Exploring psychotherapeutic issues and agents in clinical practice
A physiological effect of many noncardiac drugs, including some antidepressant and anti-psychotic medications, is an ability to delay cardiac repolarization, which can be measured as a QT interval prolongation on an electrocardiogram (ECG) tracing. The QT interval varies according to heart rate and its measurement is adjusted accordingly (referred to as the corrected QT [QTc] interval). Although an abnormally prolonged QTc interval is associated with an increased risk of developing Torsade de Pointes (TdP), a cardiac ventricular tachyarrhythmia associated with sudden death, many other risk factors for developing TdP exist (Hasnain & Vieweg, 2014).
Despite the fact that there is little evidence that QTc prolongation alone is a good predictor of TdP or sudden cardiac death, there continues to be undue concern about the safety of psychiatric medications based on their QT interval effects. Late last year, for example, I was party to a series of e-mail comments among colleagues (i.e., several psychiatrists, a clinical pharmacist, and a nurse) pertaining to the QTc-prolonging risk of selective serotonin reuptake inhibitor (SSRI) and other antidepressant drugs. I will describe this brief e-mail exchange to highlight the uncertainty and concern that this topic generates, and then review other data to put the risk in perspective.
E-Mail Exchange About the Safety of Antidepressant Medications
Psychiatrist P.G. We’ve gotten a lot of questions about SSRIs and QTc prolongation, and some primary [medical] teams that have expressed concern about the QTc effects of these medications. Personally, I haven’t been terribly worried about the effects. Should I be? Do you have any good resources or review articles on this topic?
Pharmacist R.C. Interesting. Out of curiosity, are you seeing concern as a class wide effect or just citalopram [Celexa®]/escitalopram [Lexapro®]? I generally only have concern (moderate at most) when it is in an individual with congenital long QT or other risk factors. Even then, as long as they aren’t borderline or prolonged at baseline, I am not concerned with the SSRIs. As far as review articles, the only one I have seen recently is below [Wenzel-Seifert, Wittmann, & Haen, 2010]. It is fairly good, but doesn’t add much more than we already know.
Psychiatrist P.G. R.C. is one of the pharmacists at our institution. Psychiatrist J.H. and I e-mailed him because we’ve been hearing some concerns from [medical] teams about SSRIs and QTc prolongation. Have others had similar experiences?
Psychiatrist B.B. I had a patient who had TdP from Prozac® [fluoxetine] and did some research; apparently all the SSRIs can cause QTc prolongation, especially Cymbalta® [duloxetine] and anything mixed with ciprofloxacin [an antibiotic drug associated with QT interval prolongation].
Nurse M.L. Interesting…I believe that we had a patient here at our institution at one point who cardiology was concerned that Effexor® [venlafaxine] was causing prolonged QT.
Psychiatrist S.Z. I found this article [Funk & Bostwick, 2013] from 2013; maybe this clears up the issue, maybe it just clouds it even more, I just don’t know.
Psychiatrist S.Z. This article [Castro et al., 2013] from BMJ in 2013 on antidepressants and QTc prolongation seems more useful than the other one I sent.
As can be seen from this brief e-mail exchange, the topic of QTc prolongation reveals uncertainty, rather than clarity, among an interdisciplinary group of mental health colleagues working within a general medical (hospital system) setting, who must also field questions from medical practitioners about this issue. Three articles were cited, including two limited reviews focused only on SSRI drugs (Funk & Bostwick, 2013; Wenzel-Seifert et al., 2010) and one observational study based on electronic health records data from a single health care system (Castro et al., 2013). None of these articles provide clear or consistent guidance on the QTc phenomenon. Indeed, the two review articles have conflicting conclusions about the QTc safety of fluoxetine. Most importantly, the mortality risk associated with antidepressant drugs is not addressed by these articles or by the individuals in these e-mails.
Antidepressant and Antipsychotic Drug Use Rates and Sudden Cardiac Death Rates
According to data from the Centers from Disease Control and Prevention, approximately 11% of Americans (>35 million individuals) take antidepressant medications, and the rate of antidepressant drug use has increased 400% since 1988, when fluoxetine was first marketed (Pratt, Brody, & Gu, 2011).
