Transcranial Magnetic Stimulation for Depression: Not so Effective, but FDA Approved

Apparently, the FDA will approve just about anything as an antidepressant. Despite patients indicating that they don't perceive Abilify to work as an antidepressant, the FDA approved it, likely leading to tens of thousands of Americans being able to enjoy a taste of akathisia while getting all the psychological benefits of a placebo. Good work, FDA. The shift of antipsychotics into antidepressants has been documented in many places and is, ironically, very depressing (1, 2, 3, 4).

The FDA's "anything goes" attitude regarding antidepressants apparently extends to mediocre medical devices. In 2007, a paper in Biological Psychiatry presented results from a large trial comparing TMS to sham TMS. The article concluded that the treatment was a fantastic option for depression. Well, close to that anyway. That actually wrote that "Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder."

Before all of us poor depressed souls get in line for some sweet magnetic stimulation, maybe we should, like, look at the evidence. On the primary measure of outcome, the Montgomery-Asberg Depression Rating Scale, the results weren't quite statistically significant. So the sponsor tried to convince the FDA Neurological Devices Panel that the secondary measures showed super-impressive results. The problem: They didn't. The FDA review panel thought a few things (as can be seen in its entirety here):

• The Panel’s consensus was that the efficacy was not established; some stated that the device’s effectiveness was “small,” “borderline,” “marginal” and “of questionable clinical significance.” The Study 01 endpoint with a p value of 0.057 per se was not considered a fatal flaw in the study analysis. The Panel did not believe that clinical significance was demonstrated with these results.
• In general, the panel believed that the analyses of the secondary effectiveness endpoints did not contribute significant information to help establish the effectiveness of the device.
• The Panel agreed that unblinding was greater in the active group, and considering the magnitude of the effect size, it may have influenced the study results. (35.8% of people receiving TMS reported pain at the application site compared to only 3.8% in the sham TMS group. This is a quick way to make a study unblind, as people experiencing pain could logically surmise that they were receiving TMS).
• The Panel stated that there were too many non-random dropouts to reliably interpret these results. The Panel’s consensus was that the Week 6 data was of limited value and did not provide supportive data for establishing effectiveness. (After week 4, patients who did not show adequate improvement were given the option to quit the double-blind study; over half of patients departed the study after week 4).
  

One more doozy. A quote follows from a letter to the editor in Biological Psychiatry in which TMS is taken to task.

The authors note that some patient outcome measures were collected in the trial but omitted from the article. Of the 15 secondary end points the authors included in the paper, 11 were statistically significant. Of 11 secondary end points not included, 2 were statistically significant. Thus, the published end points were three times more likely to be statistically significant than the unpublished ones.

TMS was denied FDA-approval in January, 2007. But in October 2008, the FDA had a change of heart, approving the device. I'm not quite sure what changed the mind of the FDA.

The following disclaimer on the device's website is a bit funny:

NeuroStar TMS Therapy has not been studied in patients who have not received prior antidepressant treatment. Its effectiveness has also not been established in patients who have failed to receive benefit from two or more prior antidepressant medications at minimal effective dose and duration in the current episode.

So it's only demonstrated (weak) efficacy in people who have failed one (not zero, not more than one) antidepressant trial. Impressive, eh? To summarize, the sponsor and its affiliated academics wrote a paper in a major psychiatry journal in which positive outcomes were three times as likely to be reported as negative outcomes. The efficacy data were unimpressive according to an FDA panel -- and these panels are not known for being particularly choosy about efficacy data. It seemed that TMS was dead in the water, only to be resurrected in the form of a surprising FDA approval. And if being resurrected from the grave doesn't make for a great Halloween post, then what does?

