Sex Differences in PSD 1 Sex differences in the prevalence of post-stroke depression: A systematic review Abstract Objective: Depression after stroke occurs in 33% of individuals. It is grossly underdiagnosed and untreated. Sex differences in the prevalence of post-stroke depression (PSD) have not been adequately studied, and may have important implications for clinicians. Method: We performed a systematic review of five databases of all observational studies which measured the prevalence of PSD. Only those studies that stratified their results by sex were included. Results: Fifty-six publications including 47 primary studies between 1982 and 2006 met eligibility criteria and were included in the review. A total of 75131 subjects comprised these studies, with 11910 women and 62899 men. The prevalence of depression among women was higher in 35 studies. Moreover, the prevalence was generally higher among inpatient populations (both acute care and rehabilitation facilities) than community-dwelling subjects. Conclusions: PSD is highly prevalent in both sexes, but appears to be slightly more common among women than men. Untreated depression after stroke can lead to a reduced quality of life, poorer prognosis and increased mortality. All stroke patients should be routinely screened for depression, and further research is needed to determine if there are sex-specific differences in response to treatment. Sex Differences in PSD 2 Background Stroke is the third most common cause of death in developed countries, exceeded only by coronary heart disease and cancer. The World Health Organization (WHO) estimates that 15 million people worldwide suffer a stroke each year and of these, 5 million die and another 5 million are left permanently disabled . This burden is projected to rise from 38 to 61 million Disability-Adjusted Life Years globally between 1990 and 2020 . Among stroke survivors, the sequelae of physical and psychological changes can be devastating. One of those psychological changes is Post-Stroke Depression (PSD). Morris et al  reported that over a ten year period, depressed stoke patients were 3.4 more times likely to die than their non-depressed counterparts. Depression is thought to have a detrimental effect on stroke recovery through a number of mechanisms. For instance, a depressed patient may be less motivated to participate in stroke rehabilitation, due to persistent fatigue or a lack of hope for example . Cognitive impairment may also impede the recovery process [4-7] causing non-adherence to treatment schedules, which may lead to increased mortality [8-10]. PSD is common among men and women. In 2005, a systematic review of 51 primary articles by Hackett et al  estimated the overall frequency of PSD to be 33% (95% CI 29 – 36). The WHO reports that after a first stroke, women are kept in hospital longer, are less likely to be referred to rehabilitation programs and remain more disabled than men receiving similar care . It is plausible that these discrepancies in medical care and rehabilitation are reflected in a difference in the prevalence of PSD between the sexes. Despite the magnitude of studies included in the review outlined above, few stratified their PSD prevalence results by sex. Thus, the effect of sex on PSD is not well documented. The aim of this study was to determine the Sex Differences in PSD 3 sex-specific prevalence of PSD by systematically reviewing the literature on the prevalence of PSD among men and women. To our knowledge, this is the first systematic review of sex differences in the prevalence of PSD. Materials and Methods This systematic review used the methods of the Canadian Task Force on Preventive Health Care , and the US Preventive Services Task Force  and included the following steps. First, comprehensive literature searches by a professional librarian (ME) were conducted of MEDLINE, EMBASE, CINAHL, PSYCHINFO, and the Cochrane Library from 1966 to June, 2006. The search strategy was limited to English language studies that examined the prevalence of PSD among adult stroke patients. The search strategy combined several approaches used by other groups (Cochrane) and is shown in Figure I. Figure I. Medline Search Strategy Citations from all databases were reviewed by one of the authors (BP), and irrelevant citations were omitted. Next, the abstracts of relevant citations were reviewed by the same author (BP). The original articles of relevant abstracts were obtained by another author (MS). In addition, primary studies included in Hackett et al  and Paradiso et al  that were not captured in our search strategy were also obtained. Finally, a standardized, independent review of all remaining eligible papers was performed by one of the authors (BP) according to the inclusion/exclusion criteria below. All English-language articles were considered eligible if they met the following criteria: (i) a primary, observational study, (cross-sectional, prospective or retrospective cohort); (ii) whose subjects had to be men and/or women (>15 years of age) who had experienced at least one cerebrovascular accident (ischemic or haemorrhagic, cerebral or cerebellar); (iii) diagnosed with or reporting depression (including major and minor depression, Sex Differences in PSD 4 dysthymia, and depressive symptoms); and (iv) prevalence and/or incidence estimates of depression were reported. Papers were excluded if: (i) they did not report data collection dates; (ii) results were not stratified by sex; (iii) 30 subjects or less; (iv) results included bipolar or other psychotic disorders; or (v) methods were not reported. Meta-analyses, systematic reviews, experimental studies, published letters, comments, editorials, case-series and case reports, and non-peer reviewed publications (e.g., dissertations) were also excluded from this review. Eligibility was conducted by two independent reviewers (BP, ND). Finally, two authors (ND, MK) independently assessed all the included studies for quality, using previously validated criteria [15;16]. All discrepancies were