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Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie logoLink to Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie
. 2015 May;60(5):206–214. doi: 10.1177/070674371506000502

Impact of Age and Sex on QT Prolongation in Patients Receiving Psychotropics

Simon W Rabkin 1,✉
PMCID: PMC4484689  PMID: 26174524

Abstract

Objective:

To assess older age and female sex, 2 of the major risk factors for potentially fatal cardiac arrhythmias or sudden cardiac death in patients prescribed psychotropics, within the context of electrocardiographic evidence of time between start of Q wave and end of T wave (QT) interval prolongation, which is an indicator of an increased risk for potentially fatal cardiac arrhythmias.

Method:

The literature on the relation between age, sex, and QT interval with respect to psychotropic drugs was reviewed.

Results:

The QT interval must be corrected (QTc) for heart rate. Because slower heart rates prolong and faster heart rates shorten the QT interval, people with faster heart rates may have a prolonged QT interval that is not apparent until the correction is performed. QTc values for apparently healthy post-pubertal people are less than 450 ms for males and less than 470 ms for females. The longer QT intervals in women may account for their increased risk of potentially fatal cardiac arrhythmias on psychotropics. QTc increases with increasing age. Assessment of QTc in older people is especially important to identify people with a longer QTc who are more likely to attain a serious QT level with drugs that prolong QTc. The age-related increase in QTc is more evident in men than women, suggesting that male sex does not afford protection against potentially fatal arrhythmias at older age.

Conclusion:

The association of increasing age and female sex with greater QT intervals indicates the need to have an increased awareness of the QTc prior to use of these psychotropics and to evaluate the QTc after initiation of therapy.

Keywords: QT interval, age, sex, psychotropics, cardiac sudden death

Pharmacologic agents have dramatically advanced the treatment of patients with psychiatric disorders in their widest scope. The use of any drug needs to be weighed against its adverse effects, which, in turn, need to be understood, minimized, or avoided. The potential seriousness of drug-induced adverse effects is highlighted by the capacity of some psychotropics to increase the risk of cardiac sudden death. Estimates are that a large number of people are prescribed drugs that have the potential to have adverse cardiac effects.1 There are well-defined risk factors for sudden cardiac death in patients prescribed these agents; foremost among them is age. Another leading risk factor is the female sex. The QT interval on the routine 12-lead ECG is an important indicator of a potential adverse effect of drugs on the heart and one that predicts the development of potentially fatal cardiac arrhythmias. The purpose of this article is to examine the ability of psychotropics to induce adverse cardiac effects, the effect on the QT interval, the impact of age and sex, and their interaction with other factors.

Antipsychotics Increase the Risk of Cardiac Sudden Death

Antipsychotic use has been reported to be associated with a 2- to 3-fold increase in sudden death. The use of antipsychotics was associated with a 2.4-fold increase in the occurrence of cardiac sudden death, compared with nonuse of these kinds of drugs, in a cohort of 481 744 people, enrolled in a US Medicaid-based study.2 Sudden death occurrence was greater in people receiving higher, compared with low, doses of traditional antipsychotics.2 In another study, patients with schizophrenia treated with clozapine, HPD, risperidone, or thioridazine had a 1.7- to 3.2-fold higher rates of cardiac arrest and ventricular arrhythmia, compared with a control group of patients with glaucoma or psoriasis.3 Sudden death rates were higher in users of typical as well as atypical antipsychotics, compared with nonusers of antipsychotics.4 Specifically, cardiac sudden death rates were increased in people receiving clozapine, olanzapine, quetiapine, and risperidone, as well as HPD or thioridazine.4 In a case–control study in primary care groups in the Netherlands, use of antipsychotics was associated with a 3-fold increase in risk of sudden cardiac death.5 While studies of association are not proof of causality, they nevertheless are a component of the evidence essential for establishing causality. Regardless, data on association raise concerns about the potential for cardiac sudden death in patients on antipsychotics.

Clinical Implications

  • The QT interval must be corrected for heart rate otherwise prolonged QT intervals at faster heart rates will not be recognized.

