Escitalopram Treatment for Depressive Disorder Following Acute Coronary Syndrome: A 24-Week Double-Blind, Placebo-Controlled Trial

Escitalopram Treatment for Depressive Disorder Following Acute Coronary Syndrome: A 24-Week Double-Blind, Placebo-Controlled Trial

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ABSTRACT

Objective: Depression is common after acute coronary syndrome (ACS) and has adverse effects on prognosis. There are few evidence-based interventions for treating depression in ACS. This study investigated the efficacy and safety of escitalopram in treating depressive disorders identified 2-14 weeks after a confirmed ACS episode.

Method: A total of 217 patients with DSM-IV depressive disorders (121 major and 96 minor) and ACS were randomly assigned to receive escitalopram in flexible doses of 5-20 mg/d (n = 108) or placebo (n = 109) for 24 weeks. The study was conducted from 2007 to 2013. The primary outcome measure was the Hamilton Depression Rating Scale (HDRS). Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Clinical Global Impressions-Severity of Illness scale (CGI-S), Social and Occupational Functioning Assessment Scale (SOFAS), and World Health Organization Disability Assessment Schedule-12. Cardiovascular safety outcomes included echocardiography, electrocardiography, laboratory test, body weight, and blood pressure results.

Results: Escitalopram was superior to placebo in reducing HDRS scores (mean difference = 2.3, P = .016, effect size = 0.38). Escitalopram was also superior to placebo in decreasing depressive symptoms evaluated by the MADRS, BDI, and CGI-S and in improving SOFAS functioning level. Escitalopram was not associated with any harmful changes in cardiovascular safety measures. Dizziness was significantly more frequently reported in the escitalopram group (P = .018), but there were no significant differences in any other adverse events.

Conclusions: These results indicate that escitalopram has clinically meaningful antidepressant effects with no evidence of reduced cardiovascular safety in depressive disorder following ACS.

Trial Registration: ClinicalTrials.gov identifier: NCT00419471

J Clin Psychiatry 2015;76(1):62-68

Submitted: June 3, 2014; accepted July 21, 2014.

Online ahead of print: October 14, 2014 (doi:10.4088/JCP.14m09281).

Corresponding author: Jin-Sang Yoon, MD, PhD, Department of Psychiatry, Chonnam National University Medical School, 160 Baekseoro, Dong-gu, Kwangju 501-757, Republic of Korea (jsyoon@chonnam.ac.kr).

Depression and acute coronary syndrome (ACS) including myocardial infarction (MI) or unstable angina are leading causes of disability.1 Depression is common in ACS, with the prevalence of major depression ranging from 15% to 27%.2 Both major and minor depressive disorders are associated with new cardiovascular events and cardiovascular mortality.3

Although there is a clear need for treating depressive disorders in patients with ACS, and a number of randomized controlled trials have evaluated pharmacologic interventions, mostly selective serotonin reuptake inhibitors (SSRIs), published results have been mixed. Early trials of paroxetine4 and fluoxetine5 indicated efficacy but were limited by small sample sizes and short treatment periods. In the largest trial to date, the Sertraline Antidepressant Heart Attack Randomized Trial (SADHART), 369 patients with depression following ACS were given sertraline or placebo for 24 weeks.6 Sertraline was found to be safe, but overall efficacy was less clear and was restricted to a subgroup with recurrent or more severe depression. Mirtazapine was evaluated in a 24-week placebo-controlled trial in 91 patients with post-MI depression, as a part of the larger Myocardial Infarction and Depression-Intervention Trial (MIND-IT)7; however, completion was low (n = 40), and there was no effect on the primary outcome, although the intervention was found to be safe and effective on secondary outcomes. Citalopram was found to be safe and superior to placebo in reducing depressive symptoms at 12 weeks in the Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial8; however, the sample comprised patients with moderate-to-severe depression at a late stage after hospitalization for cardiac reasons.

