Wednesday, May 30, 2007
I had the good fortune to read the Journal of Clinical Psychiatry supplement which featured Dr. Henry Nasrallah (the author) sneaking in some friendly messages about ziprasidone (Gedon), the antipsychotic from Pfizer that has been dwarfed by its competitors such as Zyprexa, Seroquel, and Risperdal. The piece discusses the findings of the CATIE study, which compared several newer antipsychotics to an older medication, perphenazine, and generally found that the newer and older drugs were of roughly equal effectiveness and that olanzapine had the worst safety profile. I thank an alert reader for passing the article along.
CME Overview: The good news is that physicians can read this article and take a quiz as part of the continuing medical education (CME) that helps them maintain their licenses. The bad news is that these articles are often thinly veiled advertisements for a product or a message that supports a product.
Highlights: It is stated that the difference favoring olanzapine (Zyprexa) over ziprasidone in terms of efficacy was not significant after a statistical adjustment (granted, this seems like a legitimate argument). It then mentions that olanzapine had the worst metabolic profile in terms of effects on weight, blood glucose, glycosylated hemoglobin, cholesterol, and triglycerides. It then states “In contrast, patients treated with ziprasidone had the best overall metabolic profile.” It places some numbers in a table regarding the metabolic effects of the various drugs in the CATIE study but provides not a single statistical analysis (or reference to an analysis on CATIE data) backing its assertion that it is significantly better than all other drugs in terms of metabolic profile.
The piece then turns to a secondary phase of the CATIE study, in which patients who discontinued their medications in the first phase of CATIE were assigned to other medications. It mentions olanzapine weight gain then mentions that patients on ziprasidone lost weight. It then discusses weight loss on ziprasidone again, then moves on to ziprasidone being associated with decreases in cholesterol and triglycerides, whereas olanzapine was associated with gains in both of these measures.
In case readers have been sleep-reading through this piece, it then moves to state that “except for clozapine, olanzapine clearly caused the heaviest burden of metabolic side effects. Ziprasidone, on the other hand, was consistently associated with the most benign side effect profile.”
Then, the piece moves to scare the reader about older antipsychotics and their risk of inducing extrapyramidal symptoms [EPS]. “The clinician must carefully decide whether the lower cost of the typical antipsychotic is worth the potential striatal neurotoxicity manifested by acute extrapyramidal side effects and long-term TD [tardive dyskinesia].” Of course, he must be assuming that atypical antipsychotics never or rarely induce EPS, which appears to be wrong and that all older medications induce EPS at the same rate as Haldol, which is likewise incorrect (1, 2).
Overall Message: The bottom line message of the piece is clear. Geodon is safe; Zyprexa is unsafe. Don’t use older meds because they’ll cause EPS – ziprasidone won’t. In fact, Geodon is the safest of the second generation antipsychotics.
Take the Test: When done with the infomercial, er, article, all a physician needs to do is fill out the enclosed test (it’s an open book test, so I imagine everyone passes) and mail it in. Physicians can even complete the test online. [this section was taken directly from an earlier post]
Ghostwriter Watch. Who wrote the article? You tell me – I’m confused. Here’s what is written in the article…
This article is derived from the planning teleconference “Evaluating the Evidence: Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and Beyond,” which was held on May 10, 2006, and was independently developed by the CME Institute of Physicians Postgraduate Press, Inc., and Health and Wellness Education Partners (HWeP) pursuant to an educational grant from Pfizer and addition support from HWP Publishing
Dr. Nasrallah is a consultant for, has received honoraria from, and been on the speakers/advisory boards for Abbott, AstraZeneca, Janssen, Pfizer, and Shire and has received grant/research support from AstraZeneca, Janssen, and Pfizer.
Content development and writing support for this article was provided in part by an independent writer contracted by HWeP: Martin Korn, M.D., a psychiatrist in private practice in
. New York
I may be piecing this together wrong, but here goes… Pfizer writes a check to the CME Institute and HWeP. Nasrallah and a few other bigwigs engage in a conference call and are reimbursed (likely quite well) for their time. HWeP hires Martin Korn to write the piece, which then is reviewed, likely in a cursory manner at most, by Dr. Nasrallah. The piece is then reviewed by a member of the CME Advisory Board. These "reviews" appear to be consist of a race to grab the rubber stamp as quickly as possible.
I’m not sure if Pfizer provided the talking points directly to Dr. Korn, but it seems he got the message that Zyprexa and older meds should be slammed while Geodon should come across looking angelic. The CME Institute then stamps their approval and we call all be assured that doctors are being “educated” about the latest and greatest treatments in a purely objective fashion.
Please also feel free to read my earlier piece on CME. I recall seeing Dr. Korn's name on an earlier CME piece similar to this, but I can't seem to track it down.
Don't be confused -- I'm not defending Zyprexa. Geodon appears to be a safer drug than Zyprexa, but this quite thinly veiled advertisement that masquerades as independent education is ludicrous -- how does reading or watching commercials passing for "education" help physicians make better decisions for their patients?
