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    <recommendedItem id="20090101_19_1098"
                     title="FDA Panel Splits on New Uses for Atypical Antipsychotic"
                     score="-0.005"
                     href="http://www.medpagetoday.com/Psychiatry/Depression/tb/13667?impressionId=1265803317829"
                     
       SILVER SPRING, Md., April 8 -- An FDA advisory committee today was reluctant to recommend approval of more indications for the antipsychotic drug quetiapine (Seroquel), with studies showing substantial metabolic and cardiovascular risks.
              &lt;p&gt; 
              &lt;p&gt;Consequently, the Psychopharmacologic Drugs Advisory Committee voted down a request to market the drug for generalized anxiety disorder.
              &lt;p&gt; 
              &lt;p&gt;It gave assent to the drug for major depression, but only when patients have failed other treatments and only in combination with another antidepressant.
              &lt;p&gt; 
              &lt;p&gt;Quetiapine&apos;s manufacturer, AstraZeneca, is seeking approval for the drug as a first-line therapy for both conditions.
              &lt;p&gt; 
              &lt;p&gt;A psychiatrist on the panel said at least 10% of the U.S. population will experience either major depression or anxiety disorder in their lifetimes -- a huge number of people who could potentially receive the drug if approved as first-line therapy.
              &lt;p&gt; 
              &lt;p&gt;Panel members said expanding quetiapine to such a large population was too big of a gamble given the increased risk for weight gain, high glucose levels, and tardive dyskinesia -- persistent, involuntary, and sometimes disfiguring movements -- associated with the drug.
              &lt;p&gt; 
              &lt;p&gt;The panel agreed that AstraZeneca&apos;s trials were too short to prove that quetiapine doesn&apos;t increase the risk of sudden cardiac death. In addition, members were concerned about the risk of tardive dyskinesia with quetiapine, an issue for all antipsychotic drugs.
              &lt;p&gt; 
              &lt;p&gt;The drug&apos;s efficacy in these conditions was not much in question, with the panel voting 9 to 1 that the drug is effective in major depression, and 7 to 2 (with one abstention) that it relieves generalized anxiety disorder.
              &lt;p&gt; 
              &lt;p&gt;Instead, safety issues occupied most of the panel&apos;s attention.
              &lt;p&gt; 
              &lt;p&gt;The FDA has never approved an antipsychotic as a monotherapy for depression, said Robert Temple, M.D., director of the Office of Drug Evaluation at the FDA.
              &lt;p&gt; 
              &lt;p&gt;The panel failed to endorse the safety of the drug when used as a stand-alone treatment for depression by a vote of 4 to 4, with one panelist abstaining.
              &lt;p&gt; 
              &lt;p&gt;But the committee voted 6 to 3 that quetiapine is acceptably safe when used in addition to another drug to treat depression that has not responded to previous therapy.
              &lt;p&gt; 
              &lt;p&gt;It also voted 6 to 2, with one member abstaining, to reject the safety claim of the drug as a monotherapy to treat anxiety.
              &lt;p&gt; 
              &lt;p&gt;&quot;It&apos;s not as clear we need the alternatives as much as we do for cases of depression,&quot; said Wayne Goodman, M.D., chairman of the committee. &quot;I don&apos;t see that there&apos;s a clear advantage for this.&quot;
              &lt;p&gt; 
              &lt;p&gt;Weight gain associated with quetiapine was a major concern.
              &lt;p&gt; 
              &lt;p&gt;According to the agency&apos;s analysis of AstraZeneca&apos;s clinical trials, patients taking quetiapine gained an average of 2.6 pounds at 43 days median exposure, while the placebo group gained an average of less than half of a pound. There was some suggestion that weight gain increased over time.
              &lt;p&gt; 
              &lt;p&gt;That might seem like an inconsequential weight gain, but, said Frank Greenway, M.D., medical director Pennington Biomedical Research Center, Baton Rouge, La., &quot;it&apos;s remarkable how a small amount of weight gain can be detrimental in terms of diabetes.&quot;
              &lt;p&gt; 
              &lt;p&gt;Patients receiving quetiapine also had a significant increase in fasting blood glucose and total cholesterol.