Overall, randomized controlled trials have reported that SSRIs are safe in ACS, but antidepressant effects remain unclear because of small sample sizes, low completion rates, inconsistent results, and heterogeneous samples. Of the SSRIs, escitalopram was found to be safe and effective for preventing depression in nondepressed post-ACS patients.9 However, its antidepressant efficacy was not formally assessed. Accordingly, we conducted a randomized, placebo-controlled trial of efficacy and safety of escitalopram in patients with depressive disorders after ACS.

METHOD

Study Overview and Participants

The study outline is presented in Figure 1. The Escitalopram for DEPression in Acute Coronary Syndrome (EsDEPACS) trial reported here is from the larger Korean DEPression in Acute Coronary Syndrome (K-DEPACS) study, which investigates depressive disorders in patients with ACS using randomized and naturalistic prospective designs. The design and rationale of the EsDEPACS and K-DEPACS were published previously.10 Participants were consecutively recruited from all patients 2-14 weeks after an ACS episode that had resulted in hospitalization and had been confirmed by various examinations (N = 4,809) in the Department of Cardiology of Chonnam National University Hospital, Gwangju, Korea. Detailed inclusion and exclusion criteria are described in eAppendix 1 (available at PSYCHIATRIST.COM). Those who met eligibility criteria and agreed to participate (N = 1,152) were screened for depressive symptoms with the Beck Depression Inventory (BDI)11 as inpatients 2 weeks post-ACS and thereafter as outpatients every 4 weeks up to 12 weeks. Those with depressive symptoms (BDI score > 10) at any of these occasions received a clinical evaluation by the study psychiatrists (who were naturally aware that a BDI score > 10 had been obtained, but blind to the score itself) using the Mini-International Neuropsychiatric Interview (MINI),12 a structured diagnostic psychiatric interview for DSM-IV. Of 446 patients with a diagnosis of major or minor depressive disorder, those 300 who agreed to participate were randomized. The first patient was enrolled in May 2007, and the last patient completed the follow-up evaluation in March 2013. Written informed consent was obtained, and the study was approved by the Chonnam National University Hospital Institutional Review Board. The study was registered with ClinicalTrials.gov (identifier: NCT00419471).

Figure 1

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clinical points

  • Depression is common after acute coronary syndrome (ACS), with adverse effects on prognosis, but there is little evidence for interventions to treat depression in ACS.
  • This study indicates that escitalopram has clinically meaningful antidepressant effects along with tolerability and safety in patients with depression and ACS.
  • Current evidence supports escitalopram as an additional effective and safe treatment option for clinicians treating patients with depression and ACS.

Baseline Evaluations

Demographic data were obtained, along with self-completed BDI and psychiatrist-administered MINI diagnoses as described. Further assessment scales were administered by 2 research nurses blinded to the BDI and MINI results. Depressive symptoms were estimated by the 17-item Hamilton Depression Rating Scale (HDRS)13 and the Montgomery-Asberg Depression Rating Scale (MADRS).14 Global symptomatology was assessed by the Clinical Global Impressions-Severity of Illness scale (CGI-S)15; functioning level, by the Social and Occupational Functioning Assessment Scale (SOFAS)16; and disability, by the World Health Organization Disability Assessment Schedule-12 (WHODAS-12).17 Higher scores on BDI, HDRS, MADRS, CGI-S, and WHODAS-12 and lower scores on SOFAS indicate more severe symptomatology.

The following cardiovascular risk factors were ascertained: diagnosed hypertension and diabetes mellitus, resting blood pressure, fasting serum total cholesterol level, measured body mass index, and reported current smoking status. Diagnoses of MI or unstable angina were made. Severity of ACS was estimated by the Killip classification.18 Echocardiography results were left ventricular ejection fraction (LVEF) and wall motion scores. Electrocardiography (ECG) variables were heart rate (beats/min), PR interval (ms), QRS duration (ms), and QTc duration (ms). Serum cardiac biomarkers troponin I and creatine kinase-MB (CK-MB) were measured. Previous history of ACS was obtained. Cardiovascular medications used were recorded.

