Depression Increases Stroke Risk in Older Women
By Nancy Walsh, Staff Writer, MedPage Today
Published: August 11, 2011
Postmenopausal women with current or past history of depression are at increased risk for stroke, researchers found.
Among a cohort of more than 80,000 women followed for a six-year period, those with a history of depression had a 29% greater risk of stroke than those without depression, according to Kathryn M. Rexrode, MD, of Harvard Medical School in Boston, and colleagues.
Additionally, those with current depression had a 41% greater risk of stroke, while those with only a history of depression had a 23% greater risk, compared with women who never reported a diagnosis of depression or antidepressant medication use, according to the study published online in Stroke: Journal of the American Heart Association.
· Explain that postmenopausal women with current or past history of depression are at increased risk for stroke.
· Note that use of antidepressant medications, particularly the selective serotonin reuptake inhibitors -- the largest use category -- also increased the risk of stroke.
Those data were adjusted for age, marital status, parental history of myocardial infarction, ethnicity, physical activity level, body mass index, alcohol consumption, smoking status, menopausal status, postmenopausal hormone therapy, current aspirin use, current multivitamin use, and Dietary Approaches to Stop Hypertension dietary score, as well as history of hypertension, hypercholesterolemia, diabetes, cancer, and heart diseases.
Rexrode and colleagues had previously found that depression and use of antidepressant medication were linked with sudden death and fatal coronary heart disease (J Am Coll Cardiol 2009;53:950-958).
And although depression could influence the risk for stroke in various ways, such as through neuroendocrine and inflammatory pathways, data clarifying a potential association have been lacking.
To explore the impact of depression on stroke in older women -- ages 54 to 79 -- the researchers analyzed data from the longitudinal Nurses' Health Study, in which participants completed biennial questionnaires on their health.
In the questionnaire sent to participants in 2000, the self-reported prevalence of depression was 22.3%.
Depression status was considered positive if there had ever been a physician diagnosis of depression, if antidepressant drugs were used routinely, or if the five-item Mental Health Index (MDI-5) score was at or below 52. Depressive symptoms were assessed in 1992, 1996, and 2000.
Women reporting a history of depression tended to be younger than those without such a history, as well as to be unmarried, smokers, and to have a higher body mass index and other comorbidities.
Among the 1,033 incident strokes reported between 2000 and 2006, 538 were ischemic, 124 were hemorrhagic, and the remainder were of unknown type.
In the adjusted model, the use of antidepressant medications in women who had a history of physician-diagnosed depression or a MDI-5 score of 52 or less was associated with an increased risk of stroke (HR 1.39, 95% CI 1.15 to 1.69).
In the same model, the HR dropped to 1.18 (95% CI, 0.96 to 1.45) for women with a history of physician-diagnosed depression or a MDI-5 score of 52 or less, but not taking medication.
The HR rose to 1.31 (95% CI 1.03 to 1.67) for women who used antidepressants, but did not have a diagnosis of depression or a clinical score below the cutoff.
The selective serotonin reuptake inhibitors -- the largest use category -- increased the risk by almost 40% (HR 1.39, 95% CI 1.13 to 1.72). The risk for other medication types was only 1.14 (95% CI 0.82 to 1.58).
There has been considerable interest recently in the potential for antidepressants to contribute to cardiovascular disease, possibly through weight gain, hypertension, and inflammation.
But reports have been inconsistent, and Rexrode's group noted that the use of antidepressants may reflect the severity of depression, rather than representing a cause of heart disease or stroke.
They called for further research on antidepressants and cardiovascular outcomes, emphasizing doses and duration of treatment.
Aside from neuroendocrine mechanisms that might contribute to cardiovascular disease in depressed women, the researchers noted that the clinical manifestations of depression in an older population might relate to subclinical vascular disease.
Further contributing to stroke could be negative health factors such as smoking, lack of physical activity, and obesity.
Nonetheless, they concluded that their data "provide additional evidence that depression is associated with a moderately increased risk of incident stroke."
Limitations of the study included its fairly homogeneous white population, the possibility of selection bias, and self-report of depression.
Depression and Incident Stroke in Women - pdf attached
Download the PDF here
Stroke published online August 11, 2011
An Pan, Olivia I. Okereke, Qi Sun, Giancarlo Logroscino, JoAnn E. Manson, Walter C. Willett, Alberto Ascherio, Frank B. Hu and Kathryn M. Rexrode
"These data provide additional evidence that depression (in older women)is associated with a moderately increased risk of incident stroke. The association between current depression status, antidepressant medication use, and risk of stroke deserves further scrutiny. Further research is necessary to determine whether the risk associated with depression can be reduced by other therapies or preventive strategies.......Depression may be associated with an increased risk of stroke through a variety of mechanisms. Depression has known neuroendocrine (sympathetic nervous system activation, dysregulation of the hypothalamic-pituitary- adrenocortical axis, platelet aggregation dysfunction, and others)3 and immunologic/inflammatory effects,4 which could influence stroke risk. Late-life depression may represent a manifestation of subclinical vascular disease.2 Depression may be associated with poor health behaviors (ie, smoking, physical inactivity, poor diet, lack of medication compliance),31 obesity,32 and other major comorbidities,33 which might increase stroke risk. However, whatever the mechanism, recognizing that depressed women may be at higher risk for stroke merits additional research into preventive strategies in this group."