Friday, May 25, 2007
The kicker is that the patent has expired for Zoloft, which is why the data are now flowing more freely. I’ll make the case here that data were buried until they would no longer hurt sales to any meaningful extent, at which point data were published, at least partially as a public relations move to show just how “honest” the companies are with sharing both positive and negative results with the psychiatric community.
The Research: The latest study, which appears in the May 2007 Journal of Clinical Psychiatry, showed no benefit for drug over a 12-week period. Placebo tended to outperform Zoloft on the majority of outcome measures, though the differences were of a small and statistically insignificant degree. Patients were significantly more likely to drop out of treatment on Zoloft. It was unclear if there were any serious adverse events (e.g., suicide attempts, notable aggression, etc.) because the article did not mention them at all. Patients started this study between May 1994 and September 1996. The original draft of the study was received by the journal in March 2006. Nearly 10 years passed between study completion and writing up the data for publication.
Two prior studies found positive results found positive results for Zoloft and were published quickly, while these negative results languished until the Zoloft patent had expired. One earlier positive study did not list the dates during which the study occurred, but it seems clear that it was rushed to publication much quicker than the negative study. Another positive study was conducted between May 1996 and June 1997 and was published in 2000. It’s quite obvious why the positive studies were rushed to press and the negative study languished, is it not?
Do keep in mind that the magnitude of positive effect for Zoloft over placebo, even in the positive studies, was small to moderate. When even the positive news for antidepressants in treating PTSD show only modest improvement relative to placebo, one should tread cautiously.
Change of Heart: Drug companies have been criticized widely for failing to disclose clinical trial data (1, 2). In an effort to shore up the support of the medical community and the public at large, what could possibly make more sense than publishing negative trial results? Gee, look at how honest we are – we share the good news and the bad news! Of course, when the positive results are published as quickly as possible and the negative results are published after a 10 year delay, well after the negative results can pose any threat to corporate profits, I’m not impressed by their newfound dedication to transparency.Note:
If you are a journalist, this is the kind of story that would merit a broad audience. The plot is pretty simple to follow and it reeks of corporate malfeasance, a subject that is not new to Pfizer and its former cash cow antidepressant.
Thursday, May 24, 2007
In a related note, at the American Psychiatric Association convention, a press release featuring Dr. John Kane (a Janssen consultant with a monetary investment in Janssen) said that the main reason physicians cite for patients not complying with their medication is "poor insight into illness". I don't know if poor efficacy or side effect burden was even mentioned by this survey. These results came from a survey designed by (who else?) Janssen.
What am I getting at? Well, we've got two related surveys, one given to social workers, the other to physicians. Both of them emphasize that patients tend to not comply with their schizophrenia medications. Well, phew, Janssen, whose patent on oral Risperdal is about to expire, has the patent for an injectable form of Risperdal (Risperdal Consta), which won't expire for a while. So, they send out these surveys under the guise of research, but the point is far from research -- we already know people don't generally enjoy taking antipsychotics.
The point is marketing. People don't comply with their medications, so we have to give it to them in injectable, long-acting format so that their compliance with treatment will be acceptable.
Tuesday, May 22, 2007
Many bloggers linked to Peter Rost’s blog last week, and with damn good reason. He posted an excellent three-part series regarding a Pfizer whistleblower. And, making it yet more interesting, voodoo was allegedly involved. Mack took issue with bloggers linking to Rost, pointing out (accurately) that most who linked to Rost had little to add. I linked to Rost and admit that I added nothing to Rost’s story. Mack then stated that the reason fellow bloggers linked to Rost was because they wanted to increase their visibility, as Rost was nice enough to link back to sites that posted links to his site.
Well, allow me to differ. Do I like getting a little added traffic from Rost? You bet – I’ll take all the traffic I can get. But that is not the main reason I linked the story. I linked it because it is interesting and because I thought my readers should be exposed to it. The more exposure such a story gets, the better. After all, it appears that one thing that many pharma-related sites have in common is to shine light on dubious industry practices. Thus, I see linking to a blogger who is doing good investigative work as a large part of my blogging duties. Am I missing something?
Friday, May 18, 2007
He's also looking at drug cocktails in adults who receive state-funded mental health care, and here's what he's found:
…the number of adults taking three are [sic] more psychiatric drugs increased by 68 percent within six months last year (5,544 adults to 9,328).
Wow, that’s quite a jump for a six-month period. Regarding the increase in meds for kids…
"I challenge anyone in the state of
or anyone who works for the Department of Community Health or any doctor to prove me wrong," Hansen said. "Step forward with the data and tell me, 'Ben Hansen, what you say is happening is not happening. Our children are not being targeted by the drug companies simply because once they're on these drugs, they are patients for life.' Believe me, I'd love to be wrong about this." Michigan
Last week, he was on the phone with a foster care caseworker who told him of a boy, who had acquired a twitch in his neck and was already on at least two prescription drugs. His doctor then prescribed Adderall (an anti-ADHD medicine) to quell the twitch, and the boy suddenly died
several days later. His caseworker suspected that drugs played a role, but shied away from the story when a reporter was mentioned.