  • Women and older people have longer QTc, which may explain higher rates of fatal arrhythmias on psychotropics.

  • Women and older people can reach critical QTc levels more readily on psychotropics because of their intrinsic longer QTc.

Limitations

  • Lack of randomized clinical trials limits the ability to establish absolute levels of QTc risk for potentially fatal cardiac arrhythmias with each psychotropic drug for each age and sex.

Influence of Age and Sex on Risk of Cardiac Sudden Death With Antipsychotics

The Swedish pharmacovigilance database evaluated the occurrence of the potentially fatal kind of ventricular tachycardia called TdP and found that the most common risk factor for drug-induced TdP was age over 65 years, which occurred in 72% of cases.6 The second leading causes was female sex, which was present in 70% of cases.6 These findings were substantiated in another study, which reported that increasing age, female sex, concomitant diseases, and co-administration of other drugs increased the risks for TdP.7 A greater proportion of women but not older people was suggested but not significant in a case–control study in family practice.5 If one considers only older people, an increase in risk of death has been noted in men after institution of antipsychotic treatment.8 Although this study did not separate cardiac from noncardiac deaths,8 it does suggest that men, especially older men are not spared the risk of adverse effects of antipsychotics.

There are numerous factors that may explain the increased occurrence of potentially fatal cardiac arrhythmias or cardiac sudden death in older people receiving psychotropics (Table 1).

Table 1.

Potential reasons for the increased occurrence of potentially fatal cardiac arrhythmias or cardiac sudden death in older people receiving psychotropics

Increased corrected QT (QTc) interval in older people
Reduced drug metabolism leading to higher blood levels
Increased prevalence of cardiovascular disease (CVD) that may not be clinically apparent
Increased need for medications treatment of CVDs, such as diuretics for hypertension that induce hypokalemia or hypomagnesaemia
Increased presence of concomitant illnesses that require the use of medications, some of which may increase QTc interval
Increased presence of concomitant illnesses that require the use of medications, some of which may inhibit the metabolism of psychotropics leading to their higher blood levels
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QT Interval and Heart Rate—Importance of Adjusting for Heart Rate but Which One

The QT interval is measured from the onset of the Q wave of the QRS complex to the end of the T wave. It encompasses both electrical depolarization and repolarization of the heart. As the duration of repolarization is longer than depolarization, and the QT interval is relatively easy to measure, the QT interval is used as an index of cardiac repolarization.

The QT interval changes with heart rate—increasing at slower heart rates and decreasing at faster heart rates. There are over 20 formulae that have been proposed or used for considering the relations between QT and heart rate.9,10 Correction formulae are usually indicated by the lower case c after the QT.

Several of the more common older as well as some of the more recent formulae can be named after their principal author11: Bazett (QTcBZT)12; Fridericia (QTcFRD)13; Hodges (QTcHDG) (see Hodges et al14); Framingham (QTcFRM) (see Sagie et al15); Dmitrienko (QTcDMT) (see Dmitrienko et al16); and Rautaharju (QTcRTH) (see Rautaharju et al17).

It is important to interpret the QT interval after heart rate adjustment because slower heart rates prolong and faster heart rates shorten the QT interval. People with faster heart rates may have a prolonged QT interval that is not apparent until after the correction has been performed. It is important to recognize that there is no perfect adjustment formula. While the more recent formulae are based on larger numbers of people and appear to do a better job of adjusting for the impact of heart rate, the older formulae, mainly QTcBZT and QTcFRD, are the ones most commonly in use.

Relation Between Age and QTc

There is an increase in QTc with age. Evaluating 2 of the oldest as well as 2 recent heart rate correction formulae show the increase in QT with age for both men (Figure 1) and women (Figure 2). The data are based on several large studies. Dmitrienko et al16 evaluated the ECGs from 13 039 men and women and fit a linear model to log-transformed QT and RR (time between 2 consecutive R waves) data.16 QTcDMT provides an excellent adjustment for the impact of heart rate on the QT interval, and it shows an increasing QT with age.16 Mason et al18 reported on a data set of ECGs from 57 595 people participating in drug trials. The increase in QTc with age was evident for both QTc BZT and QTcFRD. Rautaharju et al17 used pooled data from 3 different sources—2 population studies and the Mason database—to derive 2 new equations. QTcRTH also increased with age17 (figures 1 and 2). Note, the QTc values are slightly different between all 4 different QTc formulae.

