Stroke 2012 El Husseini 1609 16

Depression and Antidepressant Use After Stroke andTransient Ischemic Attack

Nada El Husseini, MD, MHS; Larry B. Goldstein, MD; Eric D. Peterson, MD, MHS; Xin Zhao, MHS;Wenqin Pan, PhD; DaiWai M. Olson, RN, PhD; Louise O. Zimmer, MA;

John W. Williams, Jr, MD, MHS; Cheryl Bushnell, MD, MHS; Daniel T. Laskowitz, MD, MHS

Background and PurposePatients with stroke and transient ischemic attack (TIA) often have comparable comorbidities,but it is unclear whether they have similar rates of depression or antidepressant use.

MethodsThis study was a secondary analysis of a prospective cohort registry that enrolled subjects from 2006 to 2008 in theUnited States. Depression (defined by the Patient Health Questionnaire-8 score 10) and medication use were prospectivelyassessed 3 and 12 months after hospitalization in 1450 subjects with ischemic stroke and 397 subjects with TIA.

ResultsThe proportional frequency of depression after stroke and TIA was similar at 3 months (17.9% versus 14.3%,P0.09) and at 12 months (16.4% versus 12.8%, P0.08). The rates of newly identified depression between 3 and 12months were also similar (8.7% versus 6.2%, P0.12). Persistent depression (defined as Patient Health Questionnaire-8score 10 at both 3 and 12 months) was present in 134 (9.2%) of those with stroke and in 30 (7.6%) of those with TIA.Younger age, greater stroke-related disability, and inability to work at 3 months were associated with persistentdepression in subjects with stroke. Among subjects with persistent depression, 67.9% of those with stroke and 70.0%of those with TIA were not using antidepressants at either time point (P0.920).

ConclusionsStroke and TIA subjects had a similar frequency of depression at 3 and 12 months after hospitalization andsimilar rates of newly identified depression between 3 and 12 months. A high proportion of those with persistentdepression was untreated. (Stroke. 2012;43:1609-1616.)Key Words: behavioral neurology cerebral infarct cerebrovascular disease neuropsychology stroke care

transient ischemic attack

Depression is the most common psychiatric disorderaffecting patients with stroke and may contribute topoststroke morbidity and mortality.1 The frequency of post-stroke depression varies considerably across studies depend-ing on cohort characteristics and diagnostic criteria but isconsiderably higher than control populations matched for ageand sex.24 The pathophysiology of poststroke depression islikely multifactorial and influenced by the location and extentof brain injury, vascular comorbidities, and reaction to newfunctional disability.57 Patients with transient ischemic at-tack (TIA) share comorbid conditions with those who havehad an ischemic stroke, and although approximately 30% to40% may have radiographically demonstrated brain injury, bydefinition, a TIA is not associated with a long-lasting func-tional impairment. Nonetheless, there is a paucity of studiesassessing the proportional frequency of depression and anti-depressant use among patients with TIA.8,9 Furthermore,

there are little patient-level longitudinal data reflecting thepresence or absence of depression and antidepressant usewithin the year after hospitalization for stroke or TIA. Suchanalyses are needed to inform screening recommendationsand to assess the adequacy of current treatment approaches.

Various reports on depression care in the general USpopulation suggest racial and ethnic disparities in the use ofpsychiatric resources, including the use of antidepres-sants.1012 Other factors such as financial stress, lack of healthinsurance coverage, and the presence of concurrent medicalconditions may also affect antidepressant use.11,12 It is notclear whether the same factors affect antidepressant use inpatients with stroke and depression.

The primary objectives of the current study were to comparethe proportional frequency of depression, newly identified de-pression between 3 and 12 months and antidepressant use in theyear after hospitalization for stroke or TIA. The secondary

Received November 3, 2011; final revision received January 17, 2012; accepted February 1, 2012.From the Department of Medicine (N.E.H., L.B.G., E.D.P., D.M.O., J.W.W., D.T.L.), Division of Neurology (N.E.H., L.B.G., D.M.O., D.T.L.), and

Duke Clinical Research Institute (E.D.P., X.Z., W.P., D.M.O., L.O.Z., D.T.L.), Duke University Medical Center, Durham, NC; Durham Veterans Affairs(L.B.G., J.W.W.), Durham, NC; and the Department of Neurology (C.B.), Wake Forest University Health Sciences, Winston-Salem, NC.

The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.111.643130/-/DC1.

Correspondence to Nada El Husseini, MD, MHS, Duke University Medical Center, Department of Medicine, Division of Neurology, Bryan Researchbuilding, Research Drive, Suite 201A, Durham, NC 27710. E-mail [email protected]

2012 American Heart Association, Inc.Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.643130

1609 by guest on August 23, 2015http://stroke.ahajournals.org/Downloaded from by guest on August 23, 2015http://stroke.ahajournals.org/Downloaded from by guest on August 23, 2015http://stroke.ahajournals.org/Downloaded from by guest on August 23, 2015http://stroke.ahajournals.org/Downloaded from by guest on August 23, 2015http://stroke.ahajournals.org/Downloaded from by guest on August 23, 2015http://stroke.ahajournals.org/Downloaded from

objectives were to identify factors associated with undertreat-ment of depression, depression at 12 months posthospitalization,and persistent depression (depression at both 3 and 12 months)in patients with stroke.