              &lt;p&gt; 
              &lt;p&gt;The panel also worried that quetiapine may carry a risk of sudden cardiac death, apparently a class effect of atypical antipsychotics.
              &lt;p&gt; 
              &lt;p&gt;(See: &lt;a href=&quot;http://www.medpagetoday.com/Psychiatry/Schizophrenia/12453&quot; target=&quot;blank&quot;&gt;Risk of Sudden Death No Less Likely with Atypical Antipsychotics&lt;/a&gt;)
              &lt;p&gt; 
              &lt;p&gt;The panel seemed troubled as well by the 1.7% risk for tardive dyskinesia  observed in the trial.
              &lt;p&gt; 
              &lt;p&gt;&quot;When you look at the unanswered questions about tardive dyskinesia, diabetes, and sudden cardiac death, you need to answer those questions before approving, especially when there are other drugs that are safer,&quot; according to Diana Zuckerman, Ph.D., president of the National Research Center for Women and Families, who spoke during the meeting&apos;s public comment period.
              &lt;p&gt; 
              &lt;p&gt;The panel also heard tearful testimony from several spouses and parents of Iraq veterans whose loved ones either died or experienced severe side effects while taking quetiapine along with other drugs for treatment of post-traumatic stress disorder. Quetiapine is not approved for the condition.
              &lt;p&gt; 
              &lt;p&gt;Quetiapine is currently approved for treatment of schizophrenia, acute bipolar depression and mania, and for maintenance therapy of bipolar disorder as an adjunct to lithium or divalproex (Depakote).
              &lt;p&gt; 
              &lt;p&gt;The FDA does not have to follow its advisory panels&apos; recommendations, but it usually does. 
    </recommendedItem>
    <recommendedItem id="20090101_19_1056"
                     title="FDA Review Questions Cardiac, Suicide Risks for Investigational Antipsychotic"
                     score="-0.005"
                     href="http://www.medpagetoday.com/Psychiatry/Schizophrenia/tb/13619?impressionId=1265803317829"
                     
       WASHINGTON, April 6 -- Investigational antipsychotic drug sertindole (Serdolect) is effective at treating schizophrenia, but it may lead to sudden cardiac death, according to an FDA review. 
              &lt;p&gt; 
              &lt;p&gt;The agency released its review in advance of Tuesday&apos;s meeting of the Psychopharmacologic Drugs Advisory Committee, which will decide if the drug&apos;s cardiovascular risk is an obstacle to FDA approval. 
              &lt;p&gt; 
              &lt;p&gt;The advisory panel will also consider the sponsor&apos;s suicide prevention claim, and whether to recommend to the FDA that the drug is safe and effective. The vote will effectively amount to a recommendation of approval or denial.
              &lt;p&gt; 
              &lt;p&gt;Sertindole is already used in other countries to treat schizophrenia. 
              &lt;p&gt; 
              &lt;p&gt;According to the FDA review, led by psychiatrist Phillip Kronstein, M.D., sertindole is effective in treating schizophrenia, but concerns remain about the drug&apos;s potential to prolong the heart&apos;s QT interval, which can lead to sudden cardiac death. That same cardiac risk has been seen in other antipsychotic drugs similar to sertindole. 
              &lt;p&gt; 
              &lt;p&gt;Sertindole is a so-called atypical antipsychotic drug, Its specific mechanism appears to be to inhibit spontaneously active dopamine neurons in the mesolimbic ventral tegmental area without affecting dopamine neurons in the substantial nigra compacta. 
