CHD we examined the evidence for the relationship between major depressive disorder and CHD controlling for other mental disorders. In one study the odds ratio (OR) for incident MI was only slightly reduced once phobia, panic disorder and alcohol use/dependence were controlled for (4.16 95%CI 1.49-11.62 compared to 4.54 95%CI 1.65-12.44) [
36]. We therefore concluded that there is insufficient evidence for co-morbid anxiety substantially mediating the relationship between depression and CHD.
A number of studies have reported an association between use of anti-depressant medication and fatal and nonfatal CHD [
37,
38]. This raises the issue as to whether anti-depressant medication, rather than depression, is a risk factor in development of CHD. A limitation of many earlier papers considering the role of antidepressants and CHD [
37,
38] is that few controlled for the presence of depression or other mental disorders. More recent studies examining depression and CHD have controlled for the use of medications. Retrospective analysis of a primary care sample with IHD found that use, dose and duration of tricyclic anti-depressant consumption were not statistically significant in the development of ischemic heart disease when diagnosis and duration of depression were included in the regression model [
39]. In a prospective follow-up of the Baltimore Epidemiologic Catchment Area reported use of psychotropic medication had a marginal effect on the RR of incident MI in a depressed sample (RR 4.16 compared to 4.14) [
36].