Prevention of Poststroke Depression: Does Prophylactic Pharmacotherapy Work?

Prevention of Poststroke Depression: Does Prophylactic Pharmacotherapy Work? Katherine L. Salter, BA,* Norine C. Foley, MSc,* Lynn Zhu, MSc,† Jeffrey W. Jutai, PhD,‡ and Robert W. Teasell, MD*x

Background: Given the negative influence of poststroke depression (PSD) on functional recovery, cognition, social participation, quality of life, and risk for mortality, the early initiation of antidepressant therapy to prevent its development has been investigated; however, individual studies have offered conflicting evidence. The present systematic review and meta-analysis examined available evidence from published randomized controlled trials (RCTs) evaluating the effectiveness of pharmacotherapy for the prevention of PSD to provide updated pooled analyses. Methods: Literature searches of 6 databases were performed for the years 1990 to 2011. RCTs meeting study inclusion criteria were evaluated for methodologic quality. Data extracted included the antidepressant therapy used, treatment timing and duration, method(s) of assessment, and study results pertaining to the onset of PSD. Pooled analyses were conducted. Results: Eight RCTs were identified for inclusion. Pooled analyses demonstrated reduced odds for the development of PSD associated with pharmacologic treatment (odds ratio [OR] 0.34; 95% confidence interval [CI] 0.22-0.53; P , .001), a treatment duration of 1 year (OR 0.31; 95% CI 0.18-0.56; P , .001), and the use of a selective serotonin reuptake inhibitor (OR 0.37; 95% CI 0.22-0.61; P , .001). Conclusions: The early initiation of antidepressant therapy, in nondepressed stroke patients, may reduce the odds for development of PSD. Optimum timing and duration for treatment and the identification of the most appropriate recipients for a program of indicated prevention require additional examination. Key Words: Depression—meta-analysis—prevention— prophylaxis—stroke. Ó 2013 by National Stroke Association

In a review that examined data from 51 studies, Hackett et al1 reported that 33% of individuals with stroke exhibit symptoms of clinical depression at some time after an From the *Aging, Rehabilitation & Geriatric Care Program, Lawson Health Research Institute, Parkwood Hospital; †Departments of Epidemiology and Biostatistics; xPhysical Medicine and Rehabilitation, Schulich School of Medicine, University of Western Ontario, London, Ontario; and ‡Interdisciplinary School of Health Sciences, University of Ottawa, Ottawa, Canada. Received February 7, 2012; revision received March 20, 2012; accepted March 25, 2012. Address correspondence to Katherine L. Salter, BA, Research Associate, Aging, Rehabilitation and Geriatric Care Program, Room 3019C, Parkwood Hospital, 801 Commissioners Rd E, N6C 5J1, London, Ontario, Canada. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2012.03.013

index stroke event, whether in the acute, medium, or longer term. Among community-dwelling individuals who have experienced stroke, the risk for depression may be up to 6 times greater than for their stroke-free counterparts.2 Depression can impede functional recovery, impair cognition, reduce social participation and quality of life, and increase the risk for mortality.3 In addition, poststroke depression (PSD) has been associated with increasing burden or strain for informal caregivers4-6 and mounting health care use and expenditures.7,8 Given the negative impact of depression on the individual, the family, and society, there has been increasing attention placed on the potential for prevention, particularly in select high-risk groups.9,10 In examining possible strategies for prevention, interventions considered successful for treatment of PSD should be given careful consideration.11 Accordingly, the early initiation of antidepressant therapy

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poststroke has been investigated; however, individual studies have offered conflicting evidence in terms of impact on PSD. Previous attempts to pool the results of these trials have arrived at similarly conflicting conclusions. While the analyses provided by Chen et al12 revealed a significant reduction in new onset PSD associated with prophylactic antidepressant therapy, Hackett et al13 reported that there was insufficient evidence to support the administration of antidepressants as a preventative strategy. However, both of these meta-analyses incorporated data from studies that either did not limit inclusion to individuals without diagnosable PSD at baseline or failed to identify participants with existing depression at study entry and provide separate analyses for data obtained from depressed versus nondepressed participants, making it difficult to separate prophylaxis from treatment of an existing condition. In the present study, we conducted an updated review to (1) examine available evidence from published reports of randomized controlled trials (RCTs) examining the impact of pharmacologic treatment for the prevention of PSD in individuals without diagnosable PSD at baseline and (2) provide pooled analyses of data pertaining to the poststroke onset of depression.

