Hating on Antipsychotics: Are We Going Too Far?

Antipsychotics are not perfect. No drugs are. They can cause weight gain and weird movement side effects and sleepiness. But they have their uses, such as quelling racing thoughts, inner turmoil, and psychosis. There’s nothing inherently good or bad about any class of drugs. It’s up to physicians to understand the data and to prescribe medications judiciously.

With that introduction out of the way, let me describe for you a recent study that was published in the July 11 issue of JAMA. It’s called the VAST-D trial, which stands for “VA Augmentation and Switching Treatments for Improving Depression Outcomes”. In this study, researchers randomly assigned 1522 patients to thee treatments: 1. Switch from the current antidepressant to bupropion; 2. Continue the current antidepressant, and add bupropion; 3. Continue the current antidepressant and add aripiprazole (a second-generation antipsychotic that is FDA approved for adjunctive use in depression). (By the way, the study was not funded by aripiprazole’s makers, and the medication is now available in a low cost generic form).

 After 12 weeks of treatment, the aripiprazole augmentation group fared somewhat better than the others:

Outcome at 12 weeks	Aripiprazole augmentation	Bupropion augmentation	Bupropion switch
Remission rate	29% (statistically superior to bup switch)	27%	22%
Response rate	74% (statistically superior to bup switch and augmentation)	66%	62%

Aripiprazole augmentation yielded a higher remission rate than switching to bupropion, and it produced a higher response rate than either one of the bupropion strategies. But let’s look at side effects—some were more common in the aripiprazole group, others in the bupropion group. Side

Effects Statistically More Common in the Aripiprazole Group:

Side Effects	Aripiprazole augmentation	Bupropion augmentation	Bupropion switch
Akathisia	14.9%	5.3%	4.3%
Somnolence	14.5%	7.9%	7.2%
Weight increased by at least 7% at 12 weeks	9.5%	1.9%	2.3%
Weight increased by at least 7% at 36 weeks	25.2%	5.2%	5.2%

Side Effects Statistically More Common in the Bupropion Groups:

Side Effects	Aripiprazole augmentation	Bupropion augmentation	Bupropion switch
Anxiety	16.6%	22.5%	24.3%
Tremor	3.8%	10.3%	6.1%

Basically, bupropion caused more anxiety and tremor, while aripiprazole caused more weight gain, tiredness, and akathisia (a feeling of inner restlessness often caused by antipsychotics). Now, although aripiprazole caused more side effects, patients seemed to be less bothered by these side effects than those in the other treatment groups—at least as measured by the percentage of patients who withdrew from the study due to side effects. Only 5.3% of the aripiprazole patients withdrew because of side effects, as opposed to 7.3% in the bupropion augmentation group, and 10% in the bupropion switch group.

If you want to quibble with the results, there are a lot of details about the study that you can pick apart. And as is true for just about any large study, these would be reasonable points. But for me as a clinician, the bottom line is that this is the first large truly randomized study comparing antipsychotic augmentation with two other very common strategies for patients who don’t respond to the first antidepressant. And the results pretty clearly show that aripiprazole augmentation is somewhat more effective than the two other methods tested. This doesn’t mean that suddenly all my patients are going to be on aripiprazole. A quarter of patients had significant weight gain after 9 months, and about 15% had akathisia. Those can be problems, but in clinical practice, you monitor for side effects, and if they are bad, you stop the offending medication and try something else. That’s a risk/benefit decision . . . and this study implies that aripiprazole should be high on your options for treatment resistant depression.

But here’s the thing: Nobody seems to want to admit that it works.

 On Medpage Today’s Slow Medicine blog, the focus was on the side effects of aripiprazole, and how this study will definitely not convince them to use aripiprazole.

 Their commentary was titled “No Atypical Antipsychotics for Depression,” and they concluded with: “In the face of uncertainty, our Slow Medicine philosophy favors the safer, more conservative approach. VAST-D will not change our practice. Until we see clear evidence of benefits that outweigh the harms, we don't see a role for antipsychotics for most patients with depression. For now, among patients with an inadequate response to a first antidepressant, we'll try a second antidepressant, consider enhancing behavioral therapy, or think about augmenting with the safer medication, buproprion.”

Given that their philosophy is to avoid quick fixes and take a cautious approach to new treatments, I can understand this coming from Slow Medicine. But even the authors of the original JAMA article took pains to downplay the results. Here’s their conclusion:

 “Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.”