Figure 1.

Figure 1

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Mean QT interval for women at different ages

The mean QT interval for women at different ages (using the midpoint of the age group) for 4 different QT correction (QTc) formulae. The mean data for QTc, calculated with Bazett’s formula (QTcBZT) and QTc calculated with Fridericia’s formula (QTcFRD), were the numerical data from Mason et al18; the mean data for QTc, calculated with Dmitrienko’s formula (QTcDMT) and QTc calculated with Rautaharju’s formula (QTcRTH), were graphical extrapolations of the data from Dmitrienko et al16 and Rautaharju et al.17

Figure 2.

Figure 2

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Mean QT interval for men at different ages

The mean QT interval for men at different ages (using the midpoint of the age group) for 4 different QT correction (QTc) formulae. The mean data for QTc, calculated with Bazett’s formula (QTcBZT) and QTc calculated with Fridericia’s formula (QTcFRD), were the numerical data from Mason et al18; the mean data for QTc, calculated with Dmitrienko’s formula (QTcDMT) and QTc calculated with Rautaharju’s formula (QTcRTH), were graphical extrapolations of the data from Dmitrienko et al16 and Rautaharju et al.17

Relation Between Sex and QTc

There are clear differences in QTc between men and women (figures 1 and 2). Women show a longer QTc than men across most decades. Combining the data for the 4 different QTc formulae shows that there are differences between men and women in QTc (Figure 3). The sex difference is greatest in people after adolescence and extends to the sixth decade (Figure 3). However, the difference between men and women decreases at older ages.

Figure 3.

Figure 3

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Corrected QT (QTc) for men and women using the mean values for figures 1 and 2

The means for each formulae were averaged and not weighted according to their sample size because the studies varied markedly in their sample size and the largest study would bias the overall result. Further, the graph is useful for illustrative purposes rather than a precise determination of values as the different formulae cannot be readily averaged.

The difference in duration of QTc between men and women is not only evident on the resting ECG but also found on the 24-hour ECG evaluating the QT interval.19 The between-sex difference is greater at slower heart rates.19 The latter observation may explain the increased occurrences of TdP in women at a slower heart rate.20

Recognizing the sex differences in QTc interval, an American Heart Association expert committee group recommended that a QTc over the 99th percentile should be considered abnormally prolonged, which translated into QTc values, for apparently healthy post-pubertal people, of 450 ms for males and 470 ms for females.21

The intriguing question is the potential conflict between normative standards or reference values and biological differences that may explain differences in predisposition to potentially fatal cardiac arrhythmias. There remains much that is unknown about the relation between QT prolongation, cardiac arrhythmias, and sex differences in response to psychotropics. One hypothesis is that there is a threshold QT interval at which risk for TdP is high, and after which, further increases in QTc markedly increase the risk of TdP. If such a threshold level exists, then women should more readily reach this level, as their QTc is longer than men. Similarly, older people will more readily reach this level because they have longer QTc than younger people. Hypothesis to explain sex effects on QT interval would include genetic (chromosomal) or hormonal differences that affect QT interval, probably through an action on the molecular mechanisms that regulate ventricular repolarization (QT interval). Similarly, aging may alter the characteristics of one or more of the molecular mechanisms responsible for the QTc, and render them more sensitive to the cardiac action of certain psychotropic agents.

Women made up 70% of the 332 reported cases of TdP associated with the use of cardiovascular drugs that prolong QT, namely, quinidine, procainamide, disopyramide, amiodarone, sotalol, bepridil, or prenylamine. Even after adjusting for other TdP risk factors,22 these studies suggest that the greater sensitivity of women to potentially fatal cardiac arrhythmias is not limited to psychotropics. Rather, it suggests a biological difference in susceptibility to potentially fatal cardiac arrhythmias for drugs that can prolong QTc.

