The results of this meta-analysis demonstrate that the depression is prospectively associated with a significantly increased risk of developing stroke. Furthermore, the association persisted and remained statistically significant across several subgroups stratified by various study and participant characteristics. We also found a positive association of depression with fatal stroke and ischemic stroke.
Our results are consistent with a previous meta-analysis of 10 studies published before 2005 (HR, 1.43; 95% CI, 1.17–1.75).9
Our current meta-analysis, with 5 times more cases, provides strong evidence that depression is associated with increased risks of total stoke, fatal stroke, and ischemic stroke. The result is also consistent with a large case-control study, the INTERSTROKE study,47
where the investigators found that self-reported depression (for 2 or more weeks in the last year) was associated with a significantly increased risk of stroke (odds ratio, 1.35 [99% CI, 1.10–1.66]) in 3000 cases and 3000 matched controls from 22 countries. Several studies that did not met the inclusion criteria for the meta-analysis also found a positive association between depression and stroke. For example, Simonsick et al.48
found that the stroke incident rates were 2.3 to 2.7 times higher in most subgroups with high depressive symptoms compared with their non-depressed counterparts in a population of older adults with hypertension (n=3461); Nilsson and Kessing49
found that patients with depression severe enough (n=11741) to be hospitalized was associated with an increased future risk of stroke (HR, 1.22; 95% CI, 1.06–1.41) compared with patients with osteoarthritis (n=81380) in Denmark. Using a continuous variable of 20-item CES-D score, Ostir et al.50
found that depressive symptoms were associated with an increased stroke risk (HR, 1.01 per score increase; 95% CI, 1.00–1.02) in 2682 Mexican Americans aged 65 years and older.
Depression may contribute to stroke through a variety of mechanisms. First, depression has known neuroendocrine (e.g., sympathetic nervous system activation, dysregulation of the hypothalamic-pituitary-adrenocortical axis, platelet aggregation dysfunction) 6
and immunological/inflammation effects,51
which could influence stroke risk. A recent meta-analysis suggests that depression is positively associated with C-reactive protein (CRP), interleukin (IL)-1, and IL-6 in clinical and community samples,52
and these inflammatory factors have been associated with an increased risk of stroke.53
Second, depression is associated with poor health behaviors (i.e.
, smoking, physical inactivity, poor diet, lack of medication compliance)54
which might increase the risk of stroke. Adjusting for smoking or BMI somewhat attenuated the association between depression and stroke, suggesting that smoking and obesity may confound or mediate the association between depression and stroke. The magnitude of the depression-stroke association observed in this study is similar to the associations between smoking and stroke (HR, 1.51; 95% CI, 1.45–1.58; from a meta-analysis),56
between obesity and stroke (HR, 1.26; 95% CI, 1.07–1.48; from a meta-analysis).57
Third, depression is correlated with other major comorbidities, such as diabetes4
both of which are major risk factors for stroke. Finally, antidepressant medication use may contribute to the observed association. We found a positive association between the medication use and stroke risk, however, the results should be interpreted cautiously because medication use can be marker of depression severity, and many studies lacked information on dose and duration of medication use.
Several limitations of this meta-analysis should be considered. First, we found a significant heterogeneity across studies, which may result from differences in study designs, sample sizes, depression and stroke measures, analysis strategies, and participants’ characteristics. Although moderate to high heterogeneities still remained in many subgroups, the pooled HRs showed consistent positive associations in most subgroups. Second, the funnel plot indicated a possible publication bias; however, the trim-and-fill sensitivity analysis did not materially change the results (although the pooled HR was modestly attenuated). Nevertheless, the possibility of publication bias could not be fully excluded by this method. Moreover, the meta-analysis was limited to English publications, and the possibility of unpublished reports was not yet identified. Data extraction and analyses were not blinded to the authors, journals or institutions of the publications; however, the literature screening and data extraction were conducted independently by two investigators, and thus, the selection bias was unlikely. Furthermore, most studies did not have information on depression treatment and antidepressant medication use. The role of depression treatment in modulating subsequent risk of stroke needs to be studied further. Finally, further studies are needed to determine whether depression is associated with hemorrhagic stroke.
In conclusion, this meta-analysis provides strong evidence that depression is a significant risk factor for stroke. Given the high prevalence and incidence of depression and stroke in the general population, the observed association between depression and stroke has significant clinical and public health importance. More studies are needed to explore the underlying mechanisms and elucidate the causal pathways that link depression and stroke.