Really? First, they’re reminding us that we can’t generalize the results beyond the population studied (okay, we got that, it is, after all, a study of vets). Second, they are pretending that response rate was not one of the pre-specified outcome variables (it was a secondary outcome, but based on the same depression scale used for the primary outcome), and therefore they are making believe that there’s no evidence that aripiprazole was better than bupropion augmentation, not just better than switching. And finally, there’s this bizarre indirect way of saying “these results are unimpressive, don’t change your practice.” (I guess that’s what they mean by “net utility”).

 Dudes, this was a major study, and you got an interesting, clinically relevant, result!

It’s okay to brag a little. Let’s go where the data take us, even if we’ve become accustomed to hating on the drugs that come out on top.

FDA Slams Viibryd: Better Sexual Profile Claim “Not Supported by the Data”

The September 2011 issue of the Journal of Clinical Psychiatry created history in two ways.

First, the journal published this article written by FDA staff critically reviewing the efficacy and safety data of Viibryd, a new antidepressant that the same FDA staff had just approved.

Second, it was not just any journal that published the article, but the Journal of Clinical Psychiatry. Why is this so historic? Anybody who has followed this blog over the years has noticed a certain…shall we say, skepticism...toward many of the articles published in JCP, especially those published in its industry-funded supplements. But in this case I'm happy to give the journal kudos for having the courage to publish an article critical of an antidepressant made by a company that pays for drug ads.

Not that any of this information is truly new. Back in April of 2011, my own Carlat Psychiatry Report actually scooped JCP on this issue, when Jim Phelps and I reported in this article that Viibryd-funded authors had tweaked sexual side effect data to make the drug appear “cleaner” than its SSRI competitors.  (Some of this tweaking, interestingly enough, occurred in the pages of the Journal of Clinical Psychiatry).

In fact, as we reported and as this new paper elaborates, the studies proved nothing at all about Viibryd’s side effects, because they artfully omitted a crucial element—the inclusion of a comparator SSRI known to cause sexual dysfunction.

The other claim put to bed by the FDA is the idea that Viibryd is quicker to work than other antidepressants. This was based on one of Forest’s trials which showed that Viibryd separated from placebo by week one. The FDA’s article pointed out two problems. First, this data was from Trial 04, which was only one of two large trials submitted as part of the new drug application. In the other trial, Trial 07, Viibryd did not separate from placebo until week 4. Second, neither trial compared Viibryd with an already approved SSRI, meaning that no statements can be made about the new drug working faster than any other drug.

It’s nice to see the FDA stepping up to the plate and proactively publishing articles that dispel company-spread rumors about drug effectiveness. And it’s also great that a usually industry-friendly journal like JCP would publish this.

Seroquel gets the Abilify FDA Treatment

The FDA's Psychopharmacological Advisory Committee voted last week to recommend that Seroquel be approved as an adjunctive treatment for depression, but it rejected AstraZeneca's request that the drug be approved as monotherapy treatment for depression or generalized anxiety disorder.

According to this article in The Philadelphia Inquirer, "Panel members, including scientists from outside the FDA and consumer advocates, said Seroquel's risks in depression and anxiety outweighed its benefits."

One of the panel members, Richard Malone, explained that "the risks are fairly well-documented, and I don't think they are acceptable for this use."

While I agree with the committee's rejection of two indications, I'm concerned that they were inappropriately impressed by the Seroquel augmentation data. As far as I know, the augmentation studies have not been published, but a summary can be found on page 27 of AZ's briefing document. It looks like they used the same research design as BMS did in their Abilify augmentation studies, and that the Seroquel results were equally unimpressive (see this article at Clin Psych for a slam of the Abilify data). Seroquel reduced the MADRS depression score by about 15 points, while placebo decreased it by about 12 points. This 3 point advantage is tiny, considering that the MADRS is a 60 point scale. Personally, I don't think that this 5% advantage (3 divided by 60 possible points) is worth Seroquel's side effects.

Particularly since this recently published randomized trial showed that when Seroquel was added to Prozac, it yielded no advantages over placebo, aside from helping patients sleep better over the first few weeks. This was not a study of treatment-resistant patients (unlike the FDA data) but it nonetheless shakes my confidence in the potency of the medication.

If the full FDA decides to go along with the committee's recommendation, AZ will mount the kind of mega direct-to-consumer marketing campaign that we have seen with Abilify (for background, see two excellent LA Times pieces here and here), and consequently there will be a little epidemic of obesity among depressed patients. Now that's what I call depressing!

Seroquel XR and Marcia Angell's Blueprint for the FDA

There's a nice editorial by Marcia Angell (former editor of New England Journal of Medicine and author of the classic book The Truth About Drug Companies) in today's Boston Globe.