Intervention

The efficacy and safety of flexible doses of escitalopram (5, 10, 15, or 20 mg) were investigated using a randomized, double-blind, placebo-controlled design. Patients were randomly assigned to treatment in a 1:1 ratio following computer-generated randomization codes provided by a statistician independent of recruiting clinicians. Drugs were stored at a dispensary attached to the study hospital and were provided to patients by pharmacists who were blind to patients’ status. Outcome measurement (by nurses) and adverse event monitoring (by psychiatrists) were carried out blind to treatment allocation. Examinations were scheduled at baseline and at weeks 4, 8, 12, 16, 20, and 24 thereafter, with a 7-day allowable window. The initial escitalopram dose at baseline was 10 mg/d generally. After the second evaluation (week 4), the medication doses could be changed and determined by the investigators’ clinical decision considering the response and tolerability. Medications were taken once daily per orally after the supper meal. Adherence was checked by pill counts at every visit and was defined as acceptable if at least 75%.

Outcomes

The primary efficacy outcome measure was the HDRS score change from baseline to endpoint. HDRS was chosen in order to maximize the comparability of our results with those from the SADHART6 and CREATE8 trials, in which HDRS was also used as the primary outcome. Secondary depressive outcome measures were MADRS, BDI, and CGI-S score changes from baseline to endpoint. Other efficacy outcome measures were SOFAS and WHODAS-12 score changes from baseline to endpoint. These measures were used for outcomes only and were not used as enrollment criteria.

For general safety outcomes, adverse events were recorded at all visits. Serious adverse events, both clinical and laboratory, were assessed. Reasons for discontinuation were recorded.

For cardiovascular safety outcomes, the following variables were measured: echocardiography for LVEF and wall motion; ECG for heart rate, PR interval, QRS duration, and QTc duration; laboratory tests for troponin I, CK-MB, and total cholesterol; and body weight. These measures were conducted at the last follow-up (week 24) where possible. Resting blood pressure was measured at every follow-up visit.

Statistical Analysis

Subjects evaluated at least once after baseline comprised the efficacy dataset. Those who exited after baseline were excluded in later analyses, because treatment effects could not be investigated further. Baseline data were compared between escitalopram and placebo groups using t tests or χ2 tests as appropriate. These factors were compared again between those followed and those not followed after the baseline evaluation.

For the efficacy analyses, the primary outcome measure was the HDRS score at endpoint, examined at a significance level of .05. A repeated-measures analysis of covariance in a mixed model was used with baseline HDRS scores as covariates. Multiple imputation by chained equations was used for missing data due to discontinuation after the second visit postbaseline (week 4) by treatment group, demographics (age and gender), and baseline HDRS and Killip scores. For clinical relevance, time to HDRS remission/response and numbers needed to treat between the treatment groups are described in eAppendix 2 and Supplementary eFigure 1. For the secondary outcomes on MADRS, BDI, CGI-S, SOFAS, and WHODAS-12, repeated-measures analyses of covariance in a mixed model were used with corresponding baseline scores as covariates. To maintain an overall type I error rate of .05 with 5 outcomes, a P value of .01 (.05/5) was used to define statistical significance by Bonferroni correction.

For general safety analyses, adverse events that occurred during the treatment period were compared between the 2 treatment groups using χ2 tests. A repeated-measures analysis of covariance in a mixed model was used for echocardiography, ECG, laboratory tests, and body weight over the 24-week treatment period after adjustment for corresponding baseline values and Killip scores. Statistical analyses were carried out using SPSS 18.0 (IBM) and STATA 12.0 (StataCorp) software.

With respect to sample size, the EsDEPACS trial was designed to have 80% power to detect small to medium effect sizes (0.35) on the primary efficacy outcome (ie, a mean difference in HDRS scores of 2 points, assuming an SD of 5 to 6) assuming 2-sided tests at α = .05. A sample size of 106 patients per group was calculated as required. A previous Korean naturalistic study of antidepressant treatment outcomes reported that a considerable proportion of subjects (30%) exited the study after baseline evaluation.19 With the prediction of a 30% exit, 150 subjects per group were enrolled, for a total of 300 patients with ACS and depression.

