Akathisia-gate Scandal in Wall Street Journal

Akathisia-gate, Bristol-Myers Squibb's ongoing efforts to distract attention from the major side effect of its blockbuster antipsychotic drug Abilify, has expanded into a scandal that was covered on the front page of today's Wall Street Journal.

Staff writer Shirley Wang profiles Andy Behrman, a man with bipolar disorder who gained notoriety when he published the book Electroboy: A Memoir of Mania. According to the article, representatives of BMS approached Behrman after the book's publication and asked him to do promotional speeches for Abilify, which was about to gain FDA approval for the treatment of mania. He initially signed a contract for $40,000, and eventually made up to $10,000/day.

The problem is, soon after he started taking Abilify, Behrman noticed restless sensations in his legs--akathisia. He said he told his BMS handlers about the side effect, which the company denies. At any rate, apparently the money he was receiving was just too good for him to tell the truth about his side effects, and he continued providing glowing endorsements. He said that the company provided him with talking points, and instructed him to reiterate in his talks that Abilify had no side effects and to avoid mentioning that he was being paid by BMS.

Of course, the company denies any malfeasance, claiming that Behrman requested an exhorbitant $7.5 million for further talks, and that the company refused the offer. The implication is that Behrman is simply a disgruntled former hired gun. We may never know the entire truth of the matter. But knowing the sordid history of pharmaceutical marketing tactics, I'm giving Behrman the benefit of the doubt here.

Abilify and the Great Akathisia Cover-up, Part 2

Yesterday, I described a patient who experienced transient severe jitteriness and shakiness on Abilify 5 mg/day. She did not want to discontinue it yet, and as I mentioned, I'll provide an update when I see her next.

Today, I saw a woman in her 30s who has suffered recurrent depression and anxiety for years. I had recently added Wellbutrin SR to her Effexor XR and Klonopin. This seemed to help decrease her crying jags initially, but after a few months she became depressed and hopeless again. She was seeing her therapist regularly, but that wasn't doing the trick. So at her last visit in March, I had her discontinue the Wellbutrin and I added Abilify at 10 mg a day. Today, she said that she stopped the Abilify after 2 weeks, because "I felt like I was having 10 cups of coffee per day." She couldn't sleep, despite taking Ambien 10 mg at night.

Nonetheless, she feels less depressed today because over the couple of months since she stopped the Abilify, she began seeing her therapist more often, up to twice a week. She feels she has more perspective on some of her stressors (an ill father, financial difficulties).

She's doing okay, but this is another case in which the much vaunted Abilify fails as a augmentation for depression, and reveals its true colors as the antipsychotic most likely to cause akathisia. Clearly, starting her at 10 mg was a mistake, and when I use it in the future, I will start at the lowest possible dose, which is 2 mg.

Meanwhile, BMS is funding plenty of CME about using antipsychotics in depression and is making sure to contract with education companies that will hire key opinion leaders who can be depended upon to go easy on Abilify's side effects. For example, here is how Abilify's side effects are discussed by a noted academic in this online symposium created by CME, LLC:

"Adverse event dropouts; you always want to know, How well were these drugs tolerated? And in this first study it was pretty darned good. I mean, it looked very placebo-like in terms of ability to stay on the drug. The data for both studies when they’re put together in the package insert have a dropout rate of about 6% for aripiprazole. So it’s a bit higher than placebo. A lot of restlessness, a lot of akathisia, you know, people sort of a little bit unable to sort of stay still, but they could tolerate the drug. That’s 23%, 25% in the package insert. So some side effects, but overall pretty good tolerability."

Hmmm...."sort of a little bit unable to sort of stay still, but they could tolerate the drug." This is the beauty of industry-funded CME. You're not buying outright deception and therefore a public relations disaster, but you are buying someone who will handle your product's liabilities with kid gloves.

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.

Charles Nemeroff, Unleashed

It looks like Dr. Charles Nemeroff has found a way to wriggle out of the already loose leash clapped around his neck by Emory University.

For those who have forgotten about Dr. Nemeroff’s recent trials and tribulations, here’s a brief recap. He was the principal investigator of a $3.95 million NIH grant to study several drugs by GlaxoSmithKline. But he was at the same time making hundreds of thousands of dollars doing promotional talks for the same company, orders of magnitude higher than the NIH maximum allowed. In order to skirt these regulations, Nemeroff simply lied to Emory officials. According to the New York Times, he signed a letter dated July 15, 2004, promising Emory that he would keep his earning from GlaxoSmithKline to less than $10,000 per year. But that same day, Nemeroff was at the Four Seasons Resort in Jackson Hole, Wyoming, where he was earning $3000 for a talk for GSK, part of $170,000 in income he earned from the company that year—17 times the figure that he had agreed to.

