Psychosomatics 44:216-221, June 2003
© 2003 The Academy of Psychosomatic Medicine
A Double-Blind, Placebo-Controlled Study of Sertraline in the Prevention of Depression in Stroke Patients
Alice Rasmussen, M.D., Ph.D.,
Marianne Lunde,
Dorte Loldrup Poulsen, M.D.,
Karen Sørensen, M.D.,
Susanne Qvitzau, M.D., and
Per Bech, M.D., D.M.Sc.
Received Oct. 11, 2002; revised Dec. 9, 2002; accepted Jan. 17, 2003. From the Department of Psychiatry, Copenhagen University Hospital, Frederiksberg, Denmark; the Department of Neurology, Copenhagen University Hospital, Hvidovre, Denmark; Pfizer, Ballerup, Denmark; and the Psychiatric Research Unit, Frederiksberg General Hospital, Hillerød, Denmark. Address reprint requests to Dr. Rasmussen, Liaison Psychiatric Department, Copenhagen University Hospital, Bispebjerg Hospital C15, Bispebjerg Bakke 23, 2300 Copenhagen NV, Denmark.
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ABSTRACT
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The authors tested the effect of sertraline in the prevention of poststroke depression. After experiencing an acute ischemic stroke, nondepressed patients (N=137) were randomly assigned to 12 months of double-blind treatment with either sertraline (N=70) or placebo (N=67). Kaplan-Meier analysis showed sertraline to have significantly superior prophylactic efficacy compared with placebo. Two definitions of clinical depression were used: total score >18 on the HAM-D17 and score  9 on the HAM-D6. Approximately 10% of the sertraline-treated group developed depression according to either definition, whereas 30% developed depression in the placebo group. On the HAM-D6 the superiority of sertraline to placebo was demonstrated already after 6 weeks of therapy. Treatment was well tolerated; patients treated with sertraline experienced significantly fewer adverse events.
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INTRODUCTION
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Depression is one of the most common sequelae of stroke, with prevalence estimates averaging approximately 30%–35%, at least half of which represent major depressive disorder.1 Other neuropsychiatric sequelae of stroke include pathological affect—most commonly pathological crying—as well as anxiety reactions and catastrophic reactions.1,2
The development of poststroke depression has been found to be associated with significantly increased cognitive decline,1,3 although a proportion of patients suffering a stroke may have had clinically significant cognitive impairment before the index event.4 A long-term follow-up study showed that the incremental cognitive impairment associated with depression typically disappears along with the depression.3 Poststroke depression is also associated with significant impairment in recovery of function and quality of life as well as significant increases in mortality risk.1–5
Very little information is available concerning the effect of acute treatment of poststroke depression on either symptomatic improvement or on associated outcomes such as cognitive function, behavioral recovery, or survival. Preliminary studies suggest that antidepressants have efficacy that is approximately equivalent to their efficacy in primary major depression.1
Given the high incidence of poststroke depression and the negative impact on recovery associated with the development of depression, prophylactic treatment would appear to be an important treatment option.
Sertraline has been shown to have significant efficacy in the treatment of depression in elderly patients6 as well as in patients with significant medical comorbidity, including myocardial infarction, Alzheimer's disease, diabetes, and Parkinson's disease. Furthermore, in elderly patients treated with sertraline, improvement in depression has been associated with significant improvement in both functional status and quality of life6 as well as significant improvement in cognitive function.7 In a large (N=267) open-label study,8 sertraline demonstrated efficacy in the acute treatment of poststroke depression. Similarly, sertraline has shown efficacy in the treatment of pathological crying and other forms of mood lability among poststroke patients who were not depressed.9
Several large studies have found sertraline to have significant prophylactic efficacy in preventing the development of depression among patients who have recently recovered from an episode of major depression10,11 as well as among patients who are well but in a high-recurrence risk group.12 For these reasons, we undertook a prophylactic study to evaluate the efficacy of sertraline in the prevention of poststroke depression.
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METHOD
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Patients
Consecutive patients diagnosed with stroke who were admitted to the neurology departments of the Frederiksberg and Hvidovre Copenhagen University Hospitals between January 1996 and May 1998 were examined for inclusion in this study. The WHO definition of stroke was used, and the diagnosis of stroke was made according to clinical criteria.