Offending Study:
O’Reardon, J., Solvason, H., Janicak, P., Sampson, S., Isenberg, K., Nahas, Z., McDonald, W., Avery, D., Fitzgerald, P., & Loo, C. (2007). Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial Biological Psychiatry, 62 (11), 1208-1216 DOI: 10.1016/j.biopsych.2007.01.018

Letter to Editor:
Yu, E., & Lurie, P. (2009). Transcranial Magnetic Stimulation Not Proven Effective Biological Psychiatry DOI: 10.1016/j.biopsych.2009.03.026

Lend Me Your Name

Journalism regarding the horrors of ghostwritten papers in medical journals is all the rage these days (1, 2, 3). Here's my very small contribution. The document shown below from a medical writing company has been described elsewhere. But it is worth seeing in its glory firsthand. The document is from Wyeth's ghostwriting firm, DesignWrite. It was part of the Premarin/hormone replacement therapy disaster (see below). Perhaps you remember the era when hormone replacement therapy was being prescribed for all sorts of people because it was supposedly a wonder treatment. So what if it increased risk for breast cancer and perhaps other conditions as well? Not to worry, DesignWrite could get around that...

In layman's terms, it goes like this... Wyeth -- you give us some hints about the marketing spin you'd like us to put on your studies. We'll then write up the studies accordingly and have big-name academics sign off as if they had something to do with our oh-so-objective "research". And don't worry, Wyeth, you get to review all papers we write up to make sure we market your drug appropriately.

We now know that several academics participated in this program. To quote one ethicist, regarding the academics who lent their names as authors: "They sold their credentials for false credit and money." DesignWrite's current slogan is: "Where we put clinical data to work." Hmmm. DesignWrite gets paid, Wyeth gets paid, and the academics who lend their names get paid and/or get another publication to boost their stock in the academic world.

Oh, and patients, what did they get out this... breast cancer. But who cares about them anyway -- patients are just little buckets of money; it's not like they're real human beings.

A summary of the results that led to the downfall of hormone replacement therapy

Three years after stopping hormone therapy, women who had taken study pills with active estrogen plus progestin no longer had an increased risk of cardiovascular disease (heart disease, stroke, and blood clots) compared with women on placebo. The lower risk of colorectal cancer seen in women who had taken active E+P disappeared after stopping the intervention. The benefit for fractures (broken bones) in women who had taken active E+P also disappeared after stopping hormone therapy. On the other hand, the risk of all cancers combined in women who had used E+P increased after stopping the intervention compared to those on placebo. This was due to increases in a variety of cancers, including lung cancer. After stopping the intervention, mortality from all causes was somewhat higher in women who had taken active E+P pills compared with the placebo.

Based on the findings mentioned above, the study’s global index that summarized risk and benefits was unchanged, showing that the health risks exceeded the health benefits from the beginning of the study through the end of this three year follow-up. The follow-up after stopping estrogen plus progestin confirms the study’s main conclusion that combination hormone therapy (E+P) should not be used to prevent disease in healthy, postmenopausal women. The most important message to women who have stopped this hormone therapy is to continue seeing their physicians for rigorous prevention and screening activities for all important preventable health conditions.

I'm glad to see that ghostwriting is now the topic du jour in health journalism. But in a few weeks, the attention will vanish as the drug industry and its associated writing firms will agree to allegedly stringent guidelines that ensure this never happens again. And nothing will actually change. I mean, seriously, do you think academic researchers are going to write their own papers? Do you think drug companies are going to stop hiring writers to expertly spin the data? The current system works too well for it to simply go away.

Thanks to an alert reader for sending this document along. You can search for more documents at the Drug Industry Document Archive, including those from Wyeth and DesignWrite. Happy digging!

Wanted: Drug Pimp/Key Opinion Leader

Daniel Carlat from the Carlat Psychiatry Blog received an invitation to the key opinion leader club from the good people at Schering-Plough. The company wanted him to read their slides to other physicians in order to promote their brand spanikn' new antipsychotic/mood stabilizer Saphris (asenapine). Because, of course, if he reads the slides, they are more credible than if read by one of those sleazy drug reps; it's so much more classy and believable if an "independent" psychiatrist reads the company's marketing copy.