The basis for the greater sensitivity of women to drug-induced cardiac arrhythmias may be explained, in part, by the greater QT interval in women from the age of puberty to old age. The biological basis for the longer QTc is due in part to differences between the outward potassium currents in the heart—the major determinants of the repolarization phase of the cardiac action potential. Female rabbit ventricular myocytes have significantly lower outward potassium (IKr and IK1) currents and current densities than ventricular myocytes from male rabbits.23 The finding that the QT shortens after puberty in men but not women suggests that sex hormones modulate repolarization.24 Drici et al25 evaluated the effects of ovariectomy followed by estradiol or dihydrotestosterone treatment on factors responsible for QT duration in isolated rabbit hearts. Oophorectomy shortened QT interval and estradiol replacement lengthened the QT interval.25

Kannankeril et al26 concluded that “although sex hormones play a role in QTc differences between men and women, they explain only part of the observed differences.”p 773 While there is a role of female hormones in modulating QT interval,25 the concept is conflicted by the data that testosterone can also lengthen QT interval and may have an action, independent of its role on QTc, to increase the resistance to ventricular arrhythmias induced by some drugs.25 Thus sex hormones alter cellular processes that alter QTc, but the relevant hormones and their detailed actions requires further study to define more clearly the mechanism for the sex differences in QTc.27

Other mechanisms, such as hormonal modulation of pharmacokinetics of psychotropics, and their binding to potassium channels, may also play a role in the action of drugs to induce cardiac arrhythmias.28

QT Interval and Sudden Death

The importance of considering the impact of psychotropics on the QT interval rests on the link between QT prolongation and cardiac sudden death. A succinct opinion is the FDA statement:

While the degree of QT prolongation is recognized as an imperfect biomarker for pro-arrhythmic risk, in general there is a qualitative relationship between QT prolongation and the risk of TdP, especially for drugs that cause substantial prolongation of the QT interval.29, p 2

The FDA further concluded that

It is difficult to determine whether there is an effect on the mean QT/QTc interval that is so small as to be inconsequential, but the risk of arrhythmias appears to increase with the extent of QT/QTc prolongation.29, p 6

The FDA warned that both for males and females, a QTc greater than 500 ms is highly abnormal.29

Psychotropics and QTc Prolongation

In a survey of 6790 psychiatric inpatients, HPD, phenothiazines, fluoxetine, and citalopram (including escitalopram) were significantly more common in patients with drug-induced long QT and potentially fatal ventricular arrhythmias.30 In the Kaiser Permanente Medical Care Program of Northern California, there were significant increases in QTc for HPD, thioridazine, imipramine, citalopram, venlafaxine, clozapine, ziprasidone, sertraline quetiapine, nortriptyline, and risperidone.31

In a meta-analysis, using a Bayesian-framework with both direct and indirect comparisons of randomized controlled trials comparing 15 antipsychotics and placebo in the acute treatment of schizophrenia, Leucht et al32 found that most antipsychotics were associated with an increase in QTc. However, there are considerable differences in the magnitude of the increase in QTc between drugs.32 Most clinical trials evaluating drugs used for the treatment of psychiatric conditions enrolled mainly younger people.

Harrigan et al33 compared the change in QTc from baseline in men and (or) women, aged 18 to 59 years, who required chronic treatment of a psychotic disorder and reached steady-state on either HPD 15 mg/day, thioridazine 300 mg/day, ziprasidone 160 mg/day, quetiapine 750 mg/day, olanzapine 20 mg/day, or risperidone 6–8 mg/day increased to 16 mg/day. Each of the antipsychotics studied was associated with a measurable prolongation of the QTc interval.33

Haloperidol

HPD significantly increased QTc in a meta-analysis of antipsychotics.32 Many of the studies were in younger people. For example, in 27 people, aged 35.7 years, HPD produced a 7.1 ms increase in QTc.33 In 18 people, aged 41 years, who received 5 to 10 mg/day, HPD was associated with a much greater QTcBZT than a control group.34 The duration of the QT interval predicted the occurrence of HPD-induced TdP in patients with critical illness.35

To illustrate the impact of age and sex on HPD’s effect on QTc, data from over 1000 people was used.36 This construct showed that QTc approaches 500 ms in men in their late 60s for those whose response to HPD was only 1 SD greater than the mean response (Figure 4).37 This effect is somewhat more apparent in one ECG database18 than the other.16 The impact of HPD on QTc was evident in women as well as men (Figure 4B). These effects of HPD are noteworthy, even though HPD does not produce as great an increase in QTc as chlorpromazine (Figure 4).

