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ORIGINAL ARTICLES |
From the Departments of Psychiatry (J.J.M.H.S., A.H., A.H.P.L., P.M.J.C.K., H.M.V.P.) and Cardiology (E.C.C., P.M.J.C.K., M.F.P.M.H.J.J.W.), University Hospital Maastricht; Department of Psychiatry (J.J.M.H.S., A.H., R.L.), University of Maastricht; and Eli Lilly Netherlands (H.G.T.-Q.), Nieuwegein, The Netherlands.
Address reprint requests to: Jacqueline J. M. H. Strik, MD, University Hospital Maastricht/University of Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. Email: Jacqueline.Strik{at}spsy.azm.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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METHODS: Fifty-four patients with major depression after MI were randomly assigned to receive a flexible-dose regimen of fluoxetine or placebo for the first 9 weeks of a double-blind, placebo-controlled trial. Patients without serious adverse effects who wished to continue participating in the study were given fluoxetine or placebo for an additional 16 weeks. To evaluate the efficacy of fluoxetine, the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Hostility Scale of the 90-item Symptom Check List (SCL-90) were used as primary measures of outcome. To evaluate the safety of fluoxetine, cardiac function was measured before and after treatment with echocardiography and electrocardiography.
RESULTS: The a priori difference in antidepressive efficacy (4-point difference in HAMD-17 scores between the fluoxetine and placebo groups) was not met. However, the response rate among patients receiving fluoxetine was significantly greater than that among patients receiving placebo at week 25 (48 vs. 26%, p = .05). Among patients with mild depression (HAMD-17 score 
21), HAMD-17 scores were significantly different (p < .05) between the fluoxetine and placebo groups at weeks 9 (by 5.4 points) and 25 (by 5.8 points). Also, hostility scores at week 25 were significantly reduced among patients receiving fluoxetine (p = .02). Analysis of electrocardiographic and echocardiographic parameters revealed no decrease in cardiac function as a result of treatment with fluoxetine.
CONCLUSIONS: Although the overall difference between the fluoxetine and placebo groups was not significant, there was a trend favoring fluoxetine in this relatively small sample. The response rate in the group receiving fluoxetine was comparable with that observed in other studies of patients with cardiovascular disease. In addition, fluoxetine seemed to be particularly effective in patients with mild depression and was associated with a statistically significant reduction in hostility. The results of this study suggest that fluoxetine can be safely used to treat patients with post-MI depression beginning 3 months after the event.
Key Words: fluoxetine • major depression • myocardial infarction.
Abbreviations: ASAT = aspartate aminotransferase; ATVI = aortic time velocity integral; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, third edition revised; E/A ratio = early or passive/active or late mitral inflow ratio; HAMD-17 = 17-item Hamilton Depression Scale; LVEF = left ventricular ejection fraction; MI = myocardial infarction; QTc = corrected QT interval; SCL-90 = 90-item Symptom Check List; SSRI = selective serotonergic reuptake inhibitor.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Data on the efficacy of SSRIs in patients with post-MI depression are limited. In elderly depressed patients with cardiovascular disease, both paroxetine and nortriptyline have been shown to reduce depression (7). Fluoxetine was found to be less effective than nortriptyline in older, severely depressed patients with heart disease (8). Data on the treatment of hostility are even more scarce. Fluoxetine has been found to reduce hostility in patients with personality disorder (9), healthy volunteers (10), and depressed patients (11). No data on its effect on increased aggression in depressed post-MI patients are available.
Tricyclics are reported to increase heart rate, induce orthostatic hypotension, slow intraventricular cardiac conduction, and suppress ventricular premature depolarizations in depressed patients with or without heart disease (12–15). Although SSRIs are thought to be less cardiotoxic than tricyclics, available data on the safety of SSRIs in patients with ischemic heart disease or MI are limited, and these agents have not been evaluated in a double-blind, placebo-controlled trial ( Table 1). SSRIs have been found to have no cardiotoxic effects in healthy volunteers or elderly patients (16–18). Studies of the adverse cardiovascular effects of SSRIs in patients with somatic disease have been mainly restricted to evaluation of patients with ischemic heart disease. In an open-treatment trial of elderly patients with heart disease, fluoxetine was found to decrease heart rate and increase supine systolic pressure and ejection fraction (19). In a comparative study with nortriptyline in depressed patients with ischemic heart disease, no adverse cardiovascular effects of paroxetine were reported (7). Fluoxetine and fluvoxamine were not found to have a negative effect on cardiac functioning (measured by echocardiography) of middle-aged and elderly depressed patients (20).