Methods Electronic searches of the published literature were performed for the years 1990 to 2011 using the PubMed, CINAHL, EMBASE, PsychINFO, Cochrane Collaboration, and Web of Science databases and included the following search terms; stroke AND depression AND (prevention OR prophylaxis). Searches were limited to clinical trials with adult human participants and publication in English. Search strategies and the application of limitations were modified slightly to accommodate varying requirements of individual database platforms. Reference lists of each full article retrieved for evaluation were searched by hand in order to identify additional citations not located with searches of the electronic databases. Inclusion criteria for the present review and metaanalysis were as follows: (1) RCTs examining prevention of PSD by comparing the use of pharmacotherapy with a control condition; (2) the presence/absence of depression determined using a standardized diagnostic interview procedure or valid rating scale for depression; and (3) study participants limited to individuals with no clinically diagnosable PSD at baseline. Studies that included both depressed and nondepressed individuals were considered for inclusion only if results were reported separately for those individuals identified as nondepressed at baseline and study outcomes included clinical diagnosis (presence vs absence) of depression. Published abstracts, conference proceedings, and letters to the editor were excluded because they lack reporting detail. The titles and abstracts of each of the citations retrieved through the search process were reviewed independently

for potential inclusion by 2 investigators. Consensus after discussion was used to resolve conflicts over the eligibility of identified articles.

Data Abstraction and Quality Assessment Abstraction was performed by 2 trained research associates (K.S. and N.F.) who were experienced in this method of data collection. Abstractors were each blinded to the other’s results and reviewed all articles independently. The review process consisted of 2 parts. In the first part, data pertinent to the study were collected, including sample size, antidepressant therapy used, treatment timing and duration, method of assessment used to determine the presence/absence of PSD, and study results pertaining to the onset of PSD. In the second part, study quality was assessed based on the Jadad scale.14 The Jadad scale is a widely used, reliable, and valid tool15 that examines specific elements of design known to be possible sources of systematic bias that could affect study validity (ie, randomization, blinding, and adequate description of withdrawals/dropouts). Given that a biased treatment effect may be reported if study participants are not included in the analysis according to the results of randomization, the use of intentionto-treat analysis was also examined.16 Two independent raters, each experienced in the use of quality assessment tools and blinded to each other’s ratings, applied the expanded Jadad scale to each study. A third reviewer resolved any disagreements in ratings.

Data Synthesis Pooled analyses were conducted to establish whether prophylactic treatment with antidepressants was associated with reduced risk for depression after stroke, based on cases of depression recorded at the end of treatment in each study. Additional analyses to examine the impact of duration of treatment and antidepressant class on the risk for PSD were performed. Fixed effects models were used and statistical heterogeneity assessed using the I2 statistic. Odds ratio (OR) and 95% confidence intervals (CIs) are reported. All pooled analyses were conducted using Comprehensive Meta-Analysis software (version 2.0; Biostat, Inc, Englewood, NJ). Publication bias was examined using the funnel plot regression method.17 The regression intercept provides a measure of funnel plot symmetry, such that the further the value is from 0, the greater the asymmetry present. The level of significance for identification of asymmetry was set at P , .1.17

Results Based on the stated inclusion criteria, 7 RCTs were identified for the present review.18-25 The process of study identification and selection is illustrated in Figure 1.

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Potentially relevant references identified on literature searches (6 databases) n = 377 Excluded by title/abstract review: (n=368) Duplicates: 96 Not stroke-specific: 153 Not a randomized controlled trial: 70 Not PSD: 33 Not a prevention study: 10 Not pharmacotherapy: 3 Abstract/conference proceedings: 3 Articles identified via handsearching = 6

Figure 1.