Emory removed him as department chair shortly thereafter, but inexplicably kept him on as full professor and allowed him to re-apply for more NIH grants within two years. Nemeroff’s public statement revealed an alarming lack of remorse: “I regret the failure of full disclosure on my part that has led me to the current situation. I believe that I was acting in good faith to comply with the rules as I understood them to be in effect at the time.” Translation: “I’m bummed out that this is happening to me. I didn’t do anything wrong.”

Meanwhile, Emory’s “punishment” still allows Nemeroff to take drug company money for promotional talks in the guise of ACCME accredited activities. According to Emory’s letter: “He will be limited to accepting payment for ACCME-accredited speaking engagements sponsored by academic institutions or professional societies.”

But Dr. Nemeroff has already found a way to escape from this restriction. In February, Dr. Nemeroff will co-chair this CME series supported by Bristol-Myers Squibb called “Measurement Based Care Strategies for Depression.”

It is “jointly sponsored” by the University of North Texas Health Science Center (UNTHSC) and an obscure outfit called “Letters & Sciences.” Letters & Sciences (L & S) is presumably a MECC but a Google search shows that they have no website. They are listed as being an “approved provider” of CE credit for nurses by both the New Jersey State Nurses Association (NJSNA) and the California Board of Registered Nursing.

It is clear that L & S is on a Bristol-Myers Squibb gravy train, making their money by producing promotional CME encouraging doctors to prescribe plenty of Abilify for bipolar disorder and depression. They teamed up with UNTHSC to produce this recent CME series as well, which presumably pushes the use of Abilify for kids.

By teaming up with this shadowy MECC, Nemeroff is complying with the letter of his punishment but is playing fast and loose with its spirit. In specifying that Nemeroff is limited to CME events “sponsored by academic institutions and professional societies,” Emory is asking that legitimate institutions create and control the content. But in this case, we see the usual CME shell game in which a private MECC is creating the content and is paying a nominal “co-sponsor” to provide CME credit.

If I were Senator Grassley, I’d be sending letters to L&S, UNTHSC, ACCME, Nemeroff, etc…, asking:

--How did L & S obtain the grant from BMS for this program?
--What is L & S? Where are they? Who is on their staff? Which medical writers are creating the content? How much money are they making from BMS? What percentage of their total income comes from events supported by BMS?
--What, exactly, is UNTHSC doing as “co-sponsor” of the event? Are they simply extracting a healthy fee from L & S, in return for a cursory review of their paperwork and disclosure forms? Or are they actually managing the event and producing content?

Leashes always chafe, especially when the wearer feels no guilt. Sometimes, however, loosening the leash is precisely the wrong thing to do.

Hat tip to Bernard Carroll.

Bad News on the Election Front

For those looking for relief from the Obama-Clinton tiffs, I unfortunately have some bad news about the American Psychiatric Association election: Alan Schatzberg beat Donna Norris.

As I covered in a prior post, Norris heads the task force charged with scrutinizing the conflicts of interests of potential DSM-5 committee members. Schatzberg, on the other hand, is a great champion of industry-funded CME. He is on the clinical advisory board of "neuroscienceCME," a new MECC portal owned by CME Outfitters. This company produces a blizzard of CME in different formats, each funded by a single drug company whose product shines more brightly than its competitors in the neuroscienceCME version of reality. Schatzberg is also the editor-in-chief of the new journal, "The International Journal of Sleep and Wakefulness," which is produced by the MECC CECentral, funded entirely by Cephalon, and is a blatant full journal advertisement for Provigil. BUT WAIT, THERE'S MORE! Schatzberg is co-chair, along with star hired gun Charles Nemeroff, of a series of fancy CME meetings traveling across the country on behalf of Bristol-Myers Squibb and Otsuka, makers of Abilify. Entitled Current Concepts and Approaches in Treatment Resistant Depression, these meetings were created in order to highlight recent data showing that Abilify has some mild effectiveness as an augmenter of antidepressants.

But the election news was not all bad. David Fassler was elected as the secretary-treasurer and Dilip Jeste as trustee-at-large. Neither of them accepts industry money and Dr. Jeste made a conscious decision one year ago to sever his industry connections because of his concerns regarding industry influence.

Primary Psychiatry: Pharma's New Mule

Granted, everyone’s entitled to make a buck, medical publishers included. This almost always involves doing some advertising for drug companies. There’s nothing inherently wrong with this, as long as the advertising doesn’t infiltrate the content of the articles. This firewall between marketing and editorial content is crucial, and some journals are very good at maintaining this separation—journals such as Lancet and New England Journal of Medicine come to mind.

And then, on the other hand, there is Primary Psychiatry.