Another interesting finding was that, in Michigan alone, almost 13,000 children on Medicaid or foster care were prescribed atypical antipsychotics (Risperdal, Zyprexa, Seroquel, etc.) last year.
Rost continues to bring the hammer down on Pfizer. I won't even bother to summarize his work, suffice to say that it involves a combination of...
- Money laundering
- Retaliation toward a Pfizer whistleblower
Part one. Part two. Part three.
Below are a few articles you may enjoy regarding Covington & Burling's stalwart representation of Big Tobacco, and how they covertly got involved with the "science" surrounding the health effects of secondhand smoke. I highly advise reading them, then thinking about the current Zyprexa controversy.
- Center for Indoor Air Research
- The Latin Project
- Playing with Airline Cabin Science
- More on the "Center for Indoor Air Research"
- Center for Diabetes Studies
- Center for Weight Management Research
- Institute for The Appropriate Marketing of Pharmaceuticals
As pointed out by Ed at Pharmalot, Utah is now added to the list of states suing Lilly over its promotion of Zyprexa. Read some of the statements from Attorney General Mark Shurtleff regarding the lawsuit. The lawsuits just keep stacking up.
It must suck to be Lilly these days. The documents that may incriminate Lilly are just hanging out in full public view. Any enterprising attorney general just needs to get their feet wet by looking through a handful of documents (which can be downloaded here and here) and by perhaps taking a peek at a few posts by your humble correspondent and Philip Dawdy, such as the following:
Thursday, May 17, 2007
One group is skeptical about this new disorder and not impressed with the new study which suggests SBD is not being treated appropriately.
Another group appears to believe that the newly minted SBD is legit and doubting it is a sign that you might be a "pop psych pundit." Here are some snippets and links to each camp, along with my occasional commentary [in brackets].
- Polarcoaster said:
Yes, this “subthreshold” stuff is ridiculous, but within limits, I like the idea of the bipolar spectrum because it makes people aware of things that actually are bipolar symptoms but aren’t necessarily the most classic ones. It’s when you start pathologizing mild things that occur infrequently that it gets to be harmful.
No, I don’t know where the line should be drawn. But I’d say somewhere way before “subthreshold bipolar disorder” as defined in that journal article, anyway. [I agree that many mental conditions exist on a spectrum and agree that the line in this case is too inclusive.]
- Dr. X said:
My prediction: treatment will be good for pharmaceutical stocks and will cause patients to gain a lot of weight. [Cynical, but I have no evidence that Dr. X is wrong]
- Bipolar Chicks Blogging said:
We're not doctors here; but we do have years of combined experience and you may read stuff here that you won't hear from your physician or on television and more and more, what you hear coming from your doc's mouth mimics what is spewed from drug advertising; and the bitch is, none of it is hard science. [Good point -- especially in the latest SBD study, the argument for treating SBD is currently science-free]
- Ruth at Off-Label hilariously wrote:
"The problem is all inside your head", he said to me
The answer is easy - you just take it orally
I'd like to help you in your quest for normality
For there are 21 ways to be subthreshold bipolar
Have you increased your goal-directed activity?
Are you subject to distractibility?
Engaged in an unrestrained buying spree?
There are 21 ways to be subthreshold bipolar
You been flat on your back, Jack
Making grand plans, Stan
Cheatin' on your boy, Roy
Well, listen to me
Hop on the shortbus
We don't need to discuss much
Just drop this off at the pharmacy
And get yourself free... [And it goes on further -- you must read it!]
- Empirical Insanity said:
Check this post out, in which the author, whose bio states that he is an academic with clinical experience, starts with that article and works up to arguing that anyone who isn't bipolar type I should not be receiving long-term medication because "there is scant if any research on what appropriate medication is for bipolar II and there is not a damn bit of research attesting to medication for SBD" (subthreshold bipolar disorder).
I do not think he is an academic with training on the research side of psychology. He also seems to have difficulty understanding that different diagnoses of bipolar disorder almost certainly involve similarities in etiology which are relevant to treatment. [If anyone can locate a single study showing positive treatment results for SBD, I'd love it see it.]
- Maddy said:
...I'm BPI but this kind of thing still pisses me off. How can they completely discount another persons condition? Calling it "Life's little ups and downs" is such bullshit. Don't they realize how they are contributing to the mental health stigma? Not to mention the fact that by not controlling mania/hypomania can cause even more serious issues down the road?
AARRRGGGHHH! I just want to rip these idiots a new asshole or two![I question whether people should receive meds for a questionable diagnosis in the face of no evidence and thus I'm an idiot who needs to be ripped a new orifice.]
- reddog said:
- herrfous said:
A relatively newly-adopted but pervasive maxim of modern allopathic medicine is "treat the patient, not the symptoms".
It seems that these pop-psych pundits (and perhaps a few doctors) haven't yet gotten past "treat the symptoms, not the DSM-coded diagnosis". [And if someone has one minor symptom of hypomania [i.e. has SBD], these symptoms require treatment?]
