The results of our meta-analysis of 30 prospective cohort studies with 40 independent reports suggest that depression is associated with a significantly increased risk of CHD and MI. Participants with depression, compared with those free of it, experienced a significant increased risk of 30% for CHD and MI. Furthermore, the association remained significant in the groups adjusted for potential confounders, such as lifestyle factors and socio-demographic factors.
Comparison with previous studies
The present meta-analysis showed that the pooled adjusted RRs were 1.30 (95% CI, 1.22–1.40), 1.30 (95% CI, 1.18–1.44) for CHD and MI, respectively, which were much lower than those from a previous meta-analysis published 2007 for CHD (RR, 1.48; 95% CI, 1.29–1.69) and for MI (RR, 1.60; 95% CI, 1.34–1.92). Our meta-analysis included 19 new prospective cohort studies with larger sample size and many more cases, which significantly enhanced statistical power to detect the potential associations of depression with CHD and MI. In addition, we also fully explored the potential publication bias. Although potential publication bias may exist, correction for this bias using trim-and-fill method remained statistically significant. More important, compared with the previous meta-analysis in 2007, the associations differed between populations of different ethnic backgrounds was investigated. We found that the association trended to be stronger for participants from the United States than for European participants. There was null statistically significant risk of CHD in Hong Kong, which might result from the limited number of included studies (One study with two reports comprising 62,839 participants). Given that the studies included in our meta-analysis were conducted in affluent countries (areas) in North America, Western Europe, and Hong Kong, the results should not be extended to developing countries. In order to make the finding generalize to other populations, more studies conducted in other populations from Asia, Africa and South America are warranted.
Our subgroups analyses identified two important and valuable findings. A major finding was that depression increased the risk of CHD in the group of less than 15 years follow-up, but did not have statistically significant association for equal to or more than 15 years follow-up, which was a very interesting phenomenon. One possible explanation to this finding was that most studies have usually measured depression only one time at the beginning of the study, and have assessed the outcomes at the end of the follow-up. It was well known that depression was treatable and depressive individuals could recover during the follow-up. The longer the follow-up duration, the more people could recover, which might weaken the association between depression and CHD risk. In turn, the finding confirmed that the depression was associated with CHD risk.
Another finding was that depression could be an independent risk factor for CHD. In our subgroup analyses, studies adjusted for smoking, BMI, hypertension, diabetes, physical activity, and socioeconomic status did not influence the result of positive association, which suggested that adequate adjustment was not definite to weaken the pooled effect estimate and conclusion [
58].
In the subgroup analysis type of depression measurement, it was notable that the association was much stronger in these studies that identified depression using self-reported scales rather than structured clinical diagnostic interviews or clinical diagnosis. One possible interpretation was that the estimates of depression may differ depending on the use of dimensionally versus categorically based depression assessment tools [
59]. Structured psychiatric interviews would definitely exclude individuals with subsyndromal depressive symptoms from case status. Conversely, utilization of self-reported symptom scales would allow the inclusion of a lot of people with clinically significant depressive symptoms who failed to meet formal criteria for diagnostic and statistical manual of mental disorders (DSM) diagnosis, but a large body of evidence showed that subsyndromal depressive symptoms, like clinical syndromes, were significantly associated with adverse functional outcomes, disability, morbidity and mortality [
60]. Therefore, inclusion of people with subsyndromal depression in the reference category may weaken the risk estimates of studies with categorically based depression definition. More important, there were quite clear differences present that go opposite to a dose–response association between depression and CHD. The interesting finding deserves attention from related researchers. More studies investigating the association between depression and CHD risk based on the use frequency of self-report instruments and interviews over time are needed, which will help to explore the dose–response relationship with them. Specially, in our meta-analysis, a majority of studies defined depression status by self-reported symptom scales, thus our findings much more trended to generalize to the populations who had depression symptoms.
On the basis of our research findings, it was expected that treatment with antidepressants would reduce the risk of development of CHD. Conversely, some observational studies [
40],[
61] suggested treatment with antidepressants was associated with increasing risk of CHD. However, the results should be interpreted cautiously because medication use could be a marker of depression severity [
62], evidence from a meta-analysis of clinical trials showed that treatment with antidepressants was beneficial for CHD [
63]. Thus, patients with antidepressants medication use were more likely to have severe depressive symptoms, and the increased risk of CHD may be attributable to depression severity rather than the antidepressant medication use.
Interestingly, although the evidence from observational studies on the association between depression and the risk of CHD seemed to be robust, the evidence from randomized controlled trials (RCTs) did not find an effect of the intervention [
64],[
65]. We noted that evidence from RCTs had suggested that the treatment response and medical prognosis of different patient subgroups appear different [
66]. For example, among post–acute coronary syndrome patients, depression, particularly if mild, might be monitored for remission without treatment. On the contrary, persistent depression, particularly if treatment recalcitrant, should be treated, taking into considering the link to adverse post-acute coronary syndrome outcomes [
66]. In addition, studies suggested that gender might play a different role in affecting the medical outcomes from psychotherapy [
67],[
68]. Therefore, more research is needed to further investigate the prognosis of subgroups based on depression severity and/or onset and gender, which would help to reveal the relationship between depression and CHD.
Study strengths and limitations
Our review is very valuable and crucial though it is an updated meta-analysis. Firstly, we not only included the prospective cohort studies, also included 19 more new studies and 759,922 more new participants than the previous reviews, which provided stronger and more sufficient evidence. Secondly, on the basis of our subgroup analysis, an important methodological finding was worth paying attention to. In cohort studies with longer follow-up, exposure (such as depression) might be mutative, but the exposure measurement frequency was often inadequate, which should arouse the investigator’s attention in the population-based observational epidemiological studies.
A few limitations of our meta-analysis should be acknowledged. Firstly, we observed robust and consistent associations across different subgroups via sensitivity analyses and subgroup analyses. Yet as a limitation, there was the evidence of heterogeneity across the studies used for the analysis of association between depression and the risk of CHD. The heterogeneity might result from the difference of participants’ characteristic, sample sizes, study designs, and diagnostic criteria of depression. Thus, the results of this meta-analysis should be interpreted cautiously. Secondly, the measurement of depression mostly used the self-reported symptom scales, which could cause the misclassification of exposure [
9], and might underestimate the reported association. Thirdly, the publication bias were observed, however, we used trim-and-fill method to correct the bias, which did not obviously alter the positive association. Fourthly, the receipt and type of depression treatment were not taken into consideration, and many studies lacked information on depression treatment and antidepressant medication use. The role of depression treatment in modulating subsequent risk of CHD needs to be studied further.