resolved through consensus with a third investigator (BP). Standardized data extraction was conducted by one of the authors (BP), and was double checked by a second author (MS). Among included studies, we determined duplicate cohorts from the studies if the recruitment site and times, and the number of study participants were identical between studies. In this case, the earliest publication was included in the review. Fifteen articles that were not captured with our search strategy but that were included in Hackett et al  or Paradiso et al  were also reviewed. A flow chart of our literature review method is presented in Figure II. Figure II. Eligibility of studies considered for inclusion into the systematic review Analysis results Our search strategy identified 1233 non-duplicated references. Of these, 365 citations were relevant. After reviewing their abstracts, 141 articles were retrieved to be assessed. Of these, 51 articles met our eligibility criteria, and another five articles that met eligibility criteria were found through the sources mentioned above. Eighty-seven articles were excluded with an Sex Differences in PSD 5 additional ten articles being found by other sources (refer to Figure II for details on exclusion criteria). In total, 56 articles were included, comprising 47 primary studies that were used in our data extraction. Three articles could not be located. Study Characteristics A total of 56 articles including 47 primary studies were included in this review. The studies were a combination of prospective cohort and survey studies conducted between 1982 and 2006. The majority of the studies measured the point-prevalence of depression at a given time after a stroke occurred. Three studies measured the cumulative incidence of depression in a post-stroke population over a specified time period [17-19]. Seven studies received a ‘good’ rating, thirty-five studies received a ‘fair’ rating and five studies received a ‘poor’ rating on the quality assessment (see Table I for details). Subject Characteristics A total of 75131 study subjects are included in this systematic review; 11910 women and 62899 men. The largest study  accounted for more than 68% of the total subjects. It was comprised of more than 98% men, hence the discrepancy between the overall number of men and women included in this review. Three populations are represented in the studies: acute hospital settings, rehabilitation facilities and community-dwelling subjects, but some articles included subjects from more than one setting. The time that had lapsed between stroke and the measurement of PSD varied from less than two weeks [14;17;20-25] to 15 years . Diagnosis of PSD A variety of self-administered patient questionnaires as well as semi-structured clinical interviews were used in the studies to determine the presence of depression. In total, 11 studies employed semi-structured interviews conducted by clinicians, and 31 studies used standardized Sex Differences in PSD 6 questionnaires. In one study, the authors asked the subjects “do you feel depressed?” , in another study, the authors created their own depression scale , and in two studies, the method of diagnosis was not clear [18;29]. The three diagnostic interviews that were used included the Composite International Diagnostic Interview (CIDI), the Present State Exam (PSE), and the Structured Clinical Interview for DSM Axis I Disorders (SCID). Eight different self-report depressive symptom scales are represented across the studies: Beck Depression Inventory (BDI), the Centre for Epidemiologic Studies–Depression Scale (CES-D), Geriatric Depression Scale (GDS), General Health Questionnaire (GHQ), Hamilton Depression Rating Scale (HAM-D), Montgomery Åsperg Depression Rating Scale (MADRS), Wakefield Depression Inventory (WDI) and the Zung Depression Scale (ZDS). Cut-off scores for each of the scales varied between studies. The definition of depression among studies ranged from self-reported depressive symptomatology cut-off scores to those meeting the DSM III or IV standardized criteria for Major Depressive Disorder through diagnostic interviews. Prevalence of PSD There was significant variation in PSD prevalence across studies, due, at least in part, to the varied populations, time since stroke, and means of diagnosing depression. As shown in Table II, the overall prevalence of depression among studies ranged from 4.7%  to 66.7% , but was generally higher among inpatient populations (both acute care and rehabilitation facilities) than community-dwelling subjects. The prevalence rate among women ranged from 5.9%  to 78.3% , and the prevalence rate among men ranged from 4.7%  to 65.2% . The prevalence rate of PSD was higher among women in 35 of 45 studies (one study did not include any women ). Sex Differences in PSD 7 Three of the included studies [17;18;32] reported the incidence of PSD from the time of stroke. All three of these studies received a fair rating on the quality assessment. Andersen  found that the incidence of PSD over one year was 49.5% for women and 28.6% for men. Rachele  reported that the incidence of PSD over 18 months was 68.0% for women and 52.3% for men. Finally, Williams  found that over three years, the incidence of PSD was 5.9% in women and 4.7% in men. Related Studies In addition to the included studies, there were three studies which did not record prevalence data but which stated higher odds ratios for women developing PSD [33-35]. One study calculated the hazard ratio for women developing PSD to be 0.6 , and another study stated that women were significantly more likely to develop PSD than men . Four studies reported that women had higher scores on self-reported depressive symptom scales than males [38-41]. Only one study reported that male sex was significantly associated with higher rates of PSD . There were six other studies which indicated no significant differences in the prevalence of PSD between the sexes [5;43-47]. Discussion The lifetime prevalence rate of major depression in the general population