              &lt;p&gt; 
              &lt;p&gt;A recent study found that atypical antipsychotics carry a risk of sudden cardiac death similar to that associated with older schizophrenia drugs.  (See: &lt;a href=&quot;http://www.medpagetoday.com/Psychiatry/Schizophrenia/12453&quot; target=&quot;blank&quot;&gt;Risk of Sudden Death No Less Likely with Atypical Antipsychotics&lt;/a&gt;) 
              &lt;p&gt; 
              &lt;p&gt;Sertindole has been approved in the U.K. since 1996. But use of the drug was temporarily suspended after an online database indicated that sertindole might cause more deaths than risperidone (Risperdal). The drug&apos;s manufacturer, Lundbeck, agreed to perform a large randomized parallel-group study comparing all-cause death, cardiac death, and suicide for sertindole versus risperidone.
              &lt;p&gt; 
              &lt;p&gt;Based on results from that nearly 10,000-patient study, which did not show an increase in all-cause mortality with sertindole, the restrictions on the drug were lifted. 
              &lt;p&gt; 
              &lt;p&gt;But in Lundbeck&apos;s analyses to prepare for U.S. approval, the FDA reviewers didn&apos;t think the comparable all-cause mortality data was exactly a home run for sertindole, &quot;given the relatively higher mortality in this population from multiple causes,&quot; Dr. Kronstein said. 
              &lt;p&gt; 
              &lt;p&gt;More relevant are the cardiac deaths, in light of sertindole&apos;s connection to heart problems, he said. The FDA review found that patients taking sertindole had a significantly higher risk of cardiac death compared with those taking risperidone (&lt;em&gt;P&lt;/em&gt;=0.002). 
              &lt;p&gt; 
              &lt;p&gt;Thirteen patients died suddenly from cardiac causes in the sertindole group, compared with three who were taking risperidone. 
              &lt;p&gt; 
              &lt;p&gt;&quot;This is a significant and concerning result, indicating that sertindole-treated patients had an approximately five times higher risk of sudden cardiac death,&quot; according to the review.
              &lt;p&gt; 
              &lt;p&gt;The other major question for the committee is whether Lundbeck can justifiably claim that sertindole prevents suicidality better than other antipsychotic drugs.
              &lt;p&gt; 
              &lt;p&gt;Lundbeck has proposed to include such a claim in the product&apos;s label. In the company&apos;s trials, there were 14 suicide deaths among sertindole patients and 21 in the risperidone group.
              &lt;p&gt; 
              &lt;p&gt;But the FDA&apos;s staff review disagreed with the way Lundbeck examined suicide risk, and requested that the company analyze all suicide attempts instead of only those that succeeded.
              &lt;p&gt; 
              &lt;p&gt;According to the briefing documents for the meeting, this second analysis found that 46 patients attempted suicide during treatment and up to 30 days after in the sertindole group, compared with 62 in the risperidone group, with the difference failing to reach statistical significance.
              &lt;p&gt; 
              &lt;p&gt;The panel is to vote on whether the data show that sertindole reduces suicidality in schizophrenic patients.
              &lt;p&gt; 
              &lt;p&gt;As for the drug&apos;s efficacy in schizophrenia symptoms, two clinical trials have adequately proved the short-term antipsychotic efficacy of between 12 mg and 20 mg daily doses of sertindole, according to the FDA&apos;s Dr. Kronstein. 
              &lt;p&gt; 
              &lt;p&gt;There are no adequate and well-controlled data to address long-term efficacy, he said. 
              &lt;p&gt; 
              &lt;p&gt;The FDA does not have to follow the advice of the panels, but it usually does.
    </recommendedItem>
    <recommendedItem id="20090101_19_1082"
                     title="FDA Panel Recommends Limited Use of Investigational Antipsychotic"
                     score="-0.005"
                     href="http://www.medpagetoday.com/Psychiatry/Schizophrenia/tb/13646?impressionId=1265803317829"
                     
       SILVER SPRING, Md., April 7 -- An FDA advisory panel voted to recommend FDA approval for sertindole (Serdolect) to treat schizophrenia, but only for a subgroup of patients that the agency would have to define.
              &lt;p&gt; 
              &lt;p&gt;The lukewarm backing came in part because of studies showing that patients taking sertindole were more than four times as likely to die suddenly, compared with another atypical antipsychotic, risperidone (Risperdal). 
