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FDA panel deems antipsychotic safe as add-on for MDD: other recommendations prove mixed.

SILVER SPRING, MD. -- Quetiapine fumarate is safe as an adjunctive therapy for major depressive disorder and generalized anxiety disorder, according to a Food and Drug Administration panel. But the drug is safe only in certain instances as a first-line therapy for MDD and not as a standalone treatment for GAD, the panel said.

The FDA's Psychopharmacologic Drugs Advisory Committee did not define instances in which quetiapine fumarate (Seroquel XR) might be safely prescribed for MDD. But it voted 4-4, with one abstention, that the drug was acceptably safe "in certain circumstances" when used as a monotherapy for MDD.

The abstention came from Dr. Wayne K. Goodman, the committee's acting chairman. Dr. Goodman, who serves as director of the Division of Adult Translational Research and Treatment Development at the National Institute of Mental Health, said he thought that the data were insufficient to support quetiapine's use in MDD.

Panelists were clearer that quetiapine should not be used as a first-line therapy for GAD, voting 6-2, with one abstention, against that indication. Dr. Goodman said that there was not as pressing a need for alternative therapies in GAD, compared with that for MDD.

The FDA generally follows its advisory committees' recommendations. It is not yet clear how the agency will address any label change for quetiapine. The drug is already approved in the United States--and in more than 90 countries--as a monotherapy for acute treatment of bipolar depression and mania, as a monotherapy for acute and maintenance treatment of schizophrenia, and as an adjunctive therapy for acute bipolar mania.

The committee acknowledged that the drug might be more widely used without specific FDA approval for MDD and GAD. But panelist Dr. Robert Harrington, a cardiologist from Duke University, Durham, N.C., said, "We're sending a note of caution that more needs to be done."

At the meeting's outset, Dr. Thomas Laughren, director of FDA's Division of Psychiatry Products, said the agency had determined that quetiapine was effective for MDD and GAD, and that "the overall safety profile appears to be roughly similar to what we've observed for this drug for the other conditions for which it is approved."

But the agency wanted the panel to focus on the implications of approving quetiapine for MDD and GAD, which affect many more people than do schizophrenia, bipolar mania, or bipolar depression.

According to the National Institute of Mental Health. MOD is the leading cause of disability in the United States for Americans aged 15-44 years, affecting 14.8 million adults each year. About 6.8 million American adults, or about 3.1% of people over age 18, have GAD in a given year.

Wider use could likely expose more patients to quetiapine's known side effects, including a risk of tardive dyskinesia and metabolic changes that predispose patients to diabetes or cardiovascular disease. The agency also asked the Psychopharmacologic Drugs Advisory Committee to weigh the potential for increased risk of sudden cardiac death (SCD).

AstraZeneca first presented efficacy data from seven short-term studies and two longer-term trials in MDD, and four short-term trials and one longer-term study in GAD. The patients were given doses of 50-300 mg daily, depending on the study. For MDD, quetiapine was consistently effective as a short-term monotherapy, compared with placebo, judged as the change from baseline in the Montgomery-Asberg Depression Rating Score (MADRS). In the longer trial, in which patients took quetiapine for up to a year, the drug significantly reduced the risk of relapse, with a hazard ratio of 0.34.

For GAD, quetiapine also demonstrated efficacy over placebo with consistent improvement of 50% or more in the Hamilton Anxiety score over baseline. The longer-term trial demonstrated a significant reduction in the risk of relapse, with a hazard ratio of 0.19.

In a series of votes, the committee concluded that quetiapine was effective as an adjunctive therapy for MDD, and as a monotherapy for both MDD and GAD.

But the main focus was on safety.

AstraZeneca said the most frequently reported adverse events included dry mouth, somnolence, sedation, and dizziness.

In terms of more serious side effects, the company said there were small weight changes of 0.7-1.2 kg seen in the MDD and GAD studies. Serum cholesterol increased only at doses of 300 mg or more daily, and there were small decreases in HDL cholesterol at all doses, said Dr. Ihor Rak, vice president of clinical neuroscience at AstraZeneca.

He also noted that quetiapine's label already has extensive warnings about tardive dyskinesia, and said that the risk in the MDD and GAD studies was very low-- at 0.21% in the longer-term trials.

There was a lengthy discussion about SCD. Dr. Rak presented data from 26,000 patients, which included all previously conducted studies. The company also further analyzed the data based on the MDD and GAD trials. All the reports of death were adjudicated by an expert cardiologist who was blinded to treatment. The expert used the SCD definition that was described in the study of SCD risk and antipsychotics that was recently published in the New England Journal of Medicine (2009;360:225-35).

Overall, AstraZeneca concluded that there was no higher risk of SCD and no difference in all-cause mortality with quctiapine.

The author of that NEJM study, Dr. Wayne Ray, director of the division of pharmacoepidemiology at Vanderbilt University, Nashville, Tenn., presented an overview of that paper, which found that all antipsychotics, including quetiapine, increase the risk of SCD. Dr. Ray acknowledged that the trial could be limited by potential confounding variables, but stood by his findings.

However, Dr. Marc B. Stone, a senior medical reviewer in the psychiatric products division, concluded that those confounders--including the fact that antipsychotic users are more likely to be smokers and heavy smokers, and to get less medical care--likely strongly influenced the results.

The panel members said too many open questions exist about quetiapine, including whether it might increase SCD risk. Committee member James Neaton. Ph.D., professor of biostatistics at the University of Minnesota, Minneapolis, said he was concerned that AstraZeneca's studies may have been underpowered, and thus could not truly assess the risks.

"I come away feeling very uncomfortable about this," Dr. Neaton said.

The panel voted 9-0 in two separate votes that quetiapine was not safe to use as a monotherapy in either GAD or MDD.

"The long-term risks of antipsychotics are greater than I'd like to see," said Dr. Richard P. Malone, who serves as a professor of psychiatry at Drexel University, Philadelphia.
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Title Annotation:major depressive disorder
Author:Ault, Alicia
Publication:Clinical Psychiatry News
Article Type:Report
Geographic Code:1USA
Date:May 1, 2009
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