Patients were excluded from study entry if 1) the stroke had not occurred in the preceding 4 weeks; 2) the patient was currently depressed (total score >13 on the HAM-D17); 3) significant aphasia or dementia was present; 4) there was a history of schizophrenia, psychosis, or severe drug abuse; 5) a preexisting neurological illness was present; 6) treatment with antidepressants had been given in the preceding 4 weeks; or 7) current (within the preceding 6 months) cardiovascular illness was found.
Study Design
The study was approved by the local ethics committee, and study procedures were in compliance with the ethical standards outlined in the Helsinki Declaration (revised, 1983). At an initial screening evaluation (within 4 weeks of the index stroke), a complete psychiatric and medical history was obtained to determine whether the patient met study criteria. The screening evaluation included a clinical interview that used ICD-10 criteria to evaluate the presence of depression and other psychiatric diagnoses. The medical chart was also reviewed. For patients meeting criteria, written informed consent was obtained.
At the baseline visit (within 2 weeks of the screening evaluation), patients underwent a comprehensive assessment battery that included a neurological evaluation as well as assessments of depression status, cognitive function, and quality of life and overall functioning.
Study Treatment
Study treatment consisted of sertraline (50 mg) and matching placebo capsules. Patients were randomly assigned to 12 months of double-blind study treatment. Sertraline was started at a daily dose of 50 mg. The dose could be increased flexibly, according to clinical need, at any time after 2 weeks in 50-mg increments up to a maximum dose of 150 mg/day.
Outcome Assessments
Patients underwent a comprehensive battery of assessments at the baseline visit (visit 0) and at 11 postrandomization visits (occurring at approximately 4–5-week intervals). This study reports the results for the primary outcome of depression, which was evaluated with three measures. A modified version of the 17-item clinician-rated Hamilton depression scale,13 with item 14 (sexual behavior) not rated, was administered at visits 0, 3, 6, and 11. The 30-item, patient-rated Geriatric Depression Scale14 was given at all visits. The 23-item, clinician-rated Newcastle II scale15 was administered at visits 0, 2, and 4 to diagnose endogenous depression. The 7-item, clinician-rated Clinical Global Impression (CGI) severity and improvement scales16 were also administered at all visits.
Tolerability of study treatment was evaluated by using the Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale.17
Subsequent studies will report the results of neurological evaluations (with the Aphasia Severity Rating Scale, the European Stroke Scale, Neglect/Denial Scale), cognitive evaluations (with the Mini-Mental State Examination and Cambridge Cognitive Examination), quality of life and functional status (with the SF-36 and Barthel Functional Index, respectively), and recordings of pathological crying.
Statistical Analysis
The probability of remaining well during the 12 months of observation after the stroke was analyzed by using the method developed by Kaplan and Meier. The occurrence of a depressive episode was defined either by a score >18 on the HAM-D17 or by a score 9 on the 6-item subscale (HAM-D6) covering the core items of depression: depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and tiredness.18 To test the null hypothesis that the Kaplan-Meier survival curves for patients receiving sertraline or placebo would be the same, the Mantel-Haenszel test (or the log-rank test) was used. This test gives equal weight to early and late recurrences of depression. It is a cumulative chi-square test, i.e., a two-tailed test. The level of statistical significance was p 0.05.
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RESULTS
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A total of 155 patients were initially screened, of whom 137 (88.4%) met study criteria at baseline and were randomly assigned to 12 months of double-blind treatment. Patients were fairly evenly divided in terms of gender and those over versus under 65 years of age (Table 1), with patients receiving sertraline being somewhat older on average. Among all patients, only five strokes were hemorrhagic. Ninety-seven patients suffered ischemic strokes with a temporoparietal location. For the total patient group, only 36 patients (26.3%) had essentially normal levels of functioning (Barthel Functional Index 95). Consistent with entry criteria that excluded patients with depression, the mean HAM-D17 score at baseline was approximately 7. Ten patients were excluded from study entry due to the presence of depression. Of the 70 patients randomly assigned to sertraline, 35 (50.0%) completed 12 months of study treatment, while 32 (47.8%) of the 67 patients randomly assigned to placebo completed the study.