Figure 4.

Figure 4

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Effects of CPZ and HPD on QTc

The 99th percentile of the QT interval for men and women adjusted for heart rate by QTcFRD, according to age, using the midpoint of each decade, was used for graphical presentation according to the data of Mason et al18 upper panel and Dmitrienko et al16 lower panel. (A): The data are presented for the 99th percentile, plus the mean change in QTc for CPZ, as well as the change in QTc plus 1 SD with CPZ; (B): The data are presented for the 99th percentile, plus the mean change in QTc for HPD, as well as the change in QTc plus 1 SD with HPD.

CPZ = chlorpromazine; HPD = haloperidol; QT = time between start of Q wave and end of T wave; QTc = corrected QT; QTcDMT = QTc calculated with Dmitrienko’s formula; QTcFRD = QTc calculated with Fridericia’s formula

This figure is reproduced, with permission, from Rabkin.37

The effects of HPD on QTc is consistent with the data that HPD treatment of schizophrenia is associated with a 2.2-fold higher rate of cardiac arrhythmias, cardiac arrests, or cardiac deaths.3,38

Olanzapine

Olanzapine significantly increased QTc in a meta-analysis of antipsychotics.32 The ages of people in studies are often young. For example, in 17 people, age 34 years who received 5 to 20 mg/day (average 15 mg/day), olanzapine was associated with a much greater QTcBZT than a control group.34 In 24 people, aged 38.3 years, olanzapine, 20 mg/day, produced a minimal 1.7-ms increase in QTc.33 In 13 people aged 35 years (39% men) there was about a 10-ms increase in QTcBZT with olanzapine, which was not significant but the sample size was very small.39 However, 2 of the 13 patients (15%) showed a very large increase in QT of more than 75 ms.39 The relatively young age of the people in these trials should be considered when this drug is used in older people and women who have longer QTc intervals before treatment.

Olanzapine has electrophysiological effects to increase cardiac monophasic action potential duration.40 The mechanism is the property of olanzapine to produce a concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current in HEK [Human Embryonic Kidney] 293 cells transfected with human ether-à-go-go-related gene,40 which is a major determinant of cardiac repolarization and the QT duration.

Sex differences are important for this drug. Olanzapine had a greater impact on prolonging the QTc interval, compared with risperidone—an effect that is more evident in women than men.41

Risperidone

Risperidone significantly increased QTc in a meta-analysis of antipsychotics.32 Although in a small (25-person) group, aged 38.1 years, risperidone produced a minimal 3-ms increase in QTc.33 Other studies disagree with this conclusion. Considering age and sex, older people and women would be expected to show more of a greater QTc prolongation when receiving this drug.37

Quetiapine

Quetiapine significantly increased QTc in a meta-analysis of antipsychotics.32 Although there is some concern as to the strength of the evidence implicating quetiapine,42 a randomized, double-blind, placebo-controlled study showed a small but definite increase in QTc with quetiapine treatment.43 In a study in 29 patients (24% female, mean age 39 years), there was a 5.7-ms increase in QTc.33 In a study of 33 people (ages between 18 and 64 years) receiving 375 mg twice daily of quetiapine for less than 2 weeks, there was a small 1.3-ms increase in QTcFRM.44

In a study of 20 Japanese people who were switched from olanzapine, aripiprazole, or risperidone to quetiapine, there was a significant increase in QTc after the switch.45 Of note, there was considerable variability in the extent of QTc prolongation after switching to quetiapine, suggesting some people did not show much of a change, while others showed a marked increase in QTc.45 Quetiapine had a greater impact on the QTc interval compared with risperidone—an effect that was more evident in women than men.41