Wednesday, May 16, 2007
The emphasis on decorum and status explains why the BBC had to conduct it's own investigation [Link] of the worrying events surrounding clinical trials of the drug Seroxat and the company GlaxoSmithKline (GSK) as the medicines regulator (the MHRA) simply dragged it's feet for years conducting an internal investigation of its own collusion with the deception. And to cap it all, key figures within the MHRA are previous employees of GSK.Blumsohn points out that there sure is a lot of emphasis on style (i.e., oh, be nice and proper) as opposed to substance (um, this drug can be dangerous OR this professor is getting railroaded by the administration, etc.). Also, those in the highest roles of authority/"prestige" are off-limits -- they can do whatever they want without consequence. Do read his entire post -- it's well worth your time.
In the world of cat poop and schizophrenia, Stephany at Soulful Sepulcher has a post that is very interesting. Say WHA, you may be thinking, but you'll just have to read her post to find out. I suppose that as a lifelong cat owner, I can thank my lucky stars I didn't develop psychosis. Or something like that.
Tuesday, May 15, 2007
For my vote, can we go with DUMBASS-$ (Diagnosing Usually Mundane Behavior As Seroquel Scripts $oar) That's my off-the-cuff take, but others have already offered much better. Sigh...
Monday, May 14, 2007
Friday, May 11, 2007
My reading of this is that much of that increase is linked to an expanded definition of bipolar disorder as a spectrum disorder (spectrum disorders are all the rage these days) with SBD being the catch basin for all the soft bipolar researchers claim they are detecting in America these days. And so begins the war on the weird, the productive and the agitated of America.Much more at his site.
I posted in lengthy form yesterday about the newly legitimated "subthreshold" bipolar disorder (hereafter referred to as SBD) that 2.4% of Americans allegedly will develop during their lifetime. The press releases and "news" stories have predictably followed. Let's start with something called Medical Condition News. Prepare for some bad journalism...
The headline reads as follows: "4 percent of US adults have some form of bipolar disorder"
Sure, a newly minted disorder (SBD) that actually appears nowhere in the official diagnostic manual accounts for most of that, but whatever.
Here's how the news piece characterized SBD:
...a milder, sub-threshold bipolar disorder that involves hypomania with or without depression, otherwise classified as bipolar disorder "not otherwise specified" in the current diagnostic nomenclature of the American Psychiatric Association.
Except that SBD did not require hypomania -- SBD actually required more like half of hypomania. Note to journalists: Read the article, then write on it.
How about treatment? Here's what the article said:
Except that SBD did not require hypomania -- SBD actually required more like half of hypomania. Note to journalists: Read the article, then write on it.
However, over the previous 12 months, only 25 percent of those with bipolar disorder I, 15.4 percent with bipolar disorder II and 8.1 percent with sub-threshold bipolar disorder received appropriate medication
Remember, there is scant if any research on what appropriate medication is for bipolar II and there is not a damn bit of research attesting to medication for SBD. Remember, the article said that appropriate medication included mood stabilizers, antipsychotics, and lithium. Who cares that this is just pulled out of a hat?
This one has appeared on a few different sites. Duck and cover.
However, only a few [who current were in an "episode"] received appropriate medication (25.0% for bipolar I, 15.4% for bipolar II, and 8.1% for subthreshold bipolar disorder). Appropriate maintenance medication for currently asymptomatic patients was even lower (17.9%, 15.6%, and 3.2%, respectively).
Again, this is suggesting that there is an appropriate medication treatment for bipolar II and SBD, when the data just ain't there. If the mainstream press jumps on this, this could be a big problem.
The Zyprexa Connection
The rich irony of this is that Lilly has been shamed by the disclosure of internal documents (like this one) showing that it pimped Zyprexa to primary care doctors for a condition similar to SBD. Apparently Lilly was just ahead of their time. Lilly must be shaking their heads -- they get negative media coverage while researchers have now just sneakily endorsed the treatment of watered-down bipolar disorder with... drugs like Zyprexa. Please read my earlier post to see how this all ties together. There was no science behind the treatment for faux bipolar when Lilly was offering it, and there is still no science behind it today.
Peter Rost directs his displeasure at John Kerry, Ted Kennedy, Evan Bayh, Frank Lautenberg, and several others whose helped to ensure that the drug reimportation from Canada will remain a no-no. PharmaGossip and edrugsearch.com were likewise not amused, and they point to Big Pharma doing a helluva job buying votes.
They're just representing the people, as millions of Americans demand direct to consumer advertising and want to pay more for their drugs, right?