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TABLE 1. Demographic and Clinical Characteristics at Baseline of Stroke Patients Randomly Assigned to 12 Months of Double-Blind Treatment With Sertraline or Placebo
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Analysis of Depression Outcome
Occurrence of depression was operationally defined according to two Hamilton depression scale criteria: a total score of >18 on the HAM-D17 and a score 9 on the HAM-D6. Kaplan-Meier analyses (Figure 1) showed the efficacy of sertraline for depression prophylaxis to be statistically significant. After 52 weeks of treatment with sertraline or placebo, the depression occurrence rate according to total score on the HAM-D17 was 8.2% (90% CI=2.4%–13.9%) versus 22.8% (90% CI=13.7%–32.0%), respectively. The depression occurrence rate according to the HAM-D6 was 11.5% (90% CI=4.8%–18.2%) versus 28.1% (90% CI=18.3%–37.9%). However, using the HAM-D6, sertraline was demonstrated to be already superior to placebo after 6 weeks of treatment; this superiority was not demonstrated until 21 weeks of treatment using the HAM-D17.
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FIGURE 1. Time to Onset of Depression Among Stroke Patients Randomly Assigned to 12 Months of Double-Blind Treatment With Sertraline or Placebo
aConsists of six Hamilton depression scale items: depressed mood, guilt feelings, work and interests, psychomotor retardation, psychic anxiety, and tiredness.
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Assessment of emergent depressive symptoms with the age-specific Geriatric Depression Scale yielded results that were consistent with Kaplan-Meier (Figure 2), with a logistic regression analysis finding a significant treatment-by-time interaction effect after 20 weeks of therapy.
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FIGURE 2. Emergence of Depressiona Among Stroke Patients Randomly Assigned to 12 Months of Double-Blind Treatment With Sertraline or Placebo
aScore >16 on the Geriatric Depression Scale, indicating depression of at least moderate severity. Logistic regression analysis showed a significant time-by-treatment interaction ( 2=20.7, df=10, p=0.02).
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Results of global measures showed numerical, but not statistically significant, efficacy advantages for sertraline over placebo at study endpoint. Last-observation-carried-forward analyses showed that the percent of patients rated as having a CGI severity score 3 (in the mild-to-severe range) was 18.0% among those given sertraline and 29.8% for those receiving placebo (p=0.12). Similarly, 26.0% of patients given sertraline, compared with 42.0% receiving placebo, were rated as having mild or greater clinical worsening from baseline (p=0.07).
Safety and Tolerability of Treatment
The mean daily sertraline dose was 62.9 mg, with 78.6% of patients (N=55) treated with the 50-mg dose.
There were no significant differences in the incidence of treatment-emergent adverse events, evaluated with the UKU scale, between the patients given sertraline and those given placebo (tiredness: 44% and 50%, respectively; restlessness/tension: 37% and 49%; depressed mood: 36% and 47%; dizziness: 23% and 24%; poor concentration: 20% and 32%; insomnia: 16% and 25%; constipation: 11% and 16%; diarrhea: 16% and 11%; nausea: 16% and 11%; increased sleep: 11% and 10%; headache: 9% and 10%; and poor memory: 4% and 13%). There was no significant between-group difference in vital signs at study endpoint.
Overall, sertraline was numerically, and occasionally statistically significantly, better tolerated than placebo, with fewer patients given sertraline experiencing severe cardiovascular and noncardiovascular adverse events (Figure 3).
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FIGURE 3. Treatment-Emergent Adverse Events Among Stroke Patients Randomly Assigned to 12 Months of Double-Blind Treatment With Sertraline or Placebo
aCardiovascular adverse events include claudication, angina, palpitations, increased blood pressure, and tachycardia. Significant difference between groups (p=0.02).
bSignificant difference between groups (p=0.02).
cSignificant difference between groups (p=0.01).
