Caring for the Patient

See article by Ray et al

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Caring for the Patient

James W. Jefferson, MDa,*

Almost 3 decades ago, the American Psychiatric Association published Task Force Report 27: "Sudden Death in Psychiatric Patients: The Role of Neuroleptic Drugs."1 Among the issues discussed was psychotropic drug-associated cardiotoxicity and sudden death. QT interval prolongation and its relationship to the polymorphic ventricular tachycardia, torsade de pointes, was noted for both antipsychotics, especially thioridazine, and tricyclic antidepressants. These observations appeared just as the selective serotonin reuptake inhibitors (SSRIs) began their march to antidepressant dominance with the advent of fluoxetine in 1987 and, most recently, escitalopram in 2002.

In a safety announcement in 2011,2 which was updated in 2012,3 the US Food and Drug Administration (FDA) pointed an accusatory finger at citalopram, stating it carried a risk for causing QT interval prolongation at doses > 40 mg/d and that it should not be used at such doses. The FDA also discussed use of citalopram at any dose in patients with underlying heart disease and in those at risk for hypokalemia or hypomagnesemia. Lower doses (20 mg/d) were advised for patients > 60 years old. Furthermore, the recommendation for use in patients with congenital long QT syndrome was changed from "contraindicated" in 2011 to "not recommended" in 2012, acknowledging that there may be some circumstances in which low doses could be justified.

It should be noted that while long QT syndrome is often readily apparent on the electrocardiogram, there is also a subclinical (silent) variant in which QT interval is normal under basal conditions but which may become pathologically prolonged by acquired causes, including drugs.4,5 Whether SSRIs as a group or individually increase this risk remains to be determined.

The citalopram story began in the 1980s, when toxicology studies in beagle dogs found QT interval prolongation and fatal arrhythmias.6 These deaths were ascribed to high concentrations of didesmethylcitalopram, a toxic metabolite which, fortunately, was noted to be present in quite low concentrations in humans. Vieweg et al7 muddied the safety waters a bit by pointing out that persons who are cytochrome P450 2D6 ultrarapid metabolizers could reach high concentrations of this cardiotoxic metabolite and actually be at increased risk for potentially lethal arrhythmias.

In 2004, Isbister et al8 reported on the toxicity of SSRIs in overdose and found that QTc interval prolongation was greater with citalopram than with fluoxetine, fluvoxamine, paroxetine, or sertraline. They concluded that, except for citalopram, SSRIs are relatively safe in overdose.

Ten years later, Beach et al,9 in a meta-analysis of SSRI-associated QTc prolongation, concluded that "citalopram was associated with more QTc prolongation than most other SSRIs."(p e441)

Not unexpectedly, a number of authors have risen to the defense of citalopram. In a 2-part article, Howland10,11 critically evaluated the cardiac toxicity of citalopram and concluded, "Three studies comparing citalopram overdoses to other antidepressant overdoses do not demonstrate clinically meaningful differences in cardiotoxic effects"10(p13) and also that dose limitations in the FDA safety announcement "do not have strong clinical justification."11(p13)

Furthermore, in a cohort study of a US Department of Veterans Affairs database involving citalopram (N = 618,450) and sertraline (N = 365,898), Zivin et al12 concluded that risks of ventricular arrhythmia, all-cause mortality, and noncardiac mortality were actually lower at citalopram doses > 40 mg/d than at daily doses of < 20 mg/d. Although not stated in the article, perhaps the implication is that undertreating depression carries a substantial risk of lethality.

The counterpunch came from a commentary by the FDA13 that concluded "clinical trial data, case reports, and studies in animals provide clear evidence for dose-dependent QT prolongation with citalopram," and that the 18.5-millisecond prolongation at 60 mg/d remains of concern, "especially since this dosage was not more effective than 40 mg/day in clinical trials."(p18) (Most clinicians are aware that lack of statistical significance in clinical trials does not exclude the possibility that certain individuals may respond to higher doses.) The commentary by Zivin et al14 followed immediately, noting that their study of over 600,000 patients taking citalopram found no increased risk of arrhythmias or mortality from any cause at doses > 40 mg/d compared to lower doses or to sertraline.

Ray et al15 in the current issue of JCP, conducted a retrospective study of 54,220 Tennessee Medicaid outpatients treated with high doses of citalopram, escitalopram, fluoxetine, paroxetine, and sertraline. The primary end point was sudden unexpected deaths, which included sudden cardiac deaths (n = 95), other cardiovascular deaths (n = 24), and unintentional drug overdose deaths (n = 26). The authors concluded that the risk of sudden unexpected death was not significantly greater for citalopram than for the other SSRIs. The fact that there were only 145 sudden unexpected deaths in such a large sample is testament to the overall safety of SSRIs. On the other hand, the number of sudden unexpected deaths associated with each of the 5 SSRIs was quite low, raising the possibility that the statistical lack of difference could represent a type II error, a false-negative finding.