RESULTS

Recruitment and Baseline Characteristics

The recruitment process is described in Figure 1. Three hundred patients comprised the EsDEPACS population and were randomized, of whom 83 (28%) exited the study after baseline. The remaining 217 formed the efficacy sample, of whom 108 received escitalopram and 109 received placebo: 142 (65%) enrolled as inpatients and 75 (35%) as outpatients. Baseline characteristics of the 2 treatment groups are summarized in the first and second columns of Table 1; there were no significant differences between the 2 groups in any characteristic (all P values > .2). The serum CK-MB level was significantly higher in patients exiting after baseline evaluation compared to those followed up (P = .043), but there were no significant differences in any other characteristic at baseline between them (all P values > .1), as summarized in the third and fourth columns of Table 1. Between the 41 escitalopram and 42 placebo subjects who exited after baseline, there were no significant differences in any baseline characteristic (all P values > .05), as summarized in Supplementary eTable 1.

Table 1

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Drug Treatments and Discontinuation

The mean (SD) time from ACS to the start of study medication was 29.0 (24.1) days. Most patients were taking 5-mg or 10-mg daily doses of treatment medication (first 4 rows of Supplementary eTable 2) at the final visit. The mean (SD) doses at the last visit were 7.6 (3.7) mg for the escitalopram group and 8.5 (3.9) mg for the placebo group, and the mean (SD) treatment durations were 138.3 (22.4) and 138.0 (22.9) days, respectively. Adherence to medications was ≥ 75% in 100 of 108 people (93%) receiving escitalopram and in 103 of 109 people (95%) receiving placebo. Frequencies of the classes of cardiovascular medications used are summarized in the lower part of Supplementary eTable 2. The mean (SD) number of concomitant cardiovascular medications was 5.5 (1.6). In each group, 30 patients (28%) discontinued allocated treatments during the study, leaving 78 escitalopram and 79 placebo patients completing the trial. Reasons for discontinuation are listed in Figure 1, the most common being loss to follow-up. Overall, there were no significant differences in any aspects related to study drug treatments, concomitant medications, or discontinuation between the escitalopram and placebo groups.

Efficacy Results

The mean HDRS scores from baseline to 24 weeks of the escitalopram and placebo groups are displayed with the sample sizes at each follow-up point in Supplementary eFigure 2. Efficacy results are summarized in Table 2. For the primary outcome measure, escitalopram was superior to placebo in reducing HDRS scores over the treatment period with an effect size of 0.38. Results from the additional analysis, comparing HDRS score changes in those who completed the 24-week trial (N = 159), are displayed in Supplementary eFigure 3. For the secondary depressive outcome measures, escitalopram was superior to placebo in decreasing depressive symptoms evaluated by MADRS, BDI, and CGI-S. For the other psychiatric outcomes, escitalopram was superior to placebo in improving SOFAS scores significantly, but differences in WHODAS-12 score trajectories did not reach statistical significance. After applying Bonferroni corrections for the secondary depressive and other psychiatric outcomes, statistical significance remained for MADRS, BDI, CGI-S, and SOFAS (all P values < .01). When the same analyses were repeated after excluding 11 participants with a previous history of depression, the results were not changed substantially (data not shown). Additional analyses further adjusting for concomitant cardiovascular medications did not result in substantial changes (data not shown).

Table 2

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Safety Results

Adverse events during the study period are summarized in Table 3. Dizziness was more frequently reported in the escitalopram group compared to the placebo group (13.9% vs 4.6%, P = .018). However, there were no significant differences between the 2 treatment groups in any other adverse events. Reports of these adverse events were not frequent in either the escitalopram group (3%-14%) or placebo group (1%-14%) and were mild and tolerable. Serious adverse events were rare in both treatment groups. Discontinuation from the study occurred in 2 patients from the escitalopram group (stroke and MI) and in 1 patient from placebo group (stroke).

