A safety warning issued by the US Food and Drug Administration (FDA) advising clinicians not to prescribe the antidepressant citalopram (multiple brands) at dosages higher than 40 mg/day resulted in worsening depressive symptoms and more psychiatric hospitalizations among patients whose conditions had previously been stabilized with higher doses of the drug.

“Reduction of prescribed citalopram dosages to a new safety limit was associated with a higher rate of hospitalization in a large patient population who had been treated with substantially higher dosages,” the investigators, led by Thomas S. Rector, PharmD, PhD, from the Minneapolis VA Health Care System and the University of Minnesota, write.

“Stipulating a safety limit for citalopram dosages before the benefits and risks of doing so were firmly established appears to have had unintended clinical consequences,” they add.

The study was published online May 10 in the American Journal of Psychiatry.

Poor Mental Health Outcomes

On August 24, 2011, as reported by Medscape Medical News, the FDA issued a safety warning stating that the daily dosage of citalopram should no longer exceed 40 mg because of a risk for dose-dependent QT interval prolongation.

The Department of Veterans Affairs (VA) Center for Medication Safety followed suit and within a week issued a similar national safety bulletin.

“Dosages exceeding 40 mg/day had been used in several clinical trials and were frequently prescribed despite a lack of unequivocal evidence of additional therapeutic benefit,” the investigators note.

But the lack of evidence regarding the incidence of life-threatening QT interval prolongation, as well as the effectiveness of higher dosages in clinical practice, left it up to clinicians to decide whether the risk of worsening mental health disorders outweighed the risk of continuing to prescribe higher dosages of citalopram.

The aim of limiting the daily prescribed dosage to 40 mg/day was to reduce fatalities and health problems due to QT interval prolongation.

The investigators write that they began to notice several cases of suicidal ideation and hospitalization for worsening depression after citalopram dosages were reduced.

“Given the seemingly low incidence of the targeted adverse effect and the frequent clinical use of higher dosages of citalopram for presumably more difficult-to-treat cases, unintended increases in suicide and hospitalization due to worsening depression could offset the intended benefits of limiting citalopram dosage levels,” they write.

The researchers investigated this possibility in a retrospective study of VA Health Administration national electronic medical records. They compared rates of hospitalizations and mortality in an at-risk veteran population whose prescribed dosages of citalopram were >40 mg/day at the time the safety warning was issued and whose dosages were either reduced to ≤40 mg/day after the warning or were not reduced.

The analysis included a total of 35,848 veterans (mean age, 58 years; standard deviation [SD] = 11 years; 92% men). The average citalopram dosage was 64 mg/day (SD = 8.3).

After the warnings, dosages were reduced for 18,407 patients; for 17,441 patients, dosages were not reduced.

The investigators found that all-cause hospitalizations or deaths were significantly increased after reductions in citalopram (adjusted hazard ratio [AHR] = 4.5, 95% confidence interval [CI] = 4.1 – 5.0).

A similar result was found for hospitalizations for depression or all-cause death (AHR = 2.2, 95% CI = 1.8 – 2.6).

There was no decline in mortality (AHR = 1.0, 95% CI = 0.8 – 1.3), hospitalizations for arrhythmias, or all-cause deaths (AHR = 1.3, 95% CI = 1.0 – 1.7) with the citalopram dosage reductions.

“Rapidly reducing dosages from >60 mg/day to <40 mg/day may have precipitated worsening symptoms of depression, PTSD, and other mental health disorders,” the authors write.

In addition, the dosgee reduction did not have the desired effect of reducing hospitalizations for cardiac arrhythmias.

“Although citalopram can prolong the QT interval in a dose-dependent manner, the mortality risk may have been too low to detect even in this large cohort of patients who had survived high dosages of citalopram,” the authors note.

“We hope this research will encourage more empirical studies of patient outcomes after risk mitigation initiatives and thereby help to improve medication safety warnings and clinical risk management,” they conclude.

Critical Safety Issue

Commenting on the study for Medscape Medical News, Stanley N. Caroff, MD, professor, Perelman School of Medicine, University of Pennsylvania, in Philadelphia, said the investigators “perform a valuable service by utilizing the power of data from large samples of veterans documented in the VA Health System to address a critical patient safety issue.”

Dr Caroff noted that although postmarketing surveillance of the safety of medications is very important in guiding clinical practice, careful study of recommendations is also important to avoid unforeseen consequences.

“The authors conducted a state-of-the-art retrospective review of the consequences of recent recommendations on lowering the dose of citalopram, a popular antidepressant, to prevent arrhythmias resulting from QTc interval prolongation.

“They found that there was a significant increase in all-cause and mental health–related hospitalizations after the dose of citalopram was reduced below the recommended safety limit of 40 mg/day in veterans who had previously been stabilized on doses above the limit and conversely found there was no reduction in hospitalization or mortality related to cardiac arrhythmias,” he said.

“Their findings suggest that blanket reductions in dosing for all patients on higher doses may not be without risk, and a careful, individualized assessment of each patient, balancing medical and psychiatric risks and benefits, is the best approach,” Dr Caroff added.

The authors and Dr Caroff report no relevant financial relationships.

Am J Psychiatry. Published online May 10, 2016. Abstract