Posted by Phillipa on June 7, 2013, at 18:20:45
Medscape Medical News > PsychiatryFDA Citalopram Warning 'Without Merit'
Deborah Brauser
Jun 05, 2013
Contrary to a recent warning by the US Food and Drug Administration (FDA), higher doses of the antidepressant citalopram may not increase the rate of cardiovascular complications and mortality risk after all, new research suggests.Issued in August 2011, the FDA warning cautions that daily doses of the medication higher than 40 mg may lead to arrhythmias, including torsades de pointes.
However, a large cohort study of data from the Veterans Health Administration (VHA) on more than 600,000 individuals showed that, when compared with daily doses ranging between 1 and 20 mg, doses greater than 40 mg of citalopram were actually linked to a lower risk for ventricular arrhythmia and all-cause and noncardiac mortality.
"This study provides evidence on outcomes associated with citalopram...use in the largest samples, to our knowledge, ever analyzed," write Kara Zivin, PhD, assistant professor of psychiatry at the University of Michigan Medical School in Ann Arbor and research investigator for the Department of Veterans Affairs (VA) in Ann Arbor, and colleagues.
"These findings raise questions regarding the continued merit of the FDA warning and provide support for the question of whether the warning itself will cause more harm than good," they add.
The study was published in the June issue of the American Journal of Psychiatry.
No Systematic Assessment
According to the researchers, the FDA approved citalopram in 1998, and it had been used by more than 80 million people in 60 countries just a year later. Its patent expired in 2004.
However, an FDA drug safety alert was issued in August 2011 warning clinicians that "citalopram should no longer be prescribed at dosages above 40mg/day because of potential abnormal changes in electrical activity of the heart."
In March 2012, as reported by Medscape Medical News, the FDA updated the warning to recommend that daily doses greater than 20 mg should not be used in adults older than 60 years.
Still, Dr. Zivin and colleagues note that these risks had not been systematically assessed.
"This is critical to do because citalopram has been well tolerated by many patients over a long time, is available in a low-cost generic formulation, and is an antidepressant of choice on many prescription formularies."
In fact, the medication is 1 of 4 selective serotonin reuptake inhibitors (SSRIs) on the formulary for the VHA.
For the study, the researchers assessed data for the period from 2004 through 2009 from the VHA National Registry for Depression (NARDEP) on both in- and outpatients who received a prescription for citalopram (n = 618,450) or for sertraline, a comparison medication not subject to the FDA warning (n = 365,898). More than 90% of both groups were men.
The NARDEP data were linked to data from the National Death Index, as well as to codes from the ninth and tenth revisions of the International Classification of Diseases (ICD-9 and ICD-10), to measure clinical and mortality outcomes.
No Increased Risk
Results showed that only 1.1% of all patients who received a prescription for any dose of citalopram had ventricular arrhythmia compared with 1.1% of those who received sertraline.
Of all patient deaths that occurred during the study period, 3.3% of deaths among those using citalopram were due to a cardiac cause vs 4% for those using sertraline.
The participants receiving dosages of citalopram greater than 40 mg/day had no significantly increased risk for ventricular arrhythmia or all-cause, noncardiac, or cardiac mortality.
In fact, the high dosages were associated with lower risk for the first 3 measures compared with daily doses between 1 and 20 mg (ventricular arrhythmia: adjusted hazard ratio [HR], 0.68, 95% confidence interval [CI], 0.61 - 0.76; all-cause mortality: HR, 0.94, 95% CI, 0.90 - .099; noncardiac mortality: HR, 0.90, 95% CI, 0.86 - 0.96).
Although lower risks for ventricular arrhythmia were found for daily doses of 21 to 40 mg compared with doses of 1 to 20 mg (HR, 0.80; 95% CI, 0.74 - 0.86), there were no differences between the 2 dosage ranges in risk for all-cause mortality.
"The sertraline cohort revealed similar findings, except there were no significant associations between daily dose and either all-cause or noncardiac mortality," report the investigators.
"Currently, clinicians and patients who perceive benefits from high-dosage citalopram must make a trade-off between adhering to the FDA warning and possible worsening depression if patients receive too low a dosage," they add.
"Given the strength of the methods used in our study and the low likelihood of a definitive controlled trial, we question the continued merit of the warning."
The study was supported by grants from the US Department of Veterans Affairs (VA) and from the VA Health Research and Development Services. One of the investigators reports having served as a consultant to the Hazelden Foundation. The other study authors have reported no relevant financial relationships.
Am J Psychiatry. 2013;170:642-650. Abstract
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