Table 3

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The cardiovascular safety results are summarized in Table 4. Except for the analysis of changes in blood pressure, which included all 217 subjects, these analyses were carried out in subgroups of 157 subjects who completed the trial and 20 subjects who discontinued after the postbaseline visits, for a total of 177 of 217 subjects (82%). There were no statistically significant differences in any of the cardiovascular safety outcomes between the 2 treatment groups. Additional analyses further adjusting for concomitant cardiovascular medications did not result in substantial changes (data not shown).

Table 4

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DISCUSSION

Principal findings of the EsDEPACS 24-week, randomized, double-blind, placebo-controlled study indicate that escitalopram was effective for treating depressive disorders in patients with recently developed ACS. This was found not only for the primary outcome (HDRS) but also for several secondary depressive outcomes (MADRS, BDI, CGI-S) and on improvement in social and occupational functioning (SOFAS). Escitalopram was also found to be safe and well tolerated, and no significant associations were found with any harmful changes in cardiovascular measurements.

To our knowledge, this is the first trial to evaluate the efficacy and safety of escitalopram for treating depression following ACS. Several study design issues should be considered prior to interpretations. First, we included minor depressive disorder in this study a priori, based on previous research indicating significant negative effects on cardiac prognosis and therefore a need for treatment.20,21 Furthermore, several meta-analyses have suggested that antidepressant effects are substantial only in severely depressed patients,22 although other studies have demonstrated antidepressant efficacy as sufficiently robust to recommend treatment for patients with nonsevere depressive symptoms.23 Because of this inclusion criterion, levels of depression in EsDEPACS participants were less severe (mean baseline HDRS score = 16) than in the SADHART, MIND-IT, and CREATE trials (mean baseline HDRS scores, 17-23).6-8 No attempt was made to stratify the randomization by depression severity, but the severity was similar between randomization arms. Second, we recruited participants a relatively short time after an ACS episode (2-14 weeks, mean = 29 days), focusing on this period because of previous research showing that depression at this acute stage of ACS frequently persists and is associated with worse cardiac prognosis.24

Bearing in mind these considerations, a robust effect of escitalopram was found. The difference in favor of escitalopram over placebo was clinically relevant, with an effect size of 0.38 for mean change from baseline to endpoint. This effect size was greater than that reported in the CREATE trial (0.33),8 possibly due to the longer treatment period (24 weeks in EsDEPACS vs 12 weeks in CREATE). Our positive finding was largely supported by secondary outcomes on 3 other depression assessment scales different from the HDRS in some aspects: the MADRS excludes somatic symptoms of depression, the BDI is a self-report measure, and the CGI-S assesses global symptomatology. Furthermore, escitalopram was associated with significantly improved functioning level, consistent with CREATE study findings.8

In the SADHART and CREATE studies, antidepressant effects were more apparent in participants with prior histories of depression,6,8 whereas in our study, the main findings were not different when analyses were repeated after excluding patients with previous history of depression. The difference between those studies and ours might be due to the fact that previous depression was infrequently reported (4.7%) in our participants compared to the previous studies (40%-50%), although the prevalence in our study is consistent with a nationwide Korean epidemiologic study reporting a 1-year prevalence of major depression of 1.8%.25

Low escitalopram doses (mean = 7.6 mg/d) were used, lower than doses in the CREATE trial (citalopram 33-34 mg/d, equivalent to escitalopram 16-17 mg/d).8 Ethnic differences have been reported in response to psychotropic medications, and lower doses have been suggested as sufficient for achieving similar responses in East Asians compared to Caucasians.26 However, this finding may be also be related to the milder depression severity in EsDEPACS compared to CREATE.8

Escitalopram was generally safe and well tolerated, and only dizziness was significantly more frequently reported in the escitalopram group. This finding differs from CREATE, which reported higher frequencies of adverse events in the citalopram treatment group.8 The difference may be due to the relatively low doses used in EsDEPACS. In addition, we found no evidence for harmful effects of escitalopram over placebo on any cardiovascular profiles evaluated by echocardiography, ECG, laboratory results, body weight, and blood pressure. Recently, there has been concern about the use of higher doses of citalopram and escitalopram in relation to QTc prolongation, a surrogate marker of cardiotoxicity.27 In EsDEPACS, we found no group difference in QTc duration. Although this finding may be related to the low escitalopram doses used, similar results were found in the CREATE study with higher citalopram doses.8 Serious cardiovascular adverse events occurred in less than 5% of both groups.

