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.

Abilify, the Journal of Clinical Psychiatry, and "Akathisia-gate"

Clin psych has posted this enlightening and relevant article about the efforts of Otsuka and Bristol-Myers Squibb to distract our attention from the major side effect of Abilify, which is akathisia. As he mentions, in the trials leading to Abilify's FDA approval for augmentation of antidepressants (you can watch one of their recent TV commercials here, but do so quickly, before BMS forces YouTube to take it off their site) the rate of akathisia, or extreme and debilitating restlessness, was 25% on Abilify as opposed to 4% in the placebo group.

Here's what Abilify's akathisia looks like outside of the scrubbed fantasy land of hired guns and PR companies. For several years I have treated a woman in her 40s with bipolar disorder who had been fairly stable on Tegretol, an anticonvulsant that is FDA approved for the treatment of manic episodes. But over the last few months, she has become involved in a pyramic marketing scheme and has ended up in serious debt. We both agreed this represented a manic episode, and decided to switch her from Tegretol to another medication, preferably one that did not cause any weight gain. She had not responded well to lithium in the past, Depakote and most of the atypical antipsychotics were out of the question because of their weight gain side effects, so I recommended a trial of Abilify.

"Let's start at 5 mg a day," I said, "then we can increase to 10 mg if we need to."

This was on a Thursday, and over the weekend, she left messages at my office saying that she felt incredibly "shaky," anxious, had insomnia, and just felt all around terrible. She didn't call my emergency coverage, but on Monday I spoke to her and found out that she had in fact increased the Abilify to 10 mg after a couple of days, clearly worsening her akathisia. I recommended she stop it, but she was reluctant, saying she wanted to give it a shot. So I prescribed the tranquilizer Klonopin, and told her to decrease the Abilify dose back to 5 mg. Over the next few days, she became less shaky, and calmer.

Her case is a work in progress, and I'll provide updates in the future. The point here is that this is the side effect that is so common for Abilify, and one that authors paid by BMS chose to play down in a paper apparently written by an employee of Phase V, a medical education company paid for by BMS.

Will my patient ultimately do well on Abilify? I hope so. But it is crucially important for BMS, Otsuka, and their various minions to be accurate about the dangers of the drug, so that doctors can use it appropriately and prevent the kinds of side effects my patient suffered. Publishing an article that was carefully crafted to draw attention away from Abilify's main liability was shameful, and is exactly the kind of deceptive editorial practice that we as a society can no longer tolerate.

Spinning and Spinning for Cymbalta

I was browsing the January issue of the Journal of Clinical Psychiatry in order to get ideas for the "Research Updates" section of The Carlat Psychiatry Report, and I happened upon two articles, one for those intrepid counter-detailers out there, and the other for Lilly drug reps.

The first one, "Time to Rehospitalization in Patients with Major Depressive Disorder Taking Venlafaxine or Fluoxetine," is an article important for evaluating the long term usefulness of Effexor, but one which, I can guarantee you, will not show up in the hands of your Effexor rep. In this study, depressed patients in a Taiwan psychiatric hospital were discharged with instructions to continue either Effexor or Prozac, depending on which medicine made them better in the hospital. The two groups were compared to see whether Effexor would better protect patients from rehospitalization than Prozac. The results? About 45% of patients in both group were eventually reshospitalized. For patients on Effexor, the average time to rehospitalization ("survival time") was 223 days, and for patients on Prozac, it was 222 days. What does this prove? Not much, since patients were not randomly assigned to treatments. However, it's certainly no endorsement of Effexor's vaunted superiority over SSRIs. As the authors (who have no pharma relationships) state: "Our findings do not support the notion that venlafaxine, a dual reuptake inhibitor, is associated with less relapse/tachyphylaxis."

The next article, on the other hand, will be parlayed into a "teaching point" by your Eli Lilly rep, although there's precious little to teach. Entitled "Switching to Duloxetine from Selective Serotonin Reuptake Inhibitor Antidepressants: A Multicenter Trial Comparing 2 Switching Techniques," this Lilly-funded study identified 368 depressed patients who had not responded to at least 6 weeks of SSRI treatment. These patients were then randomly assigned to either abruptly switching to Cymbalta, or gradually switching to Cymbalta. They were then maintained on Cymbalta for 10 more weeks to see if they would respond. Before we get to the results, think carefully about the design of this study, and what questions one might reasonably be able to answer, or to not answer.