Thursday, May 10, 2007
Just how many people have bipolar disorder AND what is the deal with “subthreshold” bipolar disorder? Research in the latest Archives of General Psychiatry attempts to answer just these questions. There is some strange stuff going on in this article. Suffice to say that if you hear a giant sucking sound – it is the sound of people with bipolar II and (worse) subthreshold bipolar disorder being sucked into long-term treatment with medications that lack evidence for their conditions. Warning: This is a long post. Read on…
Regarding prevalence of bipolar disorder in the
Well, here is their definition. To qualify for subthreshold BP, you must have had the following symptoms more than once:
A. A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual non depressed mood.
B. During the period of mood disturbance, two (or more) of the following symptoms have persisted and have been present to a significant degree:
(1) inflated self-esteem or grandiosity
(2) decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
(3) more talkative than usual or pressure to keep talking
(4) flight of ideas or subjective experience that thoughts are racing
(5) distractibility (i.e., attention too easily drawn to unimportant or irrelevant
(6) increase in goal-directed activity (either socially, at work or school, or
sexually) or psychomotor agitation
(7) excessive involvement in pleasurable activities that have a high potential for
painful consequences (e.g., the person engages in unrestrained buying sprees,
sexual indiscretions, or foolish business investments)
C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic.
D. The disturbance in mood and the change in functioning are observable by others.
So, if you have twice or more had a time when your mood was persistently irritable or high (A) and you didn’t need much sleep (2) and you felt pretty full of yourself (1), then you, my friend, qualify for subthreshold BPD. Or, if you, on a few occasions, were full of energy (A) and feeling much better than average (A) for, say a week, and your self-esteem was notably increased as well (1) and you got much more than usual accomplished (6) – then you also have subthreshold BPD. Let’s not forget that the second author has been saying for years that we exist on a “bipolar spectrum” with many cases of “soft bipolar” (subthreshold bipolar) being missed by unwary clinicians. Maybe he's right, but this type of definition does not give me the impression that "soft bipolar" is a big time problem.
Feel free to play more mix and match in the comment section of this post. I’m sure that most people diagnosed with subthreshold bipolar were more severely impaired than this, but these criteria are clearly too loose.
Oh, and when one goes to the comment section of the article (page 547), the authors state that their “prevalence estimate of subthreshold BPD is likely to underestimate bipolar spectrum disorder in the population”. Huh? That’s because their “definition of subthreshold BPD is still more restrictive than the definitions proposed by clinical researchers.” Oh, okay then. Because some researchers are willing to play even looser with their criteria, then we should just accept that there are a lot more people out there who have this so-called disorder.
The authors also looked at “severity of role impairment.” This analysis was based on people who had recently suffered from bipolar or subthreshold BPD. They found that among people with subthreshold BPD, 46% has “severe” role impairment, and 42% had “moderate” role impairment due to their “subthreshold mania”. Role impairment was defined as participants’ highest score of their impairment across four domains: home management, work, social life, and personal relationships. So if a participant scored no or mild impairment in three of four areas, but scored moderate on one area, then the person was counted as having moderate impairment. That’s what I call rounding up! I’d also like to see other some sort of other measure used besides this quickie disability scale. What were the real-life consequences associated with their subthreshold hypomania? That question remained unaddressed.
One other thing. On page 546, the authors state that the average number of “episodes” – either manic, depressive, hypomanic, or subthreshold hypomanic was 77.6 for those diagnosed with bipolar I, 63.6 for those diagnosed with bipolar II, and 31.8 for those diagnosed with subthreshold BPD. It strikes me that these numbers may as well have been pulled out of a hat. How the hell could somebody recall, in their life, how many “episodes” they’ve had and say, “Oh, geez, I think maybe 87.” I could be wrong, but I ain’t buying these figures.
Treatment: Warning – this is both sneaky and scary. The article goes on to essentially say that psychiatrists are much more apt to provide appropriate medical treatment for bipolar disorder than are non-psychiatrist physicians. It mentioned that those who had experienced “subthreshold” bipolar in the last year only received appropriate treatment 8.1% of the time. Earlier in the paper, appropriate treatment was defined as treatment with mood stabilizers (e.g., lithium), anticonvulsants (e.g., Depakote) and antipsychotics (e.g., Zyprexa, Seroquel, Risperdal). Rant on this to come in next paragraph -- it gets worse.
Now pay close attention. Only 3.2% of people who had a subthreshold diagnosis during their lifetime, but had not experienced an episode during the past year received “appropriate medication maintenance” treatment. WHAT?? Back up. There is scant, if any, data, saying that people with this newfangled diagnosis of “subthreshold” bipolar benefit from short-term treatment and there is not a *blanking* shred of evidence to say that people with “subthreshold” bipolar benefit from treatment with antipsychotics, mood stabilizers, or lithium in the long-term. How the hell did this section sneak through peer review? So it is now officially “appropriate” for people to receive Zyprexa or Seroquel for their “subthreshold” bipolar disorder in the long-term, even when they are experiencing no symptoms? Incredible. The paper also implies that people with bipolar II should receive constant treatment – again, where is the data to support such a recommendation. The long-term data on bipolar I treatment is also not great, but it dwarfs the data on bipolar II and “subthreshold” BP.