Results of the literature search. Full articles retrieved for evaluation n=15 Further exclusions: (n=7) Abstract/progress report: 2 Chinese language only: 2 Did not exclude cases of depression at baseline or report outcomes separatelyfor depressed vs. non-depressed pts.: 2 Did not include onset of depression as outcome: 1 Studies included in the present review n=8

Summary information abstracted from the 8 studies identified for inclusion is provided in Table 1. Two studies included 2 active treatment conditions in addition to a placebo condition. In the case of Narushima et al,19 results from both active treatment conditions (nortriptyline and fluoxetine) were combined for the purposes of the analysis of overall treatment effect only. Robinson et al23 included a condition examining the effectiveness of problem-solving therapy. Data obtained from patients assigned to this condition were excluded. A single study22 used the depression portion of the Hospital Anxiety and Depression Scale (HADS) to identify cases of depression. The HADS is a reliable and valid self-report tool that has shown acceptable sensitivity and specificity when used to identify possible PSD.26 The remaining studies used structured, interview-based assessments to determine the presence or absence of depression (Table 1). Pooled analysis, based on observations collected from 776 patients, revealed a significantly reduced risk for depression associated with pharmacologic treatment overall (OR 0.34; 95% CI 0.22-0.53; P , .001; Fig 2). There was no significant statistical heterogeneity identified between studies (Q 9.44; P 5 .22; I2 25.81). The duration of treatment ranged from 3 months19,25 to 1 year in the majority of studies.18,20,21,23,24 While the results of one of the longer duration studies did not appear to favor preventive therapy, pooled analysis of trials with treatment duration of at least 1 year found a significant reduction in odds for depression (OR 0.31;

95% CI 0.18-0.56; P , .001). Of the 3 studies in which treatment duration was ,1 year, only the most recent had a significant effect in favor of prophylaxis.25 Five of the identified studies examined the use of selective serotonin reuptake inhibitors (SSRIs) for the prevention of PSD.19,20,22,23,25 Two studies examined the use of a tetracyclic antidepressant (TeCA),18,21 while Narushima et al19 included a treatment condition using nortriptyline, a tricyclic antidepressant (TCA), and Tsai et al24 examined the use of the serotonin–norepinephrine reuptake inhibitor (SNRI) milnacipran. Pooled analyses of studies by class of antidepressant (Fig 3) revealed that the use of SSRIs for the prevention of depression was associated with a significant reduction in the risk for PSD (OR 0.37; 95% CI 0.22-0.61; P , .001).

Quality Assessment All studies included in the present review were of similar methodologic quality (Table 2). All were RCTs which, with the exception of the sole open label trial,21 were double-blinded. Three trials did not report the use of an intention-to-treat analysis.21,24,25 Removal of the trial with the weakest reported methodology21 did not substantially alter the results of the overall pooled analysis (OR 0.38; 95% CI 0.24-0.60; P , .001).

Publication Bias The regression intercept calculated for the overall analysis was 22.46 (P 5 .22), indicating no significant

Intervention

Treatment/Placebo Time since stroke

Drug, dose (mg/day) Mianserin (60)

Age

Palom€aki et al18 (1999)

51/49

56/55

70.6/65.3

,30 d

Narushima et al19 (2002)

17/15/16z

NR

88/46.7/75

#6 mos

Rasmussen et al20 (2003)

70/67

72/68

50/50.7

,4 wks

Niedermaier et al21 (2004)

35/35

66/64

68/65.7

1d

Almeida et al22 (2006)

48/51

68/67

67.3/62.5

,2 wks

Sertraline (50)

Robinson et al23 (2008)

59/58x

61/64

64.4/63.8

,3 mos

Escitalopram (10 if ,65 yrs old; 5 if .65 yrs old)

Chollet et al25 (2011)

57/56

66.4/62.9

63/59

,10 d

Fluoxetine (10-40), nortriptyline (25-100) Sertraline (50)

Mirtazapine (30)

Fluoxetine (20)

Length 1 yr

Ax method* HRSD21, DSM-III-R

Baseline depression scoresy 5.3/4.6

3 mos

HRSD17, DSM-IV

NR

1 yr

HRSD17, ICD-10

6.5 (2.7)/ 7.6 (2.6)

1 yr

HRSD17, DSM-IV

NR

24 wks

HADS-D

3.3 (2.3)/ 3.0 (2.4)