Carlat posted the documents used in the attempt to recruit him (cover letter, speaker bureau arrangement, pimp, er, speaker fees) Everyone should read them. Speakers are only allowed to rake in $170,000 of dirty money through this program. I suppose anything more would make them look like shameless drug pimps. But if you were to take, say, $50k for your "educational" services, that would be totally acceptable, right? I hereby nominate anyone who accepts Schering-Plough's generous offer for the much coveted Golden Goblet Award.

What's the deal with this Saphris drug, anyway? One neuropsychologist reviewed the data and found that it promises to be yet another also-ran atypical antipsychotic, at best. Some have also raised questions of whether the drug deserved FDA approval at all. Get ready for some ghostwritten articles that present the evidence surrounding Saphris in a ridiculously biased manner, for key opinion leaders to travel to conferences extolling its virtues, and for the rest of the usual marketing tricks.

Key Opinion Leader Syndrome

I ran across a rather hilarious article from Medical Hypotheses, in which David Healy described "Krapelin-Fraud Syndrome", which I have also dubbed "Key Opinion Leader Syndrome." See below for the diagnostic criteria.

In line with current neo-Kraepelinian thinking, we put forward operational criteria for this new disorder for provisional inclusion in ICD-XI or DSM-V. An affected subject should meet at least 2 of criteria A–D and 2 more from criteria E–J. Fulfillment of all criteria A–D in the absence of any other features of the disorder will make the diagnosis, although this may represent a syndromal variant.
(A) A pervasive pattern of travelling to scientific conferences and talking about research data that he has had no involvement in generating.
(B) Episodic logosagnosia.
(C) Unusual abilities to compartmentalise information.
(D) Will have a significant number of ‘‘ghost-written” articles.
(E) Actively seeks admiration by peers and subordinates.
(F) An exaggerated sense of own talents, which can be inferred from expectations of recognition as an expert in the absence of commensurate achievements. Happy in the role of opinion leader.
(G) Has a sense of entitlement, i.e. unreasonable expectations of favorable treatment from symposium and congress organisers.
(H) Liable to profound dysphoria if not involved with the ‘‘academic action”.
(I) May be unreasonably envious of the scientific achievements of others and is liable to denigrate these. Would also be unhappy if his colleagues had appeared on ‘‘educational” videos and he had not.
(J) Is unaware of the disorder quality of the syndrome.

Two case studies are included, one of which reads in part:

One of the striking features of his lecturing is the dissociation between his reputation as a critical and skeptical lecturer when dealing with topics on the main programme of the meeting and the extent to which he may be prepared to offer apparently enthusiastic and uncritical endorsement for a compound in a satellite symposium. Very frequently this uncritical endorsement will involve the recycling of outdated ideas, which it is difficult to believe that either B or indeed many of his audience can conceivably believe and which indeed he may contradict within the hour at another symposium.

Hmmmm. Enthusiastic and uncritical endorsement of [insert product name here]. That reminds me of a post or two I've written... I made a rough list of symptoms for KOL Syndrome in July 2008. Different symptoms, but same idea.

The Asenapine Chronicles?

I'm not sure what to make of this. A lot of documents have become available on the Shearlings Got Plowed blog, which deal with the new antipsychotic drug asenapine. If I had the time, I'd be burying myself in the documents, as SGP claims that something fishy is going on. I encourage all interested readers to take a good, long look at the documents to see what (if anything) is happening.

Documents such as this one will catch your interest...

Thanks For Your Service, Now Take This Pill

According to a freshly published study, one in five depressed patients receiving services through the VA healthcare system in the United States is taking an antipsychotic. Of those taking antipsychotics, 43% were taking them at high doses (schizophrenia doses rather than lower doses typically used in treating depression). The study, published in the Journal of Clinical Psychiatry, excluded patients with schizophrenia or bipolar diagnoses -- this means that the antipsychotics given to the depressed folks weren't mainly used to treat psychosis or mania. The sample size was over 190,000 patients, so one can't fault the study for not including enough patients. The researchers examined drugs taken within one week of their last antipsychotic prescription and found that 24% of patients were taking multiple antipsychotics at that point.