is 6% for men and 13% for women . Our review and others reporting on the prevalence rate of depression after stroke demonstrate that this population is particularly at risk [11;49]. To our knowledge there are no systematic reviews to date that contrast the prevalence of PSD between men and women. This is a conspicuous gap given the established sex differences in depression rates in the general and other medical populations. There is one primary study by Paradiso et al , included in this review, which focused on the etiology of sex differences in PSD and listed nine Sex Differences in PSD 8 other primary studies in which sex differences were incorporated into the PSD prevalence analyses. The overall results of this systematic review suggest that the prevalence of depression among women compared to men was higher in 78% of included studies. There are a number of potential reasons for the variability in the prevalence rates of PSD reported. First, the type of population studied can affect the results. Acute inpatients tended to have the highest prevalence rates of PSD, followed by rehabilitation facility patients and then community- dwelling patients [10;50] . Second, the time since stroke onset has also been reported to affect results, with the rate of PSD being highest within the first few months after stroke and then decreasing [47;51]. However, these findings were refuted in the Hackett et al (2005) review . Third, different diagnostic tools were used to diagnose depression, from self-administered questionnaires, to semi-structured or structured interviews administered by a trained health professional. Moreover, cut-off scores varied between studies using the same diagnostic tools. Finally, the variability may be due to inclusion and exclusion criteria of the primary studies. Many studies exclude severely cognitively impaired or aphasic patients or patients with a history of depression. These are some of the highest risk patients and excluding them could grossly underestimate the frequency of PSD in the population . Sinyor et al  suggests that excluding patients with a history of psychiatric disorder may mask sex differences in the frequency of PSD . In studies that include aphasic patients, communicative and cognitive impairments may impede the diagnostic process further, and reduce the reliability of the tools used. Reasons for greater prevalence of PSD among women may include postulated factors explaining the greater prevalence in the general population such as genetic factors and psychosocial inequities, and may also include issues related to recovery, differential support and Sex Differences in PSD 9 access to rehabilitation. For instance, Paradiso et al  comments that differences in brain functioning and organization may contribute to the sex discrepancy, and further suggests that depression is associated with left-sided stroke in women, but not men. With regard to psychosocial risk factors for PSD , in women these included younger age, personal history of psychiatric disorder, and cognitive impairment. Among men, risk factors for PSD included younger age, impairment in activities of daily living and social functioning . Future study is required to explore what factors may explain the greater rate of PSD among women. The clinical implications of this systematic review include the need for screening and identification of PSD among female stroke patients in particular, and then provision of appropriate treatment. A 2004 Cochrane review by Hackett et al  which examined pharmacological and psychotherapeutic management of depression after stroke, concluded that there is insufficient randomized evidence to support the routine use of antidepressants or psychotherapy for PSD . Interestingly, there is increasing evidence that supports the use of psychosocial rehabilitation in people with depression and heart disease . Specifically, this literature demonstrates a response in women with depression and heart disease to exercise rehabilitation , but potential harm due to general psychosocial intervention when compared to men (i.e., M-HART). Clearly, more sex-specific research is needed to examine the effectiveness of psychotherapeutic and psychopharmacological interventions vis-a-vis reducing depression in a post-stroke population. There are several limitations to our study: (i) the systemic review was qualitative and we did not pool the data into a meta-analysis; (ii) it was limited to studies reported in English; (iii) it did not separate studies into discrete populations, so our prevalence rates vary dramatically and include both acute, severely compromised patients and patients who experienced a stroke more Sex Differences in PSD 10 than ten years ago with no reported neurological sequelae; finally (iv) including studies from different countries can also result in the comparison of seemingly similar groups of patients from different health care systems with different standards, and it is unclear to what extent these populations may differ . In conclusion, PSD is highly prevalent in both sexes, but appears to be more common among women than men. Untreated depression after stroke can lead to a reduced quality of life, poorer prognosis and increased mortality. All stroke patients should be routinely screened for depression, and further research is needed to determine if there are sex-specific differences in response to treatment. As clinical researchers, stratifying study results by sex should be the norm to determine if differences exist in prevalence, symptoms, treatment, or outcomes. By not inquiring about sex differences, we are silently contributing to inequitable health outcomes, which is no longer good enough [57;58]. Sex Differences in PSD 11 Reference List  Mackay J, Mensah G. The Atlas of Heart Disease and Stroke. 1-112. 2004. World Health Organization.  Morris PL, Robinson RG, Andrzejewski P, Samuels J, Price TR: Association of depression with 10-year poststroke mortality. Am J Psychiatry 1993;150:124-129.  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