FDA Responds to AJP Manuscript on Citalopram Safety

On June 1, 2013, the American Journal of Psychiatry (AJP)published an evidence-based article questioning the 2011 Food and Drug Administration (FDA) decision to warn health care professionals against prescribing citalopram at doses that exceed 40 mg due to risk of abnormal changes in the heart’s electrical activity. On January 3, in AJP in Advance, the FDA responded to the 2013 article in a commentary in which it stood by its decision and questioned the validity of the study in which its ruling was the primary target of criticism.

In late spring 2013, Kara Zivin, Ph.D., an assistant professor of psychiatry at the University of Michigan, and colleagues published “Evaluation of the FDA Warning Against Prescribing Citalopram at Doses Exceeding 40 mg” in AJP, a studythat assessed the relationship between the use of the antidepressant and the induction of ventricular arrhythmia.

“We conducted this research,” Zivin told Psychiatric News, “because we and others have found that FDA warnings can have an impact on the use of medications that can have both positive and negative effects on patients.”

University of Michigan

In the study, Zivin and colleagues evaluated medical records of more than 618,000 veterans who were prescribed citalopram to treat depression from 2004 to 2009. Results showed that individuals taking citalopram at daily doses greater than 40 mg had a 38.5 percent lower risk for experiencing ventricular arrhythmia than those who were administered doses between 1 mg and 40 mg. In addition, Zivin and colleagues found that participants taking higher doses of citalopram were seven times less likely to have an increased risk for cardiac nonrelated mortalities than those prescribed citalopram at lower doses.

“Our findings raise questions about the continued legitimacy of the FDA warning and provide support for the question of whether the warning will do more harm than good,” said Zivin in a 2013 press release.

She concluded that “clinicians whose patients benefit from high dosages of citalopram must choose between following the FDA’s warning or risking worsening depression if patients receive too low a dosage.”

In response to Zivin’s study and comments, FDA officials stated in the AJP in Advance commentary that “the approach the authors [Zivin et. al] took . . . was unlikely to detect differences in potentially life-threatening arrhythmias.”

During an interview with Psychiatric News, Marc Stone, M.D., coauthor of the commentary and senior medical reviewer in the FDA Division of Psychiatry Products, said that previous studies have shown that citalopram doses at 60 mg per day can prolong the ventricular QT interval—the heart’s electrical cycle—and increase risk for potentially fatal torsade de pointes, an arrhythmia characterized by uncommonly rapid heartbeats that range between 150 and 250 beats per minute. Normal rate ranges between 60 and 100 beats per minute.

“This is just one potential adverse reaction; risk of adverse reactions of all kinds is higher with higher dosages,” said Stone. Also, without evidence showing that citalopram dosages above 40 mg are more effective than lower dosages, “there can be no justification for such use.”

Furthermore, the FDA officials stated in commentary that a person who develops fatal arrhythmia as a result of torsade de pointes will rarely be identified as having torsade because the cardiac event is quite transient and goes undetected by electrocardiography. They explained that this will lead to less-specific outcomes such as any mortality, as reported by Zivin and colleagues, and will include outcomes unrelated to QT prolongation—diluting a signal of QT prolongation-induced torsade or sudden cardiac death.

Stone also raised concerns about the patient population evaluated in Zivin’s study. “All this paper shows is that higher dosages of citalopram and sertraline [used as an active control] are prescribed to healthier people. The paper states ‘both older patients and patients with higher comorbidity levels received lower dosages of both citalopram and sertraline.’ ”

Columbia University Medical Center/Courtesy of www.pharmapar.ca

Peter Shapiro, M.D., a professor of psychiatry at Columbia University Medical Center and director of the Fellowship Training Program in Psychosomatic Medicine at New York-Presbyterian Hospital, who was not involved in the study, agreed. He explained that the low rates of adverse events reported by Zivin in the high-dose citalopram cohort might be attributed to those patients being more healthy—offsetting a dose-related hazard.

Though Shapiro suggested that Zivin’s study had significant limitations, he told Psychiatric News that it did confirm that high doses of citalopram can be prescribed to relatively “healthy” patients.

“None of this is to say that we should be unconcerned about QT prolongation and risk of arrhythmias. . . . Clinicians should be wary if patients have preexisting cardiac conditions, family history of heart disease and of sudden death, or are taking drugs that could interact with antipsychotics and result in QT-prolongation.”

Shapiro said because recent data from Medicaid have shown that there is one sudden cardiac death for every 667 people taking antipsychotics per year, patients’ general medical health should be evaluated when prescribing any psychiatric drug. ■