The most used medication was Seroquel. This is not suprising. Patients seen in mental health speciality clinics were the most likely to receive antipsychotics. So what are the consequences? Well, let's see. There's the high rate of akathisia and medicore efficacy of Abilify. And there's some tricky research involving Risperdal that seemed to suggest the manipulation of the statistics was more impressive than the actual drug in treating depression. Seroquel's unimpressive efficacy and problematic side effects are also not a ball of fun. And so forth. Isn't "progress" beautiful?

I know what some people are thinking, so before you waste your valuable time with a comment, consider this. I'm aware that many of these patients are suffering much more than a simple case of the blues. That doesn't mean we should throw heavy duty antipsychotics at them, particularly at high doses. Certainly there has to be something else. What might that be? Some psychotherapy, some medications, some case management - I ain't saying it'll be easy. But I'm willing to bet that chucking antipsychotics at them en masse is not the solution.

Will Pharma's (Tax) Free Speech Be Limited?

Dan Neil has an absolutely marvelous column in the LA Times about pharma's bitching/moaning regarding increased regulation of its advertising and its potential loss of tax writeoffs associated with drug ads. It's nice to know that when I'm watching a misleading advertisement for, say, Cymbalta or Abilify, pharma is writing off the advertising cost on its tax bill. Big Pharma's legal consultants have weighed in for years on this topic, using such terms as "starkly unconstitutional," "censorship," "plainly violates the First Amendment", and adding that taking away the tax deduction is "Draconian punishment" - see this document from the pharma-friendly Washington Legal Foundation and just try to keep a straight face.

Neil writes that:

Currently in draft form, these [FDA] rules would dramatically raise the legal bar for risk disclosure. Not only would advertisements have to fully explicate serious side effects, the nature of adverse reactions, the risk of dependence, dangerous drug interactions and so on, but all of that would also have to be communicated in the most direct, unambiguous and, if you will, artless form possible.

And, picking some of the low-hanging fruit, Neil goes on to describe two of my most hated ads:

Consider, the current 75-second spot for Abilify, a powerful antipsychotic drug marketed as a potential add-on to antidepressants. At the 33-second mark, the warnings start: "thoughts of suicide," "elderly dementia patients . . . have an increased risk of death or stroke," "uncontrollable muscle movements [that] may become permanent" and so on. The astonishing thing is that Bristol-Myers Squibb spent more than $35 million in the first quarter alone to market this witch's brew.

Seizures, death, trouble swallowing. Jeez, I get depressed just watching the ad. Maybe that's the idea.

Another wonder drug -- as in, I wonder if this will kill me? -- is Wyeth's Pristiq. Again, the potential adverse reactions are alarming: "Antidepressants can increase suicidal thoughts and behaviors in children, teens and young adults," the ad says. "May cause or worsen high blood pressure, high cholesterol and glaucoma."

Scary stuff. And yet, the FDA might say, not scary enough. Because the voice-over rambles on with a litany of potential side effects, some of which is quite hard to follow, the commercial seems to violate the FDA's constraint that advertisements not overwhelm viewers' "cognitive load." On a more prosaic level, the imagery of this suffering woman suddenly redeemed by this medication, so that now she's playing with her family at the park, seems to vastly over-promise relief.

Vastly over-promising relief, indeed. Watching Congress, the FDA, the pharma-funded academic hired guns, and lawyers on these issues will make for an entertaining spectator sport. Not nearly as engrossing as watching the DSM-V drama unfold (1, 2, 3), but still a lot cheaper than going to a Yankees game.

Award Winning Journalism (?)

