Review
Cardiovascular adverse effects of newer antidepressants Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Imperial College London on 06/16/14 For personal use only.
Expert Rev. Neurother. 14(5), 539–551 (2014)
Rajnish Mago1, Neeta Tripathi2 and Chittaranjan Andrade*3 1 Department of Psychiatry and Human Behavior, Mood Disorders Program, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA 2 Hamilton Cardiology Associates, Hamilton, NJ, USA 3 Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore, India *Author for correspondence: Tel.: +91 080 2699 5109 Fax: +91 080 2656 4830 [email protected]
Newer antidepressants that are more selective in their neurotransmitter effects include the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others (agomelatine, bupropion, mirtazapine, reboxetine, vilazodone, vortioxetine). This article systematically reviews data from a variety of sources regarding the potential adverse effects of these medications on various cardiovascular parameters. Potential biochemical mechanisms by which these antidepressants may adversely affect the cardiovascular system are also discussed. Antidepressants that are associated with higher cardiovascular risk (SNRIs, reboxetine), lower risk (SSRIs), and without current evidence of cardiovascular risk (agomelatine, mirtazapine, vilazodone, vortioxetine) are identified. The FDA’s recommendations regarding citalopram are organized and summarized, and situations with higher risk of cardiovascular adverse effects are identified. KEYWORDS: adverse effects • antidepressants • blood pressure • cardiovascular • electrocardiogram • orthostatic hypotension • QT interval • side effects • serotonin-norepinephrine reuptake inhibitors • selective serotonin reuptake inhibitors
The 12-month prevalence of major depressive disorder (MDD) in the USA is 6.7% [1]. This prevalence is higher in patients with cardiovascular disease (CVD) [2]. Reciprocally, patients with depression are at increased risk of coronary artery disease [2,3]. Therefore, there is increasing emphasis on efforts to prevent CVD in patients with depressive disorders and to treat depression in patients with CVD. The potential cardiovascular effects of tricyclic antidepressants (TCAs) are well known; for example, TCAs can cause orthostatic hypotension, slowed cardiac conduction and increased heart rate [4], and the use of TCA can worsen cardiovascular outcomes [5]. TCAs are therefore best avoided in patients with preexisting CVD. Although antidepressants introduced in the mid-1980s and later are safer, they are not devoid of the risk of cardiovascular adverse effects (AEs). Knowledge of such risks is important, especially in subgroups of patients at higher risk of developing adverse cardiovascular events. In this article, we critically review possible cardiovascular AEs of newer antidepressants and make recommendations regarding their use. Potential cardiovascular benefits of antidepressants [6] are beyond the purview of this article. informahealthcare.com
10.1586/14737175.2014.908709
Methods
We present a qualitative review of representative data; there is too much literature to permit a comprehensive review. In order to attribute an AE to a drug, we compared the incidence of abnormal outcomes between drug and placebo in the same study. For this, we used a variety of sources of data; if the data converged, confidence in the associations (or lack thereof) was enhanced. Studies were identified by a PubMed search of the MEDLINE database and by reviewing the references of the articles retrieved. Given the extensive confusion and disagreement in the literature, we have taken a somewhat novel approach. The study of uncommon AEs that are hard to detect in usual clinical trials can be enhanced by combining the use of animal studies, studies of normal volunteers, metaanalyses of clinical trials, use of unusually high doses of the medication, use of the medication in populations that are more vulnerable (patients who were elderly or had underlying cardiac disease), and studies of overdose on the medication. It is these types of studies that are the main substance of our paper. Where available, we also examined postmarketing surveillance studies because these provide large
2014 Informa UK Ltd
ISSN 1473-7175
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samples that allow the detection of uncommon AEs. We considered the studies of supratherapeutic doses and reports of overdose to be helpful in a limited way: if an AE does not occur (or occurs rarely) on supratherapeutic doses or after overdose, it is unlikely that that the AE would occur at therapeutic doses. On the other hand, though, occurrence of an AE in supratherapeutic or overdose circumstances does not necessarily indicate that that the AE will also occur at therapeutic doses. We deliberately excluded observational studies (of which there are many) because while associations found in these studies are tantalizing, residual effects of known and unknown confounders cannot be fully ruled out. We also excluded case reports, but case series were included for data on overdose because no alternative is feasible. Case reports and observational studies are invaluable and absolutely essential for initial identification of a potential problem, but have high potential for bias. We did not review uncontrolled studies because these do not offer a yardstick against which outcomes can be compared. Where possible, we also avoided reference to clinical trials where fewer than 100 patients received the drug because, being underpowered, such studies might offer false reassurance. Exceptions were made where larger studies were not available and when the trial was conducted in a high-risk population. We followed the recommendations of Mago et al. [7] regarding methodological issues that are important in studying AEs of drugs. Since mean changes in a variable may mask the presence of clinically significant changes in a few patients, we examined the incidence of clinically defined abnormal values, instead. Considerable interest has focused on prolongation of ventricular repolarization, represented by prolongation of the QT interval on the ECG. This is a surrogate marker of risk of cardiac arrhythmias, though the QT interval alone might not correspond directly to the risk of torsades de pointes [8]. The QT interval is interpreted after correction for heart rate, most commonly using the Bazett (QTcB = QT/(R–R)½) or Fridericia (QTcF = QT/(R–R)1/3) formulae. As the QTcB overcorrects when the heart rate is >100 beats per minute (bpm), the QTcF should be used when tachycardia is present. Mechanisms underlying & variables mediating antidepressant-induced cardiovascular AEs
That serotonin affects the cardiovascular system should not be surprising since serotonin was first isolated from serum (sero-) in the mid-twentieth century and was noted to promote constriction of smooth muscle (-tonin) [9]. Stimulation of serotonin receptors can affect cardiovascular functioning both directly and indirectly – directly in the heart and peripheral vasculature and indirectly through central effects. Noradrenergic effects on the heart have likewise long been recognized. A detailed discussion on the physiology of serotonin and noradrenaline in relation to the cardiovascular system is beyond the scope of this review; however, in order to establish biological plausibility for the rest of this review, we briefly mention some important mechanisms through which serotonin and noradrenaline and serotonergic 540
(e.g., selective serotonin reuptake inhibitor [SSRI]) and noradrenergic antidepressant drugs may trigger cardiovascular AEs. Direct effects of serotonin & SSRI drugs on cardiovascular physiology
Serotonin is found in the heart, where it has many complex and even opposing effects [10]. Serotonin receptors are present on cardiac myocytes as well as on the vagus and sympathetic nerves [11]. In humans, stimulation of 5-HT4 receptors leads to increased heart rate [10], and serotonin tends to increase atrial and ventricular activity as well as atrial and ventricular arrhythmias in humans mainly through activation of 5-HT4 receptors [12]. Serotonin effects on 5-HT1B, 5-HT1D and 5-HT2A receptors may cause vasoconstriction of coronary arteries, especially if these arteries are affected by atherosclerotic changes [13–16]; ischemic events may be triggered by these effects [6,17]. SSRIs have been shown to inhibit the delayed rectifier potassium (IKr) ion channel that is involved in cardiac repolarization; this ion channel is coded by the human ether-a-gogo-related gene (hERG) [18]. The dose-dependent QT prolongation associated with SSRIs may be related to this effect rather than to their primary action of blockade of serotonin reuptake [19–21]. Indirect effects of serotonin on cardiovascular physiology
Stimulation of 5-HT1 receptors on sympathetic nerve terminals inhibits the release of norepinephrine [10]. Stimulation of central 5-HT1A receptors reduces sympathetic activity and increases vagal activity, both of which decrease blood pressure [22]. On the other hand, stimulation of central 5-HT2A receptors can increase blood pressure [23]. SSRI drugs: cardiovascular effects of metabolites & enantiomers
It is possible that specific metabolites of an antidepressant are particularly associated with cardiovascular AEs. For example, citalopram is metabolized by CYP2C19 and 3A4 to desmethylcitalopram, and then by CYP2D6 to didesmethylcitalopram. Didesmethylcitalopram, which was associated with QT prolongation in beagle dogs, is usually a minor metabolite in humans; however, in CPY2D6 ultrarapid metabolizers, its levels may increase, and this may lead to an increased risk of QT prolongation [24]. It is also possible that specific optical isomers of SSRIs may be associated with cardiovascular AEs. For example, QTc prolongation in overdose is more common with racemic citalopram than with escitalopram (which suggests that R-citalopram carries a greater burden of cardiovascular risk); and R-fluoxetine, the active enantiomer of fluoxetine, also prolongs the QTc, the action of which is relatively absent with racemic fluoxetine [25]. Other effects of serotonin & SSRI drugs on cardiovascular physiology
Heart rate variability (HRV) is a less studied measure of the cardiovascular effects of antidepressants. HRV describes Expert Rev. Neurother. 14(5), (2014)
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beat-to-beat changes in heart rate in response to fluctuating environmental demands. HRV is mediated by cardiac autonomic control and requires a healthy myocardium. Decreased HRV indicates a decreased capacity of the heart to respond to environmental needs. A decrease in HRV has been associated with ventricular arrhythmias, other adverse cardiac events and cardiac mortality, including sudden cardiac death [26,27]. Some data suggest that SSRIs probably do not significantly affect the HRV [28]. However, in a small study of patients with MDD and healthy volunteers, treatment with SSRIs was associated with increased pulse pressure and with decreased vagal activity as indicated by decreased cardiac baroreflex function and HRV [29]. There is a dearth of published data about HRV with most other antidepressants. The relationship between serotonin and pulmonary arterial hypertension (PAH) was brought into the limelight due to the association of various diet pills with PAH. It is now known that serotonin is involved in both pulmonary arterial vasoconstriction (mediated by 5-HT1B receptors) and pulmonary vascular remodeling, and thus plays a role in clinical and experimental PAH [30]. In this regard, it is significant to note that an association between maternal use of SSRIs in the third trimester and neonatal persistent pulmonary hypertension of the newborn (PPHN) [31].
