What could be worse than Bristol-Myers Squibb marketing its powerful and risky antipsychotic Abilify for simple depression, when there are so many effective and safer alternatives? How about AstraZeneca marketing its equally powerful and risky antipsychotic Seroquel for depression and generalized anxiety? A few days ago the FDA heard arguments from the company to do just that; lengthy background material as well as evaluations by FDA staffers are available here.
Here are the words of one FDA scientist reviewing AstraZeneca’s claims that Seroquel is safe and effective for major depressive disorder (MDD):
[T]he safety profile we are seeing in the MDD population is not different from the profile we have already observed in other populations. However, it is of some concern that approving these claims will likely greatly expand the use of this product. Thus, we need to think carefully about the risks and benefits of such expanded use, particularly with regard to longer-term risks which are not yet fully established.
Unfortunately, the comments of other FDA reviewers did not express this concern.
FDA approval of antipsychotics for non-psychotic conditions is hardly a new practice. The typical antipsychotic Stelazine (trifluoperazine) was FDA approved for non-psychotic anxiety decades ago. This 1973 journal ad shows, in addition to the awkward sexism of the era, the same lopsided presentation we see now: modest benefits overshadowing serious risks. Of course, trifluoperazine has been available generically and inexpensively for years; there is no economic incentive to promote this particular agent anymore. In contrast, there is great economic incentive for the makers of Abilify, Seroquel, and similar products to tap expanded markets.
One argument offered in favor of approving atypical antipsychotics for depression goes like this: Even with 25 approved medications already out there (accurate figure), it’s a net benefit to have a 26th that might help the occasional patient. Why not leave the weighing of risks and benefits in the hands of the doctor, as long as the drug does what it claims?
This highlights a central question: What does FDA approval mean? Physicians are already free to prescribe “off-label,” and to weigh risks and benefits on a case by case basis. For example, the FDA has not approved the use of atypical antipsychotics as sleeping aids, yet according to some reports, over half of all Seroquel is prescribed for sleep and other non-approved uses. FDA approval must mean more than “doctors have the right to prescribe it,” since we already do. The public reasonably assumes that FDA approval adds an endorsement, something like “it’s usually a good idea for doctors to prescribe it for this particular indication.” The latter is a complex judgment that weighs risks as well as benefits, and that takes existing alternatives into account. In my view it is hard to justify stamping such an imprimatur on the use of powerful antipsychotics for common, relatively minor problems that already have good treatments. FDA approval gives a drug maker permission to market its product for the approved use. Antipsychotics are already being (mis)used in various ways even without such marketing. The wheels of commerce hardly need to be greased by a federal agency charged with public safety.
I haven’t said much about the generalized anxiety indication, but this could be a huge public health misstep if approved. In the 1960s the tranquilizer Valium was the most prescribed drug in the US. It was generally effective and well tolerated. Its major drawback was addiction and withdrawal effects, shortcomings shared by its contemporary successors such as Ativan, Xanax, and Klonopin. If the FDA approves Seroquel for anxiety, the aggressive marketing campaign for Seroquel will strongly emphasize its lack of addiction or withdrawal effects, issues that many physicians are wary of, and somewhat sensitive about. In an effort to sidestep the real (but manageable) problem of addiction, patients will receive Seroquel instead, even though it carries far more serious medical risks and is hugely more expensive (especially the time-release version AstraZeneca is promoting, the rationale for which is dubious at best). Seroquel could become the new “Mother’s Little Helper” — resulting in a bumper crop of obese, diabetic mothers (and fathers).
Interesting additional discussion on Seroquel and its new proposed indications can be found here.