Erroneous reporting wins prestigious award, starring Charles Nemeroff. Oy. Brought to you courtesy of Health Care Renewal. Read the full story and shake your head. Teaser:

Something about the simultaneously complex and sympathetic nature of mental health reporting is making reputable journalistic organizations and well-meaning reporters sloppy.

New American Psychiatric Association Prez: We Want Money

In a recent speech, incoming American Psychiatric Association president Alan Schatzberg was quoted as saying:

"As the recent attacks on APA and leaders of the profession have occurred, it has struck me that some of the detractors in the press have voiced concern that some folks have earned too good a living, often by doing presentations," he said. "I have heard from colleagues and directly from one reporter asking me about one of my colleagues having too high an annual income. I can assure you these detractors would not ask the same question of a surgeon or radiologist earning 10 times the amount paid our colleagues. None of us do what we do for money. Yet, it is also time for us to realize that our members and residents have never taken vows of poverty, and the complexity of the work deserves to be recognized. We need to ask ourselves how we have contributed to our own devaluation with which others seem to resonate, and we need to reverse the course. The rewards for our dedication should not be limited to a sense of pride, but we are also entitled to be paid commensurate to the challenge.

So Schatzberg must be diving into dumpsters, begging at interstate off-ramps, and the like. Oh, wait a minute. This is the same Alan Schatzberg who in 2007 owned close to 5 million shares of Corcept (which translates into roughly 5 million dollars). I have no idea how many shares he owns currently. Corcept, in case you missed it, has shown its drug mifepristone (aka RU-486: "The Abortion Pill") is ineffective in relieving depression among patients with psychotic depression. Schatzberg, at one time, was the chief scientific officer of Corcept and was also the cofounder of the company. According to Corcept's website, he is still a scientific advisor. Despite the stuides of mifepristone showing negative results, the results were spun in a manner to make them sound as if they were positive (1, 2, 3, 4). In a press release, Schatzberg was quoted as saying that mifepristone "may be the equivalent of shock treatments in a pill." Right, with all of the negative studies, it's definitely shock treatment, meditation, and running a marathon all wrapped together in a capsule. Should he be paid "commensutate to the challenge" of trying to weave positive findings from negative results? I don't know what role, if any, he played in the misleading publications surrounding mifepristone. But in his role as chief of the scientific advisory board, I'd venture a guess that he had some involvement. But worry not, the negative results were not spun into positive findings for the sake of money, but for an altruistic love of patients with depression. I'm touched.

Schatzberg was also busted by yours truly putting his name on a duplicate publication that pimped Cymbalta, Lilly's antidepressant. The study presented data from the same set of patients who were involved in a previously published Cymbalta study. Scientific results are not meant to be published in nearly identical form in two different journals. But that didn't stop Schatzberg and his coauthors. If you've not read the lengthy post on this topic, please feel free to check it out in order to understand my cynicism regarding his recent speech.

Another quote from his talk:

We need to sit down with industry and come up with ways of interacting that are acceptable to both sides and fit with future guidelines. I have pledged to follow up on recent initiatives and work with Dr. Scully [APA's medical director] and our Board of Trustees to effect a new partnership—a partnership we can be proud of for what it contributes to the well-being of our patients and our profession.

I can only wonder what type of mutually agreeable interactions would meet Schatzberg's standards. Duplicate publication, serving as a scientific advisor for a company that writes scientifically dubious papers? And it appears that he's encouraging psychiatrists to be greedy -- take the money and don't feel bad about it. Taking industry money is perfectly acceptable in some instances, but it needs to be transparent, and there are plentiful examples of academics getting paid by industry and slanting science in a sponsor-friendly way.

And the clincher:

"The time has come," he said, "to be proud of what we do and to advocate for what we and our patients justly deserve."

Right, psychiatrists deserve to make as much money as possible bending science for corporate sponsors -- and they should be proud of it too. Am I being too cynical? Maybe. But when a guy with Schatzberg's record starts talking about psychiatrists needing to rake in more money from industry, it makes me think I'm living in Bizarro World. Get ready, APA memebers; it's going to be an interesting ride.