1 yr

HRSD17, DSM-IV

7.1 (4.5)/ 7.2 (4.2)

MADRS, clinical assessment

5.6 (5.9)/ 5.2 (5.5)

3 mos

Outcome At baseline, 5 cases of depression were identified (3 assigned to treatment, 2 to placebo). At end of treatment, 5 cases were identified in both the treatment and placebo conditions. There were no significant between group differences on depression assessments over time At end of treatment, 1 minor depression was reported in the nortriptyline group, 3 in the fluoxetine group, and 5 in the placebo group After 1 year of treatment, 6 patients (8.2%) in the treatment group developed depression compared to 15 patients (22.8%) in the placebo-treated group Fourteen (40%) patients in the untreated control group developed poststroke depression versus 2 (5.7%) treated patients (P 5 .001) By 24 weeks, 8 patients in the placebo condition and 11 of patients in the treatment condition met the criteria for depression (OR 0.8; P 5 .59) Five cases of depression were identified in patients receiving escitalopram versus 13 cases in the placebo condition. Patients assigned to the placebo condition were more likely to develop depression than individuals receiving either therapy with escitalopram (HR 4.5; 95% CI 2.4-8.2; P , .001) or problem-solving therapy (HR 2.2; 95% CI 1.4-3.5; P , .001), adjusted for previous history of mood disorders Four cases of depression were identified in the treatment group versus 17 in the group receiving treatment with fluoxetine (P 5 .002). Examination of change over time revealed a significant increase in MADRS scores in the placebo group versus no change in the treatment group (P 5 .032) (Continued )

K.L. SALTER ET AL.

N

Sex (% male)

Study (y)

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Table 1. Studies included in the present review

Abbreviations: CI, confidence interval; DSM, Diagnostic and Statistical Manual for Mental Disorders; HADS-D, Hospital Anxiety and Depression Scale–Depression; HR, hazard ratio; HRSD, Hamilton Rating Scale for Depression; OR, odds ratio. *Assessment methods included the HRSD (17- or 21-item versions), DSM, and HADS-D. yMean and standard deviation of baseline depression rating scales reported for the treatment/placebo conditions, respectively. zIn the fluoxetine, nortriptyline and placebo conditions, respectively. In the overall analysis, active treatment conditions were combined. xIn the escitalopram and placebo conditions, respectively. Data from patients assigned to a problem-solving intervention were not included.

Over 12 months, 8 patients were diagnosed with poststroke depression; 1 in the treatment versus 7 in the placebo condition. Incidence of depression was reported as 2.22% v 15.22% in the treatment and placebo groups, respectively (P 5 .048) 4.4 (2.9)/ 4.6 (2.7) HRSD21, DSM-IV 1 yr Milnacipran (50; titrated to 100 by 1 wk) ,4 wks 65.2/63 61/64.9 46/46

N

Age

Sex (% male) Study (y)

Tsai et al24 (2011)

Length

Baseline depression scoresy Ax method* Drug, dose (mg/day)

Intervention

Time since stroke Treatment/Placebo

Table 1. (Continued )

Outcome

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asymmetry in the funnel plot. However, the negative value of the regression intercept may suggest the presence of an insignificant trend toward the publication of smaller studies that found more pronounced benefits associated with treatment than the larger studies included in the review.17 The use of fixed analysis may have compensated for this effect, because this process does not favor small studies to the same degree as a random effects model.27 While it has been shown that English-only language restrictions placed on inclusion do not tend to produce biased estimates in meta-analyses of conventional therapies, such as drug interventions,28 it is prudent to attempt to be as inclusive as possible. Although literature searches were limited to English publications, 2 Chinese articles were identified in the process of hand-searching the reference lists. These were retrieved and translated. One study29 did not meet the remaining inclusion criteria; however, the second study did.30 The addition of the data abstracted from this study to the pooled analysis did not significantly alter the overall result (OR 0.33; 95% CI 0.21-0.50; P , .001), estimates of heterogeneity (Q 9.74; P 5 .28; I2 17.89), or of publication bias (Egger intercept 5 22.43; P 5 .16).