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This is the first study to investigate the antidepressant efficacy, antihostility efficacy, and cardiac safety of fluoxetine in patients with post-MI depression using a double-blind, placebo-controlled design. We hypothesized that fluoxetine would be superior to placebo in reducing depression and hostility and would have no significant adverse cardiovascular effects.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Patients scoring above the cutoff on the SCL-90 Depression Scale (
23 for men and 28 for women) (24) at screening were invited for an interview by a psychiatrist or trained physician to determine whether they met DSM-III-R criteria for major depression. During this interview, the severity of depression was measured using the HAMD-17 (25). Patients fulfilling DSM-III-R criteria for a major depressive episode, diagnosed by use of a DSM-III-R checklist based on sections 6, 7, 8, and 21 of the Schedules for Clinical Assessment in Neuropsychiatry (26), and having a HAMD-17 score >17, could be enrolled in the trial from month 3 to month 12 after MI. During the first 3 months after MI, it can be difficult to distinguish depressive symptoms as either 1) components of a major depressive episode, 2) sequelae of a sudden catastrophic cardiac event, or 3) signs of a temporary decrease in cardiac functioning. In addition, some patients participated in a routine cardiological rehabilitation program, consisting of physical therapy and psychological education, that lasted up to 3 months after the MI. Our treatment design did not permit any concurrent psychosocial or therapeutic intervention.
Exclusion criteria were psychotic symptomatology, a second psychiatric diagnosis, history of mania, current pregnancy or lactation, life-threatening noncardiac physical illness, concurrent use of psychotropic drugs (except oxazepam up to 50 mg/d), hypersensitivity to fluoxetine, and liver or severe kidney dysfunction (creatinine clearance <10 ml/min). We included all post-MI patients except those with a right ventricular filling pressure >30 mm Hg and a low systolic volume or an ATVI <20 cm. High filling pressure and low output may result in listlessness and a lack of energy and drive, a condition mimicking depression (27). Impairment of LVEF was not used as an exclusion criterion. The study was approved by the ethics committees at the two sites. The study was completely described to the subjects, who then provided written informed consent.
Subjects were recruited from May 1994 to December 1997. The number of eligible patients was 556, of whom 357 (64%) agreed to participate and 199 (36%) declined to participate. Of these 357 subjects, 4 died between 1 and 3 months after MI, and 68 met DSM-III-R criteria for major depression (Figure 1). Of the 68 depressed patients, 12 dropped out at a later stage, and 2 were excluded because of an ATVI <20 cm and a right ventricular filling pressure >30 mm Hg. Nonparticipants did not differ from participants in age, gender, or maximum ASAT. Hence, 54 patients were included in the study, of whom 31 were diagnosed with a major depressive episode at 3 months after MI; 17, at 6 months; and 6, at 12 months. These 54 patients were randomly assigned to receive fluoxetine (N = 27) or placebo (N = 27).
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Data Collection
Depression, hostility, adverse effects and events, and concurrent use of medications were assessed at baseline and weeks 1, 3, 6, and 9; thereafter these parameters were measured monthly. Serious adverse events were defined as death, rehospitalization due to cardiac events, and noncardiac life-threatening disease. Blood pressure, height, and weight were measured at baseline and at weeks 6, 9, and 25 (except weight). Blood and urine samples were collected at the same time points for hematological testing, clinical chemistry screening, and measurement of plasma concentrations of fluoxetine and norfluoxetine. Electrocardiography and echocardiography were performed at baseline and weeks 6 and 25.
Response and remission were assessed for patients who had at least one assessment after initiation of treatment. Response was defined as a 50% or greater reduction in the HAMD-17 score. Remission was defined as a HAMD-17 end-point score <7. Changes in scores on the SCL-90 Hostility Scale were used to assess the efficacy of fluoxetine as a treatment for hostility. According to Dutch SCL-90 standards, a score of 9 to 11 indicates a high level of hostility; 8 to 9, moderate; and <8, low (23). Because there is no clear consensus on hostility response or remission, no cutoff was operationalized.
The present study focused not only on changes in cardiac conduction and blood pressure but also on changes in cardiac output. Safety measures therefore were electrocardiographic variables, systolic and diastolic blood pressures, and echocardiographic variables. Electrocardiographic variables consisted of heart rate, PR interval, QRS interval, and QTc interval. Impaired conduction may lead to an increase in the QRS interval. Enlargement of the QTc interval has been related to arrhythmias. LVEF and ATVI were monitored by echocardiography. ATVI was used as an indirect measure of stroke volume (28, 29), which is related to cardiac output. ATVI multiplied by the aortic valve area (Doppler method) was used to calculate stroke volume. Parameters to assess diastolic function or filling pressures were defined as early or passive/active or late mitral inflow (E/A ratio) (30).
