FDA Panel Issues Mixed Decision on Quetiapine in Depression and Anxiety

A new formulation of extended-release quetiapine, an atypical antipsychotic medication, should not be approved as a monotherapy for major depressive disorder and generalized anxiety disorder because of serious cardiac and metabolic adverse events associated with use of the drug, according to an advisory panel to the US Food and Drug Administration (FDA). The panel, however, voted in favor of approving more limited use of quetiapine as an adjunctive therapy in treatment-refractory depression.

Quetiapine fumarate, sold under the brand name Seroquel (AstraZeneca Pharmaceuticals, Wilmington, Del), is currently approved for the treatment of schizophrenia and acute episodes of mania and depression in patients with bipolar disorder. But the drug's maker is seeking approval for wider use of another formulation of the drug, quetiapine maleate. The FDA ultimately will decide whether to allow wider marketing of this new formulation, although the agency usually follows the advice of its advisory committees.

On April 8, 2009, the FDA's Psychopharmacologic Drugs Advisory Committee was asked to advise the agency on whether it should approve marketing of quetiapine for depression or anxiety. In the background materials provided to the committee, Thomas P. Laughren, MD, director of the FDA's Division of Psychiatry Products, notes that although the sponsor's data support the efficacy of quetiapine in the treatment of depression and anxiety, the agency is concerned about the public health ramifications of exposing a larger population of individuals to the drug (http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4424b2-01-FDA.pdf). Laughren noted that the drug is associated with a long-term risk of metabolic problems and tardive dyskinesia and that recent data suggest an increased risk of sudden cardiac death.

Wayne Goodman, MD, the panel's acting chair and director of adult translational research at the National Institute of Mental Health, explained that the panel found quetiapine to be acceptably safe for adjunctive use in depression (by a vote of 6 to 3) and that the decision was not precedent-setting because the agency had previously approved the antipsychotic agent aripiprazole for such use. However, the long-term risk of patients developing metabolic syndrome and, to a lesser extent, the short-term risk of sudden cardiac death weighed heavily in the panel's unanimous decision against recommending use of this drug as a monotherapy in a wider population when other less risky drugs are available, he said.

Recent data suggesting that taking quetiapine and other atypical antipsychotics doubles the risk of sudden cardiac death also were presented to the panel (Ray WA et al. N Engl J Med. 2009;360[3]:225-235). Using Tennessee Medicaid records, Wayne A. Ray, PhD, director of the division of pharmacoepidemiology at the Vanderbilt University School of Medicine in Nashville, Tenn, and colleagues conducted a retrospective cohort study of more than 40 000 patients who took atypical antipsychotics, more than 40 000 users of typical antipsychotics, and more than 180 000 matched controls who were not taking antipsychotics. They found that, contrary to the belief that newer atypical antipsychotics carry less cardiac risk, the 2 classes of drugs were associated with comparable risk. Anecdotal reports by individuals testifying at the meeting about loved ones who died suddenly and unexpectedly while taking quetiapine were consistent with his data on sudden cardiac death, said Ray.

Ray explained that the cardiac risks he documented are acute and not related to the long-term metabolic effects of the drug. “As soon as therapeutic blood levels are achieved, this risk increased,” he said.

The findings are the latest in a growing body of data suggesting that typical and atypical antipsychotics have a similar safety and efficacy profile. Unlike the older antipsychotic drugs, however, quetiapine and other atypical antipsychotics have gone on to become blockbuster drugs, with sales of quetiapine reaching nearly $4.5 billion in 2008.

Such sales are driven in part by large-scale off-label use. A recent analysis of a large commercial database of prescribing practices identified quetiapine as the drug most frequently prescribed for indications lacking adequate supporting evidence (Walton SM et al. Pharmacotherapy. 2008;28[12]:1443-1452). The analysis found that the most common off-label uses for this drug were for maintenance treatment for bipolar disorder, depression, and dementia.

Surrey M. Walton, PhD, the study’s lead author, noted that there may be good clinical reasons for off-label use, and that such use is not necessarily harmful but often is not supported by evidence. He recommended further research on off-label uses of quetiapine.

Given the worrisome safety data, some scientists urge caution that the drug should not be used to treat conditions for which safer options exist. Ray noted that there may not be alternatives for patients with schizophrenia or psychosis, but for patients with bipolar disorder, other options such as mood stabilizers should be considered first. For off-label indications, he said, such atypical antipsychotics should be considered only as a last resort.

Robert A. Rosenheck, MD, professor of psychiatry at Yale University School of Medicine in New Haven, Conn, noted that the data supporting the efficacy of quetiapine as an adjunctive therapy for depression considered by the FDA are based on a pair of 6-week trials in which the drug plus an antidepressant were compared with a placebo plus an antidepressant. Long-term studies, comparative effectiveness studies, and cost-effectiveness studies are needed, he said.

“We need to know more before [quetiapine] is widely used in depression,” Rosenheck said.