MethodsStudy Population and DesignThis is a secondary analysis of a multicenter prospective cohortregistry (Adherence eValuation After Ischemic stroke Longitudinal[AVAIL] study), which was designed to assess adherence to strokeprevention medications from hospital discharge to 1 year in patientsadmitted with stroke or TIA. The AVAIL study methodology hasbeen previously published.13 Briefly, 2889 patients with stroke orTIA were recruited from hospitals participating in the Get With TheGuidelines (GWTG)Stroke program from July 2006 through July2008. The 12-month follow-up was completed in August 2009.Outcome Sciences, Inc served as the data collection and coordinatingcenter for GWTGStroke. The Duke Clinical Research Instituteserved as the data analysis center for both GWTG and AVAIL. Eachparticipating site obtained Institutional Review Board approvalbefore enrolling patients into AVAIL.

SubjectsThe inclusion criteria for the AVAIL registry were: age 18 years;hospitalization with a primary diagnosis of acute ischemic stroke orTIA based on the GWTGStroke identified International Classifica-tion of Diseases, Ninth Edition Codes; direct admission based onphysician evaluation or arrival through the emergency department;patient or legally authorized representative consent to participate;and inclusion in the GWTGStroke program. AVAIL subjects wereexcluded from the present analysis if baseline data were missing; the3- or 12-month Patient Health Questionnaire-8 (PHQ-8) was notcompleted; if antidepressant doses were missing; or if the subjectdied before 12 months. The enrolling sites were both academic(73.3%) and nonacademic (26.3%) hospitals; 30.3% were in theMidwest, 23.6% in the Northeast, 25.3% in the South, and 18.2% inthe West. Duke Clinical Research Institute research personnelconducted telephone interviews at 3 months and 12 months afterhospital discharge using standardized scripts.13

Outcomes and CovariatesThe primary outcomes for this analysis were depression (assessedwith the PHQ-8) and antidepressant use (at doses at or above thoserecommended for treatment of depression). The PHQ-8, based onsymptoms within the prior 2 weeks, includes 8 of the 9 criteria fromthe Diagnostic and Statistical Manual of Mental Disorders, FourthEdition for diagnosis of major depressive disorder.14 The PHQ-8yields a score from 0 to 24 with a score of10 indicating a clinicallysignificant depressive disorder.15 This cutoff has a sensitivity andspecificity of 88% and positive predictive value of 57% for majordepression.15,16 Persistent depression was defined as PHQ-8 10 atboth 3 and 12 months regardless of antidepressant use. Incidentdepression was defined as having a PHQ-8 10 at 12 months inthose with PHQ-8 10 at 3 months.

Medication use was subject-reported and ascertained through aseries of questions aimed at comparing current and previous use.Antidepressants used at an approved dosage were identified based ona previously validated algorithm (online-only Data SupplementalTable I).17 Undertreatment was identified when subjects were notusing antidepressants at 3 or 12 months but had PHQ-8 10 at bothtime points.

Trained hospital personnel abstracted baseline time-independentdemographic characteristics from inpatient medical records as part ofthe GWTGStroke admission. Time-dependent subject characteris-tics were self-reported by subjects on follow-up at each time point aspart of the AVAIL protocol.13 The modified Rankin Scale (mRS)was scored at each follow-up based on the standardized telephoneinterview.13,18 A cutoff of 3 was used to differentiate mild from

moderate/severe stroke, because a mRS 3 is usually associatedwith the ability to maintain independent living.19

Statistical AnalysisFrequency distribution was used for categorical variables. Medianand interquartile ranges were calculated for continuous variables.Chi-squared tests were used to compare categorical variables andWilcoxon rank-sum tests to compare continuous variables. Keydemographic variables were compared between included and ex-cluded subjects. The observed proportional frequency of depressionwas compared between stroke and TIA at 3 and 12 months beforeand after adjusting for gender, age, disability (mRS), previoushistory of stroke/TIA, and history of smoking using multivariablelogistic regressions. The modified Wald method was used to calcu-late CIs. To account for the possible confounding effect of previousstroke/TIA on the frequency of depression, the proportional fre-quency of depression was also compared between stroke and TIAafter excluding subjects with a history of cerebrovascular events. Thefrequency of newly identified depression was calculated by dividingthe number of those with both PHQ-8 10 at 12 months and PHQ-810 at 3 months by the sample size within each group. Subject-levellongitudinal data about depression and antidepressant medicationswere described.

Multivariate logistic modeling was used to assess the associationof prespecified variables with persistent depression and depression at12 months in subjects with stroke. The variables included: sex,race/ethnicity (white versus other), age, mRS at 3 months (range,05), work status at 3 months (work, home by choice, versus homenot by choice), living situation at 3 months (with someone versusother), use of antidepressants at 3 months, and history of coronaryartery disease/myocardial infarction at baseline. Depression at 3months was included only as a predictor variable for depression at 12months. Backward selection of covariates with a probability value of0.1 was performed in both models. The rate of missing covariatedata was low with the values imputed. A similar analysis in subjectswith TIA was not performed because the number in the TIA groupwas too small to support a valid multivariate analysis. The associa-tion of prespecified variables with undertreatment of persistentdepression was assessed with univariate logistic analysis; a multi-variable logistic regression was not planned because of sample sizelimitations for this outcome.

Although the primary end point was based on self-reportedsymptoms of depression, subjects using antidepressants may carry adiagnosis of depression even if symptoms are adequately con-trolled by treatment. To address this possibility, a sensitivity analysiswas performed by redefining depression as PHQ-8 10 and/or theuse of antidepressants at an appropriate dose. All probability valuesare 2-sided with P0.05 considered statistically significant. Allanalyses were performed using SAS software Version 9.2.