Discussion Depression is a major cause of disease burden, accounting for approximately 12% of total years lived with disability worldwide.31 Stroke may be viewed as a fixed marker identifying a group of individuals at high risk for depression11 associated with elevated morbidity and mortality as well as increasing health care use and related costs. Reduction of burden associated with the presence of depression may be achieved in part by developing preventive strategies that reduce the number of new cases, particularly in select high-risk groups.32 The results of the present review and analysis suggest that, after stroke, individuals without clinical depression who receive prophylactic antidepressant therapy (particularly using an SSRI) may be significantly less likely to develop depression than nondepressed individuals with stroke who do not receive prophylactic therapy. In addition, prophylactic treatment may be most effective when continued over a period of at least 12 months. Previously published studies in selected prevention of mental health issues (including depression) have shown that interventions provided prophylactically can reduce the incidence of the targeted disorder.33 However, the impact of prevention interventions may be most significant in cases of indicated rather than selected prevention32; that is, in groups of individuals experiencing some symptoms of depression without fulfilling all diagnostic criteria. In the studies identified for this analysis, participants did not have clinically diagnosable depression at baseline. However, reported results of baseline assessments suggest

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Figure 2. Pooled analysis: prevention of depression.

that a substantial proportion of participants—particularly in the Rasmussen et al,20 Robinson et al,23 and Chollet et al25 trials—may have been experiencing either mild or subsyndromal depression. In this case, these studies may be describing indicated prevention in which provision of early treatment for a prodromal condition or precursor to PSD limits the development of a clinical depression.32,33 Early intervention is, of course, an important aspect of indicated prevention. It has been reported previously that the majority of diagnosable cases of PSD develop in the first 6 months after the stroke event, after which the risk for depression declines.34 Paolucci et al35 reported that, of 1064 patients included in the DESTRO study (an Italian multicenter observational study of depression in stroke), 36% of patients developed depression. Eighty percent of these became depressed within the first 3 months of the stroke event. In addition, patients with earlier onset depression experienced more significant symptoms, but were also more likely to improve over time than individuals with later onset depression.36 It would, therefore, seem advisable to implement a program of indicated prevention during this early poststroke period (0-3 months) during which the risk for PSD is greatest and the treatment of depressive symptomatology may be most beneficial. Indeed, the majority of studies included in the present analysis did begin treatment within 3 months of the index stroke event. Only Narushima et al19 extended

the inclusion criterion for time since stroke to 6 months. When the overall pooled analysis was repeated excluding this single study, the results remained the same (OR 0.34; 95% CI 0.21-0.54; P , .001). Although early initiation and longer duration of treatment both appeared to be successful strategies based on the results of the present analysis, there was considerable variation in both the reported time since stroke (1 day to 6 months) and length of intervention (12 weeks to 1 year). Additional study is required to determine the optimal timing and duration of treatment. Successful strategies for indicated prevention, such as targeting high-risk individuals and implementation during the initial, critical months of recovery poststroke, could limit the impact of depression on physical and cognitive recovery, decrease the associated risk for mortality, and reduce both total health care use and overall costs of care.9,37-39 In a recent, large, observational, cohort study (n 5 405), Lyness et al10 examined a wide range of possible predictors for incident depression in individuals $65 years of age and found that (1) functional deficits in activities of daily living, (2) a history of depression, and (3) the presence of subsyndromal depression identified a group most at risk for incident depression. These 3 variables associated with increased risk as reported by Lyness et al10 also appear in studies attempting to identify those individuals at most risk for PSD. Results from the DESTRO35 and Auckland Regional Community Stroke (ARCOS)40

Figure 3. Use of selective serotonin reuptake inhibitors for the prevention of poststroke depresssion.