Funded By: The study was funded by various government agencies, the Robert Wood Johnson Foundation, and the John W Alden Trust. “Preparation of [the] article was supported by AstraZeneca.” As my astute readers know, AstraZeneca makes Seroquel, which is one of the “appropriate” treatments in this study. How does a company support the preparation of an article? Does this mean it was ghostwritten? I’m not accusing; I am just curious how a company would help to prepare an article? It would, after all, be to AZ’s benefit to suggest Seroquel was appropriate for people with “subthreshold” bipolar. Maybe I’m being too conspiratorial?
As I write this, I am thinking that I must have misinterpreted the article – there’s no way that the authors would endorse short-term and “maintenance” treatment for bipolar II and “subthreshold” bipolar given the lack of evidence. Please let me know if I misinterpreted something – I would really like to be wrong!Hat Tip: Furious Seasons.
The patient who gets the most coverage in the story is Anya Bailey, who, at age 12, apparently developed an eating disorder and was prescribed Risperdal. I’ve never seen a shred of evidence to support such a prescription, but the doctor was apparently thinking the side effect of weight gain would be a bonus in her case.
Anya developed a “crippling knot in her back” as a result of treatment. Her mother alleges that she was never told that the evidence base behind such a prescription was nonexistent. The authors say it nicely (highlighting added):
Just as surprising, Ms. Bailey said, was learning that the university psychiatrist who supervised Anya’s care received more than $7,000 from 2003 to 2004 from Johnson & Johnson, Risperdal’s maker, in return for lectures about one of the company’s drugs.
Doctors, including Anya Bailey’s, maintain that payments from drug companies do not influence what they prescribe for patients.
But the intersection of money and medicine, and its effect on the well-being of patients, has become one of the most contentious issues in health care. Nowhere is that more true than in psychiatry, where increasing payments to doctors have coincided with the growing use in children of a relatively new class of drugs known as atypical antipsychotics.
These best-selling drugs, including Risperdal, Seroquel, Zyprexa, Abilify and Geodon, are now being prescribed to more than half a million children in the United States to help parents deal with behavior problems despite profound risks and almost no approved uses for minors.
From 2000 to 2005, drug maker payments to
psychiatrists rose more than sixfold, to $1.6 million. During those same years, prescriptions of antipsychotics for children in Minnesota ’s Medicaid program rose more than ninefold. Minnesota
Those who took the most money from makers of atypicals tended to prescribe the drugs to children the most often, the data suggest. On average, Minnesota
psychiatrists who received at least $5,000 from atypical makers from 2000 to 2005 appear to have written three times as many atypical prescriptions for children as psychiatrists who received less or no money.
Key Opinion Leaders: Let's talk about folks who are quick to try out new drugs, often for uses that have little supporting evidence. They are called “high flyers” or early prescribers, as well as some other terms. These are the docs most highly targeted by drug companies because they tend to yield the highest return on investment. How do you target docs? With key opinion leaders. Find a "respected" physician to talk with the high flyers (though other docs are also targeted). Use a KOL who will be seen as "objective" -- this will help convince the doctor to start using the new drug(s). Read the following snippet from a company that contracts with Big Pharma to develop KOLs to influence prescribing habits. All emphases are mine.
The professional networks of physicians play an important role in product adoption. A decision to adopt a product can be profoundly influenced by Key Opinion Leader (KOL) peers who have already formed a positive opinion about a product.
Through our uniquely created patent pending process we target those KOL’s focused on top prescribers of treatments for a given specialty. These leaders significantly influence the opinions, and behaviors of others through their knowledge, advice and enhanced perspective, creating advocates which, then help gain the adoption of the product.
In this case our highly trained engineers delivered a solution using the latest technology and our proven process in a matter of weeks. Our Successful KOL program strategies are based on systematic and rigorous methods for identification, new research techniques, and the use of the latest technologies. We leveraged these strategies so that BMS could establish long-term relationships of mutual trust with these leaders built on integrity and continuity.
Through our user-friendly methodology we have proven that successful marketing and adoption of a product requires a minimum of four steps. We incorporate these four steps as the basis for this successful solution:
1. Awareness: The physician recognizes the product by name.
2. Agreement: The physician evaluates and agrees to the theoretical premise of the product.
3. Adoption: The physician decides to use the product on a trial basis.
4. Integration: The physician incorporates the product into his daily practice of medicine.
Stumping for Drug Companies: From the NYT piece...
, psychiatrists collected more money from drug makers from 2000 to 2005 than doctors in any other specialty. Total payments to individual psychiatrists ranged from $51 to more than $689,000, with a median of $1,750. Since the records are incomplete, these figures probably underestimate doctors’ actual incomes. Minnesota
Anya’s doctor, George Realmuto gave several educational marketing speeches for Concerta, manufactured by Johnson & Johnson, which also makes Risperdal. He had the following to say (and I hope he was misquoted) when asked about why he gives marketing speeches for drugs.
“To the extent that a drug is useful, I want to be seen as a leader in my specialty and that I was involved in a scientific study,” he said. [i.e. I wanna be a key opinion leader???]
The money is nice, too, he said. Dr. Realmuto’s university salary is $196,310.