ResultsComparison of Included and Excluded SubjectsOf AVAIL subjects (n2889), 1042 (36%) were excluded fromthe present analysis because baseline data were missing, the 3- or12-month PHQ-8 was not completed, antidepressant doses weremissing, or the subject died before 12 months (Figure) leaving atotal of 1847 AVAIL subjects from 99 hospitals. Subjects whowere excluded were more likely to be older (median age, 69years; interquartile range, 5880 years, versus 65 years; inter-quartile range, 5574.5 years; P0.0001), to have been dis-charged to an institution (45.7% versus 26.8%; P0.0001), to beliving in an institution at 3 months (2.3% versus 0.4%;P0.001), to have less than a college education (63.4% versus52.4%; P0.001), to report that household income did not meetneeds (7.9% versus 5.2%; P0.0001), to be unmarried (44.4%versus 38.9%; P0.004), to report their work status as homenot by choice (13.4% versus 10.3%; P0.0001), to have a

1610 Stroke June 2012

by guest on August 23, 2015http://stroke.ahajournals.org/Downloaded from

history of previous stroke/TIA (29.4% versus 23.1%;P0.0002), and to have a history of coronary artery disease/myocardial infarction (29.1% versus 24.3%; P0.005). In ad-dition, because subjects rather than a proxy had to complete thePHQ-8, those with aphasia or significant cognitive impairmentswere more likely to be excluded. The excluded group did notdiffer with respect to sex (female 46.5% versus 45.5%;P0.734), race (white versus nonwhite 83.0% versus 80.6%;P0.108) or medical history of carotid stenosis (4.7% versus5.6%; P0.296), diabetes mellitus (28.7% versus 31.6%;P0.088), peripheral vascular disease (3.7% versus 4.2%;P0.4691), hypertension (78.7% versus 79.2%; P0.444),smoking (25.0% versus 26.9%; P0.227), or dyslipidemia(48.4% versus 45.6%; P0.254).

Comparison of Stroke and TIA SubjectsSubjects with stroke (N1450) were more likely than thosewith TIA (N397) to be men (55% versus 45%; P0.002),younger (median age, 64 versus 68 years; P0.003), smokers(27.6% versus 15.1%; P0.0001) and have a mRS 3 at 3months (23.0% versus 14.2%; P0.0001). Subjects with TIAwere more likely to have a history of stroke/TIA (30.3%versus 21.2%; P0.0003; Table 1).

Proportional Frequency and Frequency of NewlyIdentified Depression and Antidepressant Use inSubjects With Stroke and TIAThe proportional frequency of depression was similar insubjects with stroke and TIA at 3 months (17.9% versus14.3%; P0.09) and at 12 months (16.4% versus 12.8%;P0.08), even after adjustment for disability, history ofstroke/TIA, history of smoking, and baseline demographicvariables (Table 2). After excluding subjects with previousstroke/TIA in both groups, the proportional frequency ofdepression was higher after stroke compared with TIA at 3months (17.4% versus 12.4%, respectively; P0.038) but

was not different at 12 months (15.9% versus 12.0%, respec-tively; P0.100). The frequency of newly identified depres-sion between 3 and 12 months was similar after stroke andTIA (8.7% versus 6.2%, respectively; P0.12). When de-pression was redefined as PHQ-8 10 and/or use of antide-pressants, the proportional frequency of depression and thefrequency of newly identified depression between 3 and 12months (11.3% versus 7.8%, respectively; P0.08) remainedcomparable (Table 2).

The proportion of antidepressant use at 3 months (13.9%versus 15.4%, respectively; P0.45) and 12 months (16.0%versus 14.6%; P0.50) and new antidepressant use between3 and 12 months (5.1% versus 3.6%; P0.237) were similarbetween stroke and TIA (Table 2).

Longitudinal Follow-Up of Depression andAntidepressant Medications in Subjects WithStroke and TIAThe pattern of depression and antidepressant use was similarafter stroke and TIA (online-only Data Supplemental FiguresIII). The proportional frequency of depression over the yearafter stroke and TIA was constant due to a similar proportionof subjects who had resolving depression and subjects whohad new-onset depression between 3 and 12 months (resolv-ing versus new onset: 7.1% versus 8.7% in stroke; 6.8%versus 6.2% in TIA). Of the 134 subjects with stroke and 30subjects with TIA who were persistently depressed (PHQ-810 at both 3 and 12 months), 67.9% of subjects with strokeand 70.0% of subjects with TIA were not using antidepres-sants at either time point (P0.920). Only a minority ofsubjects with stroke (N28 [1.9%]) and TIA (6 [1.5%]) hadpersistent depression despite antidepressant use. Of the 205subjects with stroke and 43 with TIA who were depressed andnot using antidepressants at 3 months, 112 (54.6%) and 22subjects (51.2%), respectively, continued to have depressivesymptoms and/or were treated with antidepressants at 12

Stroke/TIA Initial AVAIL cohort

N=2889 Stroke N=2417

TIA N=472

TIA

N=397

Stroke

N=1450

Exclusions: 1) Without GWTG enrollment admission (N = 9) 2) Follow-up not done at 3 or 12 months (N = 315) 3) Died before 12 months interview (N = 84) 4) Proxy records-PHQ-8 not done (N = 526) 5) PHQ-8 missing at 3 or 12 months (N=46) 6) Antidepressant dose missing at 3 or 12 months (N=62)

Figure. Study cohort. TIA indicates Transient Isch-emic Attack; AVAIL, Adherence eValuation AfterIschemic stroke Longitudinal study; GWTG, GetWith The GuidelinesStroke Program; PHQ,Patient Health Questionnaire.