The Nurses' Health Study cohort was established in 1976 when 121 700 female registered nurses aged 30 to 55 years residing in 11 states responded to a mailed questionnaire regarding their medical history and health practices. Follow-up questionnaires were administered biennially after baseline to update information on lifestyle practice and occurrence of chronic diseases.15 Follow-up rates through 2006 exceeded 94%. The study protocol was approved by the Institutional Review Boards of Brigham and Women's Hospital and Harvard School of Public Health.
Background and Purpose-Depression has been associated with an increased risk of coronary heart disease, but prospective data for the association with stroke are limited.
Methods-We followed-up 80 574 women aged 54 to 79 years in Nurses' Health Study without a history of stroke from 2000 to 2006. Depressive symptoms were assessed at multiple time points by a Mental Health Index score (1992, 1996, and 2000), and clinical significant depressive symptoms were defined as a score ≤52. Antidepressant medication use was asked biennially beginning in 1996, and physician-diagnosed depression was reported biennially beginning in 2000. Depression was defined as currently reporting or having a history of any of these 3 conditions.
Results-During 6 years of follow-up, 1033 incident strokes were documented (538 ischemic, 124 hemorrhagic, and 371 unknown strokes). Having a history of depression was associated with a multivariate-adjusted hazard ratio (HR) of 1.29 (95% confidence interval [CI], 1.13-1.48) for total stroke. Women who used antidepressant medications were at increased risk for stroke, whether they also had a Mental Health Index score ≤52 or diagnosed depression (HR, 1.39; 95% CI, 1.15-1.69) or not (HR, 1.31; 95% CI, 1.03-1.67). Furthermore, for each cycle, participants who reported current depression had an increased risk of stroke (HR, 1.41; 95% CI, 1.18-1.67), whereas individuals who only had a history of depression were at nonsignificantly elevated risk (HR, 1.23; 95% CI, 0.97-1.56) compared with women who never reported a diagnosis of depression or antidepressant medication use.
Conclusions-Our results suggest that depression is associated with a moderately increased risk of subsequent stroke.
Stoke is the third leading cause of death in the United States, and nonfatal stroke is a leading cause of permanent disability and economic loss as a result of impairment.1 Late-life depression may be a marker of subclinical cerebro- vascular disease,2 indicating increased stroke risk. Depression may also influence stroke risk via neuroendocrine, immunologic, and inflammatory effects.3,4 Several prospective studies investigating the association between depression and incident stroke have been conducted; however, studies using clinically diagnosed depression as the predictor have yielded mixed results.5-9 Few studies have been conducted specifically among middle-aged and elderly women,10 in whom the prevalence of depression is high,11 and the risk of stroke is substantial.12
We previously found that depression was associated with an increased risk of sudden death and fatal coronary heart disease.13 In the present study, we aimed to examine the association between depression and incident stroke among middle-aged and elderly women of the Nurses' Health Study during 6 years of follow-up. We also examined the association of antidepressant medication (ADM) use with stroke risk, because a recent report suggested an increased risk of subsequent stroke with use of these medications.14
The mean age of the participants was 66 years (range, 54 -79) in 2000. The reported prevalence of depression was 22.3% in 2000. Compared to participants without a history of depression, depressed women were younger, more likely to be single, had a higher body mass index, smoked cigarettes, and were less likely to be physically active (Table 1). The prevalence of major comorbidities was also higher in depressed women.
During 6 years of follow-up, 1033 incident strokes were documented (538 ischemic, 124 hemorrhagic, and 371 unknown types of strokes). In age-adjusted analyses, depression was associated to an increased risk of total stroke with a hazard ratio (HR) of 1.49 (95% CI, 1.30-1.70; Table 2). The HR was attenuated but remained significant after controlling for various covariates including major comorbidities (HR, 1.29; 95% CI, 1.13-1.48). Results were not significant for either hemorrhagic or ischemic stroke separately, possibly because of lower power. No significant interactions between depression, age, and major comorbidities with total stroke risk were found (Supplemental Table I, http://stroke.ahajournals.org).
Increased risk of stroke was seen among women who used ADM, with (HR, 1.39; 95% CI, 1.15-1.69) or without (HR, 1.31; 95% CI, 1.03-1.67) a MHI-5 score =52 or diagnosed depression, compared with nondepressed women (Table 2). Furthermore, compared with women without a history of clinical depression (having physician-diagnosed depression, regular ADM use, or both), women with a history of clinical depression had a nonsignificantly elevated risk (HR, 1.23; 95% CI, 0.97-1.56), whereas those currently reporting clinical depression for the particular 2-year questionnaire period had a significantly increased risk (HR, 1.41; 95% CI, 1.18- 1.67; Table 3). Finally, women who used ADM were at increased risks for stroke (HR, 1.30; 95% CI, 1.08-1.55; Supplemental Table II). The risk was significant for selective serotonin reuptake inhibitors (HR, 1.39; 95% CI, 1.13-1.72), the largest use category, but not for other ADM (HR, 1.14; 95% CI, 0.82-1.58).