and conduction [33]. Thus, when serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit norepinephrine reuptake, they can potentiate sympathetic vasoconstriction in a dosagedependent manner [34]. Data suggest that, like TCAs, venlafaxine may also block sodium channel conductance in the heart [35]. Duloxetine is known to increase norepinephrine levels peripherally and to increase sympathetic tone [36]. In vitro studies of human atrial myocytes have, however, failed to show any AE of duloxetine on any of the human cardiac ion channels tested, including cardiac sodium current, transient outward potassium current, sustained current or the inwardly rectifying potassium current which is associated with prolongation of the QT interval [37]. Most noradrenergic drugs also have serotonergic effects (e.g., venlafaxine, duloxetine), and so some serotonergic mechanisms, at least, would be recruited in the cardiovascular actions of these noradrenergic antidepressants.
Serotonin & SSRI drugs: what is the net effect?
SSRIs & blood pressure
The net result of various effects of serotonin on the cardiovascular system is that in different areas of the vasculature, serotonin can cause either vasoconstriction or vasodilatation, and may increase or decrease blood pressure [10]. It is important to note that despite the data on the various physiological effects of serotonin, for example, vasoconstriction or increase/decrease in blood pressure, these mechanisms do not necessarily translate into a clinical effect. Thus, precedence must be given to the empirical data discussed in the rest of this paper rather than to potential underlying mechanisms. Also, given the many ways in which serotonin and SSRI drugs can affect cardiovascular functioning, there is no way of predicting effects in the individual patients; results would obviously depend on individual variations in pharmacokinetics and pharmacodynamics. As our review will show, SSRI drugs enjoy a wide margin of cardiac safety. Nevertheless, there are specific though uncommon situations of risk.
The effect of SSRIs on blood pressure remains unclear. While fluoxetine was found in one study to increase blood pressure in some patients [40], other studies found no significant effect on blood pressure in humans [10].
Noradrenaline & noradrenergic drugs
Noradrenaline (norepinephrine) has a variety of peripheral effects that contribute to increasing blood pressure including increase in heart rate and contractility, vascular tone, reabsorption of sodium by the kidney and activity of the renninangiotensin system [32]. The norepinephrine transporter (NET) is the key factor regulating norepinephrine concentrations both centrally and peripherally, and it plays a role in the pathophysiology of several CVDs [32]. Norepinephrine binds to a and b adrenergic receptors in the myocardium and blood vessels, which results in increased heart rate, blood pressure, contractility informahealthcare.com
SSRIs & cardiovascular AEs SSRIs & heart rate
Both citalopram and fluoxetine are associated with small decreases in heart rate compared to placebo [38–40]. This decrease in heart rate may occur early on, within the first 2 weeks [39], suggesting that reduction in anxiety may not explain this change.
SSRIs & the QT interval
Much evidence shows that SSRIs have far greater cardiovascular safety than the TCAs. For example, in an early paper evaluating the cardiac safety of citalopram (10–60 mg/d), no significant effect on cardiac conduction or repolarization over short- or long-term treatment was found [38]. A review of the effects of various psychotropic medications on the electrocardiogram suggested that sertraline, paroxetine and citalopram were not associated with significant changes in the QT interval [41]. In beagle dogs, citalopram in doses four times higher than those used in humans was noted to cause QT prolongation and death [38]. Concerns were expressed in humans, as well. In August 2011, the United States Food and Drug Administration (FDA) [42] issued a Drug Safety Communication stating that citalopram causes dose-dependent QT interval prolongation and therefore should not be prescribed at >40 mg/day, and not at all in patients with congenital long QT syndrome. The guidance was brief and without detail. Subsequently, in March 2012, the FDA [43] issued revised recommendations with guidance regarding various situations as summarized in BOX 1. The FDA communication was based on two strands of evidence: post-marketing reports of QT interval prolongation and torsades de pointes arrhythmias associated with use of citalopram and 541
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Box 1. FDA’s revised recommendations for citalopram and risk of abnormal heart rhythms. Patient selection Citalopram is not recommended for patients who: • Have congenital long QT syndrome • Have bradycardia • Have hypokalemia or hypomagnesemia • Had a recent acute myocardial infarction, or uncompenExpert Review of Neurotherapeutics Downloaded from informahealthcare.com by Imperial College London on 06/16/14 For personal use only.
sated heart failure • Are taking other drugs that prolong the QT interval
Dosing The maximum recommended dose of citalopram is 20 mg/day for patients: • > 60 years old • With hepatic impairment • Who are CYP 2C19 poor metabolizers • Who are taking a CYP2C19 inhibitor
Patient education • Patients should be told to contact a healthcare professional
immediately if they have symptoms like dizziness, palpitations, or syncope that may indicate a problem with the heart rate or rhythm Recommended monitoring • Electrolyte and/or ECG monitoring in ‘certain circumstances’ • Serum potassium and magnesium at baseline and periodi-
cally in patients at risk for significant electrolyte disturbances • More frequent ECG monitoring in patients for whom citalo-
pram use is not recommended, but is considered essential Recommended actions • Hypokalemia and/or hypomagnesemia should be corrected
before starting citalopram • If the QTc is persistently > 500 msec, citalopram should be
discontinued • If symptoms like dizziness, palpitations, or syncope occur,
further evaluation and monitoring should be done Data taken from [43].
review of two unpublished ‘thorough’ [44] QT studies. In these two randomized, double-blind, placebo-controlled, crossover studies (n = 119 and 113 for the citalopram and escitalopram studies, respectively), subjects were randomized to citalopram (20 mg/d, 60 mg/d) or escitalopram (10 mg/d, 30 mg/d) with moxifloxacin 400 mg/d and placebo as controls. These studies showed that citalopram caused QT prolongation that was clinically significant at 60 mg/d. The FDA therefore recommended that citalopram should not be used at doses above 40 mg/d. At doses of up to 20 mg/day, escitalopram was not associated with QTc prolongation, and the label for escitalopram was not modified. In a recent placebo-controlled study in elderly patients with Alzheimer’s disease [45], citalopram was associated with greater increase in the QTc interval than placebo. Four patients (three 542
on citalopram and one on placebo) showed QTc prolongation, defined as >450 msec for men and >475 msec for women. Is the risk of QT prolongation limited to citalopram among the SSRIs? In 469 cases of overdose on an SSRI, QT prolongation after overdose on citalopram was greater than that after overdose on other SSRIs [46]. In 68% of overdoses on citalopram, the QTc was >440 msec. It should be noted that in the study described in the FDA communication, at 30 mg/d, escitalopram was associated with QTc prolongation greater than at 20 mg/d and similar to that with moxifloxacin. Caution with regard to escitalopram is also supported by the frequency and type of ECG effects of overdose on escitalopram being similar to those after overdose on citalopram [47]. Potential risk for torsades de pointes was found in 14% and bradycardia in 11% of patients who had overdosed on escitalopram. The European Medicines Agency has made changes to the Summary of Product Characteristics for both citalopram [48] and escitalopram [49] that are very similar to those made by the FDA for citalopram (BOX 1). For escitalopram, the initial dose for patients >64 years of age was reduced to 5 mg/day with the option to increase to 10 mg/day based on response. The EMA noted that, in addition to other known risk factors, the risk of QT prolongation is greater in female patients [49]. In July 2013, the FDA issued a safety warning for fluoxetine, as well, citing postmarketing reports of QT prolongation and ventricular arrhythmias, including torsades de pointes, associated with the use of fluoxetine [50]. Precautions similar to those for citalopram were recommended. Another type of study that supports the potential of SSRIs to cause QT prolongation compared the QTc intervals in neonates exposed to SSRIs immediately before birth (n = 52) to those in 52 matched control neonates [51]). The mean QTcB (replicated using QTcF) was statistically significantly longer in neonates exposed to SSRIs as compared with controls. Using a cut-off of >460 msec (widely used for neonates), five neonates exposed to SSRIs had prolonged QTc (up to 543 msec) compared to none in the control group. The QTc prolongation returned to normal in all cases. JT intervals were also longer in neonates exposed to SSRIs, indicating delayed cardiac repolarization. The authors recommended that ECGs be considered in neonates who were exposed to an SSRI immediately prior to birth. SSRIs & HRV
