Towards Limiting QT Interval Prolongation and Arrhythmia Risk in Citalopram Use Yihong Zhang1, Adrian Baranchuk2, Jules C

Cardiology Journal 2014, Vol. 21, No. 5, pp. 454–457 DOI: 10.5603/CJ.2014.0076 Copyright © 2014 Via Medica REVIEW ARTICLE ISSN 1897–5593 Towards limiting QT interval prolongation and arrhythmia risk in citalopram use Yihong Zhang1, Adrian Baranchuk2, Jules C. Hancox1 1School of Physiology and Pharmacology and Cardiovascular Research Laboratories, Medical Sciences Building, University of Bristol, Bristol, United Kingdom 2Department of Cardiology, Kingston General Hospital, Queens University, Kingston, Ontario, Canada Psychotropic actions of citalopram and [7, 8]). Citalopram has been reputed to have and escitalopram a good safety profile within the clinical concentration range making it an attractive alternative to tricyclic Citalopram is a serotonin-selective reuptake antidepressants [2, 9]. However, there is some inhibitor (SSRI) widely used in the treatment of evidence of QT prolongation and arrhythmia with major depression and sometimes also anxiety- citalopram (for reviews see [7, 8, 10]). Reviews of -associated conditions, obsessive compulsive data from United States and Swedish adverse effect disorder and behavior disturbances associated registries note ~20 cases of TdP associated with with dementia [1, 2]. Citalopram is relatively well citalopram [8, 11], with a number of additional case tolerated and has been considered to have compa- reports in the literature (for a recent review see: ratively low potential for drug–drug interactions [12]). Some case reports of QT prolongation have and anti-adrenergic and anti-cholinergic effects, also now emerged for escitalopram (e.g. [13–16]). making it an attractive treatment option for elderly Potential dangers with normal use of citalo- patients [1, 2]. The drug is chiral and the serotonin pram came to prominence in safety updates from reuptake inhibitory activity of citalopram resides the United States Food and Drug Administration in the S(+)-enantiomer (available as escitalopram) (FDA) [17, 18] as well as from other regulato- with no therapeutic benefit of the R(–)-enantiomer. ry agencies including the European Medicines There is limited evidence that at equivalent doses Agency (EMA) [19] and United Kingdom Medi- (i.e. matched concentrations of the S-enantiomer), cines and Healthcare Products Regulatory Agen- escitalopram is more effective clinically than is cy (MHRA) [20]. In August of 2011 [17] and in citalopram, raising the possibility of a potential in- a subsequent update in March 2012 [18], the FDA hibitory effect of the R-enantiomer [3–5]. Data from produced revised recommendations and warnings studies, in which serotonin reuptake transporter for citalopram, limiting the maximum daily dose (SERT) occupancy has been examined in humans, for all patients and reducing this further for older suggest that on repeated dosing with racemic ci- patients. The safety advisory information resulted talopram, R-citalopram levels may exceed those of from evaluation of ‘thorough QT’ data from rando- the S-enantiomer, leading to reduced S-citalopram mized, double-blind, placebo-controlled cross-over occupancy of SERT [6]. human subject studies on citalopram and escita- Citalopram, escitalopram lopram. Dose-dependent QTc prolongation was and QT prolongation found for both drugs in healthy volunteers, with greater effects for citalopram than therapeutically A number of psychotropic drugs are associated equivalent concentrations of escitalopram. The with prolongation of rate-corrected QT (QTc) inter- extent of QTc prolongation seen with given doses val and the associated risk of torsades de pointes of citalopram compared to therapeutically equiva- (TdP) arrhythmia (see: www.crediblemeds.org lent escitalopram doses was suggestive of cardiac Address for correspondence: Jules C. Hancox, PhD, FSB. FBPharmacolS, School of Physiology and Pharmacology and Cardiovascular Research Laboratories, Medical Sciences Building, University of Bristol, Bristol, BS8 1TD, United Kingdom, e-mail: [email protected] Received: 31.05.2014 Accepted: 21.07.2014 454 www.cardiologyjournal.org Yihong Zhang et al., Cardiac safety of citalopram actions of both citalopram enantiomers. Indeed, the citalopram and escitalopram, with approximately si- FDA safety announcement included a speculation milar IC50 values for citalopram and of escitalopram. that whilst antidepressant effects of citalopram are The R-enantiomer was not directly investigated limited to the S-enantiomer, the difference between in that study [27]. We have compared S(+), R(–) the two forms of drug on the QTc interval “presu- citalopram enantiomers and the racemic mixture mably means that the QT effects are not limited on hERG channels using patch clamp recording at to the S-isomer” [18, 21]. physiological