PREVENTION OF POSTSTROKE DEPRESSION

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Table 2. Results of quality assessment Study

RCT

Double-blinding

Withdrawals/dropouts

Intention-to-treat

Palomaki et al18 (1999) Narushima et al19 (2002) Rasmussen et al20 (2003) Niedermaier et al21 (2004) Almeida et al22 (2006) Robinson et al23 (2008) Chollet et al25 (2011) Tsai et al24 (2011)

U U U U U U U U

U U U Open label U U U U

U U U U U U U U

U U U 3 U U 3 U

Abbreviation: RCT, randomized controlled trial.

studies both identified previous stroke and functional dependence (based on the modified Rankin Scale and Barthel Index, respectively) as important predictors for the development of PSD. In addition, Hackett et al41 suggested that, based on post hoc analysis of data from ARCOS and the Stroke Outcomes Study, a significant proportion of individuals with stroke may experience subsyndromal depression, characterized by such depressive symptomatology as feelings of worthlessness, hopelessness, or thoughts that life may not be worth living. Although the development of a simple, reliable, and valid predictive tool has not been achieved,40 and the use of a screening tool alone may be insufficient for the identification of risk,41,42 attention to these 3 significant factors early in the poststroke period could help to determine the most appropriate, high-risk candidates for an effective program of indicated prevention. In the high-risk group identified by Lyness et al,10 the number needed to treat (NNT) to avoid a single new case of depression was 5. Of course, the potential benefits associated with the indicated prevention of PSD must be weighed against the risks associated with the use of antidepressive agents.43,44 Based on data reported by 570 general practices in the United Kingdom between 1996 and 2007, Coupland et al43 found that, in individuals $65 years of age, the use of any type of antidepressant therapy was associated with an increased risk for mortality, attempted suicide/ self-harm, falls, fractures, and upper gastrointestinal bleeding. However, patterns of risk varied with the type of antidepressant used. The use of SSRIs, the most commonly prescribed antidepressant, was also associated with increased risk for stroke/transient ischemic attack, myocardial infarction, seizures, and hyponatremia. It should be noted that, although approximately 10% of patient records included in the study by Coupland et al43 were obtained from individuals with previous stroke, there were no analyses reported that examined the use of antidepressant agents within this subgroup specifically. Instead, analyses of risk were adjusted for the presence of previous stroke as a potentially confounding factor.43 In addition, given that this was an observational

study susceptible to bias, the results should be interpreted with appropriate caution.

Limitations The reporting of standardized or systematic assessment of side effects and/or adverse events in the identified studies was generally poor, making it difficult to undertake a reliable and meaningful evaluation of the relative risks for side effects/adverse events associated with prophylactic therapy. However, 4 studies evaluating the use of SSRIs did include a comprehensive assessment of side effects.20,22,23,25 The most commonly reported side effects included tiredness/fatigue, dizziness, and gastrointestinal upsets (most often nausea and diarrhea). The only significant between-group differences in side effects were reported by Almeida et al.22 In that study, tremors and agitation were reported significantly more often by individuals receiving treatment with sertraline than those assigned to the placebo condition. With the exception of the single open label trial, studies appeared to be of satisfactory methodologic quality, reporting accepted methods of randomization. However, only 3 studies18,22-25 also reported a suitable mechanism for concealed allocation. While it is possible that all randomization schedules were concealed but the process not reported,45 in interpreting the results presented here, one should note that inadequately concealed allocation has been associated with inflated treatment effects,46 and the inclusion of these studies in a metaanalysis could result in a biased point estimate.47 The external validity of the studies included in the present analysis may be limited by inclusion/exclusion criteria that restricted participation to those individuals with no aphasia (or significant communication dysfunction) and/or no significant cognitive impairment. This may have altered the composition of the participant groups to be less than representative of individuals with stroke who might receive prophylactic treatment for PSD outside of the confines of a clinical trial. Certainly, individuals with greater functional deficits after a more severe

1250

stroke who are at an elevated risk for depression also experience increased risks for both aphasia48 and cognitive impairment or dementia.49 Future studies examining the use of prophylactic treatments for PSD should attempt to include a more representative sample of individuals with stroke who might receive such treatments. Based on the results of the present meta-analysis, antidepressant prophylaxis for PSD initiated within the first few months after stroke is associated with reduced odds for the development of PSD. Additional study is required to determine the optimal timing and duration for treatment and the most appropriate recipients for an effective program of indicated prevention.