Since 1989, relative rates of sudden cardiac death have been declining (Go et al., 2013; Zheng, Croft, Giles, & Mensah, 2001). The incidence of sudden cardiac death ranges from 180,000 to 450,000 cases per year (Deo & Albert, 2012). Even if the highest incidence (i.e., 450,000 cases) were to be attributed entirely to antidepressant drug use (which is not likely), then less than 2% of the 35 million antidepressant medication takers are at risk of sudden cardiac death.
Various second-generation anti-psychotic drugs (the so-called atypical antipsychotic drugs) were introduced between 1990 and 2002. Data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Survey showed that during the 8-year period from 1996 to 2003, an estimated 47.7 million adult ambulatory care visits involved mention of an anti-psychotic drug (Sankaranarayanan & Puumala, 2007). During this time period, visits involving atypical antipsychotic drugs and combination antipsychotic drugs (i.e., visits mentioning at least one typical antipsychotic drug and atypical antipsychotic drug) increased by 195% and 149%, respectively. Relative to typical or combination antipsychotic drug visits, more atypical antipsychotic drug visits involved antidepressant drugs.
Since 2003, rates of atypical anti-psychotic drug use are likely to have escalated even further, as these drugs are commonly used to treat not only schizophrenia, but also bipolar disorder, treatment-resistant depression, and other psychiatric disorders. Because antidepressant and antipsychotic drug use is increasing and rates of sudden cardiac death are decreasing, the proportion of sudden cardiac death cases that may be attributed to these drugs (either used alone or in combination with each other) is likely to be exceedingly small compared to other more likely and more prevalent risk factors (e.g., older age, obesity, diabetes, hypertension, smoking, pre-existing cardiovascular disease).
How Strong Is the Link Between QTc Prolongation and the Risk for TdP?
Hasnain and Vieweg (2014) comprehensively reviewed published literature to determine whether it supported the link between QTc interval prolongation and TdP for the 11 second-generation antipsychotic agents and seven second-generation antidepressant agents commonly implicated in these complications. They identified four thorough QT studies (one each for iloperidone [Fanapt®], ziprasidone [Geodon®], citalopram, and escitalopram), 40 studies specifically designed to assess QTc interval prolongation or TdP, 58 publications based on data from efficacy and safety trials, 18 toxicology studies, and 102 case reports. Thorough QT studies, QTc prolongation-specific studies, and studies based on efficacy and safety trials did not link drug-associated QTc interval prolongation with TdP. These investigations only showed that the drugs reviewed caused varying degrees of QTc interval prolongation, but that information was not clear and consistent enough to stratify individual drugs for this risk.
If QTc prolongation is a dose-related phenomenon, it would be predicted that 100% of cases of overdoses would demonstrate QTc prolongation. However, toxicology studies reviewed by Hasnain and Vieweg (2014) do not confirm this prediction, nor do they support a high mortality risk associated with overdose.
Among the case reports reviewed by Hasnain and Vieweg (2014), at least one additional well-established risk factor for QTc prolongation was present in 92% of cases. Of the 28 cases of TdP, six (21.4%) experienced it with a QTc interval of less than 500 ms (a commonly used threshold of concern) and 75% of TdP cases occurred at therapeutic drug doses. Hasnain and Vieweg (2014) concluded that there is little evidence that psychotropic drug–associated QTc interval prolongation by itself is sufficient to predict TdP.
Randomized clinical trials have shown that therapeutic cooling (i.e., induction of hypothermia for therapeutic use) can limit neurological injury and improve outcomes in patients with cardiac arrest, and this is considered a standard of care practice (Storm et al., 2011). Although therapeutic hypothermia is associated with prolonged QTc, it does not lead to significant ventricular arrhythmias or TdP (Gachoka et al., 2012; Storm et al., 2011), suggesting that QT interval prolongation itself is not necessarily a critical factor.