Greedy and Ghostly Scientists

Story one: Zachary Stowe, psychiatrist at Emory University becomes Charles Nemeroff, Jr. Read all about it the Carlat Psychiatry Blog and University Diaries. And check out the WSJ Health Blog as well. The gist is that Stowe apparently did not report all of his external income from his many pharmaceutical industry gigs. Better yet, he was a frequent speaker for GlaxoSmithKline, which had the gall to cancel two of his commercial talks. He then wanted GSK to pay him even though he wasn't going to give the speeches. Read the relevant emails toward the bottom of this document. After reading about Stowe, refresh your memory about Golden Goblet Lifetime Achievement Award Winner, former Chair of Psychiatry at Emory University: Charles Nemeroff. Is there something in the water at Emory? Or is that just how we roll in modern academic psychiatry? Stowe is hereby nominated for a coveted Golden Goblet for his string of emails in which he attempted to shake down GlaxoSmithKline. Sometimes I think that the only thing worse than drug companies are the narcissistic academics who they employ as "key opinion leaders." Not all key opinion leaders are jerks; some are probably even able to reasonably balance their industry cash with being good scientists. But Stowe didn't really portray himself as Mr. Nice Guy in his string of soon to be infamous emails.

Oh, and this little gem:

"Especially disturbing is an email between employees at GSK and a public relations (PR) firm that the GSK hired. The email was titled “For your review/Paxil Breast Milk Press Release” and states:

"[P]lease review the attached press release and forward me any comments/edits.
As you may know, Dr. Stowe is on board for publicity efforts and NAME
REDACTED and I are coordinating time to meet with him next week to arm him
with the key messages for this announcement, which is slated for early February.
We are sending the release for your review at the same time in efforts to secure
distribution on Emory letterhead (as you know, would provide further credibility
to data for the media)."

In his testimony, Dr. Stowe confirmed that the press release was written by the PR
firm and concerned his research on Paxil and its presence in breast milk. He also
explained that placing the press release on Emory letterhead, as opposed to GSK letterhead, would make the data more credible to the public."

If I have this straight, Stowe was willing to place a press release written by a PR firm hired by GSK on official university letterhead to enhance its credibility. Apparently he wasn't concerned about his own credibility. Read the full document of Senator Charles Grassley's investigation of Dr. Stowe.

Part 2: Enter the Ghostwriters

One snippet, then go to Bloomberg for the rest:

Ensuring that medical journal articles presented Zyprexa study results in a positive light was one way for Lilly to reach its sales goal, company officials said in its plan, according to the documents. To do that, Lilly officials hired ghostwriters to prepare submissions to journals such as Progress in Neurology and Psychiatry, according to the unsealed documents. “The paper for the Progress in Neurology and Psychiatry supplement has been completed and sent to the journal for peer review,” Kerrie Mitchell, an employee of the public relations agency Cohn & Wolfe, wrote in a Feb. 23, 2001, e-mail to Michael Sale, a Lilly marketing official. The message was among the unsealed files. “We ‘ghost’ wrote this article and then worked with author Dr. Haddad to work up the final copy,” Mitchell said in the e- mail. Eric Litchfield, a spokesman for Cohn & Wolfe, didn’t immediately return a call requesting comment.

The Bloomberg story is based on a recently released set of internal Lilly documents. That's right -- more Zyprexa documents are on the loose. And the first round of documents provided some good stuff (1, 2, 3), so I can't wait to see what kind of chicanery will be revealed by the latest round. In one sense, it's not exactly news that Lilly ghostwrote Zyprexa papers. We all know that ghostwriting is rampant. How else do key opinion leaders get their names on dozens of papers per year when they are also flying around the country pimping drugs, holding administrative meetings, and doing all sorts of other tasks? But it's nice to have it officially documented that Lilly was playing the ghostwriting game with Zyprexa.