              &lt;p&gt; 
              &lt;p&gt;In fact, the Psychopharmacologic Drugs Advisory Committee voted 12 to 1 that the drug is not &quot;acceptably safe&quot; for the general schizophrenic population.  
              &lt;p&gt; 
              &lt;p&gt;But the panel unanimously agreed the drug is effective and then voted 8 to 2, with three members abstaining, that some patients might benefit from having sertindole as an option. 
              &lt;p&gt; 
              &lt;p&gt;The committee did not clearly identify those patients, however, leaving it to the FDA to decide which patients, if any, should receive the drug, manufactured by Lundbeck and currently marketed in other countries.
              &lt;p&gt; 
              &lt;p&gt;One panelist suggested that sertindole only be prescribed for schizophrenics who have not responded to other drugs, and another suggested performing cardiac tests to give some hint of whether a patient might be at increased risk for heart problems. 
              &lt;p&gt; 
              &lt;p&gt;&quot;I would hope this is a treatment of last resort,&quot; said Gail Griffith, M.S., the consumer representative on the panel.
              &lt;p&gt; 
              &lt;p&gt;Sertindole prolongs the heart&apos;s QT interval, which may lead to major cardiac problems, including sudden death. In the sponsor&apos;s trial, there were 13 sudden cardiac deaths among patients taking sertindole and three among patients taking risperidone (&lt;em&gt;P&lt;/em&gt;=0.002).
              &lt;p&gt; 
              &lt;p&gt;&quot;The cardiovascular risk is real, but I think that is counterbalanced by the need for other treatment,&quot; said Sheryl Kelsey, Ph.D., professor of epidemiology at University of Pittsburgh. Kelsey is a temporary member of the Cardiovascular and Renal Drugs Advisory Committee, which had three of its members voting on Tuesday&apos;s panel. 
              &lt;p&gt; 
              &lt;p&gt;Sudden cardiac death has been seen in other antipsychotic drugs similar to sertindole.
              &lt;p&gt; 
              &lt;p&gt;(See: &lt;a href=&quot;http://www.medpagetoday.com/Psychiatry/Schizophrenia/12453&quot; taraget=&quot;blank&quot;&gt;Risk of Sudden Death No Less Likely with Atypical Antipsychotics&lt;/a&gt;) 
              &lt;p&gt; 
              &lt;p&gt;The panel also swatted away Lundbeck&apos;s proposed claim that sertindole could help prevent suicide among schizophrenic patients. About half of all schizophrenic patients attempt suicide, according to the drugmaker. 
              &lt;p&gt; 
              &lt;p&gt;But the committee voted 12 to 1 that patients taking sertindole are no less likely to contemplate, attempt, or succeed in taking their lives, compared with those taking antischizophrenia drug risperidone.  
              &lt;p&gt; 
              &lt;p&gt;An FDA analysis found that 36 sertindole-treated patients attempted suicide, compared with 54 in the risperidone group, but the difference failed to reach statistical significance.
              &lt;p&gt; 
              &lt;p&gt;The efficacy data on which the panel based its vote came from the sponsor&apos;s trials involving more than 10,000 patients.
              &lt;p&gt; 
              &lt;p&gt;These studies adequately proved the short-term antipsychotic efficacy of 12- to 20-mg daily doses of sertindole, according to the lead FDA staff reviewer, psychiatrist Phillip Kronstein, M.D.
              &lt;p&gt; 
              &lt;p&gt;The FDA does not have to follow the advice of its advisory panels, but it usually does.  
              &lt;p&gt; 
              &lt;p&gt;(See: &lt;a href=&quot;http://www.medpagetoday.com/Psychiatry/Schizophrenia/13619&quot; target=&quot;blank&quot;&gt;FDA Review Questions Cardiac, Suicide Risks for Investigational Antipsychotic&lt;/a&gt;)
    </recommendedItem>
    <recommendedItem id="20090101_3_104"
                     title="Invega (paliperidone), Son of Risperdal (risperidone), Wins  FDA Okay for Schizophrenia"
                     score="-0.006"
                     href="