The September issue of Primary Psychiatry is the encapsulation of the worst of the worst of what might be called "greed journalism." Rather than serving as a medical journal, Primary Psychiatry has become a mule for various sponsoring pharmaceutical companies, heaving promotional CME programs into our offices. An almost exquisite example of journal as marketing vehicle, the September issue is the very Mona Lisa of CME corruption.

It arrived in my office “polybagged” with three industry-funded educational activities. Polybagging entails wrapping the journal in plastic wrap and throwing in stuff that drug companies want you to see. The September issue contains:

1. A DVD funded by Bristol-Myers Squibb, coyly entitled, Akathisia: Problem of History and Concern of Today. BMS markets Abilify, widely acknowledged as the atypical most likely to cause akathisia—an inconvenient truth for BMS, because this drives down Abilify’s market share. Thus, BMS paid i3CME (you remember them--the producers of the great Lindsey DeVane fiasco) to find speakers who would play down this liability, and they got exactly what they paid for in these Three CME-usketeers: Prakash Masand, Naveed Iqbal, and Tim Lambert. Abilfy’s association with akathisia is conveniently not mentioned by any of these key opinion leaders. Instead, we hear that Risperidal, Zyprexa, Clozapine, and even Seroquel (!) can cause it. If you can stomach watching this biased presentation, you'll quickly discover that its promotional message is: (1) Akathisia is more common with first generation antipsychotics; (2) There’s no real difference between the atypicals; (3) It’s often caused by SSRIs rather than atypicals; (4) Don't worry, prescribe Abilify.

2. The second prize is a newsletter called “Wake up!”, produced by Steven Stahl and funded by Cephalon. An 8-page advertisement for Provigil, it contains articles written by a Who’s Who panel of industry-funded psychiatrists, including Wallace Mendelson, famous for his ghost-written trazodone-bashing article in the Journal of Clinical Psychiatry (2005;66:469-476; see my New York Times op-ed on his work for Sepracor here). For those who don’t know, Stephen Stahl, founder of the company Neuroscience Education Institute, is one of the more industry-conflicted psychiatrists in the profession, right up there with Charles Nemeroff. The “wake up!” newsletter oozes Cephalon and Provigil, with exhortations to diagnose more people with "excessive sleepiness" and to treat them with Provigil and other meds. Cephalon pays Stahl tens of thousands to say good things about Provigil, and then pays Primary Psychiatry even more to mule the newsletter to 60,000 physicians.

3. Finally, the actual journal is covered with an overwrap advertisement for an Eli Lilly-sponsored educational event on bipolar disorder. No, I didn't spend any more of my precious time enduring that telesession. I'm assuming it will argue that patients with bipolar disorder are at a higher risk for diabetes regardless of which medication they use, so don't worry about slamming them with Zyprexa.

The "Pharmatorial" content doesn’t end with the plastic goody bag. Inside the journal, synergizing nicely with a three-page ad for Lilly’s Cymbalta, is an entire section on pain in psychiatry, including an article on "Psychopharmacology of Chronic Pain." The author, Michael R. Clark of Johns Hopkins, is listed as having “no affiliation with or financial interest in any organization that may pose a conflict of interest.” This fib can be checked out by going to Google and typing in “Michael Clark, M.D. and disclosures.” The first page of results shows that Dr. Clark has been the course director of two CME conferences on pain management this year, supported by educational grants from Lilly, King Pharmaceuticals, and Cephalon.

It isn't easy being a mule. But the money helps.

DeVane Mounts Defense of his CNS Spectrums Article

Lindsay DeVane, the Medical University of South Carolina professor who had described this article in CNS Spectrums as "commercial crap," is now defending said crap from its detractors.

Possibly responding to this letter just published in Psychiatric News, in which Harvard psychiatrist Alan Stone advocates officially "shaming" unethical colleagues who participate in ghost-writing, Dr. DeVane sent me the following e-mail:

"Dear Dr. Carlat, I am writing to say there should be no doubt about the integrity of the CNS Spectrums publication as an i3 CME certified activity. In particular, my unflattering characterizations of the CNS Spectrums article reflect the inherent limitations in providing practicing clinicians with fundamental descriptions of complicated issues. The initial draft of the article that was eventually published was written directly from the transcripts of the live CME televised broadcast last December and was not ghost-written. All three co-authors were heavily involved in multiple edits before agreement was reached on a final manuscript. Although my opinion is that antidepressant drug-drug interactions of major clinical significance are rare events, we all know that interactions can occur and the need for such awareness was a theme in the broadcast and article. My Neuropsychopharmacology commentary allowed a more complete discussion of some scientific issues, but there should be no question about the integrity of the CNS Spectrums publication as a CME activity. Lindsay DeVane."

I can only assume that Dr. DeVane must have been severely pressured by multiple parties to change his tune. You can read his earlier, and very different take, on the article in my prior posting here. At that time, Dr. DeVane called the first draft of the article a “ridicuous text… parts of it were inaccurate, simplistic, and [contained] over-generalizations.” The fact that he is now saying that this article was "written directly from transcripts of the live CME televised broadcast" is not exactly an endorsement of that Hawaiian event, which was funded by Bristol-Myers Squibb.