A review of the data on the effects of SSRIs on HRV [27] noted that in studies with recordings of short duration, a significant decrease in heart rate and an increase in HRV were found. On the other hand, two 24-h recording studies did not find any significant changes in HRV. A meta-analysis of the effects of depression and antidepressants on HRV also did not find SSRIs to either increase or decrease HRV [28]. SSRIs in patients with CVD
In a randomized controlled trial (RCT) of 81 patients with a depressive disorder and ischemic heart disease, patients received paroxetine 20–30 mg/d or nortriptyline (serum level, 50 to Expert Rev. Neurother. 14(5), (2014)
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150 ng/ml) [52]. Patients on paroxetine had a significantly lower incidence of adverse cardiac events (2%) compared those on nortriptyline (18%). Nortriptyline but not paroxetine was associated with increased heart rate. Neither drug significantly affected blood pressure or cardiac conduction. In a small study, 27 elderly depressed patients with congestive heart failure, cardiac conduction disturbances and/or ventricular arrhythmias were treated with fluoxetine (up to 60 mg/d) for 7 weeks or nortriptyline (50–150 ng/ml) for 3 weeks [53]. Fluoxetine was not associated with tachycardia, cardiac conduction abnormalities, ventricular arrhythmias, orthostatic hypotension or decrease in ejection fraction. Instead, there was a 6% decrease in heart rate, a 2% increase in supine systolic blood pressure and a 7% increase in ejection fraction in patients with a baseline ejection fraction £50%. Cardiovascular adverse events occurred in 4% of patients on fluoxetine versus 20% of those on nortriptyline. In a small (n = 54), placebo-controlled RCT of fluoxetine vs placebo in MDD patients recruited 3 to 12 months after an MI, no AEs of fluoxetine were observed on ECG and echocardiography assessments [54]. An important RCT provided reassurance about the safety of sertraline in patients with MDD and acute ischemic heart disease (SADHART) [55]. Patients (n = 369) with acute myocardial infarction (75%) or unstable angina (25%) within the last 30 days were randomized to treatment with sertraline or placebo. Detailed safety assessment over 6 months of followup using ECG, Holter monitoring, echocardiograms and other parameters found no statistically significant difference in the incidence of serious cardiovascular events (14.5% on sertraline vs 22.4% on placebo; NS). Similarly, no significant differences between sertraline and placebo were found for left ventricular ejection fraction, QT interval and other safety measures. No differences on any cardiovascular outcome measure between sertraline and placebo were found among 469 patients with MDD and congestive heart failure (SADHART-CHF RCT) [56]. The safety and indeed the possible benefits of SSRIs in patients with CVD were recently reviewed [6], and readers are referred to this review for more information on the subject. SSRIs & overdose
Of 26 cases of overdose on citalopram, 8 of 24 subjects with ECG available had a QTc of >450 msec [57]. However, the Bazett correction was used, which could be misleading in the presence of tachycardia that was present in 15 of the 26 patients. Bundle branch block and severe bradycardia occurred in three patients and one patients, respectively. Other studies of overdose on SSRIs have been discussed in an earlier section. Adding support to the relationship between citalopram overdose and QTc prolongation is the finding that in the 52 patients who had overdosed on citalopram, QTc was linearly related to the predicted plasma citalopram concentration [58]. informahealthcare.com
Review
Summary
SSRIs appear to have good cardiovascular safety, including in patients with preexisting CVD. They do not appear to cause hypertension but may be associated with changes in heart rate. Nevertheless, it should not be disregarded that in patients with other high risk factors, SSRIs (citalopram, escitalopram and fluoxetine in particular, especially in higher relative to lower doses) may be associated with prolongation of the QTc, thereby increasing the risk of serious ventricular arrhythmias. In such high-risk situations, caution and increased monitoring are strongly recommended. It must also be kept in mind that SSRIs may be responsible for indirect risks in patients with CVD. These risks may arise from pharmacokinetic or pharmacodynamic interactions with cardiovascular drugs [6,59–62]. Pharmacokinetic drug–drug interactions mediated by the cytochrome P450 system are more likely to occur with fluoxetine and paroxetine that are potent inhibitors of CYP2D6 (substrates include various b blockers, clonidine, etc.) and fluvoxamine that is a potent inhibitor of CYP1A2 (substrates include verapamil, propranolol, warfarin, etc.). Serotonin-norepinephrine reuptake inhibitors
In contrast to the SSRIs, SNRIs have been associated with a higher incidence of cardiovascular AEs. Sibutramine, an SNRI approved for promoting weight loss, was withdrawn from the market in 2010 due to association with increased blood pressure, cardiovascular adverse events and stroke [63]. Venlafaxine Healthy volunteers
Venlafaxine decreased HRV, prolonged the dilatation phase of the vasoconstrictor response and increased resting pupil diameter. Venlafaxine also decreased the amplitude of the pupillary light reflex, increased its latency and shortened its recovery time [64]. These findings suggest that venlafaxine increases sympathetic activity in cutaneous blood vessels and the iris and increases centrally mediated parasympathetic inhibition. Meta-analysis of placebo-controlled clinical trials
A venlafaxine (25–375 mg/d; n = 2817) meta-analysis found that the incidence of sustained elevation in supine diastolic blood pressure (DBP) was 4.8% on venlafaxine versus 2.1% on placebo. There was a strong dose effect with increase in supine DBP prominent at higher doses; on venlafaxine >300 mg/day the incidence was 9.1% [65]. This dose relationship is also consistent with serotonin reuptake inhibition being the main effect of venlafaxine at lower doses and norepinephrine reuptake inhibition becoming clinically significant at higher doses. The risk of elevation in DBP was greater in older patients and in men. Unusually high doses
In a small study (n = 37) of the use of higher dose venlafaxine (mean, 346 mg/d), no changes in ECG were found [66]. 543
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Overdose
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In a study of 369 cases of overdose on 75 to 13,500 mg of venlafaxine [67], tachycardia, mild hypertension, severe hypertension and hypotension occurred in 54, 40, 3 and 5% of cases, respectively. No arrhythmias were found on continuous telemetry, and QRS was >120 msec in 7% cases. In another study of 235 cases of overdose on venlafaxine (919–2800 mg), tachycardia, hypertension and QTc >450 msec occurred in 40, 28 and 11% of cases, respectively [68].
Overdose: We did not find any published reports of desvenlafaxine overdose, and the Prescribing Information updated in 2013 [49] refers only to venlafaxine overdose [71]. Duloxetine Laboratory studies
In a study of 71 normal adult females given a single dose of desvenlafaxine 200 or 600 mg/d to assess effects of the drug on QTcF, no significant changes were found [69].
In conscious rodent and canine models, duloxetine did not significantly affect heart rate or blood pressure [72]. Similarly, 1 year of treatment with duloxetine did not significantly affect canine heart rate, rhythm or conduction [72]. In vitro data suggest that inhibitory effects of duloxetine on cardiac hERG channels are probably negligible in therapeutic concentrations of the drug; however, hERG block may occur in duloxetine overdose and when the drug is administered to patients who are susceptible to drug-induced QT prolongation [73].
Review of placebo-controlled clinical trials
Meta-analysis of placebo-controlled clinical trials
In a review of all short-term registration RCTs of desvenlafaxine (50–400 mg/d) for MDD [70] (readers are reminded that the recommended dose of desvenlafaxine is 50 mg/d), changes in pulse and BP were as follows:
The cardiovascular AEs of duloxetine were assessed using data from all placebo-controlled RCTs (n = 8504 on duloxetine) [72]. QRS and QTcF intervals were decreased from baseline in patients on duloxetine and increased in patients on placebo. Duloxetine did not prolong the QTcF interval. Small increases in heart rate on duloxetine and small decreases on placebo were observed. In another analysis of placebo-controlled RCTs in diabetic patients with or without a history of CVD, patients treated with duloxetine were not found to differ in the incidence of cardiovascular adverse events, mean changes in blood pressure or rates of sustained hypertension [72].
