The cardiovascular safety profile of escitalopram

https://doi.org/10.1016/j.euroneuro.2013.05.011Get rights and content

Abstract

The cardiovascular effects of escitalopram were examined in a large group of participants in double-blind, randomized, placebo-controlled studies. Escitalopram (n=3298) was administered at doses between 5 and 20 mg/day. Patients were treated in acute (8–12 weeks) and long-term (24 weeks) studies. Assessment of cardiovascular safety included heart rate, blood pressure (BP), treatment-emergent adverse events (TEAEs) and electrocardiograms (ECGs). In the short-term, there was a small, but statistically significant 2 beats per minute decrease in heart rate with escitalopram compared with placebo. The difference compared to placebo in systolic or diastolic BP was not clinically or statistically significant. Valid ECG assessments at both baseline and last assessment were available for 2407 escitalopram patients and 1952 placebo patients. Escitalopram–placebo differences in mean changes in ECG values were not clinically meaningful. The mean difference to placebo in the corrected QT [Fridericia's (QTcF)] interval was 3.5 ms (all escitalopram doses); 1.3 ms (escitalopram 10 mg) and 1.7 ms (escitalopram 20 mg) (p=0.2836 for 10 versus 20 mg). One out of 2407 escitalopram patients had a QTcF interval >500 ms and a change from baseline >60 ms. The incidence and types of cardiac-associated adverse events were similar between patients treated for 8–12 weeks with placebo (2.2%) or escitalopram (1.9%) and for 24 weeks with placebo (2.7%) or escitalopram (2.3%). Analyses of data from long-term studies and studies of the elderly showed similar results. In conclusion, these data demonstrate that escitalopram, like other SSRIs, has a statistically significant effect on heart rate and no clinically meaningful effect on ECG values, BP, with a placebo-level incidence of cardiac-associated adverse events.

Introduction

Escitalopram oxalate [S-(+)-1-[3-(dimethylamino)propyl]-1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile] is the therapeutically active enantiomer of the racemic antidepressant citalopram. Like other selective serotonin reuptake inhibitors (SSRIs) and the serotonin–noradrenaline reuptake inhibitors (SNRIs) venlafaxine and duloxetine, escitalopram has a high affinity for the primary binding site on the serotonin transporter protein. Escitalopram also binds to the allosteric site on serotonin transporter (Chen et al., 2005a, Chen et al., 2005b), which decreases the dissociation rate of escitalopram from the primary site and may have a stabilising, or self-potentiating, effect on the escitalopram–transporter complex. Such allosteric binding has led to escitalopram being described as an allosteric serotonin reuptake inhibitor (Sánchez, 2006, Ali and Lam, 2011).

The cardiovascular safety of antidepressants has been the subject of recent debate and, in particular, the prescribing information and recommended dosing for citalopram have been modified to address concerns about the risk of QTc prolongation (Beach et al., 2013, Vieweg et al., 2012). Therefore, the present analysis of patient-level data was undertaken to evaluate the effect of escitalopram on cardiovascular safety measures in more than 3000 patients from randomised, double-blind placebo-controlled clinical studies in major depressive disorder (MDD), social anxiety disorder (SAD), generalised anxiety disorder (GAD), obsessive compulsive disorder (OCD), and panic disorder (PD).

Section snippets

Patients

The individual patient data come from all randomised placebo-controlled studies sponsored by H. Lundbeck A/S or Forest Laboratories, Inc in which ECGs were performed at baseline and at last assessment. Escitalopram was dosed once daily using a fixed dose or flexible dose design to a maximum of 20 mg/day. Patients treated with 20 mg/day were administered 10 mg/day for the first week. All protocols were approved by institutional review boards/independent ethics committees at each study site in

Short-term data

There are 17 randomised placebo-controlled studies (14 short-term and 3 long-term) (Table 1). ECGs were performed at baseline and at end of study or at last assessment in 12 of these studies [7 studies in MDD (8 or 12-weeks duration), 3 in GAD (8-weeks duration), 1 in PD (10-weeks duration) and 1 in SAD (12-weeks duration)], in which 2164 patients were treated with escitalopram and 2050 patients with placebo. Patients treated with escitalopram had a mean age of 42.2 years, 60.5% were women, and

Discussion

The present analysis of placebo-controlled clinical trials of escitalopram assessed the effects of escitalopram on heart rate, blood pressure, and ECGs in a large group of patients. Central autonomic dysfunction associated with MDD can lead to changes in vagal or sympathetic modulation, resulting not only in symptoms such as hyperhydrosis, but also in changes in heart rate or blood pressure regulation. Cardiac vagal control, as measured by the beat-to-beat variability in the timing of heart

Conclusion

A systematic review of individual patient data from a large group of patients participating in placebo-controlled studies indicates that escitalopram appears to have a benign cardiovascular profile, both in short-term and longer-term studies, as well as two studies that included old adults. This is further supported from epidemiological analysis and clinical trials in patients with cardiac diseases.

Role of the funding source

H. Lundbeck A/S sponsored the study. Lundbeck was involved in the study design, in the collection, analysis and interpretation of data, in the writing of the study reports, and in the decision to submit the paper for publication.

Contributors

Authors Thase and Kennedy wrote the first draft of the manuscript. Larsen undertook the statistical analysis. All authors (Thase, Larsen, Reines and Kennedy) contributed to and have approved the final manuscript.

Conflicts of interest

ME Thase is an advisor/consultant for H. Lundbeck A/S. During the past 5 years, he has had similar relationships with Alkermes; AstraZeneca; Bristol-Myers Squibb Company; Cephalon, Inc.; Eli Lilly & Co.; Forest Laboratories, GlaxoSmithKline; Janssen Pharmaceutica; MedAvante, Inc.; Merck; Mylan Laboratories; Neuronetics; Novartis; Organon Inc.; Otsuka; PamLab; Pfizer, Inc.; PharmaNeuroboost; Rexahn; Roche Laboratories; Sanofi Aventis; Schering-Plough; Shire US, Inc.; Sunovion; Takeda; Teva;

Acknowledgements

The authors thank D.J. Simpson (H. Lundbeck A/S) and Ms. Christine Johnson (Pittsburgh, Pennsylvania) for technical assistance in the preparation of the manuscript.

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