“Academics don’t get paid very much,” he said. “If I was an entertainer, I think I would certainly do a lot better.”
Hey, can someone fetch me the Kleenex? Making $196,310 per year is a sign that he does not “get paid very much.” Cry me a river. In-blanking-credible.
As the interview continued, Dr. Realmuto said that upon reflection his payments from drug companies had probably opened his door to useless visits from a drug salesman, and he said he would stop giving sponsored lectures in the future.
Good for him. Now I’m not saying that his Concerta gig made him prescribe Risperdal in Anya’s case. Might having a cozy relationship with J & J lead to prescribing more J & J products? Perhaps, but I don’t know. What concerns me most is that, if he was quoted correctly and in context, he really thinks that a $200k salary is not enough income. If that’s the case, and he’s willing to put his stamp of approval on a drug via marketing speeches because a $200k salary is insufficient, then that level of greed is astounding by most standards.
The drug industry and many doctors say that these promotional lectures provide the field with invaluable education. Critics say the payments and lectures, often at expensive restaurants, are disguised kickbacks that encourage potentially dangerous drug uses. The issue is particularly important in psychiatry, because mental problems are not well understood, treatment often involves trial and error, and off-label prescribing is common.
The analysis of
Minnesotarecords shows that from 1997 through 2005, more than a third of ’s licensed psychiatrists took money from drug makers, including the last eight presidents of the Minnesota Psychiatric Society. Minnesota
The psychiatrist receiving the most from drug companies was Dr. Annette M. Smick, who lives outside
, and was paid more than $689,000 by drug makers from 1998 to 2004. At one point Dr. Smick was doing so many sponsored talks that “it was hard for me to find time to see patients in my clinical practice,” she said. Rochester, Minn.
“I was providing an educational benefit, and I like teaching,” Dr. Smick said.
Even the immediate past president of the American Psychiatric Association, Dr. Steven Sharfstein, chimed in, pointing out that it’s sure odd that Lexapro is the most prescribed antidepressant in the absence of evidence that it’s better than generic antidepressants – could it be that Lexapro still has key opinion leaders talking up the drug, Forest Labs has reps pushing Lexapro in office visits, and that Lexapro is featured in quite a bit of medical journal advertising? Hey, do you think that the meteoric rise of Cymbalta might also be due to marketing rather than scientific evidence?
Child and Adolescent Bipolar: The controversy continues. From the NYT article…
The sudden popularity of pediatric bipolar diagnosis has coincided with a shift from antidepressants like Prozac to far more expensive atypicals. In 2000,
spent more than $521,000 buying antipsychotic drugs, most of it on atypicals, for children on Medicaid. In 2005, the cost was more than $7.1 million, a 14-fold increase. Minnesota
doctors, including the president of the Minnesota Psychiatric Society, said drug makers and their intermediaries are now paying them almost exclusively to talk about bipolar disorder. Minnesota
On to the “research” regarding treating bipolar in children and adolescents. As discussed in the NYT article, there was a study done, in which 30 adolescents took either Depakote + placebo or Depakote + Seroquel. The combined treatment group did better at the end, but about half of the adolescents in the Depakote + Seroquel group dropped out of the study. So basically the study was a wash. Yet, in the published paper, it was stated that Depakote + Seroquel “is more effective for the treatment of adolescent bipolar mania” than just Depakote + placebo. Nice.
Melissa DelBello (author of aforementioned study) and Robert Kowatch (both of the
There have been a few other studies done, but it is safe to say the evidence base is pretty weak for treatment of child and adolescent bipolar disorder. Data on longer-term (like longer than a month or two) treatment is sorely lacking.
Here’s what one
“We don’t have time to wait for them to prove us right,” said Dr. Kent G. Brockmann, a psychiatrist from the Twin Cities who made more than $16,000 from 2003 to 2005 doing drug talks and one-on-one sales meetings, and last year was a leading prescriber of atypicals to Medicaid children.
Wait a minute, Kent Brockmann – take away one ‘n’ on his name and you’ve got this guy. HA! Anyway, Dr. Brockman needs to give kids atypicals because it is urgent – maybe he buys into the 75% of “bipolar” children become suicidal line. This line of "prescribe new meds because it's an urgent, urgent emergency" makes me wonder if the docs who are all over the atypicals now are the same ones who were prescribing Neurontin for everything as well because they "couldn't wait" for the data to vindicate their prescribing practices. As it turns out, Neurontin for psych disorders turned out to be a flop, but that didn't stop it being prescribed like candy by many docs. Maybe I'm wrong -- the Neurontin crowd could be entirely different than the atypicals for everything (and bipolar is everywhere) crowd -- I'm just taking a guess.
Oh, and as for safety…
In 2006, the Food and Drug Administration received reports of at least 29 children dying and at least 165 more suffering serious side effects in which an antipsychotic was listed as the “primary suspect.” That was a substantial jump from 2000, when there were at least 10 deaths and 85 serious side effects among children linked to the drugs. Since reporting of bad drug effects is mostly voluntary, these numbers likely represent a fraction of the toll.