Desvenlafaxine Healthy volunteers
• There were small increases in mean systolic blood pressure (SBP), DBP and pulse rate in desvenlafaxine patients that were statistically significantly greater than those in placebo patients. • ‘Clinically important’ changes in BP occurred in 2% of patients on desvenlafaxine versus 1% of those on placebo. • Using a higher threshold based on regulatory criteria for potentially clinically important changes in SBP (increase by ‡20 mmHg and value ‡180 mmHg; decrease by ‡20 mmHg and value £90 mmHg), DBP (increase by ‡15 mmHg and value ‡105 mmHg; decrease by ‡15 mmHg and value £50 mmHg) and pulse rate (increase by ‡15 bpm and value ‡120 bpm; decrease by ‡15 bpm and value £50 bpm), the incidence of such changes was £1% and did not differ from placebo. Sustained elevation of supine DBP (increase by ‡10 mmHg and value ‡90 mmHg for three consecutive visits) was reported in 2.3% of patients on 400 mg/day of desvenlafaxine versus 0.5% on placebo. No significant ECG differences were found between desvenlafaxine and placebo: • The QRS interval in patients on desvenlafaxine 400 mg/day was decreased from baseline relative to the lower dose groups and to placebo but, overall, there was no significant change in the QRS interval from baseline in patients on desvenlafaxine. • The mean QT interval in patients on desvenlafaxine was statistically significantly decreased (–1.17 msec) from baseline compared to those on placebo (+5.39 msec). • In the fixed-dose studies, patients on 50 mg/day or 100 mg/ d had a significant increase in QT interval from baseline, whereas the 400 mg/day group had a significant decrease. • Potentially clinically significant (PCS) ECG findings occurred in similar percentages of patients in the desvenlafaxine and placebo groups. 544
Supratherapeutic doses
The cardiovascular effects of supratherapeutic doses of duloxetine were assessed in a study of 117 women, aged 19–74 years, in whom the dose of duloxetine was increased over 16 days from 120 mg/d to 400 mg/d [74]. Increases in supine pulse rate, SBP and DBP (maximum increase, 12 bpm, 12 mmHg and 7 mmHg, respectively) were found along with orthostatic changes in pulse and BP that were usually asymptomatic. The increase in blood pressure was not specific to patients who had high normal BP at baseline, indicating that those patients were not at higher risk of such increase. A companion paper based on the same study [75] compared the effects of supratherapeutic doses of duloxetine on the ECG, with placebo and moxifloxacin as controls. No increase in QTcF was found; the upper limits of the two-sided 90% confidence intervals for duloxetine versus placebo were 445 ms or an increase from baseline of >36 ms. Levomilnacipran
Levomilnacipran is an SNRI that was approved by the FDA in 2013 for the treatment of MDD. It is twice as potent at norepinephrine relative to serotonin reuptake inhibition, which differentiates it from SNRIs like duloxetine and venlafaxine that have greater potency for serotonin relative to norepinephrine reuptake inhibition [76]. Expert Rev. Neurother. 14(5), (2014)
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Blood pressure
Clinical trials
In short-term clinical trials of levomilnacipran, sustained systolic hypertension (SBP ‡140 mm Hg and increase of ‡15 mm Hg from the baseline for three consecutive visits) or sustained diastolic hypertension (DBP ‡90 and ‡10 mm Hg increase for three consecutive visits) was found in 1.8% of patients on levomilnacipran and 1% of placebo patients [77]. Sustained systolic and sustained diastolic hypertension were both observed in 0.3% of levomilnacipran patients versus 0.1% of placebo patients. In a 1-year extension study [78], elevated BP that was considered to be a treatment-emergent adverse event (TEAE) was reported in 4.5% of levomilnacipran patients; six patients prematurely discontinued this study due to elevated blood pressure. Orthostatic hypotension (systolic or diastolic) was reported in 11.6% of patients on levomilnacipran and 9.7% of patients on placebo [77].
The Prescribing Information reports the incidence of palpitations to be greater on bupropion 400 mg/day versus placebo (6 vs 2%).
Heart rate
In short-term clinical trials, there was a mean increase in heart rate of 7.4 bpm in patients on levomilnacipran versus a mean decrease of 0.3 bpm in patients on placebo [77]. While one study [79] noted that no patient in the levomilnacipran group met PCS criteria for change in heart rate, the other short-term studies did not report the proportion of patients meeting criteria for a clinically meaningful increase in heart rate. Mago et al. [76] suggested that in this situation the reporting of increased heart rate as a TEAE, though not based on standardized criteria, may be considered a proxy for significantly increased heart rate. In some of the short-term studies [80,81], increased heart rate was reported as a TEAE in more patients on levomilnacipran than on placebo. In the open-label phase of a relapse prevention study [82], increased heart rate was reported as a TEAE in 7.4% of patients on levomilnacipran. QT interval
While small increases in QTcB that were greater than those on placebo were found in short-term studies of levomilnacipran, these may be attributed to the increased heart rate. In the 1-year extension study [78], no patient had a QTcF >500 msec. Overdose
There are no published reports of overdose on levomilnacipran. The Prescribing Information [77] notes that in clinical studies, cases of ingestion of levomilnacipran up to 360 mg daily were reported without any fatalities.
High-risk populations
The cardiovascular safety of bupropion was assessed in an RCT of bupropion (300 mg/day) for smoking cessation in 248 smokers admitted for acute CVD (mainly myocardial infarction and unstable angina) [83]. Bupropion and placebo groups did not differ significantly in cardiovascular mortality at 1 year (0 vs 2%), in BP at follow-up or in cardiovascular events at end-of-treatment (16 vs 14%) or end of 1 year (26 vs 18%) analyses. No difference between bupropion and placebo was found in vital parameters or cardiovascular adverse events in 151 patients with acute coronary syndrome (myocardial infarction or unstable angina) randomized to the two groups [84]. An RCT of 300 patients with untreated stage 1 hypertension (SBP 140–159 mmHg and/or DBP 90–99 mmHg) were randomly assigned to 4 weeks of treatment with bupropion sustained release 150, 300 or 400 mg/day, or to placebo [85]. Importantly, assessments included ambulatory monitoring of blood pressure. The proportion of patients with an increase of ‡10 mmHg in SBP and/or ‡6 mmHg in DBP was not significantly different between bupropion and placebo groups. However, an increase in heart rate of ‡10 bpm at any two consecutive visits or ‡15 bpm at any single visit occurred in 30 and 15% of patients on bupropion 400 mg/day and placebo, respectively, which was a statistically significant difference. Overdose
The Prescribing Information [86] notes that overdoses on bupropion alone have been associated with sinus tachycardia and with ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. However, a review of 7348 cases of bupropion-only overdose [87] confirmed the findings of previous studies of bupropion overdose that except for tachycardia, which occurs in about a third of cases, cardiovascular AEs are rare after overdose. Summary
It appears that, with the exception of tachycardia, bupropion is unlikely to be associated with significant cardiovascular AEs.
SNRIs: summary
Mirtazapine
Overall, different sources of information converge to demonstrate that SNRIs are associated with a small but definite risk of tachycardia, hypertension and orthostatic hypotension. However, in therapeutic doses, they do not seem to cause QTc prolongation.
Mirtazapine is an antagonist of central a2 adrenergic autoreceptors and heteroreceptors. This action of mirtazapine leads to increased release of norepinephrine and serotonin. Mirtazapine also blocks 5-HT2 and 5-HT3 receptors.
Bupropion
Heart rate variability
Bupropion is an antidepressant that weakly inhibits the reuptake of norepinephrine and dopamine and does not belong to any other class of antidepressants.
In a small study in patients with unipolar depression, 4 weeks of treatment with mirtazapine (n = 10) did not normalize preexisting abnormalities in HRV [88]. Rather, it was associated
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with an increase in heart rate and a decrease in HRV, though less so than imipramine (n = 10).
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Placebo-controlled clinical trials
The Prescribing Information for mirtazapine [89] notes that this drug was not associated with any cardiovascular symptom or sign at a frequency greater than that with placebo. The Merck list is limited to events occurring in at least 1% of patients, and chest pain, palpitations, tachycardia and postural hypotension are excluded from the list because they occurred with equal or greater frequency in patients on placebo. Though the mean change in QTc in 338 patients in short-term trials of mirtazapine was +1.6 msec for mirtazapine and –3.1 ms for placebo, prolongation in QTc to ‡500 msec was not observed in any patient. Mirtazapine and placebo were associated with a mean increase in heart rate of 3.4 versus 0.8 bpm, respectively.
Clinical trials
In patients on reboxetine or placebo, tachycardia and hypotension were reported in 5 versus 2% [95] and in 10.7 versus 0% [96], respectively, of patients. In a longer-term study, sinus tachycardia on ECG and hypertension occurred in 5 versus 0% and in 3 versus 1%, respectively, of patients on reboxetine and placebo [95]. Heart rate variability
In patients with MDD, reboxetine was not associated with any decrease in vagally mediated measures of HRV [97]. A decrease in absolute and relative low frequency power, indicating reduction in central sympathetic outflow, was noted that, however, was reversed with continued use of reboxetine. Overdose
No ECG abnormalities were reported after overdose with reboxetine alone [98].
High-risk population
In a placebo-controlled RCT in 91 depressed post-myocardial infarction patients, mirtazapine 30–45 mg/d was not associated with significant changes in heart rate, BP or PR, QRS and QTc intervals [90]
Vilazodone
The Prescribing Information [89] notes that since mirtazapine was introduced, four cases of torsades de pointes were reported that were temporally related to use of the drug. However, in three of the four cases, other drugs were implicated. All four patients were noted to have recovered.