Dr. Angell lays out seven specific recommendations for changes in FDA policy, all of which are sensible and will encourage better drug pipelines and safer medications.

Before presenting them, I want to highlight her recommendation number 5, which is that the FDA should be able to require drug companies to compare new drugs with existing drugs of the same type. This is especially relevant in the context of an upcoming meeting of the FDA's Psychopharmacological Advisory Committee. Tomorrow it will begin a two day meeting to discuss, among other things, AstraZeneca's application to approve Seroquel XR for generalized anxiety disorder (GAD) and major depression (you can learn the particulars here).

Seroquel XR is, indeed, more effective than placebo for both depression and GAD. Nonetheless, the application should be soundly rejected, unless AZ can show that Seroquel XR works better than the dozens of other drugs that are already available for these conditions. Why approve an antidepressant that causes weight gain, diabetes, and cardiac death, when there are equally effective alternatives that cause none of these side effects?

I doubt that AZ has done such comparative studies, because they were not forced to do so. From their stockholders' perspective, they would be foolish to conduct such studies, because there's a good chance that Seroquel would do no better than drugs like Zoloft or Celexa. Its disadvantageous side effect profile would be highlighted in a head-to-head trial. And as we know from recent court documents, AZ has done everything it can to bury the truth about Seroquel's side effects.

Marcia Angell's Seven Recommendations for a Better FDA:

1. Congress should repeal the Prescription Drug User Fee Act.

2. Consultants for drug companies should no longer be permitted to serve on FDA advisory panels.

3. The agency should see that the post-marketing studies it mandates are actually carried out.

4. The FDA should review generic drugs as fast as brand-name drugs.

5. Congress should give the FDA the authority to require drug companies to compare new drugs with existing drugs of the same type.

6. The FDA should stop approving me-too drugs on the basis of surrogate endpoints.

7. The FDA should prohibit direct-to-consumer advertising for three years after drugs are approved.

FDA Candidates, Through The Carlat Lens

According to Reuters, President Obama will be naming his choice for FDA Commissioner within “days.” Most sources say that he has narrowed his choices down to the following four candidates: Joshua Sharfstein, head of Baltimore's health department; Robert Califf, cardiologist at Duke University; Cleveland Clinic cardiologist Steve Nissen; and Susan Wood, former head of the FDA's Office of Women's Health. However, the rumor mill seemingly churns hourly--now, according to Drug Wonks, former New York City Health Commissioner Margaret Hamburg is also in the running (Hamburg's name surfaced too late for me to give her a mini-review).

I’m not sure who I would pick. I personally know Dr. Steve Nissen and think he would be an fantastic choice, because he amply understands the challenges and imperfections of the FDA and has clear plans for fixing the agency. And, of course, it doesn’t hurt that he has never been afraid to call out drug companies for hiding inconvenient data about drug side effects. Dr. Nissen, if you’ll recall, was the one who broke the Avandia story . But he is hardly anti-pharmaceuticals. As chair of cardiovascular medicine of the Cleveland Clinic, he has conducted industry-funded research, and he has focused on using intravascular ultrasound (IVUS) imaging for treating coronary atherosclerosis. His disclosures are listed here, but note that he receives no personal income from these relationships, insisting that companies donate all honoraria to charity.

Susan Wood is another great choice. A heroine when it comes to women’s rights, Wood was the FDA’s Director of the Office of Women's Health until 2005, when she resigned on principle over the delay in approving “Plan B,” an emergency over–the–counter contraception (not to be confused with the “abortion pill,” RU-486). She is currently a professor in the School of Public Health at GW University. You can read up on her here and here. As far as I know, she has no financial relationships with any pharmaceutical company, and she is the only candidate who is not an M.D., for better or for worse.

Josh Sharfstein, who is currently head of the Baltimore Health Department, has an interesting psychiatric connection in that his father, Steve Sharfstein, is the former president of the American Psychiatric Association. Steve Sharfstein made a splash by publishing this column in which he urged clearer boundaries between physicians and industry enticements. Josh Sharfstein has an equally strong sense of ethics, and has in the past called Pfizer onto the carpet for improper promotion (he once alerted the New England Journal of Medicine that Pfizer was inviting docs to a “rack ‘em up and toss ‘em down” event including billiards and lots of alcohol). He has also worked on the staff of Representative Henry Waxman, who is now chair of the powerful House Energy and Commerce Committee. Sources tell me that he has no financial relationships with the pharmaceutical industry.