El Husseini et al Depression and Antidepressant Post Stroke and TIA 1611


Table 1. Characteristics of Subjects With Stroke and TIA

Stroke (N1450) TIA (N397) P Value*

Age, y, median (IQR) 64.0 (55.074.0) 68.0 (56.576.0) 0.003

Sex

Female 641 (44.2%) 217 (54.7%) 0.0002

Race/ethnicity

White 1194 (82.3%) 339 (85.3%) 0.737

Black 161 (11.1%) 39 (9.8%)

Hispanic 36 (2.4%) 9 (2.2%)

Asian 11 (0.7%) 1 (0.2%)

Other/undetermined/missing 40 (2.8%) 9 (2.3%)

Education (baseline)

College or above, yes 663 (45.7%) 187 (47.1%) 0.631

Marital status, baseline

Married, yes 873 (60.2%) 248 (62.4%) 0.424

Medical history prestroke

Atrial/fibrillation/flutter 142 (10.8%) 35 (10.0%) 0.672

Previous stroke/TIA 279 (21.2%) 106 (30.3%) 0.0003

CAD/prior MI 308 (23.4%) 96 (27.5%) 0.117

Diabetes mellitus 384 (29.2%) 94 (26.9%) 0.396

Peripheral vascular disease 54 (4.1%) 7 (2.0%) 0.062

Hypertension 1020 (77.6%) 288 (85.5%) 0.049

Smoker 363 (27.6%) 53 (15.1%) 0.0001

Dyslipidemia 622 (47.3%) 182 (52.1%) 0.112

Discharge status

Left against medical advice ordiscontinued care

2 (0.1%) 0 (0%) 0.0001

Transfer to acute care facility 24 (1.7%) 0 (0%)

Rehabilitation 395 (27.2%) 8 (2.0%)

Skilled nursing facility 63 (4.3%) 5 (1.3%)

Home 959 (66.1%) 384 (96.7%)

Living situation at 3 mo

In rehabilitation institution 0 (0%) 1 (0.2%) 0.453

In nursing home/hospice 5 (0.3%) 2 (0.5%)

With friend(s) 21 (1.4%) 5 (1.2%)

With relative(s) 98 (6.7%) 22 (5.5%)

With spouse/significant otherand/or children

983 (67.8%) 272 (68.5%)

Alone 336 (23.1%) 94 (23.6%)

Household income meetsneeds, 3 mo

Refused 19 (1.3%) 3 (0.8%) 0.162

Do not know 31 (2.1%) 4 (1.0%)

More than adequate 246 (17.0%) 94 (23.7)

Adequately 789 (54.4%) 203 (51.1%)

Somewhat 264 (18.2%) 69 (17.4%)

Not at all 76 (5.2%) 20 (5.1%)

Work status, 3 mo

Home not by choice 153 (10.5%) 38 (9.5%) 0.139

Home by choice 659 (45.5%) 203 (51.1%)

Working 628 (43.3%) 154 (38.8%)

(Continued)



months, whereas the rest had spontaneous resolution ofdepressive symptoms. Of those subjects who did not havespontaneous resolution of depressive symptoms, only 18.7%of subjects with stroke and 4.5% of TIA (P0.04) were usingantidepressants at 12 months, suggesting a low rate ofdepression recognition and treatment. Among those usingantidepressants at both 3 and 12 months (N168 with strokeversus 46 with TIA), 62.5% of subjects with stroke and65.2% of subjects with TIA were not depressed at either timepoint (P0.862).

Factors Associated With Lack of AntidepressantMedication Use in Subjects With Stroke andPersistent DepressionAmong subjects with stroke who were persistently depressedand not using antidepressants (N91), there was no association

between the lack of antidepressant use and age (P0.516), sex(P0.092), race (P0.274), living situation (P0.612), mRS(P0.215), medication insurance status (P0.894), or interimfollow-up with a primary care physician (P0.363) or a neurol-ogist (P0.844) when compared with those who were depressedand untreated at 3 months but using antidepressants by 12months (N21).

Factors Associated With Depression at 12 Monthsand Persistent Depression in Subjects With StrokeUnivariate analyses showed that depression at 12 months(N238) in subjects with stroke was associated with youngerage (P0.0001), female sex (P0.031), nonwhite race(P0.031), inability to work (P0.0001), higher mRS at 3months (P0.0001), using an antidepressant at 3 months(P0.004), and being depressed at 3 months (P0.0001).

Table 1. Continued

Stroke (N1450) TIA (N397) P Value*

mRS at 3 mo

5severe disability 26 (1.8%) 1 (0.3%) 0.001

4moderately severe disability 74 (5.1%) 12 (3.0%)

3moderate disability 232 (16.0%) 43 (10.8%)

2slight disability 513 (35.4%) 90 (22.7%)

1no significant disability 254 (17.5%) 69 (17.4%)

0no symptoms at all 345 (23.8%) 180 (45.3%)

mRS at 3 mo

mRS 3 1112 (76.7%) 339 (85.4%) 0.0001

mRS at 12 mo

mRS 3 1157 (79.8%) 335 (84.4%) 0.04

TIA indicates transient ischemic attack; IQR, interquartile range; CAD, coronary artery disease; MI, myocardialinfarction; mRS, modified Rankin Scale.

*P values were calculated by 2 tests for categorical variables and Wilcoxon rank-sum test for continuous variables.All P values were calculated by comparing only nonmissing row values.