Vilazodone, introduced in the US in 2011, is a partial agonist at 5-HT1A receptors and an inhibitor of the serotonin transporter. The Prescribing Information [99] notes that in placebocontrolled trials, palpitations were reported by 2% of patients on vilazodone versus
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Expert Rev. Neurother. 14(5), 539–551 (2014)
Rajnish Mago1, Neeta Tripathi2 and Chittaranjan Andrade*3 1 Department of Psychiatry and Human Behavior, Mood Disorders Program, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA 2 Hamilton Cardiology Associates, Hamilton, NJ, USA 3 Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore, India *Author for correspondence: Tel.: +91 080 2699 5109 Fax: +91 080 2656 4830 [email protected]
Newer antidepressants that are more selective in their neurotransmitter effects include the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others (agomelatine, bupropion, mirtazapine, reboxetine, vilazodone, vortioxetine). This article systematically reviews data from a variety of sources regarding the potential adverse effects of these medications on various cardiovascular parameters. Potential biochemical mechanisms by which these antidepressants may adversely affect the cardiovascular system are also discussed. Antidepressants that are associated with higher cardiovascular risk (SNRIs, reboxetine), lower risk (SSRIs), and without current evidence of cardiovascular risk (agomelatine, mirtazapine, vilazodone, vortioxetine) are identified. The FDA’s recommendations regarding citalopram are organized and summarized, and situations with higher risk of cardiovascular adverse effects are identified. KEYWORDS: adverse effects • antidepressants • blood pressure • cardiovascular • electrocardiogram • orthostatic hypotension • QT interval • side effects • serotonin-norepinephrine reuptake inhibitors • selective serotonin reuptake inhibitors
The 12-month prevalence of major depressive disorder (MDD) in the USA is 6.7% [1]. This prevalence is higher in patients with cardiovascular disease (CVD) [2]. Reciprocally, patients with depression are at increased risk of coronary artery disease [2,3]. Therefore, there is increasing emphasis on efforts to prevent CVD in patients with depressive disorders and to treat depression in patients with CVD. The potential cardiovascular effects of tricyclic antidepressants (TCAs) are well known; for example, TCAs can cause orthostatic hypotension, slowed cardiac conduction and increased heart rate [4], and the use of TCA can worsen cardiovascular outcomes [5]. TCAs are therefore best avoided in patients with preexisting CVD. Although antidepressants introduced in the mid-1980s and later are safer, they are not devoid of the risk of cardiovascular adverse effects (AEs). Knowledge of such risks is important, especially in subgroups of patients at higher risk of developing adverse cardiovascular events. In this article, we critically review possible cardiovascular AEs of newer antidepressants and make recommendations regarding their use. Potential cardiovascular benefits of antidepressants [6] are beyond the purview of this article. informahealthcare.com
10.1586/14737175.2014.908709
Methods
We present a qualitative review of representative data; there is too much literature to permit a comprehensive review. In order to attribute an AE to a drug, we compared the incidence of abnormal outcomes between drug and placebo in the same study. For this, we used a variety of sources of data; if the data converged, confidence in the associations (or lack thereof) was enhanced. Studies were identified by a PubMed search of the MEDLINE database and by reviewing the references of the articles retrieved. Given the extensive confusion and disagreement in the literature, we have taken a somewhat novel approach. The study of uncommon AEs that are hard to detect in usual clinical trials can be enhanced by combining the use of animal studies, studies of normal volunteers, metaanalyses of clinical trials, use of unusually high doses of the medication, use of the medication in populations that are more vulnerable (patients who were elderly or had underlying cardiac disease), and studies of overdose on the medication. It is these types of studies that are the main substance of our paper. Where available, we also examined postmarketing surveillance studies because these provide large
2014 Informa UK Ltd
ISSN 1473-7175
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samples that allow the detection of uncommon AEs. We considered the studies of supratherapeutic doses and reports of overdose to be helpful in a limited way: if an AE does not occur (or occurs rarely) on supratherapeutic doses or after overdose, it is unlikely that that the AE would occur at therapeutic doses. On the other hand, though, occurrence of an AE in supratherapeutic or overdose circumstances does not necessarily indicate that that the AE will also occur at therapeutic doses. We deliberately excluded observational studies (of which there are many) because while associations found in these studies are tantalizing, residual effects of known and unknown confounders cannot be fully ruled out. We also excluded case reports, but case series were included for data on overdose because no alternative is feasible. Case reports and observational studies are invaluable and absolutely essential for initial identification of a potential problem, but have high potential for bias. We did not review uncontrolled studies because these do not offer a yardstick against which outcomes can be compared. Where possible, we also avoided reference to clinical trials where fewer than 100 patients received the drug because, being underpowered, such studies might offer false reassurance. Exceptions were made where larger studies were not available and when the trial was conducted in a high-risk population. We followed the recommendations of Mago et al. [7] regarding methodological issues that are important in studying AEs of drugs. Since mean changes in a variable may mask the presence of clinically significant changes in a few patients, we examined the incidence of clinically defined abnormal values, instead. Considerable interest has focused on prolongation of ventricular repolarization, represented by prolongation of the QT interval on the ECG. This is a surrogate marker of risk of cardiac arrhythmias, though the QT interval alone might not correspond directly to the risk of torsades de pointes [8]. The QT interval is interpreted after correction for heart rate, most commonly using the Bazett (QTcB = QT/(R–R)½) or Fridericia (QTcF = QT/(R–R)1/3) formulae. As the QTcB overcorrects when the heart rate is >100 beats per minute (bpm), the QTcF should be used when tachycardia is present. Mechanisms underlying & variables mediating antidepressant-induced cardiovascular AEs
That serotonin affects the cardiovascular system should not be surprising since serotonin was first isolated from serum (sero-) in the mid-twentieth century and was noted to promote constriction of smooth muscle (-tonin) [9]. Stimulation of serotonin receptors can affect cardiovascular functioning both directly and indirectly – directly in the heart and peripheral vasculature and indirectly through central effects. Noradrenergic effects on the heart have likewise long been recognized. A detailed discussion on the physiology of serotonin and noradrenaline in relation to the cardiovascular system is beyond the scope of this review; however, in order to establish biological plausibility for the rest of this review, we briefly mention some important mechanisms through which serotonin and noradrenaline and serotonergic 540
(e.g., selective serotonin reuptake inhibitor [SSRI]) and noradrenergic antidepressant drugs may trigger cardiovascular AEs. Direct effects of serotonin & SSRI drugs on cardiovascular physiology
Serotonin is found in the heart, where it has many complex and even opposing effects [10]. Serotonin receptors are present on cardiac myocytes as well as on the vagus and sympathetic nerves [11]. In humans, stimulation of 5-HT4 receptors leads to increased heart rate [10], and serotonin tends to increase atrial and ventricular activity as well as atrial and ventricular arrhythmias in humans mainly through activation of 5-HT4 receptors [12]. Serotonin effects on 5-HT1B, 5-HT1D and 5-HT2A receptors may cause vasoconstriction of coronary arteries, especially if these arteries are affected by atherosclerotic changes [13–16]; ischemic events may be triggered by these effects [6,17]. SSRIs have been shown to inhibit the delayed rectifier potassium (IKr) ion channel that is involved in cardiac repolarization; this ion channel is coded by the human ether-a-gogo-related gene (hERG) [18]. The dose-dependent QT prolongation associated with SSRIs may be related to this effect rather than to their primary action of blockade of serotonin reuptake [19–21]. Indirect effects of serotonin on cardiovascular physiology
Stimulation of 5-HT1 receptors on sympathetic nerve terminals inhibits the release of norepinephrine [10]. Stimulation of central 5-HT1A receptors reduces sympathetic activity and increases vagal activity, both of which decrease blood pressure [22]. On the other hand, stimulation of central 5-HT2A receptors can increase blood pressure [23]. SSRI drugs: cardiovascular effects of metabolites & enantiomers
It is possible that specific metabolites of an antidepressant are particularly associated with cardiovascular AEs. For example, citalopram is metabolized by CYP2C19 and 3A4 to desmethylcitalopram, and then by CYP2D6 to didesmethylcitalopram. Didesmethylcitalopram, which was associated with QT prolongation in beagle dogs, is usually a minor metabolite in humans; however, in CPY2D6 ultrarapid metabolizers, its levels may increase, and this may lead to an increased risk of QT prolongation [24]. It is also possible that specific optical isomers of SSRIs may be associated with cardiovascular AEs. For example, QTc prolongation in overdose is more common with racemic citalopram than with escitalopram (which suggests that R-citalopram carries a greater burden of cardiovascular risk); and R-fluoxetine, the active enantiomer of fluoxetine, also prolongs the QTc, the action of which is relatively absent with racemic fluoxetine [25]. Other effects of serotonin & SSRI drugs on cardiovascular physiology
Heart rate variability (HRV) is a less studied measure of the cardiovascular effects of antidepressants. HRV describes Expert Rev. Neurother. 14(5), (2014)
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beat-to-beat changes in heart rate in response to fluctuating environmental demands. HRV is mediated by cardiac autonomic control and requires a healthy myocardium. Decreased HRV indicates a decreased capacity of the heart to respond to environmental needs. A decrease in HRV has been associated with ventricular arrhythmias, other adverse cardiac events and cardiac mortality, including sudden cardiac death [26,27]. Some data suggest that SSRIs probably do not significantly affect the HRV [28]. However, in a small study of patients with MDD and healthy volunteers, treatment with SSRIs was associated with increased pulse pressure and with decreased vagal activity as indicated by decreased cardiac baroreflex function and HRV [29]. There is a dearth of published data about HRV with most other antidepressants. The relationship between serotonin and pulmonary arterial hypertension (PAH) was brought into the limelight due to the association of various diet pills with PAH. It is now known that serotonin is involved in both pulmonary arterial vasoconstriction (mediated by 5-HT1B receptors) and pulmonary vascular remodeling, and thus plays a role in clinical and experimental PAH [30]. In this regard, it is significant to note that an association between maternal use of SSRIs in the third trimester and neonatal persistent pulmonary hypertension of the newborn (PPHN) [31].
