Evaluation of: Pan A, Okereke OI, Sun Q et al. Depression and incident stroke in women. Stroke 42(10), 2770–2775 (2011). In the Nurses' Health Study, 80,574 women aged between 54 and 79 years, without a history of stroke, were followed-up from 2000 to 2006. In this cohort, depressive symptoms were assessed at multiple time points utilizing the Mental Health Index score (1992, 1996 and 2000), and clinically significant depressive symptoms were defined as a score ≤52. A survey was carried out regarding antidepressant medication use biennially beginning in 1996, and physician-diagnosed depression was reported biennially from 2000. During this 6-year follow-up, 1033 incident strokes were documented. Having a history of depression was associated with an increased risk for total stroke, as well as the use of antidepressant medications with or without history of depression

Francesca Romana Pezzella

Paola Santalucia

Valeria Caso

English

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35ISSN 1745-505710.2217/WHE.11.85 © 2012 Future Medicine Ltd Women's Health (2012) 8(1), 35–37large case–control study, INTERSTROKE, for which the investigators found that self‑reported depression (for ≥2 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 [4]. Finally, antidepressant medication (ADM) use was associated with an increased incidence of stroke in the Nurses’ Health Study, con‑firmed by Pan et al. in their meta‑ana lysis [3]. The results from both of these studies need to be interpreted cautiously, as many of the ana‑lyzed studies lacked information on dose and duration of medication use. Moreover, Pan et al. suspect that ADM use is an expression of depression severity [3]. In summary, there is growing evidence that depression is a risk factor for vascular cardiac and cerebrovascular disease. Therefore, more studies are needed to explore these highly plau‑sible underlying mechanisms and elucidate the causal pathways that are responsible for the association between depression and stroke. In the meantime, clinicians need to be alert for depression and ADM use as possible stroke risk factors. ResultsPan et al. investigated whether depression is a risk factor in women included in the Nurses’ Health Study [1]. This study examined 80,574 women aged 54 to 79 years, without a history of stroke, from 2000 to 2006. Depressive symp‑toms were assessed at multiple time points utiliz‑ing the Mental Health Index score (1992, 1996 and 2000), and clinically significant depres‑sive symptoms were defined as a score ≤52. A survey was carried out on ADM use biennially from the year 1996, and physician‑diagnosed Pan et al. reported on the results from the Nurses’ Health Study concerning depression and stroke risk [1]. The same research group observed a signif icant association between depression and cardiac events [2]. This relation‑ship was strongest for fatal coronary heart dis‑ease, where the association remained significant even after controlling for vascular risk factors (hazard ratio [HR]: 1.49; 95% CI: 1.11–2.00). Depression was strongly associated with sud‑den cardiac death in multivariable models (HR: 2.33; 95% CI: 1.47–3.70), and this risk was primarily due to a specific relationship between antidepressant use and sudden cardiac death (HR: 3.34; 95% CI: 2.03–5.50). Data on a possible association between depression and stroke risk are more limited, and even more so for stroke subtypes. Pan et al. have recently performed a systematic review and meta‑ana lysis of prospective studies, assessing for an association between depression and risk of developing stroke [3]. The pooled adjusted HRs were 1.45 (95% CI: 1.29–1.63; p‑value for heterogeneity <0.001; random‑effects model) for total stroke, 1.55 (95% CI: 1.25–1.93; p‑value for heterogeneity 0.31; fixed‑effects model) for fatal stroke and 1.25 (95% CI: 1.11–1.40; p‑value for heterogene‑ity 0.34; f ixed‑effects model) for ischemic stroke. The estimated absolute risk differences associated with depression were 106 cases for total stroke, 53 cases for ischemic stroke and 22 cases for fatal stroke per 100,000 individuals per year, while the results for nonfatal stroke and hemorrhagic stroke were not significant (HR: 1.21; 95% CI: 0.91–1.62 and HR: 1.16; 95% CI: 0.80–1.70, respectively). The num‑ber of studies (n = 3 and n = 2, respectively) that separately addressed these stroke types was small. These results were also consistent with a priority papEr EvaluationDepression and stroke riskValeria Caso*, Paola Santalucia1 & Francesca Romana Pezzella2Evaluation of: Pan A, Okereke OI, Sun Q et al. Depression and incident stroke in women. Stroke 42(10), 2770–2775 (2011). In the Nurses’ Health Study, 80,574 women aged between 54 and 79 years, without a history of stroke, were followed-up from 2000 to 2006. In this cohort, depressive symptoms were assessed at multiple time points utilizing the Mental Health Index score (1992, 1996 and 2000), and clinically significant depressive symptoms were defined as a score ≤52. A survey was carried out regarding antidepressant medication use biennially beginning in 1996, and physician-diagnosed depression was reported biennially from 2000. During this 6-year follow-up, 1033 incident strokes were documented. Having a history of depression was associated with an increased risk for total stroke, as well as the use of antidepressant medications with or without history of depression. 1Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy 2UO Medicina d’Urgenza Stroke Unit, AO S Camillo-Forlanini, Rome, Italy *Author for correspondence: Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Sant’Andrea delle Fratte, 06126 – Perugia, Italy Tel.: +39 075 5782765 Fax: +39 075 5782765 vcaso@hotmail.comKeywords• antidepressant medication • depression • strokepart of36 future science groupwww.futuremedicine.compriority papEr Evaluation – Caso, Santalucia & Pezzelladepression was reported biennially from the year 2000. Overall, during the 6 years of follow‑up, 1033 incident strokes were docu‑mented (538 ischemic, 124 hemorrhagic and 371 unknown). The reported prevalence of depression was 22.3% in 2000. Compared with women without a history of depression, depressed women were younger, more likely to be single, had a higher BMI, smoked ciga‑rettes and were less likely to be physically active. The prevalence of major vascular comorbidi‑ties was also higher in depressed women. In age‑adjusted analyses, depression was associ‑ated with an increased risk of total stroke with a HR of 1.49 (95% CI: 1.30–1.70). The HR was attenuated but remained significant after adjusting for various covariates including major comorbidities (HR: 1.29; 95% CI: 1.13–1.48). Results were not significant for either hemor‑rhagic or ischemic strokes separately, and no significant interactions among depression, age and major comorbidities with total stroke risk were found. Women who used ADMs were at an 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). This 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 ADMs (HR: 1.14; 95% CI: 0.82–1.58). Furthermore, for each cycle, women who reported current depression had an increased risk of stroke (HR: 1.41; 95% CI: 1.18–1.67), whereas women who only had a history of depression were not at a significantly elevated risk (HR: 1.23; 95% CI: 0.97–1.56) compared with women who never reported a diagnosis of depression or ADM use. SignificanceThe findings from this well‑described cohort of >80,000 US women with a 6‑year follow‑up add to the growing evidence that depression is associated with stroke risk. In this study, a biennially repeated assessment of risk factors and disease outcomes was performed, and time‑dependent Cox models were utilized. Furthermore, three different sources of informa‑tion (five‑item Mental Health Inventory, ADM use and physician‑diagnosed depression) were used to determine depression status. Depression is highly prevalent in the general population, and it is estimated that 5.8% of men and 9.5% of women will experience a depressive episode over the next 12‑month period [5]. This per‑centage is even higher in the female age‑group between 55 and 75 years of age, as confirmed in this study (22.3%). This possible association between depression and stroke will hopefully open new insights into pathogenesis of stroke, which is believed to be different between men and women. In fact, the lifetime risk of stroke for women aged 55 to 75 years is approximately 20%, which is notably higher than that for men (14–17%) [6]. Given that women tend to have fewer vascular risk factors, depression may play a crucial role in stroke pathogenesis. Depression may contribute to stroke through a variety of mechanisms:• Neuroendocrine and immunological/inflam‑mation effects [7]• Poor health behaviors (i.e., smoking [8], phys‑ical inactivity or lack of medication [9])• Correlations with other major comorbidities, such as diabetes and hypertensionIn fact, in this study, women with a history of depression tended to have major vascular comor‑bidities, but their HR remained significant even after adjusting for these. Therefore, the authors hypothesize that the most likely underlying pathway in stroke pathogenesis is: depression induces sympathetic nervous system activation together with dysregulation of the hypotha‑lamic–pituitary–adrenocortical axis and, thereby, platelet aggregation dysfunction [10].Future perspectiveFurther research is necessary to confirm the role of depression as a risk factor for stroke pathogenesis in women. More importantly, future studies need to examine ethnicity, age and social groups for their specific impact on the association between depression and stroke pathogenesis. In addition, the role of ADM must be clarified in the pathogenesis of stroke due to its widespread prescription for women. Finally, future studies will also need to track the duration, dosage and types of ADM in order to obtain a complete picture of its role.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.37future science group Women's Health (2012) 8(1)Depression & stroke risk – priority papEr EvaluationExecutive summary• The history of depression was associated with a hazard ratio (HR) of 1.29 (95% CI: 1.13–1.48) for total stroke in women aged between 54 and 79 years of age without history of stroke. • Women who used antidepressant medications were at an increased risk for stroke, whether they had a diagnosed depression (HR: 1.39; 95% CI: 1.15–1.69) or not (HR: 1.31; 95% CI: 1.03–1.67).• Women with current depression had an increased risk of stroke (HR: 1.41; 95% CI: 1.18 –1.67), whereas those who only had a history of depression were not at a significantly elevated risk (HR: 1.23; 95% CI: 0.97–1.56).References1. Pan A, Okereke OI, Sun Q et al. Depression and incident stroke in women. Stroke 42, 2770–2775 (2011).2. Whang W, Kubzansky LD, Kawachi I et al. Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses’ Health Study. J. Am. Coll. Cardiol. 53, 950–958(2009).3. Pan A, Sun Q, Okereke OI, Rexrode KM, Hu FB. Depression and risk of stroke morbidity and mortality: a meta‑ana lysis and systematic review. JAMA 306, 1241–1249 (2011).4. O’Donnell MJ, Xavier D, Liu L et al.; INTERSTROKE investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case–control study. Lancet 376, 112–123 (2010).5. WHO. The World Health Report 2001 – Mental Health: New Understanding, New Hope. WHO, Geneva, Switzerland (2001).6. Seshadri S, Beiser A, Kelly‑Hayes M et al. The lifetime risk of stroke: estimates from the Framingham Study. Stroke 37, 345–350 (2006).7. Strine TW, Mokdad AH, Dube SR et al. The association of depression and anxiety with obesity and unhealthy behaviors among community‑dwelling US adults. Gen. Hosp. Psychiatry 30, 127–137 (2008).8. Shinton R, Beevers G. Meta‑ana lysis of relation between cigarette smoking and stroke. BMJ 298(6676), 789–794 (1989).9. Luppino FS, de Wit LM, Bouvy PF et al. Overweight, obesity, and depression: a systematic review and meta‑ana lysis of longitudinal studies. Arch. Gen. Psychiatry 67(3), 220–229 (2010).10. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch. Gen. Psychiatry 55, 580–592 (1998).

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