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Articles   |    
Evaluation of the FDA Warning Against Prescribing Citalopram at Doses Exceeding 40 mg
Kara Zivin, Ph.D.; Paul N. Pfeiffer, M.D.; Amy S.B. Bohnert, Ph.D.; Dara Ganoczy, M.P.H.; Frederic C. Blow, Ph.D.; Brahmajee K. Nallamothu, M.D.; Helen C. Kales, M.D.
Am J Psychiatry 2013;170:642-650. doi:10.1176/appi.ajp.2013.12030408
View Author and Article Information

Dr. Blow has served as a consultant to the Hazelden Foundation. All other authors report no financial relationships with commercial interests.

Supported by VA grant IIR 10-176-3 (to Dr. Zivin) and the VA Health Services Research and Development Services grants CD2 07-206-1 (to Dr. Zivin), CDA 10-036-1 (to Dr. Pfeiffer), and CDA 09-204 (to Dr. Bohnert).

From the Department of Veterans Affairs (VA), National Serious Mental Illness Treatment Resource and Evaluation Center, Ann Arbor, Mich.; VA Center for Clinical Management Research, Ann Arbor; and the Department of Psychiatry and Division of Cardiovascular Diseases, University of Michigan Medical School, Ann Arbor.

Address correspondence to Dr. Zivin (kzivin@umich.edu).

Copyright © 2013 by the American Psychiatric Association

Received March 29, 2012; Revised October 16, 2012; Accepted January 14, 2013.

Abstract

Objective  A recent Food and Drug Administration (FDA) warning cautioned that citalopram dosages exceeding 40 mg/day may cause abnormal heart rhythms, including torsade de pointes. The authors assessed relationships between citalopram use and ventricular arrhythmias and mortality.

Method  A cohort study was conducted using Veterans Health Administration data between 2004 and 2009 from depressed patients who received a prescription for citalopram (N=618,450) or for sertraline (N=365,898), a comparison medication with no FDA warning. Cox regression models, adjusted for demographic and clinical characteristics, were used to examine associations of antidepressant dosing with ventricular arrhythmia and cardiac, noncardiac, and all-cause mortality.

Results  Citalopram daily doses >40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio=0.68, 95% CI=0.61–0.76), all-cause mortality (adjusted hazard ratio=0.94, 95% CI=0.90–0.99), and noncardiac mortality (adjusted hazard ratio=0.90, 95% CI=0.86–0.96) compared with daily doses of 1–20 mg. No increased risks of cardiac mortality were found. Citalopram daily doses of 21–40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio=0.80, 95% CI=0.74–0.86) compared with dosages of 1–20 mg/day but did not have significantly different risks of any cause of mortality. The sertraline cohort revealed similar findings, except there were no significant associations between daily dose and either all-cause or noncardiac mortality.

Conclusions  This large study found no elevated risks of ventricular arrhythmia or all-cause, cardiac, or noncardiac mortality associated with citalopram dosages >40 mg/day. Higher dosages were associated with fewer adverse outcomes, and similar findings were observed for a comparison medication, sertraline, not subject to the FDA warning. These results raise questions regarding the continued merit of the FDA warning.

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FIGURE 1. Clinical and Mortality Outcomes for Veterans Health Administration Patients With Depression Treated With Citalopram or Sertraline (2004–2009)a

a Low dosages for citalopram and sertraline were 1–20 mg/day and 1–50 mg/day, respectively; medium dosages were 21–40 mg/day and 51–100 mg/day, respectively; and high dosages were >40 mg/day and >100 mg/day, respectively.

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TABLE 1.Clinical and Demographic Characteristics of Veterans Health Administration Patients With Depression Treated With Citalopram or Sertraline (2004–2009)
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a Score is modified to exclude depression.

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TABLE 2.Unadjusted Rates of Ventricular Arrhythmia and Mortality by Daily Dose of Citalopram or Sertralinea
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a Low dosages for citalopram and sertraline were 1–20 mg/day and 1–50 mg/day, respectively; medium dosages were 21–40 mg/day and 51–100 mg/day, respectively; and high dosages were >40 mg/day and >100 mg/day, respectively.

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TABLE 3.Cox Proportional Hazards Models of Risk of Ventricular Arrhythmias and All-Cause Mortalitya
Table Footer Note

a Bolded hazard ratios indicate significant difference (p<0.05) between patients with an outcome and patients without.

Table Footer Note

b Low dosages for citalopram and sertraline were 1–20 mg/day and 1–50 mg/day, respectively; medium dosages were 21–40 mg/day and 51–100 mg/day, respectively; and high dosages were >40 mg/day and >100 mg/day, respectively.

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TABLE 4.Competing Risks Cox Proportional Hazards Models of Risk of Cardiac and Noncardiac Mortalitya
Table Footer Note

a Bolded hazard ratios indicate significant difference (p<0.05) between patients with an outcome and patients without.

Table Footer Note

b Low dosages for citalopram and sertraline were 1–20 mg/day and 1–50 mg/day, respectively; medium dosages were 21–40 mg/day and 51–100 mg/day, respectively; and high dosages were >40 mg/day and >100 mg/day, respectively.

Table Footer Note

Indicates significant difference in the hazard ratio estimated for cardiac mortality and other mortality in the citalopram cohort, which was determined by a competing risks model with interaction terms (p<0.05).

Table Footer Note

Indicates significant difference in the hazard ratio estimated for cardiac mortality and other mortality in the sertraline cohort (p<0.05).

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