This was not a double-blind study: in fact, both patients and doctors knew that the participants were being switched to Cymbalta. Furthermore, there was neither a placebo arm, nor an SSRI continuation arm. This is crucial, because patients who don't respond to a medication after 6 weeks may well respond if continued on the same medication for an additional 10 weeks. Thus, if these patients improve after a switch to Cymbalta, we have no idea how to interpret this. It might mean that Cymbalta is better. But it might also mean that the 10 extra weeks of being in treatment worked its nonspecific placebo-related magic. After all, with enough time, many people become less depressed, no matter what treatment they receive. Thus, the design of the study allows no meaningful evaluation of Cymbalta's effectiveness. The only potentially useful information here relates to the technical issue of how to conduct a switch from an SSRI to Cymbalta. As it turns out, an abrupt switch works fine and is well-tolerated. And that's all you can conclude from the study.

However, if you read only the abstract (which is as far as most readers will venture) you'll get the uncanny sensation of having been teleported to Eli Lilly's website:

"Conclusion: Switch to duloxetine was associated with significant improvements in both emotional and painful physical symptoms of depression and was well tolerated and safe, regardless of which of the switch methods was used."

If it reads like copy written by a Lilly employee, it's because it was: Dr. Perahia, the first author, works for Lilly in England. One might have hoped that the editors of the Journal of Clinical Psychiatry would have caught this bit of blatant promotionalism before it went to press. Because of this awful oversight, now Lilly will likely end up paying the journal thousands of dollars to purchase article reprints for its drug reps--someone's head will roll!

The Journal of Abilify Psychiatry: A CME Activity

I just received the latest Supplement of the Journal of Clinical Psychiatry.

The Journal of Clinical Psychiatry, which is published by Physicians Postgraduate Press, Inc., and is edited by Alan J.
Gelenberg, has developed a reputation for publishing CME supplements which are biased in favor of the sponsoring drug company.

Thus, the current supplement, paid for by Bristol-Myers Squibb, reads like an advertisement for Abilify.

The supplement is titled "Translating the Psychopharmacology of Antipsychotics to Individualized Treatment for Severe Mental Illness: A Roadmap." Sounds promising to me, though rather vague.

The issue is billed as being the result of an "Expert Consensus Survey." This means that BMS paid a third party for-profit company, Comprehensive Neuroscience, Inc., to cherry-pick experts and to send them a list of questions about their favorite antipsychotics in various clinical situations. The responses were tabulated into a series of charts that form the backbone of this supplement.

To understand why BMS would choose this method of CME promotion, you have to understand the context. Their antipsychotic, Abilify (aripiprazole), was not included in the influential CATIE trial, because it was approved after the trial was completed. Thus, while Eli Lilly (Zyprexa), AstraZeneca (Seroquel), and Pfizer (Geodon) have been able to tweak CATIE results to their advantage, Abilify has little in the way of head-to-head science to back up claims of advantage over competitors. Commissioning an "Expert Survey" allows BMS to round up key opinion leaders who they already know have positive opinions about Abilify, choose questions about topics that will tend to play up Abilify's advantages, and then publish the pre-planned answers.

Let's look at the results of this novel form of drug comparison research.

The supplement highlights the results of 17 questions. Eight of these were questions about general strategies, and nine were quite specific, asking which of a list of specific antipsychotics the experts would favor in given situations. How do the experts rank Abilify in these nine questions comparing it with its direct competitors?

--In seven of these comparisons, Abilify is ranked number one (see page 30 of the supplement).
--In one comparison, Abilify is ranked number two (page 21).
--In one comparison, Abilify is ranked number three (page 26).

Oddly enough, Zyprexa was at the bottom or near the bottom in all of these rankings, even though some of these same experts have written elsewhere that Zyprexa was the most effective of all newer atypicals in the CATIE trial.

Why did Abilify come out on top? Because of the types of questions these experts were asked. Most questions asked which antipsychotic the experts would choose in patients who were overweight, had cardiac disease, or who had diabetes. This is a great way to stack the deck in favor of Abilify.

The expert panel's rankings would surely have been in favor of Zyprexa if they had been asked to choose an antipsychotic based on efficacy alone. Abilify would have ranked very low indeed if they had been asked to choose a treatment for patients who suffered insomnia, anxiety, or agitation. These are all important clinical questions in the field, but were not asked because the answers would not have promoted Abilify.

Shame on Journal of Clinical Psychiatry for publishing such pseudoscience.