The only truly bizarre entry on Obama’s short list is Dr. Robert Califf, vice chancellor for clinical research and professor in the cardiology department at Duke. I have no problem with his experience and extraordinary academic achievements. And I hesitate to criticize a fellow grad of UCSF Medical School. But c’mon folks, look at these industry disclosures. He took money—lots of money--from 18 different pharmaceutical or device firms. Most of this was not for research, but for consulting and speaking, including CME. If Dr. Califf believes that it is ethical for physicians to help drug companies market their products, that’s his own business. But to elevate him to a position in which he is the country’s chief watchdog over unsafe medications and foods seems a dangerous move. With money from 18 drug companies padding his bank account, he will presumably spend most of his FDA career recusing himself from crucial decisions. Not a good idea.

So, Mr. President, in my opinion you can’t go wrong with Nissen, Wood, or Sharfstein—but please keep Dr. Califf out of the running.

FDA's Indictment of Psychiatric CME

As covered in the business section of Tuesday’s New York Times , an FDA advisory committee has accused the agency of doing too little to warn physicians about the dangers of prescribing newer antipsychotics to children.

The committee reviewed data showing that more than 389,000 children and teenagers were treated last year with Risperdal, the majority of them 12 years old or younger. Risperdal is one of five newer atypical antipsychotics, drugs which comprise the bulk of antipsychotic prescriptions to both adults and children in the U.S.

While the atypicals have been extravagantly profitable for drug companies, a series of recent studies have shown that they are no more effective than older generic antipsychotics, and that some incur a higher risk of weight gain and blood lipid abnormalities. The most recent of these studies focused specifically on children with schizophrenia and schizoaffective disorder. In that study, the atypical drugs Risperdal and Zyprexa were no more effective than the generic molindone, and the children on the newer agents suffered significant weight gain—13 pounds on Zyprexa and 9 pounds on Risperdal over only 8 weeks of treatment. Molindone caused less than a pound of weight gain.

So who is to blame for the excessive enthusiasm for atypical antipsychotics in children? The FDA says: “Not us.” When asked why physicians were not learning enough about side effects, Thomas Laughren, the director of the agency’s division of psychiatry products, said that the FDA has done its job by requiring appropriate warnings on the drug labeling. According to the article:

"Dr. Laughren of the F.D.A. said the agency could do little to fix the problem. Instead, he said, medical specialty societies must do a better job educating doctors about the drugs’ side effects."

Hmmm. Now that is going to be a tall order, considering that over half of all medical education courses in the U.S. are funded by drug companies. The medical specialty societies reap millions per year in “industry supported symposia,” which are CME courses certified by the medical societies, paid for by drug companies, and which are subtle advertisements for the sponsor’s drugs.

What is the FDA doing about this corruption of medical education? Absolutely nothing. Instead, they have given this responsibility to an agency called the ACCME. The ACCME is independent of the FDA, and is funded almost entirely by organizations that have a vested interest in continued drug company funding of CME. Because of this, it has presided over an incremental approach to regulation that has moved at glacial speed. Meanwhile, children on antipsychotics are becoming obese.

It is time for the FDA to get involved in regulating doctors’ education. I suggest that they immediately form a task force to investigate why the ACCME is moving so slowly to get industry influence out of medical education.

Let’s get real about this issue. Our health, and our children’s health, are at stake.

Bifeprunox: Out for the Count, Phony CME and All

On Tuesday I posted about Wyeth/Solvay's subtle bifeprunox advertisement masquerading as a CME activity in Psychiatric Times. Their karma has caught up with them, as the FDA just rejected their application for approval of the new antipsychotic.

According to reports, FDA was unimpressed with two acute-treatment controlled studies, both of which showed that bifeprunox performed more poorly than existing atypicals. You can read a review of these efficacy trials here. One study compared bifeprunox 20 mg/day with risperidone 6 mg/day. After 6 weeks, bifeprunox lowered PANSS scores by 11.3, wherease risperidone posted a more robust symptom reduction of 15.6 (statistical significance was not reported). In a second study, bifeprunox with slammed even more harshly by Zyprexa (olanzapine). Also a 6-week study, bifeprunox 20 mg/day yielded a PANSS improvement of 13.8 vs. Zyprexa 15 mg/day's 22.0. In that trial, only Zyprexa significantly separated from placebo.

As a psychiatrist, I'm not too disappointed, because bifeprunox is essentially a me-too version of Abilify (aripiprazole). Like Abilify, bifeprunox is a partial dopamine receptor agonist, meaning that it can either block or stimulate dopamine receptors. Thus, bifeprunox appears to be a less effective version of Abilify (though no head to head trials have been reported). We don't need it.