and conduction [33]. Thus, when serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit norepinephrine reuptake, they can potentiate sympathetic vasoconstriction in a dosagedependent manner [34]. Data suggest that, like TCAs, venlafaxine may also block sodium channel conductance in the heart [35]. Duloxetine is known to increase norepinephrine levels peripherally and to increase sympathetic tone [36]. In vitro studies of human atrial myocytes have, however, failed to show any AE of duloxetine on any of the human cardiac ion channels tested, including cardiac sodium current, transient outward potassium current, sustained current or the inwardly rectifying potassium current which is associated with prolongation of the QT interval [37]. Most noradrenergic drugs also have serotonergic effects (e.g., venlafaxine, duloxetine), and so some serotonergic mechanisms, at least, would be recruited in the cardiovascular actions of these noradrenergic antidepressants.
Serotonin & SSRI drugs: what is the net effect?
SSRIs & blood pressure
The net result of various effects of serotonin on the cardiovascular system is that in different areas of the vasculature, serotonin can cause either vasoconstriction or vasodilatation, and may increase or decrease blood pressure [10]. It is important to note that despite the data on the various physiological effects of serotonin, for example, vasoconstriction or increase/decrease in blood pressure, these mechanisms do not necessarily translate into a clinical effect. Thus, precedence must be given to the empirical data discussed in the rest of this paper rather than to potential underlying mechanisms. Also, given the many ways in which serotonin and SSRI drugs can affect cardiovascular functioning, there is no way of predicting effects in the individual patients; results would obviously depend on individual variations in pharmacokinetics and pharmacodynamics. As our review will show, SSRI drugs enjoy a wide margin of cardiac safety. Nevertheless, there are specific though uncommon situations of risk.
The effect of SSRIs on blood pressure remains unclear. While fluoxetine was found in one study to increase blood pressure in some patients [40], other studies found no significant effect on blood pressure in humans [10].
Noradrenaline & noradrenergic drugs
Noradrenaline (norepinephrine) has a variety of peripheral effects that contribute to increasing blood pressure including increase in heart rate and contractility, vascular tone, reabsorption of sodium by the kidney and activity of the renninangiotensin system [32]. The norepinephrine transporter (NET) is the key factor regulating norepinephrine concentrations both centrally and peripherally, and it plays a role in the pathophysiology of several CVDs [32]. Norepinephrine binds to a and b adrenergic receptors in the myocardium and blood vessels, which results in increased heart rate, blood pressure, contractility informahealthcare.com
SSRIs & cardiovascular AEs SSRIs & heart rate
Both citalopram and fluoxetine are associated with small decreases in heart rate compared to placebo [38–40]. This decrease in heart rate may occur early on, within the first 2 weeks [39], suggesting that reduction in anxiety may not explain this change.
SSRIs & the QT interval
Much evidence shows that SSRIs have far greater cardiovascular safety than the TCAs. For example, in an early paper evaluating the cardiac safety of citalopram (10–60 mg/d), no significant effect on cardiac conduction or repolarization over short- or long-term treatment was found [38]. A review of the effects of various psychotropic medications on the electrocardiogram suggested that sertraline, paroxetine and citalopram were not associated with significant changes in the QT interval [41]. In beagle dogs, citalopram in doses four times higher than those used in humans was noted to cause QT prolongation and death [38]. Concerns were expressed in humans, as well. In August 2011, the United States Food and Drug Administration (FDA) [42] issued a Drug Safety Communication stating that citalopram causes dose-dependent QT interval prolongation and therefore should not be prescribed at >40 mg/day, and not at all in patients with congenital long QT syndrome. The guidance was brief and without detail. Subsequently, in March 2012, the FDA [43] issued revised recommendations with guidance regarding various situations as summarized in BOX 1. The FDA communication was based on two strands of evidence: post-marketing reports of QT interval prolongation and torsades de pointes arrhythmias associated with use of citalopram and 541
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Box 1. FDA’s revised recommendations for citalopram and risk of abnormal heart rhythms. Patient selection Citalopram is not recommended for patients who: • Have congenital long QT syndrome • Have bradycardia • Have hypokalemia or hypomagnesemia • Had a recent acute myocardial infarction, or uncompenExpert Review of Neurotherapeutics Downloaded from informahealthcare.com by Imperial College London on 06/16/14 For personal use only.
sated heart failure • Are taking other drugs that prolong the QT interval
Dosing The maximum recommended dose of citalopram is 20 mg/day for patients: • > 60 years old • With hepatic impairment • Who are CYP 2C19 poor metabolizers • Who are taking a CYP2C19 inhibitor
Patient education • Patients should be told to contact a healthcare professional
immediately if they have symptoms like dizziness, palpitations, or syncope that may indicate a problem with the heart rate or rhythm Recommended monitoring • Electrolyte and/or ECG monitoring in ‘certain circumstances’ • Serum potassium and magnesium at baseline and periodi-
cally in patients at risk for significant electrolyte disturbances • More frequent ECG monitoring in patients for whom citalo-
pram use is not recommended, but is considered essential Recommended actions • Hypokalemia and/or hypomagnesemia should be corrected
before starting citalopram • If the QTc is persistently > 500 msec, citalopram should be
discontinued • If symptoms like dizziness, palpitations, or syncope occur,
further evaluation and monitoring should be done Data taken from [43].
review of two unpublished ‘thorough’ [44] QT studies. In these two randomized, double-blind, placebo-controlled, crossover studies (n = 119 and 113 for the citalopram and escitalopram studies, respectively), subjects were randomized to citalopram (20 mg/d, 60 mg/d) or escitalopram (10 mg/d, 30 mg/d) with moxifloxacin 400 mg/d and placebo as controls. These studies showed that citalopram caused QT prolongation that was clinically significant at 60 mg/d. The FDA therefore recommended that citalopram should not be used at doses above 40 mg/d. At doses of up to 20 mg/day, escitalopram was not associated with QTc prolongation, and the label for escitalopram was not modified. In a recent placebo-controlled study in elderly patients with Alzheimer’s disease [45], citalopram was associated with greater increase in the QTc interval than placebo. Four patients (three 542
on citalopram and one on placebo) showed QTc prolongation, defined as >450 msec for men and >475 msec for women. Is the risk of QT prolongation limited to citalopram among the SSRIs? In 469 cases of overdose on an SSRI, QT prolongation after overdose on citalopram was greater than that after overdose on other SSRIs [46]. In 68% of overdoses on citalopram, the QTc was >440 msec. It should be noted that in the study described in the FDA communication, at 30 mg/d, escitalopram was associated with QTc prolongation greater than at 20 mg/d and similar to that with moxifloxacin. Caution with regard to escitalopram is also supported by the frequency and type of ECG effects of overdose on escitalopram being similar to those after overdose on citalopram [47]. Potential risk for torsades de pointes was found in 14% and bradycardia in 11% of patients who had overdosed on escitalopram. The European Medicines Agency has made changes to the Summary of Product Characteristics for both citalopram [48] and escitalopram [49] that are very similar to those made by the FDA for citalopram (BOX 1). For escitalopram, the initial dose for patients >64 years of age was reduced to 5 mg/day with the option to increase to 10 mg/day based on response. The EMA noted that, in addition to other known risk factors, the risk of QT prolongation is greater in female patients [49]. In July 2013, the FDA issued a safety warning for fluoxetine, as well, citing postmarketing reports of QT prolongation and ventricular arrhythmias, including torsades de pointes, associated with the use of fluoxetine [50]. Precautions similar to those for citalopram were recommended. Another type of study that supports the potential of SSRIs to cause QT prolongation compared the QTc intervals in neonates exposed to SSRIs immediately before birth (n = 52) to those in 52 matched control neonates [51]). The mean QTcB (replicated using QTcF) was statistically significantly longer in neonates exposed to SSRIs as compared with controls. Using a cut-off of >460 msec (widely used for neonates), five neonates exposed to SSRIs had prolonged QTc (up to 543 msec) compared to none in the control group. The QTc prolongation returned to normal in all cases. JT intervals were also longer in neonates exposed to SSRIs, indicating delayed cardiac repolarization. The authors recommended that ECGs be considered in neonates who were exposed to an SSRI immediately prior to birth. SSRIs & HRV