Table 2. Proportional Frequency of Depression, Antidepressant Use, and Depression and/or Use of Antidepressant in Subjects WithStroke and TIA at 3 and 12 Mo

Stroke (N1450;Proportional

Frequency; 95% CI)

TIA (N397;Proportional

Frequency; 95% CI)UnivariateOR, 95% CI P Value

MultivariateOR,* 95% CI P Value

PHQ-8 10 at 3 mo 260 57 1.3 0.09 1.05 0.79

17.9% (16.020.0) 14.4% (11.218.2) (0.91.8) (0.751.46)

Antidepressant use at 3 mo 201 61 0.89 0.45 N/A N/A

13.9% (12.215.7) 15.4% (12.119.3) (0.651.21)

PHQ-8 10 and/or use ofantidepressant at 3 mo

406 104 1.09 0.47 0.94 0.67

28.0% (25.830.4) 26.2% (22.130.7) (0.851.41) (0.721.23)

PHQ-8 10 at 12 mo 238 51 1.33 0.08 1.09 0.63

16.4% (14.618.4) 12.8% (9.916.5) (0.961.84) (0.771.55)

Antidepressant use at 12 mo 232 58 1.11 0.50 N/A N/A

16.0% (14.218.0) 14.6% (11.518.4) (0.811.52)

PHQ-8 10 and/or use ofantidepressant at 12 mo

404 96 1.21 0.14 1.08 0.58

27.9% (25.630.2) 24.2% (20.228.6) (0.941.56) (0.821.42)

TIA indicates transient ischemic attack; PHQ-8, Patient Health Questionnaire-8; N/A indicates not applicable because multivariate analyses were not performed forantidepressant use.

*Multivariate ORs represent the odds of subjects with stroke of having depression compared with those with transient ischemic attack after adjusting for gender,age, smoking, modified Rankin Scale at 3 mo, and history of stroke/transient ischemic attack at baseline.



There was no association with a history of coronary arterydisease/myocardial infarction (P0.139) or living situation at3 months (P0.292). Persistent depression (N134) wasassociated with the same variables. Multivariate analysisconfirmed that younger age, a higher mRS at 3 months, andinability to work at 3 months were associated with depressionat 12 months and with persistent depression (Table 3). Inaddition, depression at 3 months was associated with depres-sion at 12 months. Both models had good discriminatevalidity (C0.82 and C0.81, respectively).

DiscussionIn this large longitudinal study, the proportional frequencyand the frequency of newly identified depression between3 and 12 months posthospitalization were similar after strokeand TIA when assessed with the PHQ-8 scale or by thePHQ-8 and/or use of antidepressants. The frequency ofpoststroke depression varies between published studies de-pending on the setting, patient population, diagnostic criteria,time period, and inclusion and exclusion criteria. Accordingto a meta-analysis published in 2005, the pooled frequency ofdepressive symptoms among stroke survivors at any timeduring follow-up was 33% (95% CI, 29%36%). The pooledfrequencies varied when grouped by method of mood assess-ment; it was lowest in studies that used a single simplequestion to determine depression status (14%; 95% CI,14%15%) and highest when using standardized question-naires such as the Montgomery Asberg depression ratingscale (41%; 95% CI, 23%60%).2 None of the includedstudies used the PHQ-8 scale.

Consistent with previous reports, younger age, poor func-tional outcome, depression, and inability to work at 3 monthswere associated with poststroke depression at 12 months.6,20We further found that the same variables were associatedwith persistent depression. The similar frequency of depres-sion after stroke and TIA could be explained by the nature of

the stroke and TIA cohorts included in the current study. Themajority of subjects with stroke had only mild disability(mRS 3), and approximately 15% of subjects with TIA hadsevere disability (mRS 3), presumably related to previousor intercurrent stroke, or other comorbidities; 30.3% ofsubjects with TIA had also a history of stroke/TIA. However,the frequency of depression remained comparable betweenthe 2 groups even after adjusting for disability, history ofstroke/TIA, and baseline demographic factors. After exclud-ing subjects with a history of stroke/TIA, the frequency ofdepression was higher after stroke compared with TIA at 3months indicating that prior cerebrovascular events partlyexplained the high frequency of depression after TIA.8,9 At 12months, the frequency of depression after excluding previouscerebrovascular events was similar after stroke and TIA,suggesting that other factors play a more important role inlate (12 months) versus early depression (3 months).

Consistent with previous reports, these results also indicatethat the risk of depression after even mild stroke or TIA washigher than the general population with a comparable agedistribution.8 For example, the Behavioral Risk Factor Sur-veillance Survey data from 2006 and 2008 indicated that theoverall frequency of current depression in the generalpopulation using the PHQ-8 diagnostic algorithm was 9.0%(95% CI, 8.79.3); the rates were 10.0% (95% CI, 9.510.5)in the 45- to 65-year-old population and 6.8% (95% CI,6.47.2) in those 65 years old.21

The longitudinal data from AVAIL demonstrate, similar toprevious studies, that the frequency of depression is constantin the year after stroke and TIA, which argues against thehypothesis that the increased risk of depression is limited tothe first few months after a cerebrovascular event.2 In light ofthe higher frequency of depression at 3 and 12 months,screening for depression appears to be warranted in the firstyear after stroke or TIA at both time points. Althoughdepression at 3 months was a strong predictor of depression

Table 3. OR Estimates of Depression at 12 Months and Persistent Depression (3 and 12 Months) in Subjects With Stroke (N1450)After Multiple Logistic Regression

Depression at 12 Mo (N238) Persistent Depression (N134)