The findings from this well-characterized cohort of >80 000 U.S. women with a 6-year follow-up add to the growing evidence that depression is associated with stroke risk. Additionally, our data suggest that women currently reporting clinical depression are at increased risk for stroke. Finally, ADM use (particularly selective serotonin reuptake inhibitors) was associated with an increased stroke risk.
Relatively few prospective studies have examined depression as a risk factor for stroke, even though depression has been consistently identified as a significant risk factor for cardiovascular disease.3 Our previous publication in the same cohort found that depressive symptoms (measured by MHI-5) were associated with an increased risk of fatal coronary heart disease, and ADM use was associated with a significantly increased risk of sudden cardiac death.13 Our current results suggest that depression is also a significant risk factor for stroke. The present study is consistent with 2 previous cohort studies.5,21 Larson et al5 found a 2.7-fold increased risk of incident stroke associated with baseline depression status (determined by the Diagnostic Interview Schedule) among 1703 adults during a 13-year follow-up. Similarly, Liebetrau et al21 found a positive association in 401 participants aged 85 years during a 3-year follow-up. However, both studies were limited by small numbers of stroke outcomes. In contrast, Surtees et al9 observed no association between baseline major depression and stroke risk in 20 627 European participants aged 41 to 80 years during 8.5 years of follow-up. Nevertheless, a 2007 meta-analysis pooled results from both case- control and cohort studies and estimated that depressed mood was associated with an relative risk of 1.43 (95% CI, 1.17-1.75) for stroke.22 Recently, O'Donnell and the INTER- STROKE investigators23 found that self-reported depressive symptoms (for >/=2 weeks in the past year) were associated with a 35% increased odds of stroke in >3000 cases and 3000 matched controls from 22 countries.
ADM use has recently attracted much attention because of its reported potential associations with increased risks of coronary heart disease13 and stroke.14,24 ADM use has been associated with weight gain,25 increased inflammation,26 abnormal bleeding,27 and hypertension;28 thus, it may increase risk of stroke. In our study, participants who used ADM were at increased risk, with a 39% increased risk for total stroke with selective serotonin reuptake inhibitors, which is highly similar to the results from the Women's Health Initiative (HR, 1.45; 95% CI, 1.08-1.97).14 A large case-control study also found a 20% to 40% increased risk of stroke associated with ADM.24 However, null associations also have been reported.29,30 ADM use may be a marker of depression severity, rather than a causal mechanism. The results were not changed when we adjusted for depressive symptoms score in our cohort (data not shown); however, residual confounding may exist. Additionally, ADM are also used for other conditions (eg, anxiety disorders, insomnia, and neuropathic pain), and the indication for use was not available in our study. Additional studies of large sample sizes and with information on dose and duration are needed to investigate the effects of ADM on cardiovascular outcomes including stroke.
Depression may be associated with an increased risk of stroke through a variety of mechanisms. Depression has known neuroendocrine (sympathetic nervous system activation, dysregulation of the hypothalamic-pituitary- adrenocortical axis, platelet aggregation dysfunction, and others)3 and immunologic/inflammatory effects,4 which could influence stroke risk. Late-life depression may represent a manifestation of subclinical vascular disease.2 Depression may be associated with poor health behaviors (ie, smoking, physical inactivity, poor diet, lack of medication compliance),31 obesity,32 and other major comorbidities,33 which might increase stroke risk. However, whatever the mechanism, recognizing that depressed women may be at higher risk for stroke merits additional research into preventive strategies in this group.
The present study has key strengths. Biennially repeated assessments of risk factors and disease outcomes were uti- lized, and time-dependent Cox models were utilized. Furthermore, 3 different sources of information (MHI-5, ADM use, and physician-diagnosed depression) were used to determine depression status. This study also has several limitations. First, the sample was a relatively homogeneous population of predominantly white registered nurses, which may limit generalizability to other populations. Potential selection bias is possible because we had to exclude a large proportion of women without detailed information on depression measures and participants with early onset stroke. In addition, informa- tion on physician-diagnosed depression and ADM use was self-reported, and the depressive symptoms questionnaire was not updated during the follow-up; therefore, the prevalence of depression might be underestimated. Nevertheless, the life- time prevalence of depression at baseline in our study (22.3%) is consistent with that expected for women of this age group.7,34 Moreover, we could not distinguish between chronic and recurrent courses of depression because of limited information. Last, we cannot infer causation or fully exclude the possibility that the results could be explained by other unmeasured or unknown potentially related factors (eg, anxiety, dispositional optimism, and/or hostility).
These data provide additional evidence that depression is associated with a moderately increased risk of incident stroke. The association between current depression status, antidepressant medication use, and risk of stroke deserves further scrutiny. Further research is necessary to determine whether the risk associated with depression can be reduced by other therapies or preventive strategies.