A review of the data on the effects of SSRIs on HRV [27] noted that in studies with recordings of short duration, a significant decrease in heart rate and an increase in HRV were found. On the other hand, two 24-h recording studies did not find any significant changes in HRV. A meta-analysis of the effects of depression and antidepressants on HRV also did not find SSRIs to either increase or decrease HRV [28]. SSRIs in patients with CVD
In a randomized controlled trial (RCT) of 81 patients with a depressive disorder and ischemic heart disease, patients received paroxetine 20–30 mg/d or nortriptyline (serum level, 50 to Expert Rev. Neurother. 14(5), (2014)
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150 ng/ml) [52]. Patients on paroxetine had a significantly lower incidence of adverse cardiac events (2%) compared those on nortriptyline (18%). Nortriptyline but not paroxetine was associated with increased heart rate. Neither drug significantly affected blood pressure or cardiac conduction. In a small study, 27 elderly depressed patients with congestive heart failure, cardiac conduction disturbances and/or ventricular arrhythmias were treated with fluoxetine (up to 60 mg/d) for 7 weeks or nortriptyline (50–150 ng/ml) for 3 weeks [53]. Fluoxetine was not associated with tachycardia, cardiac conduction abnormalities, ventricular arrhythmias, orthostatic hypotension or decrease in ejection fraction. Instead, there was a 6% decrease in heart rate, a 2% increase in supine systolic blood pressure and a 7% increase in ejection fraction in patients with a baseline ejection fraction £50%. Cardiovascular adverse events occurred in 4% of patients on fluoxetine versus 20% of those on nortriptyline. In a small (n = 54), placebo-controlled RCT of fluoxetine vs placebo in MDD patients recruited 3 to 12 months after an MI, no AEs of fluoxetine were observed on ECG and echocardiography assessments [54]. An important RCT provided reassurance about the safety of sertraline in patients with MDD and acute ischemic heart disease (SADHART) [55]. Patients (n = 369) with acute myocardial infarction (75%) or unstable angina (25%) within the last 30 days were randomized to treatment with sertraline or placebo. Detailed safety assessment over 6 months of followup using ECG, Holter monitoring, echocardiograms and other parameters found no statistically significant difference in the incidence of serious cardiovascular events (14.5% on sertraline vs 22.4% on placebo; NS). Similarly, no significant differences between sertraline and placebo were found for left ventricular ejection fraction, QT interval and other safety measures. No differences on any cardiovascular outcome measure between sertraline and placebo were found among 469 patients with MDD and congestive heart failure (SADHART-CHF RCT) [56]. The safety and indeed the possible benefits of SSRIs in patients with CVD were recently reviewed [6], and readers are referred to this review for more information on the subject. SSRIs & overdose
Of 26 cases of overdose on citalopram, 8 of 24 subjects with ECG available had a QTc of >450 msec [57]. However, the Bazett correction was used, which could be misleading in the presence of tachycardia that was present in 15 of the 26 patients. Bundle branch block and severe bradycardia occurred in three patients and one patients, respectively. Other studies of overdose on SSRIs have been discussed in an earlier section. Adding support to the relationship between citalopram overdose and QTc prolongation is the finding that in the 52 patients who had overdosed on citalopram, QTc was linearly related to the predicted plasma citalopram concentration [58]. informahealthcare.com
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Summary
SSRIs appear to have good cardiovascular safety, including in patients with preexisting CVD. They do not appear to cause hypertension but may be associated with changes in heart rate. Nevertheless, it should not be disregarded that in patients with other high risk factors, SSRIs (citalopram, escitalopram and fluoxetine in particular, especially in higher relative to lower doses) may be associated with prolongation of the QTc, thereby increasing the risk of serious ventricular arrhythmias. In such high-risk situations, caution and increased monitoring are strongly recommended. It must also be kept in mind that SSRIs may be responsible for indirect risks in patients with CVD. These risks may arise from pharmacokinetic or pharmacodynamic interactions with cardiovascular drugs [6,59–62]. Pharmacokinetic drug–drug interactions mediated by the cytochrome P450 system are more likely to occur with fluoxetine and paroxetine that are potent inhibitors of CYP2D6 (substrates include various b blockers, clonidine, etc.) and fluvoxamine that is a potent inhibitor of CYP1A2 (substrates include verapamil, propranolol, warfarin, etc.). Serotonin-norepinephrine reuptake inhibitors
In contrast to the SSRIs, SNRIs have been associated with a higher incidence of cardiovascular AEs. Sibutramine, an SNRI approved for promoting weight loss, was withdrawn from the market in 2010 due to association with increased blood pressure, cardiovascular adverse events and stroke [63]. Venlafaxine Healthy volunteers
Venlafaxine decreased HRV, prolonged the dilatation phase of the vasoconstrictor response and increased resting pupil diameter. Venlafaxine also decreased the amplitude of the pupillary light reflex, increased its latency and shortened its recovery time [64]. These findings suggest that venlafaxine increases sympathetic activity in cutaneous blood vessels and the iris and increases centrally mediated parasympathetic inhibition. Meta-analysis of placebo-controlled clinical trials
A venlafaxine (25–375 mg/d; n = 2817) meta-analysis found that the incidence of sustained elevation in supine diastolic blood pressure (DBP) was 4.8% on venlafaxine versus 2.1% on placebo. There was a strong dose effect with increase in supine DBP prominent at higher doses; on venlafaxine >300 mg/day the incidence was 9.1% [65]. This dose relationship is also consistent with serotonin reuptake inhibition being the main effect of venlafaxine at lower doses and norepinephrine reuptake inhibition becoming clinically significant at higher doses. The risk of elevation in DBP was greater in older patients and in men. Unusually high doses
In a small study (n = 37) of the use of higher dose venlafaxine (mean, 346 mg/d), no changes in ECG were found [66]. 543
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In a study of 369 cases of overdose on 75 to 13,500 mg of venlafaxine [67], tachycardia, mild hypertension, severe hypertension and hypotension occurred in 54, 40, 3 and 5% of cases, respectively. No arrhythmias were found on continuous telemetry, and QRS was >120 msec in 7% cases. In another study of 235 cases of overdose on venlafaxine (919–2800 mg), tachycardia, hypertension and QTc >450 msec occurred in 40, 28 and 11% of cases, respectively [68].
Overdose: We did not find any published reports of desvenlafaxine overdose, and the Prescribing Information updated in 2013 [49] refers only to venlafaxine overdose [71]. Duloxetine Laboratory studies
In a study of 71 normal adult females given a single dose of desvenlafaxine 200 or 600 mg/d to assess effects of the drug on QTcF, no significant changes were found [69].
In conscious rodent and canine models, duloxetine did not significantly affect heart rate or blood pressure [72]. Similarly, 1 year of treatment with duloxetine did not significantly affect canine heart rate, rhythm or conduction [72]. In vitro data suggest that inhibitory effects of duloxetine on cardiac hERG channels are probably negligible in therapeutic concentrations of the drug; however, hERG block may occur in duloxetine overdose and when the drug is administered to patients who are susceptible to drug-induced QT prolongation [73].
Review of placebo-controlled clinical trials
Meta-analysis of placebo-controlled clinical trials
In a review of all short-term registration RCTs of desvenlafaxine (50–400 mg/d) for MDD [70] (readers are reminded that the recommended dose of desvenlafaxine is 50 mg/d), changes in pulse and BP were as follows:
The cardiovascular AEs of duloxetine were assessed using data from all placebo-controlled RCTs (n = 8504 on duloxetine) [72]. QRS and QTcF intervals were decreased from baseline in patients on duloxetine and increased in patients on placebo. Duloxetine did not prolong the QTcF interval. Small increases in heart rate on duloxetine and small decreases on placebo were observed. In another analysis of placebo-controlled RCTs in diabetic patients with or without a history of CVD, patients treated with duloxetine were not found to differ in the incidence of cardiovascular adverse events, mean changes in blood pressure or rates of sustained hypertension [72].