And although he is now saying that "all three co-authors were heavily involved in multiple edits before agreement was reached on a final manuscript," in his earlier letter, he stated, "I haven't even read the CNS piece, but from what you say, I probably shouldn't as it's likely embarassing. Please ignore it for purposes of interpreting my researchand views."

By the way, the founder of CNS Spectrums, James LaRossa, who knows all the players involved in this scandal quite well (in fact, he now publishes a different journal with both Nemeroff and DeVane on the masthead), said of the CNS Spectrums piece, "I am willing to bet dollars to doughnuts that Nemeroff never saw proofs of the article either."

As La Rossa commented further, "In truth, the CME business has become rotten to the core." I couldn't agree more.

CNS Spectrums: "A Piece of Commercial C__p"

No, that's not Carlat getting nasty and personal again. Those are the words of one of the most well-recognized names in American psychiatry, an academic of impeccable credentials who is involved in the industry-CME charade and is getting sick of it (insert the letters "r" and "a" to complete the headline--the spelled-out version was offensive to some). He will remain anonymous.

Why is he saying such terrible things about CNS Spectrums? He is referring to one of the most corrupt CME activities to hit the stands in a long time, and believe me, it takes a lot to impress this reporter.

The article in question can be found in the May 2007 Supplement to CNS Spectrums, entitled, “Antidepressant Drug-Drug Interactions: Clinical Relevance and Risk Management,” (Nemeroff CB, Preskorn SH, DeVane LC, CNS Spect 12:5 (Suppl 7) May 2007).

According to my source, this sham article was originally a televised roundtable which was adapted by medical writers to form the basis for an industry-supported supplement. The CME company in question is i3 CME, which, my source said, wrote a "ridiculous text...parts of it were inaccurate, simplistic, and had overgeneralizations."

And yet, it was published anyway, and is accredited by the ACCME for 1 hour of Category 1 PRA credit.

The details of the science are a bit murky. But the short version is the Bristol-Myers Squibb, maker of the newly approved antidepressant EMSAM (transdermal selegiline patch), commissioned the article to convince doctors that EMSAM is safe to prescribe, even though it is an MAOI, which can produce fatal interactions with other drugs and with certain foods containing the amino acid tyramine. In order to deflect attention from this liability, the article dwells primarily on a drug-drug interaction in which EMSAM is safe: interactions involving the liver's P-450 enzyme system. Indeed, EMSAM neither inhibits nor induces these enzymes, meaning that it won't affect the levels of other medications that are metabolized in the liver.

Of course, this is an "advantage" only if drug-drug interactions are problematic for other antidepressants. The article works hard to make the case that two SSRIs, Prozac (fluoxetine) and Paxil (paroxetine), are dangerous medications because of drug-drug interactions: "To put these numbers in perspective, fluoxetine and paroxetine at 20 mg/day produce approximately a 500% increase in the AUC of CYP2D6 dependent drugs" (see page 6).

But this opinion directly contradicts what one of the authors recently wrote in a non-commercially funded article published in the journal Neuropsychopharmacology, at that time edited by Dr. Nemeroff, who happens to be the first author of the CNS Spectrums piece. According to my source, Dr. Nemeroff spearheaded this CNS Spectrums EMSAM advertisement "for the sake of selling CME time."

At any rate, in that earlier unfunded article, Dr. DeVane, the third author of the CNS Spectrums piece, wrote: "Dr. Preskorn and Dr. Werder's commentary is confusing because it frequently fails to distinguish between verifiable statements and personal opinion, includes dubious extrapolations of data (eg 'lowest effective dose of fluoxetine and paroxetine produces approximately a 500% increase in the plasma concentration of co-prescribed [CYP2D6] drugs')" (Neuropsychopharmacology 31:1594-1604, 2006).

With a sprinkling of industry money, an opinion that was once a "dubious extrapolation of data" becomes a fact. While I'm no fan of industry-funded CME, in this case there was a silver lining: old foes (Dr. DeVane and Dr. Preskorn) were reunited.

By the way, I have nothing against EMSAM, but I rarely prescribe it because most patients don't want to have to hassle with wearing a patch. Generally, if I want to prescribe an MAOI, I'll prescribe oral Parnate or Nardil.

In the CNS Spectrums parallel universe, however, patients appear to be yearning for a patch. The article ends with the following promotional comment by Dr. Nemeroff: “I have had more and more patients say to me, “I really think that I would like to try selegiline transdermal system. I do not like taking pills.”

Carlat Blog Verdict: CNS Spectrums: The very definition of a "throwaway" journal.