Statistical Analyses
The required sample size was estimated using the method of Knapp and Miller (31). If previous outcome data are unavailable for depressed post-MI patients, these guidelines suggest approximating the standard deviation by dividing the range of values for the response variable (HAMD-17 score) by 6 (31). A mean of 26 HAMD points was taken as the range (32, 33). An effect size of a 4-point difference in HAMD-17 scores between the fluoxetine and placebo groups and a statistically significant difference in response rate between the fluoxetine and placebo groups was thus expected a priori (34). If the level of significance 
is set at .05, the power ß is set at 0.95, and the HAMD-17 hypothesis is tested using a one-tailed test, the required sample size is 54 (27 per group).
Statistical analyses were performed using STATA 5.0 (35) and SPSS for Windows 6.0 software (36). To analyze the efficacy data, t tests were used, given the absence of outliers and presence of normality of data tested with skewness/kurtosis test (37). Efficacy outcome was analyzed on an intention-to-treat basis: All 54 patients were analyzed as they were randomized. For patients not completing the 9 or 25 weeks of treatment, the "last observation carried forward" technique (38) was used. Increases in HAMD-17 or SCL-90 hostility scores during fluoxetine treatment were unlikely because fluoxetine has established antidepressive (32, 33) and antihostility properties (9). Therefore, tests of the primary efficacy variables (scores on the HAMD-17 and SCL-90 Hostility Scale) were one tailed. All other tests were two tailed.
To determine the safety of fluoxetine therapy, regression analyses were applied using cardiologic safety variables as dependent variables and treatment condition and fluoxetine plasma concentration as independent variables. Regression analyses were performed as described by Kleinbaum et al. (39). When there were large Cook distances (>3 SDs), a second regression model was assessed without influential cases. Patients were included in these analyses only if assessment data from baseline and week 6 or baseline and week 25 were available.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Concurrent Medications
Medications used concurrently included aspirin (N = 42, 77.8%), lipophilic ß-blockers (N = 33, 61.1%), benzodiazepines (N = 28, 51.9%), isosorbide nitrate (N = 23, 42.6%), cholesterol-lowering medication (N = 22, 40.7%), angiotensin-converting enzyme inhibitors (N = 16, 29.6%), calcium channel blockers (N = 15, 27.8%), diuretics (N = 13, 24.1%), anticoagulants (N = 6, 11.1%), and hydrophilic ß-blockers (N = 5, 9.3%). The median number of cardiovascular drugs taken was 4.9 (range = 1–9) excluding the trial medication. There were no differences in specific drugs between groups (all p values > .10). No patients were taking antidepressant or antipsychotic drugs before the study.
Adverse Effects and Events
Patients in both groups reported adverse effects, mainly chest pain, gastrointestinal complaints, and agitation ( Table 3), but there were no significant differences between groups in the number of events reported. The only serious adverse event that occurred was rehospitalization for a cardiac event (N = 7); no patients were excluded because of cancer, drug overdose, or death during this study. The mortality rate of MI patients in general in our hospital is highest during acute hospitalization and decreases to 1 to 2% between 1 and 12 months after MI (40). Patients were rehospitalized for one of the following reasons: unstable angina pectoris, anemia, ventricular fibrillation, decompensatio cordis, and catheterization. The number of rehospitalizations was higher in the placebo group (N = 6) than in the fluoxetine group (N = 1), but this difference was not statistically significant (p = .13).
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2 = 2.86, df = 1, p = .05). Remission occurred in 7 responders (26%) in the fluoxetine group and in 4 responders (14.8%) in the placebo group (p = .6). The SCL-90 hostility score decreased by 2.44 points (SD = 4.64) in patients receiving fluoxetine and by 0.07 points (SD = 2.57) in patients receiving placebo (t = 2.32, df = 52, p = .02) (Figure 3, right). Efficacy outcome was not related to plasma levels of fluoxetine. Benzodiazepines had no influence on efficacy outcome during the entire treatment phase.