Variable Adjusted OR 95% CI P Value Adjusted OR 95% CI P Value

Age, y (per 10-y increase) 0.98 0.960.99 0.009 0.96 0.940.98 0.001

Work status at 3 mo

Working 0.61 0.400.93 0.014 0.32 0.190.53 0.001

Home by choice 0.53 0.330.84 0.32 0.190.56

Home not by choice (reference)

Depression at 3 mo 6.55 4.669.19 0.001 N/A N/A N/A

mRS at 3 mo

5severe disability 1.49 1.291.73 0.001 1.93 1.622.30 0.001

4moderately severe disability (Per 1-unit increase) (Per 1-unit increase)

3moderate disability

2slight disability

1no significant disability

0no symptoms

Only final results of the models are provided.mRS indicates modified Rankin Scale; N/A, not applicable.



at 12 months, it had resolved by 12 months in approximatelyhalf of the subjects without the use of antidepressants. Thiswas possibly due to the self-limited nature of depressivesymptoms, a lower level of depression severity at baseline, orantidepressant use in the interim that was stopped before the12-month follow-up. However, the frequency of newly iden-tified depression between the 3- and 12-month follow-up wasalso significant. Subjects with stroke who are young, unableto work, and have significant disability may need morevigilance because of their higher risk for long-term andpersistent depression.

Various hypotheses regarding the etiology of poststrokedepression include the relative contribution of brain injuryrelated to stroke, reaction to new functional disability andoverall health status, including vascular comorbidities. In thecurrent study, we were not able to correlate depression withstroke location or volume, because radiographic data were notreadily available. Previous studies found a comparable inci-dence of depression among patients with stroke and thosewith similar vascular comorbidities (eg, myocardial infarc-tion) but a higher prevalence of depression among patientswith stroke compared with those with orthopedic disease withthe same level of physical disability and suggested a vascularetiology of depression.5,22,23 Our finding that the frequency ofdepression was similar between subjects with stroke and TIA isalso consistent with this hypothesis. It is possible, however, thatcontributors to depression may differ between patients withstroke and TIA. For example, in our study, functional disabilityand inability to work were independently associated with de-pression among stroke subjects. Because TIA is not associatedwith residual functional impairment, these factors would not beanticipated to play a significant role in the TIA cohort except inthose with previous or intercurrent stroke. Additional studies areneeded to investigate determinants of depression among patientswith TIA.

An important finding from the current study is that under-treatment of depression was common in subjects with eitherstroke or TIA, because more than two thirds of those withpersistent depression were not appropriately treated withantidepressants. Undertreatment was not associated with anyof the studys prespecified variables; however, this conclu-sion is limited by the small sample size of subjects for thisoutcome and warrants replication. Nonetheless, antidepres-sant use was similar for both subjects with stroke and thosewith TIA and higher than the reported rates in the generalpopulation (approximately 10%).24,25 The majority of sub-jects using antidepressants did not have symptoms of depres-sion, which implies that depression in subjects with strokeand TIA is amenable to treatment or, alternatively, thatantidepressants are used nonselectively in this population.20In addition, we cannot exclude the possibility that some of theantidepressant drugs were being used for other purposesbesides depression.

The strengths of this study were the large cohort withcomplete follow-up that prospectively and longitudinallyevaluated both depressive symptoms and antidepressant usein both subjects with stroke and those with TIA. AVAILsubjects were recruited from geographically diverse hospitalsparticipating in the American Heart Association GWTG

Stroke program. GWTGStroke hospitals do tend to belarger, urban and teaching centers. Despite these differences,a study of the representativeness of the GWTGStrokeregistry indicates that the data are generally representative ofnational fee-for-service Medicare ischemic stroke popula-tions providing support for external validity.26 However,there are several limitations. Potential inception cohort bias isalways a concern when consent is required. The demograph-ics of the AVAIL population, however, did not differ sub-stantially from the overall GWTGStroke cohort.13,27,28 Over-all 36% of AVAIL subjects were excluded from the presentanalysis (Figure). The baseline data of subjects who wereexcluded from this analysis do differ in several ways. Be-cause subjects rather than proxies were required to completethe PHQ-8, the results are also likely biased toward thosewith mild disability including those without aphasia orsignificant cognitive impairments. These differences need tobe considered and limit the generalizability of the results.Despite these limitations, this study reveals that, even inpatients with minor disability, the frequency of depressionwas high after stroke or TIA. Some of the subjects withdepression in this study may not have needed treatmentwith antidepressants, because a PHQ-8 score of 10 reflectscurrent depression, which includes major depression, otherdepressive disorders, depressed mood, or anhedonia.15 How-ever, it is very likely that those who were characterized aspersistently depressed may have had clinically significantdepression that warranted treatment. Other nonpharmacologi-cal treatments for depression such as cognitive behavioraltherapy were not captured in this study, thus possibly over-estimating the frequency of undertreatment.

Antidepressant use was self-reported based on structuredinterviews and not confirmed by alternative methods; how-ever, this method of medication assessment has good concor-dance with claims records and is likely to be valid forassessing current antidepressant use for depression therapy.29Prestroke depression, shown to be strongly associated withpoststroke depression, was not assessed in our study.30 Giventhis limitation, we cannot exclude the possibility that aproportion of subjects in the cohort had a history of depres-sion. However, we were able to determine the frequency ofnewly identified depression between 3 and 12 months byusing the 3-month assessment as the baseline. All participantswere discharged from hospitals for a stroke or TIA, limitingthe cerebrovascular event to a subset of events that wereserious enough to warrant hospitalization. Lastly, a baselineassessment of stroke severity, as determined by NationalInstitutes of Health Stroke Scale, was missing in a largeproportion of GWTGStroke subjects and therefore was notincluded in our analyses. Instead we used the mRS as anindication of functional outcome, which correlates well withstroke severity but can be confounded by depression.