Ziprasidone

Ziprasidone significantly increased QTc in a meta-analysis of antipsychotics.32 In an open-label, randomized, parallel-group, fixed-sequence study, 31 people (about 71% men), aged 38 years, ziprasidone increased QTc by 16 ms.33 In another study of 32 patients aged 18 to 64 years, receiving ziprasidone 80 mg twice daily for less than 2 weeks, there was a 9.6-ms increase in QTcFRD.44 Although, in a series of high-dose ziprasidone, there was no reported associated QTc prolongation,46 there has been a case report of ventricular tachycardia, TdP, in a patient receiving ziprasidone,47 indicating the potential for this agent to produce potentially fatal arrhythmias.

Most of the clinical trials, as noted above, were done in younger people. In a retrospective study of 23 consecutive elderly patients admitted to a neuropsychiatry service with dementia (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition) and who were given intramuscular ziprasidone, 1 person had a QTc greater than 500 ms (25% over baseline).48 This is a small sample, and retrospectively collected, but it was done in the elderly whether a 4% rate of dangerous QT prolongation was noted.48

Citalopram

Citalopram, an SSRI, is useful in the management of depression, especially in older people.49 Considering the focus of this article is on older people, it is worthwhile to examine the effect of citalopram on QTc in more detail. Although some studies suggested that citalopram did not increase QT,49–51 these studies were deficient because they had either a small sample size or used a case–comparison design, making them dependent on the nature of the reference group.

More recent clinical prospective trial data show convincing evidence of QTc prolongation with citalopram. In the Citalopram for Agitation in Alzheimer Disease (commonly referred to as CitAD) Study 186 patients, mean age 78 years, of whom 64% were men, with probable Alzheimer disease and clinically significant agitation, were randomized to receive a psychosocial intervention plus either citalopram (n = 94) or placebo (n = 92) for 9 weeks.52 Citalopram “began at 10 mg/day with planned titration to 30 mg/day during 3 weeks based on response and tolerability.”52, p 683 Citalopram was associated with a significantly greater QTc increase than placebo, and more people in the citalopram group showed a QTc increase greater than 30 ms.52,53

Citalopram, at high doses, can induce potentially fatal cardiac arrhythmias, especially when combined with certain other drugs.54–59

Other SSRIs

In a meta-analysis of 4292 patients, SSRIs were associated with a dose-dependent increase in QTc interval, compared with placebo, with citalopram showing a significantly greater QTc prolongation than sertraline as well as paroxetine or fluvoxamine.60 There is less clinical trial data, but escitalopram can induce QT prolongation.61

Venlafaxine

There is a paucity of specific data on this agent. The data from a large number (n = 2005) of users in a clinic setting found that venlafaxine use was associated with a significantly increase in QTc.31 The probability of a person having a dangerously prolonged QTc is greater in women and older person. The ability of venlafaxine to increase QTc is supported by cases of patients with markedly prolonged QT with venlafaxine treatment,62 and with venlafaxine overdose.63,64

Summary

Psychotropics have the potential to prolong QT interval. While the changes produced by some agents and at certain doses can be small, the association of increasing age and female sex with greater QT intervals highlights the need to have an increased awareness of QTc prior to use of these agents and to evaluate the QTc after initiation of therapy in women and older people.

Acknowledgments

There was no funding for this work.

The Canadian Psychiatric Association proudly sponsors the In Review series by providing an honorarium to the authors.

Abbreviations

ECG

electrocardiogram

FDA

Food and Drug Administration

HPD

haloperidol

QT

time between start of Q wave and end of T wave

QTc

corrected QT

QTcBZT

QTc calculated with Bazett’s formula

QTcDMT

QTc calculated with Dmitrienko’s formula

QTcFRD

QTc calculated with Fridericia’s formula

QTcFRM

QTc calculated with Framingham’s formula

QTcHDG

QTc calculated with Hodges’ formula

QTcRTH

QTc calculated with Rautaharju’s formula

SSRI

selective serotonin reuptake inhibitor

TdP

torsade de pointes

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