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DISCUSSION
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The results of the current study provide evidence for the efficacy of sertraline in preventing the development of depression in the first year following a stroke. The results of Kaplan-Meier analyses showed that sertraline had sparing effects of 15% and 18% when depression was defined by HAM-D17 and HAM-D6, respectively. Furthermore, sertraline was demonstrated to be already superior to placebo after 6 weeks of treatment using the HAM-D6 but not until 21 weeks using the HAM-D17. These results are very similar to those of a recently presented sertraline depression prophylaxis study in younger adults who were euthymic but had a history of recurrent major depression.19 In that study, sertraline showed a 17% sparing effect. The prophylactic advantage of sertraline was also demonstrated by the significantly lower scores on the Geriatric Depression Scale over the course of study treatment. Because depression is frequently a late-emerging complication of stroke, the benefits of prophylactic treatment (and the need for longitudinal assessment of mood) extend past 6 months.
The results of the current study are particularly impressive given the mixed results obtained for both tricyclic and SSRI antidepressants in the acute treatment of poststroke depression.1,19–22 Antidepressant efficacy, partly due the small sample sizes, has not been found to be consistently superior to placebo. Fluoxetine, one of the best-studied antidepressants in poststroke depression, illustrates the point. Three placebo-controlled studies have been reported, with one19 showing significant efficacy for fluoxetine versus placebo, whereas the other two showed a change from baseline with fluoxetine that, while an improvement, was nonetheless not significantly different from placebo.20,21
Safety and Tolerability
Given the age and medical status of the patient group under study, the safety and tolerability results for sertraline are, in some ways, almost as important as the efficacy results. In this regard, the findings are unequivocal: sertraline was a safe and well-tolerated treatment. The incidence of individual adverse events was very similar for sertraline compared with placebo. Diarrhea and nausea were the only two adverse events whose incidence was 5% higher among sertraline-treated patients than in placebo-treated patients. In contrast, tiredness, restlessness/tension, depressed mood, poor concentration, insomnia, and poor memory were all reported to have an incidence more than 5% higher in the placebo group compared with sertraline (it should be noted that adverse event rates are typically higher when a systematic inventory, such as the UKU, is used instead of relying on spontaneous patient reporting).
The safety advantage of sertraline versus placebo was even more notable when comparing both severe and serious adverse events. These favorable safety results are very similar to safety results from a recently reported study of sertraline in the treatment of depression following myocardial infarction.23 While SSRI antidepressants are recognized as well-tolerated medications, published studies in younger adults never show the SSRIs to have numerically or statistically superior tolerability to placebo. The results of the current study suggest that the physical complaint burden itself may be an efficacy domain (not simply an index of drug tolerability). If so, and this is highly speculative, then it is an outcome domain in which sertraline may be demonstrating significant prophylactic superiority over placebo.
Two previous prophylactic studies have been reported. The first24 found no significant efficacy for mianserin. In part, this was due to the lack of sufficient emergent depression: 6% of patients met criteria for depression at study entry, and 11% at the end of 1 year in both treatment groups. The second25 was a pilot study (N=15–17 per treatment group) that found some evidence of prophylactic efficacy for nortriptyline and fluoxetine.
In the current study, 10 patients were excluded from enrollment because depression had already developed by the time of the screening evaluation (within 4 weeks of the index event). This may partially account for the lower-than-expected incidence of depression in the current sample. It also suggests that use of sertraline as a poststroke prophylactic treatment should be instituted as early as possible after the occurrence of a stroke. Further research, however, is needed to confirm the prophylactic efficacy of sertraline, determine which at-risk patient groups are most likely to benefit from a preventive treatment approach, and identify the optimal time for initiating treatment following a stroke. The high prevalence of poststroke depression and its disabling consequences, together with the efficacy and tolerability of sertraline as a treatment, makes sertraline prophylaxis in this patient group a public health option that deserves to be explored.
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ACKNOWLEDGMENTS
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Supported by funding from Pfizer A/S, Gert Jørgensen legat, and the Brain Cause (Hjernesagen). The authors thank the Departments of Medicine, Psychiatry, and Neurology at the Frederiksberg University Hospital and the Department of Neurology at the Copenhagen Community Hospital in Hvidovre.
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ABSTRACT
INTRODUCTION