ConclusionsBoth subjects with stroke and those with TIA had a similarlyhigh proportional frequency and frequency of newly identi-fied depression between 3 and 12 months after hospitaliza-tion, but a high proportion of persistent depression in these 2groups was not appropriately treated. Systematic evaluation



for depression in patients with stroke or TIA may improvedetection and treatment of this condition.

Sources of FundingDr El Husseini was fully supported and Dr Goldstein and DrLaskowitz were partially supported by an American StrokeAssociation-Bugher Foundation Stroke Prevention Research Centeraward. The AVAIL project was supported by unrestricted funds fromBristol-Myers Squibb/Sanofi Pharmaceuticals Partnership and con-ducted through collaboration with the American Heart Associationand the Get With The GuidelinesStroke program. AVAIL anal-yses were also supported in part by the Agency for HealthcareResearch and Quality cooperative agreement U18HS016964.

DisclosuresDr Laskowitz serves as an associate editor for the Critical Careresearch and Practice from 2009 to the present (no compensation).He has obtained funding from (National Institutes of Health) 1D43-TW008308-01 Training for the prevention and treatment of stroke. DrGoldstein serves as a consultant for Allergan, Pfizer, Boheringer-Ingelheim, Merck, and BMS. He also served on the Neurology Execu-tive Committee RESPECT Trial (Patent foramen ovale closure, AGAMedical Corporation), Site Oversight Committee, Asymptomatic Ca-rotid Trial (Abbott), and Steering Committee for the Stroke Preventionby Aggressive Reduction in Cholesterol Levels (SPARCL) Trial(Pfizer). Dr Williams received funds for other research from the Agencyfor Healthcare Research and Quality, Veterans Affair, and the Foun-dation for Informed Medical Decision Making, Department of Defense(FIMDM). The Veterans Affairs and are on mental health topicsincluding depression but not directly related to the article. Dr Bushnellwas a co-Principal Investigator of AVAIL and received research salarysupport from Bristol Myers Squibb-Sanofi Joint Partnership for her role,but the funding ended in 2009.

References1. Chemerinski E, Levine SR. Neuropsychiatric disorders following

vascular brain injury. Mt Sinai J Med. 2006;73:10061014.2. Hackett ML, Yapa C, Parag V, Anderson CS. Frequency of depression

after stroke: a systematic review of observational studies. Stroke. 2005;36:13301340.

3. House A, Dennis M, Mogridge L, Warlow C, Hawton K, Jones L. Mooddisorders in the year after first stroke. Br J Psychiatry. 1991;158:8392.

4. Wade DT, Legh-Smith J, Hewer RA. Depressed mood after stroke. Acommunity study of its frequency. Br J Psychiatry. 1987;151:200205.

5. Dieguez S, Staub F, Bruggimann L, Bogousslavsky J. Is poststrokedepression a vascular depression? J Neurol Sci. 2004;226:5358.

6. Hackett ML, Anderson CS. Predictors of depression after stroke: a sys-tematic review of observational studies. Stroke. 2005;36:22962301.

7. Poynter B, Shuman M, Diaz-Granados N, Kapral M, Grace SL, StewartDE. Sex differences in the prevalence of post-stroke depression: a sys-tematic review. Psychosomatics. 2009;50:563569.

8. Wu KY, Liu CY, Chau YL, Chang CM. Transient ischemic attack andincidence of depression in old age: evidence from a population-basedanalysis in Taiwan. Am J Geriatr Psychiatry. 2010;18:382387.

9. Luijendijk HJ, Stricker BH, Wieberdink RG, Koudstaal PJ, Hofman A,Breteler MM, et al. Transient ischemic attack and incident depression.Stroke. 2011;42:18571861.

10. Alegria M, Chatterji P, Wells K, Cao Z, Chen CN, Takeuchi D, et al.Disparity in depression treatment among racial and ethnic minority pop-ulations in the United States. Psychiatr Serv. 2008;59:12641272.

11. Gonzalez HM, Tarraf W, West BT, Croghan TW, Bowen ME, Cao Z, etal. Antidepressant use in a nationally representative sample ofcommunity-dwelling US Latinos with and without depressive and anxietydisorders. Depress Anxiety. 2009;26:674681.

12. Melfi CA, Croghan TW, Hanna MP, Robinson RL. Racial variation inantidepressant treatment in a Medicaid population. J Clin Psychiatry.2000;61:1621.

13. Bushnell C, Zimmer L, Schwamm L, Goldstein LB, Clapp-Channing N,Harding T, et al. The adherence evaluation after ischemic stroke longi-tudinal (AVAIL) registry: design, rationale, and baseline patient charac-teristics. Am Heart J. 2009;157:428435.e422.

14. American Psychiatric Association. Diagnostic and Statistical Manual ofMental Disorders, IV ed. Washington, DC: American Psychiatric Asso-ciation; 1994.

15. Kroenke K, Strine TW, Spitzer RL, Williams JB, Berry JT, Mokdad AH.The PHQ-8 as a measure of current depression in the general population.J Affect Disord. 2009;114:163173.

16. Kroenke K, Spitzer RL. The PHQ-9: a new depression diagnostic andseverity measure. Psychiatr Ann. 2002;32:509.

17. Damush TM, Jia H, Ried LD, Qin H, Cameon R, Plue L, et al. Case-finding algorithm for post-stroke depression in the Veterans HealthAdministration. Int J Geriatr Psychiatry. 2008;23:517522.

18. Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, Van GijnJ. Interobserver agreement for the assessment of handicap in strokepatients. Stroke. 1988;19:604607.

19. Uyttenboogaart M, Stewart RE, Vroomen PC, De Keyser J, Luijckx GJ.Optimizing cutoff scores for the Barthel Index and the modified RankinScale for defining outcome in acute stroke trials. Stroke. 2005;36:19841987.

20. Eriksson M, Asplund K, Glader EL, Norrving B, Stegmayr B, Terent A,et al. Self-reported depression and use of antidepressants after stroke: anational survey. Stroke. 2004;35:936941.

21. Current depression among adultsUnited States, 2006 and 2008. MMWRMorb Mortal Wkly Rep. 2010;59:12291235.

22. Folstein MF, Maiberger R, McHugh PR. Mood disorder as a specificcomplication of stroke. J Neurol Neurosurg Psychiatry. 1977;40:10181020.

23. Aben I, Verhey F, Strik J, Lousberg R, Lodder J, Honig A. A comparativestudy into the one year cumulative incidence of depression after strokeand myocardial infarction. J Neurol Neurosurg Psychiatry. 2003;74:581585.

24. Olfson M, Marcus SC. National patterns in antidepressant medicationtreatment. Arch Gen Psychiatry. 2009;66:848856.

25. Stagnitti MN. Trends in Antidepressant Use by the U.S. Civilian Nonin-stitutionalized Population, 1997 and 2002. Statistical Brief #76. May2005. Agency for Healthcare Research and Quality, Rockville, Maryland.http://meps.ahrq.gov/mepsweb/data_files/publications/st76/stat76.pdf.

26. Reeves MJ, Fonarow GC, Smith EE, Pan W, Olson D, Hernandez AF, etal. Representativeness of the Get With The GuidelinesStroke registry:comparison of patient and hospital characteristics among medicare ben-eficiaries hospitalized with ischemic stroke. Stroke. 2012;43:4449.

27. Bushnell CD, Zimmer LO, Pan W, Olson DM, Zhao X, Meteleva T, et al.Persistence with stroke prevention medications 3 months after hospital-ization. Arch Neurol. 2010;67:14561463.

28. Fonarow GC, Reeves MJ, Smith EE, Saver JL, Zhao X, Olson DW, et al.Characteristics, performance measures, and in-hospital outcomes of thefirst one million stroke and transient ischemic attack admissions in GetWith The GuidelinesStroke. Circ Cardiovasc Qual Outcomes. 2010;3:291302.

29. Kwon A, Bungay KM, Pei Y, Rogers WH, Wilson IB, Zhou Q, et al.Antidepressant use: concordance between self-report and claims records.Med Care. 2003;41:368374.

30. Ried LD, Jia H, Cameon R, Feng H, Wang X, Tueth M. Does prestrokedepression impact poststroke depression and treatment? Am J GeriatrPsychiatry. 2010;18:624633.



STROKE/2011/643130

El Husseini 1

SUPPLEMENTAL MATERIAL

Depression and Antidepressant use after Stroke and Transient Ischemic Attack

1 eTable: Antidepressants algorithm

2 eFigures

eFigure 1: Longitudinal follow-up of depression and antidepressant* use in stroke patients

(N=1450).

eFigure2: Longitudinal follow-up of depression and antidepressant* use in TIA patients

(N=397).

STROKE/2011/643130

El Husseini 2

eTable. Antidepressant medications algorithm

Antidepressants Patient age65 years

Patient age

STROKE/2011/643130

El Husseini 3

eFigure 1. Longitudinal follow-up of depression and antidepressant* use in stroke patients (N=1450).

3 months 12 months

Numbers and percentages within each arrow represent the number and percentages of patients who moved

from each category. *Antidepressant at or above the minimal age appropriate dose.

PHQ810 Antidepressant(+) (N=55)

PHQ810 Antidepressant (-) ( N=205)

PHQ8

STROKE/2011/643130

El Husseini 4

eFigure2. Longitudinal follow-up of depression and antidepressant* use in TIA patients (N=397).

3 months 12 months

Numbers and percentages within each arrow represent the number and percentages of patients who moved

from each category. *Antidepressant at or above the minimal age appropriate dose.

PHQ810 Antidepressant (+) (N=14)

PHQ810 Antidepressant (-) (N=43)

PHQ8

Olson, Louise O. Zimmer, John W. Williams, Jr, Cheryl Bushnell and Daniel T. LaskowitzNada El Husseini, Larry B. Goldstein, Eric D. Peterson, Xin Zhao, Wenqin Pan, DaiWai M.

Depression and Antidepressant Use After Stroke and Transient Ischemic Attack

Print ISSN: 0039-2499. Online ISSN: 1524-4628 Copyright 2012 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Stroke doi: 10.1161/STROKEAHA.111.643130

2012;43:1609-1616; originally published online March 29, 2012;Stroke.

http://stroke.ahajournals.org/content/43/6/1609World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://stroke.ahajournals.org/content/suppl/2012/03/29/STROKEAHA.111.643130.DC2.htmlData Supplement (unedited) at:

http://stroke.ahajournals.org//subscriptions/is online at: Stroke Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer process is available in theRequest Permissions in the middle column of the Web page under Services. Further information about thisOnce the online version of the published article for which permission is being requested is located, click

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office.Strokein Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:


Date post:	05-Mar-2016
Category:	Documents
Upload:	nicky-adi-saputra
View:	10 times
Download:	0 times

Stroke 2012 El Husseini 1609 16

Documents