Post hoc analysis revealed that fluoxetine was more effective in patients with mild depression (HAMD-17 score 21, N = 32) than in those with severe depression (HAMD-17 score >21, N = 22); the difference in efficacy (HAMD-17 score) was 5.4 points at week 9 (p = .01) and 5.8 points at week 25 (p = .04).
Adverse Cardiovascular Effects
The echocardiographic variables LVEF, ATVI, and E/A ratio and the electrocardiographic variables heart rate, PR interval, QRS interval, and QTc interval did not change during the acute treatment phase ( Table 3). Between baseline and week 25, ATVI increased by 3.8 cm in the placebo group compared with the fluoxetine group (p = .02). QRS interval decreased by 6.3 ms in the fluoxetine group compared with the placebo group (p = .03).
Cardiac safety variables were not related to plasma levels of fluoxetine.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The difference of 2.5 HAMD-17 points between the fluoxetine and placebo groups was lower than our a priori rigorous effect size of 4.0 points. However, if we look at response rate, the commonly used efficacy outcome, the antidepressant efficacy was comparable to that reported by Roose et al. (7) and Shapiro et al. (21). In the intention-to-treat analysis, 33% (9 of 27) of patients receiving fluoxetine responded at week 9, and 48% (13 of 27) of these patients responded at week 25. Of patients included in the end-point analyses, 36% responded at week 9 and 59% responded at week 25. In the placebo group, the response rate was 30% at week 9 and 26% and week 25 in the intention-to-treat analysis and 36 and 39%, respectively, in the end-point analyses. The difference in response rate between the fluoxetine and placebo groups was statistically significant at week 25 (p = .05). The response rate in the fluoxetine group in the end-point analysis (59%) is comparable with that reported by Shapiro et al. (21), who observed a response rate of 62.5% among depressed patients treated with sertraline after an acute MI. Shapiro et al. found this response rate after 16 weeks of treatment, as compared with 25 weeks in our study.
The smaller-than-expected difference in HAMD-17 scores between the fluoxetine and placebo groups in our study may be due to the relatively high response to placebo in patients with mild depression. The self-limiting course and higher placebo response may also be related to age (41) and somatic disease (41, 42). Especially in this population, just seeing a physician in a hospital at regular intervals may be regarded as an intervention in itself, increasing the placebo response. Finally, there are studies suggesting that SSRIs are more efficacious in patients with mild depression than in those with severe depression (43–45).
Hostility levels among patients receiving fluoxetine changed from high to low by the end of the treatment period. Because hostility reportedly increases mortality after MI, a decreased level of hostility might influence a patient’s post-MI prognosis (3, 4).
There were no significant changes in echocardiographic or electrocardiographic variables or blood pressure during the acute treatment phase. During the entire treatment period of 25 weeks, ATVI decreased in the fluoxetine group as compared with the placebo group. In this same period, QRS interval decreased by 6.3 ms in the fluoxetine group as compared with the placebo group. Adverse effects (mainly chest pain, gastrointestinal symptoms, and agitation) were reported equally in both groups. Rehospitalization for cardiac events occurred mainly in the placebo group.
QRS interval decreased during the continuation phase among patients receiving fluoxetine, but a change in the QRS complex of <10 ms in patients with a QRS complex <110 ms is not considered clinically relevant, which was the case in patients of this study. Furthermore, the difference in cardiac output or ATVI between the fluoxetine and placebo groups disappeared after correction of ATVI for both heart rate and maximum ASAT. This could be explained by the fact that ATVI is influenced by maximum ASAT or severity of MI, with a larger MI leading to a lower ATVI (29). Thus, the decrease in ATVI in the fluoxetine group seemed not to be caused by fluoxetine but by cardiac variables.
The main limitation of our study was the sample size, which was probably not large enough to reach a 4-point or greater difference in HAMD-17 scores between the fluoxetine and placebo groups. Hence, generalizations based on these results must be made carefully.
In summary, the results suggest that fluoxetine can be safely used in patients with major depression starting 3 months after MI. Although the overall difference between treatment with fluoxetine and placebo was not statistically significant, there was a clear trend favoring fluoxetine in this relatively small sample. Fluoxetine was especially effective in patients with mild depression (HAMD-17 score 21), and there was a statistically significant reduction in hostility among these patients. Moreover, the rate of rehospitalization was lower among patients who received fluoxetine for post-MI depression. By affecting depression and hostility, fluoxetine may reduce the risk of increased morbidity and mortality due to affective dysregulation in post-MI patients. Follow-up studies and placebo-controlled intervention trials must be performed to verify these conclusions.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Received for publication March 17, 2000.
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p = .05.