March 25, 2009

Antipsychotic Drug Approved for Depression Treatment

Patrick Finley

If you were not responding to antidepressants, would you be willing to try antipsychotic medication? Patent protection is running out for Zyprexa, an Eli Lilly and Co. drug. It was first marketed as an anti-psychotic. Marketing was later permitted for the treatment of bipolar depression. But now the FDA has added a new approved indication for a more common condition – treatment resistant depression. The approved formulation combines Zyprexa (olanzapine) with the popular anti-depressant Prozac (fluoxetine). The combination, called Symbyax, can now be marketed to physicians and through direct-to-consumer advertising for depression that has not responded to two previously prescribed drugs. Not responding to a first or even a second prescribed antidepressant is not unusual, according to UCSF clinical pharmacist Patrick Finley, PharmD, BCPP, who staffs a depression clinic for the UCSF Women’s Health Center. A large clinical trial called STAR*D several years ago revealed that fewer than half of patients with mild to moderate depression respond to initial treatment with a common serotonin reuptake inhibitor (SSRI), Finley notes. SSRIs are now the most popular first-line drug treatment for depression. This class of drugs includes Prozac. “You’re probably looking at 20 to 25 percent who have two consecutive failed trials,” trying first one anti-depressant and then a second, Finley says. That means the potential market for Symbyax is huge. At any time, about three to five percent of US population is estimated to have diagnosable depression, Finley says. About one person in seven will experience significant depression at some time. About half who are clinically depressed go undiagnosed or do not follow through with treatment, Finley notes. But Finley is not enthused about this new addition to the armamentarium available to fight depression: “The three biggest drawbacks to this agent are that it does carry a significant risk of metabolic syndrome; it is a fixed combination, which makes it more difficult to use from a practical standpoint; and it’s going to be quite expensive.” Dramatic weight gain with Zyprexa treatment was first observed in patients taking the drug for schizophrenia. Fat metabolism is altered, too. These changes can lead to diabetes, and associated risks for heart attack and stroke. Lilly has added a warning label about these side effects to its packaging of Zyprexa and Symbyax. “If there are other options, I would not want to use this and risk metabolic syndrome,” Finley says. . In a Lilly-sponsored clinical trial co-authored by Lilly scientists, in which patients were assigned to either Zyprexa alone, Prozac alone, or a combination of the two, the patients who received the combination “did far and away the best,” Finley notes. The authors acknowledged that Prozac inhibits the metabolism of Zyprexa. “It could be that they were seeing an additional benefit in the combination, simply because the Prozac was in effect increasing the dose of Zyprexa,” Finley says. Symbyax is not the only atypical anti-psychotic approved for an indication of depression. Another drug called aripiprazole, marketed as Abilify by Bristol-Myers Squibb and Otsuka America Pharmaceuticals, Inc. also has an FDA-approved indication to treat depression in combination with an anti-depressant. This drug has fewer metabolic effects, and is regarded as “weight-neutral,” according to Finley. Finley notes that the fixed-dose formulation of Symbyax makes it difficult to adjust dose for effectiveness or to reduce the side effects caused by either of the medications. Finley says that he regards Symbyax and other atypical antipsychotics as fourth-or-fifth-line agents for treating depression, “simply because they are so expensive, and because some of them do carry these significant risks.” Ironically, after an explosion of new pharmaceuticals to treat depression becoming available over the past two decades, an old discarded class of depression drugs, MAO inhibitors, may now be coming back into favor. MAO inhibitors were not abandoned due to any lack of effectiveness. Rather, they caused common drug interactions, and patients also were unwilling to abide by major dietary restrictions required during treatment. A new patch formulation minimizes these risks, Finley says. However, the new patch also is quite expensive – with a cost of about ten to fifteen dollars per day, according to Finley. Prices may not come down until patent protection for the new formulation expires.

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