Knowing that a drug might cause QTc prolongation does not necessarily predict the risk of developing TdP or sudden cardiac death. The QTc of a particular patient depends on the patient’s gender, genetics, health, and other physiological variables. Thorough QT/QTc studies are conducted in small numbers of healthy patient populations. QTc prolongation and TdP only represent a small proportion of the causes of sudden cardiac death, and there is little evidence that QTc prolongation alone is a good (or even the best) predictor of TdP or sudden cardiac death (Deo & Albert, 2012). Information from an ECG before, during, and after treatment (if a drug is stopped) can be used to evaluate the effect of a particular drug in a particular patient, but this information alone should not be relied on when considering the cardiac appropriateness of the drug (Hasnain & Vieweg, 2014). Nurses, especially those with prescription privileges, should be familiar with the cardiac safety of psychiatric medications.
- Castro, V.M., Clements, C.C., Murphy, S.N., Gainer, V.S., Fava, M., Weilburg, J.B. & Perlis, R.H. (2013). QT interval and antidepressant use: A cross sectional study of electronic health records. BMJ, 346, f288. doi:10.1136/bmj.f288 [CrossRef]
- Deo, R. & Albert, C.M. (2012). Epidemiology and genetics of sudden cardiac death. Circulation, 125, 620–637. doi:10.1161/CIRCULATIONAHA.111.023838 [CrossRef]
- Funk, K.A. & Bostwick, J.R. (2013). A comparison of the risk of QT prolongation among SSRIs. Annals of Pharmacotherapy, 47, 1330–1341. doi:10.1177/1060028013501994 [CrossRef]
- Gachoka, D.N., Sheikh, M., Al Ahwel, Y., Grubb, B.P., Hammersley, J., Khuder, S. & Kanjwal, Y. (2012). QT prolongation during therapeutic hypothermia of sudden cardiac arrest patients does not cause predisposition to ventricular arrhythmias. Journal of Innovations in Cardiac Rhythm Management, 3, 996–1001.
- Go, A.S., Mozaffarian, D., Roger, V.L., Benjamin, E.J., Berry, J.D., Borden, W.B. & Turner, M.B. (2013). Heart disease and stroke statistics—2013 update: A report from the American Heart Association. Circulation, 127, e6–e245. doi:10.1161/CIR.0b013e31828124ad [CrossRef]
- Hasnain, M. & Vieweg, W.V. (2014). QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: A comprehensive review. CNS Drugs, 28, 887–920. doi:10.1007/s40263-014-0196-9 [CrossRef]
- Pratt, L.A., Brody, D.J. & Gu, Q. (2011). Antidepressant use in persons aged 12 and over: United States, 2005–2008 (NCHS data brief, no. 76). Retrieved from http://www.cdc.gov/nchs/data/databriefs/db76.htm
- Sankaranarayanan, J. & Puumala, S.E. (2007). Antipsychotic use at adult ambulatory care visits by patients with mental health disorders in the United States, 1996–2003: National estimates and associated factors. Clinical Therapeutics, 29, 723–741. doi:10.1016/j.clinthera.2007.04.017 [CrossRef]
- Storm, C., Hasper, D., Nee, J., Joerres, A., Schefold, J.C., Kaufmann, J. & Roser, M. (2011). Severe QTc prolongation under mild hypothermia treatment and incidence of arrhythmias after cardiac arrest—A prospective study in 34 survivors with continuous Holter ECG. Resuscitation, 82, 859–862. doi:10.1016/j.resuscitation.2011.02.043 [CrossRef]
- Wenzel-Seifert, K., Wittmann, M. & Haen, E. (2010). Torsades de pointes episodes under treatment with selective serotonin reuptake inhibitors. Pharmacopsychiatry, 43, 279–281. doi:10.1055/s-0030-1263167 [CrossRef]
- Zheng, Z.J., Croft, J.B., Giles, W.H. & Mensah, G.A. (2001). Sudden cardiac death in the United States, 1989 to 1998. Circulation, 104, 2158–2163. doi:10.1161/hc4301.098254 [CrossRef]