temperature to elicit IhERG (cf [28]). As shown in Figures 1A–C, equal concentrations Citalopram and hERG channel inhibition of citalopram, escitalopram and R-citalopram produced similar levels of IhERG inhibition and con- Virtually all drugs associated with QTc interval centration response relations (shown in Fig. 1D) share in common the ability to produce pharma- yielded similar IC50 values (of 0.68 ± 0.08 µM, cological inhibition of ion channels mediating the 0.70 ± 0.06 µM and 0.67 ± 0.02 µM) for citalopram, cardiac rapid delayed rectifier potassium current escitalopram and R-citalopram respectively, under (“IKr”) and its cloned equivalent hERG — human- our recording conditions. These results comple- Ether-à-go-go-Related Gene [22]. IKr regulates ven- ment and extend the recent findings of Chae et al. tricular action potential duration and drugs that [27] and demonstrate clearly that, whilst only the inhibit IKr/hERG consequently delay ventricular S-citalopram enantiomer is of psychotropic value, repolarization and thereby prolong the QTc inter- both S(+) and R(–) citalopram enantiomers can be val [22]. Citalopram was first reported to inhibit expected to act on IKr/hERG acutely and, thereby, the hERG potassium channel in 2002 in a study to delay repolarization. from our laboratory, with a half maximal inhibitory concentration (IC50) for hERG current (IhERG) of Limiting cardiac risk 3.97 mM, slightly less than that for another SSRI, fluoxetine, in the same study (1.5 mM) [23]. A A logical conclusion from the information now subsequent independent study confirmed hERG available on hERG-blocking actions of citalopram block by citalopram (with a lower IC50 of 0.95 mM enantiomers together with the thorough QT data [24]). Therapeutic benefits of citalopram for major reported by the FDA [18] is that escitalopram depression appear to require plasma levels of 50 should confer a lower cardiac risk than citalopram ng/mL or greater [25], with maximal levels of ~120 for therapeutically equivalent concentrations ng/mL at therapeutic doses [9]. With a caveat that and therefore should be used clinically in place citalopram is highly lipophilic (so that the possibi- of racemic citalopram. Whilst our own findings lity of tissue accumulation must be borne in mind), (Fig. 1) support such a notion, some qualification therapeutic total plasma levels are expected to be is prudent at this time. First, it is known that ad- below ~200–300 nM, though raised levels could ditional concomitant ion channel blocking effects feasibly be attained in overdose or with metabolic can mitigate consequences of hERG channel impairment. hERG block at normal concentrations inhibition and citalopram has been found to exert may therefore normally not be high, but could be an additional weak inhibition of cardiac L-type increased in situations of impaired metabolism, Ca current (ICa,L) and to modify ICa,L kinetics [23, drug overdose or be exacerbated by cardiac effects 24, 29]. It is feasible that this weak action on ICa,L of electrolyte abnormalities. may mitigate effects of hERG blockade at high Given that the R-enantiomer of citalopram is citalopram concentrations. At present it is not yet without therapeutic benefit and, consequently, that fully established how these two channel effects of for the racemate twice the total quantity of citalo- citalopram interact and, indeed, whether the ICa,L pram is present than for escitalopram for a given action of citalopram is stereoselective. Additional therapeutically effective dose of the S-enantiomer, information on these points would be helpful. it has been suggested that moving patients from Second, cardiac side effects of citalopram need citalopram to escitalopram may be prudent in terms not commence immediately following dosing/in- of reducing cardiac risk [26]. Until recently, howe- gestion. One mechanism for delayed drug effects ver, there has been little or no information as to on the QTc interval is through inhibition of hERG whether or not the two citalopram enantiomers are channel trafficking to the cell membrane but, similar in their ability to inhibit hERG. Very recen- whilst there is some evidence that citalopram and tly, however, Chae et al. [27] have reported an in vi- escitalopram are in principle able to produce this tro comparison of the hERG-blocking propensity of effect [27], marked suppression of hERG function www.cardiologyjournal.org 455 Cardiology Journal 2014, Vol. 21, No. 5 Figure 1. Comparative inhibition of hERG potassium channels by citalopram enantiomers; A–C. Upper traces show representative traces of IhERG elicited from HEK293 cells expressing hERG by the voltage clamp protocol shown in the lower panel, in control and after 1 mM of citalopram (A), escitalopram (B), R(–) citalopram (C). D. Mean (± SEM)

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