References 1. Hackett ML, Yapa C, Parag V, et al. Frequency of depression after stroke: A systematic review of observational studies. Stroke 2005;36:1330-1340. 2. Whyte EM, Mulsant BH, Vanderbilt J, et al. Depression after stroke: A prospective epidemiological study. J Am Geriatr Soc 2004;52:774-778. 3. Teasell R, Foley N, Salter K, et al. Evidence-based review of stroke rehabilitation, 14th ed. Available from www. ebrsr.com. Accessed March 20, 2012. 4. Teel CS, Duncan PW, Lai SM. Caregiving experiences after stroke. Nurs Res 2001;50:53-60. 5. Tooth L, McKenna K, Barnett A, et al. Caregiver burden, time spent caring and health status in the first 12 months following stroke. Brain Inj 2005;19:963-974. 6. Haley WE, Allen JY, Grant JS, et al. Problems and benefits reported by stroke family caregivers: Results from a prospective epidemiological study. Stroke 2009;40:2129-2133. 7. Ghose SS, Williams LS, Swindle RW. Depression and other mental health diagnoses after stroke increase inpatient and outpatient medical utilization three years poststroke. Med Care 2005;43:1259-1264. 8. Jia H, Damush TM, Qin H, et al. The impact of poststroke depression on healthcare use by veterans with acute stroke. Stroke 2006;37:2796-2801. 9. Charney DS, Reynolds CF 3rd, Lewis L, et al. Depression and Bipolar Support Alliance consensus statement on the unmet needs in diagnosis and treatment of mood disorders in late life. Arch Gen Psychiatry 2003;60:664-672. 10. Lyness JM, Yu Q, Tang W, et al. Risks for depression onset in primary care elderly patients: Potential targets for preventive interventions. Am J Psychiatry 2009;166: 1375-1383. 11. Whyte EM, Rovner B. Depression in late-life: Shifting the paradigm from treatment to prevention. Int J Geriatr Psychiatry 2006;21:746-751. 12. Chen Y, Patel NC, Guo JJ, et al. Antidepressant prophylaxis for poststroke depression: A meta-analysis. Int Clin Psychopharmacol 2007;22:159-166. 13. Hackett ML, Anderson CS, House A, et al. Interventions for preventing depression after stroke. Cochrane Database Syst Rev 2008;3:CD003689. 14. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. 15. Olivo SA, Macedo LG, Gadotti IC, et al. Scales to assess the quality of randomized controlled trials: A systematic review. Phys Ther 2008;88:156-175.

K.L. SALTER ET AL. 16. Higgins J, Green S. Cochrane handbook for systematic reviews of interventions. Cochrane Library, issue 4 ed. Chicester, UK: John Wiley and Sons, Ltd, 2006. 17. Egger M, Davey SG, Schneider M, et al. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997; 315:629-634. 18. Palom€ aki H, Kaste M, Berg A, et al. Prevention of poststroke depression: 1 year randomised placebo controlled double blind trial of mianserin with 6 month follow up after therapy. J Neurol Neurosurg Psychiatry 1999; 66:490-494. 19. Narushima K, Kosier JT, Robinson RG. Preventing poststroke depression: A 12-week double-blind randomized treatment trial and 21-month follow-up. J Nerv Ment Dis 2002;190:296-303. 20. Rasmussen A, Lunde M, Poulsen DL, et al. A doubleblind, placebo-controlled study of sertraline in the prevention of depression in stroke patients. Psychosomatics 2003;44:216-221. 21. Niedermaier N, Bohrer E, Schulte K, et al. Prevention and treatment of poststroke depression with mirtazapine in patients with acute stroke. J Clin Psychiatry 2004; 65:1619-1623. 22. Almeida OP, Waterreus A, Hankey GJ. Preventing depression after stroke: Results from a randomized placebo-controlled trial. J Clin Psychiatry 2006;67: 1104-1109. 23. Robinson RG, Jorge RE, Moser DJ, et al. Escitalopram and problem-solving therapy for prevention of poststroke depression: A randomized controlled trial. JAMA 2008; 299:2391-2400. 24. Tsai CS, Wu CL, Chou SY, et al. Prevention of poststroke depression with milnacipran in patients with acute ischemic stroke: A double-blind randomized placebocontrolled trial. Int Clin Psychopharmacol 2011;26: 263-267. 25. Chollet F, Tardy J, Albucher JF, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): A randomised placebo-controlled trial. Lancet Neurol 2011; 10:123-130. 26. Salter K, Bhogal SK, Foley N, et al. The assessment of poststroke depression. Top Stroke Rehabil 2007;14:1-24. 27. Thornton A, Lee P. Publication bias in meta-analysis: Its causes and consequences. J Clin Epidemiol 2000;53: 207-216. 28. Moher D, Pham B, Lawson ML, et al. The inclusion of reports of randomised trials published in languages other than English in systematic reviews. Health Technol Assess 2003;7:1-90. 29. He P, Kong Y, Xu LZ. Randomized controlled observation on the effect of early application of fluoxetine in preventing depression after stroke. Chinese Journal of Clinical Rehabilitation 2004;8:6016-6017. 30. Li J, He WY, Han MF. Recent effect of fluoxetine in improving neurologic impairment and preventing poststroke depression in the early stage [in Chinese]. Zhongguo Linchuang Kangfu 2004;8:1208-1209. 31. Ust€ un TB, Ayuso-Mateos JL, Chatterji S, et al. Global burden of depressive disorders in the year 2000. Br J Psychiatry 2004;184:386-392. 32. Cuijpers P, Van SA, Smit F. Preventing the incidence of new cases of mental disorders: A meta-analytic review. J Nerv Ment Dis 2005;193:119-125. 33. Cuijpers P. Examining the effects of prevention programs on the incidence of new cases of mental disorders: The lack of statistical power. Am J Psychiatry 2003;160:1385-1391.