Desvenlafaxine Healthy volunteers
• There were small increases in mean systolic blood pressure (SBP), DBP and pulse rate in desvenlafaxine patients that were statistically significantly greater than those in placebo patients. • ‘Clinically important’ changes in BP occurred in 2% of patients on desvenlafaxine versus 1% of those on placebo. • Using a higher threshold based on regulatory criteria for potentially clinically important changes in SBP (increase by ‡20 mmHg and value ‡180 mmHg; decrease by ‡20 mmHg and value £90 mmHg), DBP (increase by ‡15 mmHg and value ‡105 mmHg; decrease by ‡15 mmHg and value £50 mmHg) and pulse rate (increase by ‡15 bpm and value ‡120 bpm; decrease by ‡15 bpm and value £50 bpm), the incidence of such changes was £1% and did not differ from placebo. Sustained elevation of supine DBP (increase by ‡10 mmHg and value ‡90 mmHg for three consecutive visits) was reported in 2.3% of patients on 400 mg/day of desvenlafaxine versus 0.5% on placebo. No significant ECG differences were found between desvenlafaxine and placebo: • The QRS interval in patients on desvenlafaxine 400 mg/day was decreased from baseline relative to the lower dose groups and to placebo but, overall, there was no significant change in the QRS interval from baseline in patients on desvenlafaxine. • The mean QT interval in patients on desvenlafaxine was statistically significantly decreased (–1.17 msec) from baseline compared to those on placebo (+5.39 msec). • In the fixed-dose studies, patients on 50 mg/day or 100 mg/ d had a significant increase in QT interval from baseline, whereas the 400 mg/day group had a significant decrease. • Potentially clinically significant (PCS) ECG findings occurred in similar percentages of patients in the desvenlafaxine and placebo groups. 544
Supratherapeutic doses
The cardiovascular effects of supratherapeutic doses of duloxetine were assessed in a study of 117 women, aged 19–74 years, in whom the dose of duloxetine was increased over 16 days from 120 mg/d to 400 mg/d [74]. Increases in supine pulse rate, SBP and DBP (maximum increase, 12 bpm, 12 mmHg and 7 mmHg, respectively) were found along with orthostatic changes in pulse and BP that were usually asymptomatic. The increase in blood pressure was not specific to patients who had high normal BP at baseline, indicating that those patients were not at higher risk of such increase. A companion paper based on the same study [75] compared the effects of supratherapeutic doses of duloxetine on the ECG, with placebo and moxifloxacin as controls. No increase in QTcF was found; the upper limits of the two-sided 90% confidence intervals for duloxetine versus placebo were 445 ms or an increase from baseline of >36 ms. Levomilnacipran
Levomilnacipran is an SNRI that was approved by the FDA in 2013 for the treatment of MDD. It is twice as potent at norepinephrine relative to serotonin reuptake inhibition, which differentiates it from SNRIs like duloxetine and venlafaxine that have greater potency for serotonin relative to norepinephrine reuptake inhibition [76]. Expert Rev. Neurother. 14(5), (2014)
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Cardiovascular adverse effects of newer antidepressants
Review
Blood pressure
Clinical trials
In short-term clinical trials of levomilnacipran, sustained systolic hypertension (SBP ‡140 mm Hg and increase of ‡15 mm Hg from the baseline for three consecutive visits) or sustained diastolic hypertension (DBP ‡90 and ‡10 mm Hg increase for three consecutive visits) was found in 1.8% of patients on levomilnacipran and 1% of placebo patients [77]. Sustained systolic and sustained diastolic hypertension were both observed in 0.3% of levomilnacipran patients versus 0.1% of placebo patients. In a 1-year extension study [78], elevated BP that was considered to be a treatment-emergent adverse event (TEAE) was reported in 4.5% of levomilnacipran patients; six patients prematurely discontinued this study due to elevated blood pressure. Orthostatic hypotension (systolic or diastolic) was reported in 11.6% of patients on levomilnacipran and 9.7% of patients on placebo [77].
The Prescribing Information reports the incidence of palpitations to be greater on bupropion 400 mg/day versus placebo (6 vs 2%).
Heart rate
In short-term clinical trials, there was a mean increase in heart rate of 7.4 bpm in patients on levomilnacipran versus a mean decrease of 0.3 bpm in patients on placebo [77]. While one study [79] noted that no patient in the levomilnacipran group met PCS criteria for change in heart rate, the other short-term studies did not report the proportion of patients meeting criteria for a clinically meaningful increase in heart rate. Mago et al. [76] suggested that in this situation the reporting of increased heart rate as a TEAE, though not based on standardized criteria, may be considered a proxy for significantly increased heart rate. In some of the short-term studies [80,81], increased heart rate was reported as a TEAE in more patients on levomilnacipran than on placebo. In the open-label phase of a relapse prevention study [82], increased heart rate was reported as a TEAE in 7.4% of patients on levomilnacipran. QT interval
While small increases in QTcB that were greater than those on placebo were found in short-term studies of levomilnacipran, these may be attributed to the increased heart rate. In the 1-year extension study [78], no patient had a QTcF >500 msec. Overdose
There are no published reports of overdose on levomilnacipran. The Prescribing Information [77] notes that in clinical studies, cases of ingestion of levomilnacipran up to 360 mg daily were reported without any fatalities.
High-risk populations
The cardiovascular safety of bupropion was assessed in an RCT of bupropion (300 mg/day) for smoking cessation in 248 smokers admitted for acute CVD (mainly myocardial infarction and unstable angina) [83]. Bupropion and placebo groups did not differ significantly in cardiovascular mortality at 1 year (0 vs 2%), in BP at follow-up or in cardiovascular events at end-of-treatment (16 vs 14%) or end of 1 year (26 vs 18%) analyses. No difference between bupropion and placebo was found in vital parameters or cardiovascular adverse events in 151 patients with acute coronary syndrome (myocardial infarction or unstable angina) randomized to the two groups [84]. An RCT of 300 patients with untreated stage 1 hypertension (SBP 140–159 mmHg and/or DBP 90–99 mmHg) were randomly assigned to 4 weeks of treatment with bupropion sustained release 150, 300 or 400 mg/day, or to placebo [85]. Importantly, assessments included ambulatory monitoring of blood pressure. The proportion of patients with an increase of ‡10 mmHg in SBP and/or ‡6 mmHg in DBP was not significantly different between bupropion and placebo groups. However, an increase in heart rate of ‡10 bpm at any two consecutive visits or ‡15 bpm at any single visit occurred in 30 and 15% of patients on bupropion 400 mg/day and placebo, respectively, which was a statistically significant difference. Overdose
The Prescribing Information [86] notes that overdoses on bupropion alone have been associated with sinus tachycardia and with ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. However, a review of 7348 cases of bupropion-only overdose [87] confirmed the findings of previous studies of bupropion overdose that except for tachycardia, which occurs in about a third of cases, cardiovascular AEs are rare after overdose. Summary
It appears that, with the exception of tachycardia, bupropion is unlikely to be associated with significant cardiovascular AEs.
SNRIs: summary
Mirtazapine
Overall, different sources of information converge to demonstrate that SNRIs are associated with a small but definite risk of tachycardia, hypertension and orthostatic hypotension. However, in therapeutic doses, they do not seem to cause QTc prolongation.
Mirtazapine is an antagonist of central a2 adrenergic autoreceptors and heteroreceptors. This action of mirtazapine leads to increased release of norepinephrine and serotonin. Mirtazapine also blocks 5-HT2 and 5-HT3 receptors.
Bupropion
Heart rate variability
Bupropion is an antidepressant that weakly inhibits the reuptake of norepinephrine and dopamine and does not belong to any other class of antidepressants.
In a small study in patients with unipolar depression, 4 weeks of treatment with mirtazapine (n = 10) did not normalize preexisting abnormalities in HRV [88]. Rather, it was associated
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with an increase in heart rate and a decrease in HRV, though less so than imipramine (n = 10).
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Placebo-controlled clinical trials
The Prescribing Information for mirtazapine [89] notes that this drug was not associated with any cardiovascular symptom or sign at a frequency greater than that with placebo. The Merck list is limited to events occurring in at least 1% of patients, and chest pain, palpitations, tachycardia and postural hypotension are excluded from the list because they occurred with equal or greater frequency in patients on placebo. Though the mean change in QTc in 338 patients in short-term trials of mirtazapine was +1.6 msec for mirtazapine and –3.1 ms for placebo, prolongation in QTc to ‡500 msec was not observed in any patient. Mirtazapine and placebo were associated with a mean increase in heart rate of 3.4 versus 0.8 bpm, respectively.
Clinical trials
In patients on reboxetine or placebo, tachycardia and hypotension were reported in 5 versus 2% [95] and in 10.7 versus 0% [96], respectively, of patients. In a longer-term study, sinus tachycardia on ECG and hypertension occurred in 5 versus 0% and in 3 versus 1%, respectively, of patients on reboxetine and placebo [95]. Heart rate variability
In patients with MDD, reboxetine was not associated with any decrease in vagally mediated measures of HRV [97]. A decrease in absolute and relative low frequency power, indicating reduction in central sympathetic outflow, was noted that, however, was reversed with continued use of reboxetine. Overdose
No ECG abnormalities were reported after overdose with reboxetine alone [98].
High-risk population
In a placebo-controlled RCT in 91 depressed post-myocardial infarction patients, mirtazapine 30–45 mg/d was not associated with significant changes in heart rate, BP or PR, QRS and QTc intervals [90]
Vilazodone
The Prescribing Information [89] notes that since mirtazapine was introduced, four cases of torsades de pointes were reported that were temporally related to use of the drug. However, in three of the four cases, other drugs were implicated. All four patients were noted to have recovered.
Vilazodone, introduced in the US in 2011, is a partial agonist at 5-HT1A receptors and an inhibitor of the serotonin transporter. The Prescribing Information [99] notes that in placebocontrolled trials, palpitations were reported by 2% of patients on vilazodone versus