The EsDEPACS trial has several limitations. First, 83 of 300 randomized subjects (28%) exited the study after baseline evaluation. Since their serum CK-MB levels were significantly higher compared to those of patients who were followed up, it can be assumed that more severe ACS pathology might be associated with the attrition. However, there were no significant differences in any other baseline variables of depressive status. Furthermore, we anticipated such an exit and increased the sample size for randomization when designing this trial. Second, the study completion rate was 73%. This rate was the same as the completion rate in the 24-week SADHART study (73%)6 and higher than that in the 24-week MIND-IT mirtazapine trial (43%),7 although lower than in the 12-week CREATE study (81%).8 There were no significant differences in the rate of or reasons for discontinuation between the escitalopram and placebo groups. A third limitation is that recruitment was carried out at a single site, unlike previous studies using multicenter recruitment.6 8 This aspect of the study may limit the generalizability, and therefore replication of these findings in multicenter settings may be needed. However, a single-center study has strengths in terms of consistency in evaluating and treating patients.

In conclusion, clinically meaningful antidepressive effects were found for escitalopram compared to placebo in depressive disorder occurring with ACS, along with high tolerability and safety. As stated earlier, there have been very few evidence-based treatment options for depression in ACS to date, despite the high prevalence and negative impact of depression in these patient groups. The EsDEPACS trial supports an additional effective and safe treatment option for clinicians treating these patients.

Drug names: citalopram (Celexa and others), escitalopram (Lexapro and others), fluoxetine (Prozac and others), mirtazapine (Remeron and others), paroxetine (Paxil, Pexeva, and others), sertraline (Zoloft and others).

Author affiliations: Departments of Psychiatry (Drs J.-M. Kim, Bae, Jung, H.-J. Kang, S.-W. Kim, I.-S. Shin, and Yoon), Cardiology (Drs Hong, J.-H. Kim, Ahn, and Jeong), Biomedical Science (Dr H.-Y. Shin), and Pharmacology (Drs G. Kang and J.-K. Kim), Chonnam National University Medical School; Clinical Trial Center (Drs J.-M. Kim, Bae, Jung, H.-J. Kang, S.-W. Kim, I.-S. Shin, Hong, J.-H. Kim, H.-Y. Shin, G. Kang, Ahn, J.-K. Kim, Jeong, and Yoon) and Division of Clinical Pharmacology (Drs G. Kang and J.-K. Kim), Chonnam National University Hospital, Gwangju, Korea; and Institute of Psychiatry, King’s College in London, United Kingdom (Dr Stewart).

Potential conflict of interest: Dr J.-M. Kim has received grants from Ministry of Health and Welfare, Republic of Korea; Lundbeck; Eli Lilly; and Otsuka. Dr Stewart has received research funding from Pfizer, Johnson & Johnson, Lundbeck, and Roche. The other authors have no conflict of interest to report related to this study.

Funding/support: The study was funded by an unrestricted research grant from H. Lundbeck A/S and by grants from the Korea Health 21 R&D, Ministry of Health and Welfare, Republic of Korea (HI12C0003 and A050174) and was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2013R1A2A2A01067367). Dr Stewart is funded in part by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. Escitalopram and placebo were provided by H. Lundbeck A/S.

Role of the sponsors: The funders had no further role in paper publication design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Disclaimer: The views expressed are those of the authors and not necessarily those of the Lundbeck A/S, Ministry of Health and Welfare of Korea, or National Research Foundation of Korea.

Supplementary material: Available at PSYCHIATRIST.COM.

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