PREVENTION OF POSTSTROKE DEPRESSION 34. Whyte EM, Mulsant BH. Post stroke depression: Epidemiology, pathophysiology, and biological treatment. Biol Psychiatry 2002;52:253-264. 35. Paolucci S, Gandolfo C, Provinciali L, et al. Quantification of the risk of post stroke depression: The Italian multicenter observational study DESTRO. Acta Psychiatr Scand 2005;112:272-278. 36. Paolucci S, Gandolfo C, Provinciali L, et al. The Italian multicenter observational study on post-stroke depression (DESTRO). J Neurol 2006;253:556-562. 37. Spieler JF, Lanoe JL, Amarenco P. Costs of stroke care according to handicap levels and stroke subtypes. Cerebrovasc Dis 2004;17:134-142. 38. Ward A, Payne KA, Caro JJ, et al. Care needs and economic consequences after acute ischemic stroke: The Erlangen Stroke Project. Eur J Neurol 2005;12: 264-267. 39. Robinson RG, Spalletta G. Poststroke depression: A review. Can J Psychiatry 2010;55:341-349. 40. Hackett ML, Anderson CS. Frequency, management, and predictors of abnormal mood after stroke: The Auckland Regional Community Stroke (ARCOS) study, 2002 to 2003. Stroke 2006;37:2123-2128. 41. Hackett ML, Hill KM, Hewison J, et al. Stroke survivors who score below threshold on standard depression measures may still have negative cognitions of concern. Stroke 2010;41:478-481.

1251 42. Sagen U, Finset A, Moum T, et al. Early detection of patients at risk for anxiety, depression and apathy after stroke. Gen Hosp Psychiatry 2010;32:80-85. 43. Coupland C, Dhiman P, Morriss R, et al. Antidepressant use and risk of adverse outcomes in older people: Population based cohort study. BMJ 2011;343. d4551. 44. Smoller JW, Allison M, Cochrane BB, et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the Women’s Health Initiative study. Arch Intern Med 2009;169:2128-2139. 45. Devereaux PJ, Choi PT, El-Dika S, et al. An observational study found that authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods. J Clin Epidemiol 2004;57:1232-1236. 46. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-412. 47. Pildal J, Hrobjartsson A, Jorgensen KJ, et al. Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials. Int J Epidemiol 2007;36:847-857. 48. Kyrozis A, Potagas C, Ghika A, et al. Incidence and predictors of post-stroke aphasia: The Arcadia Stroke Registry. Eur J Neurol 2009;16:733-739. 49. Leys D, Henon H, Mackowiak-Cordoliani MA, et al. Poststroke dementia. Lancet Neurol 2005;4:752-759.