As we await the next chapter in this ongoing controversy, remember that to override the FDA’s edicts is to do so at your risk. There are always malpractice attorneys salivating in the background and ready to pounce. Nonetheless, there will be some clinical situations that clearly justify the use of higher than recommended doses. Due to variations in metabolism, blood levels of antidepressants can vary considerably among individuals taking identical doses. In addition, pharmacodynamic differences can be substantial. While the FDA commented that doses of citalopram over 40 mg/d "confer no additional benefit,"3 clinicians are well aware that some patients tolerate and benefit from higher than recommended doses. Should one choose to increase citalopram above the 40-mg limit, he or she should do so only after discussing pros and cons with the patient, obtaining informed consent, and including documentation in the patient’s chart. In addition, clinicians should be aware of the factors that may place patients at greater risk for malignant arrhythmias induced by antidepressants.

Finally, there are a considerable number of newer antidepressants (beyond tricyclics and monoamine oxidase inhibitors) on the market in addition to the SSRIs. Mago et al16 have provided a qualitative review of the cardiovascular adverse effects of these medications (including SSRIs) that is highly recommended.

Potential conflicts of interest: Dr Jefferson has no potential conflicts of interest to report.

Funding/support: None reported.

REFERENCES

1. Sudden death in psychiatric patients: the role of neuroleptic drugs. In: Simpson GM, Davis J, Jefferson JW, et al, eds. An American Psychiatric Association Task Force Report. Washington, DC: American Psychiatric Association; 2005.

2. FDA drug safety communication: abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). FDA Web site. http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm. Accessed 2015.

3. FDA drug safety communication: revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. FDA Web site. http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm. Accessed 2015.

4. Roden DM. Clinical practice: Long-QT syndrome. N Engl J Med. 2008;358(2):169-176. PubMed doi:10.1056/NEJMcp0706513

5. Makita N, Horie M, Nakamura T, et al. Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation. Circulation. 2002;106(10):1269-1274. PubMed doi:10.1161/01.CIR.0000027139.42087.B6

6. Rasmussen SL, Over׸ KF, Tangh׸j P. Cardiac safety of citalopram: prospective trials and retrospective analyses. J Clin Psychopharmacol. 1999;19(5):407-415. PubMed doi:10.1097/00004714-199910000-00004

7. Vieweg WVR, Hasnain M, Howland RH, et al. Citalopram, QTc interval prolongation, and torsade de pointes: how should we apply the recent FDA ruling? Am J Med. 2012;125(9):859-868. PubMed doi:10.1016/j.amjmed.2011.12.002

8. Isbister GK, Bowe SJ, Dawson A, et al. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42(3):277-285. PubMed doi:10.1081/CLT-120037428

9. Beach SR, Kostis WJ, Celano CM, et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry. 2014;75(5):e441-e449. PubMed doi:10.4088/JCP.13r08672

10. Howland RH. A critical evaluation of the cardiac toxicity of citalopram: part 1. J Psychosoc Nurs Ment Health Serv. 2011;49(11):13-16. PubMed doi:10.3928/02793695-20111011-01

11. Howland RH. A critical evaluation of the cardiac toxicity of citalopram: part 2. J Psychosoc Nurs Ment Health Serv. 2011;49(12):13-16. PubMed doi:10.3928/02793695-20111102-04

12. Zivin K, Pfeiffer PN, Bohnert ASB, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry. 2013;170(6):642-650. PubMed doi:10.1176/appi.ajp.2013.12030408

13. Bird ST, Crentsil V, Temple R, et al. Cardiac safety concerns remain for citalopram at dosages above 40 mg/day. Am J Psychiatry. 2014;171(1):17-19. PubMed doi:10.1176/appi.ajp.2013.13070905

14. Zivin K, Pfeiffer PN, Bohnert ASB, et al. Safety of high-dosage citalopram. Am J Psychiatry. 2014;171(1):20-22. PubMed doi:10.1176/appi.ajp.2013.13081052

15. Ray WA, Chung CP, Murray KT, et al. High-dose citalopram and escitalopram and the risk of sudden unexpected out-of-hospital death. J Clin Psychiatry. 2017;78(2):190-195.

16. Mago R, Tripathi N, Andrade C. Cardiovascular adverse effects of newer antidepressants. Expert Rev Neurother. 2014;14(5):539-551. PubMed doi:10.1586/14737175.2014.908709

17. Peabody FW. In: Strauss MB, ed. Familiar Medical Quotations. Boston, MA: Little Brown and Company, Inc; 1968:367.

aDepartment of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison

*Corresponding author: James W. Jefferson, MD, 6515 Grand Teton Plaza, Suite 100, Madison, WI 53719 ([email protected])

J Clin Psychiatry 2017;78(2):e166-e167

dx.doi.org/10.4088/JCP.15com10567

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