Summary: The bipolar diagnosis in kids is highly controversial (1, 2, 3, 4, 5, 6) and there is pert-near no evidence favoring treatment using atypical antipsychotics to manage their “bipolar” symptoms. Key opinion leaders have done a nice job of pimping atypicals – the $170 - $250k many of these folks earn in academia just ain’t enough – they have to provide “education” to their colleagues regarding these “life-saving” medications. Drug companies decide to push a diagnosis and recruit KOLs (as well as utilizing other tricks) to persuade doctors to prescribe the new meds, regardless of supporting evidence.
Thank whomever designed the law in
Also, what world do people live in when they think that a $200k salary is insufficient? Is this a sign of entitlement, poor money management, really rich tastes, or what? How many McKinnells do people think they're worth, anyway?
Hat Tip: Furious Seasons.
Wednesday, May 09, 2007
Not long ago, I invented the sarcastic Golden Goblet Award as an honor for researchers whose conflicts of interest were of truly epic proportions. Peter Rost has the story of an "independent academic" (Dr. Stephen Freedland) at
I was less than shocked to also discover that Dr. Freedland is a member of an advisory board for AZ. I'm not an expert in cancer by any means and I don't know much about Freedland's research and/or clinical practice. He may be the world's best oncologist -- I don't know.
But... When an "independent academic" lends his academic stamp of approval via speeches for one drug 68 times in one year, that's worthy of a nomination for a Golden Goblet -- though still relatively early in his career, he's got "key opinion leader" written all over him!
Lawsuits against AstraZeneca regarding its alleged failure to disclose the risks (like diabetes) of its drug quetiapine (Seroquel) are on the rise. Apparently, more than 350 cases were filed in
More details here.
Tuesday, May 08, 2007
Link to quick press release. Hat Tip (and an extended writeup): AHRP.
Friday, May 04, 2007
- The Zimulti (formerly known as Acomplia) weight loss drug has quickly become the laughingstock of the blogosphere. Check out Pharmalot, and the Pharma Marketing Blog
- In addition, PharmaGossip posted a link to a wonderful piece by Carl Elliott regarding the relationship between drug reps and physicians. Count it as a must read. While on an Elliott binge, check out Health Care Renewal's post regarding another piece including Elliott as an author. It involves ghostwriting and what should be done about it.
- Furious Seasons points out that Jim Gottstein, who helped to make the Zyprexa documents debacle public (1, 2, 3), has received an award. Here's hoping there are many more heading his direction.
- Jim Edwards continues his stalwart work on the AstrzZeneca Bucket O' Cash scandal with a neat timeline of how the scandal came to be. Despite AZ's claims that proper discipline has been meted out to some folks involved in the scandal, Edwards has some additional questions.
- Regarding the latest Pfizer ads for Viagra, which appear to use a language similar to Simlish in order to educate patients, both Health Care Renewal and Pharma Giles have chimed in. Giles did manage to return from his brief retirement for his post, and we were all glad to see him back in action.
- Let's also not forget about Pink Cupcategate. What am I talking about? Check out Peter Rost to find out.
- Oh, and the rate of spending on psych meds rose 150% from 1997 to 2004. Viva Zyprexa, anyone?
I can only hope that it will be as great of a study as a similar investigation that utilized Zyprexa for adolescents with bipolar disorder. Of course, we know (because someone at Harvard said so) that children with bipolar disorder become suicidal in 75% of cases. Did I mention I have a bridge that I'm looking to sell...
Please read Intueri's post as well as my earlier post to see just how "scientific" the diagnostic process is for kids and adolescents regarding bipolar disorder.
Thursday, May 03, 2007
I've had a couple people indicate confusion regarding the meaning of the titles of my posts that include "Uh-Oh Chuck They Out to Get Us Man"(1, 2, 3, 4, 5).
"Uh-Oh Chuck They Out to Get Us Man" is the opening lyric from the opening track (You're Gonna Get Yours) from the classic Public Enemy album Yo! Bum Rush the Show. Chuck D was the main voice in Public Enemy (not to neglect Flava Flav's notable contributions -- including the aforementioned opening lyric), and one of the people discussed in the posts is named Charles, which could be abbreviated to Chuck, though I don't believe the Charles in my posts goes by Chuck.
I wanted to find some way to throw in a PE lyric to my posts, so I did, even if it was a stretch. Next question...
Background. The study had the following phases:
1) Participants who had not responded to 1-3 antidepressants other than (es)citalopram (Celexa or Lexapro) for greater than six weeks were assigned to open-label citalopram (Celexa) treatment for 4-6 weeks
2) Patients who failed to respond to citalopram were then assigned to open label risperidone (Risperdal) augmentation (add-on) treatment for 4-6 weeks
3) Patients whose depression remitted were then assigned to 24 weeks of either risperidone + citalopram or citalopram + placebo and the differences between risperidone and placebo for depressive relapse were examined.
Please read the linked posts for more detail on the following…
Conflicts of Interest. Nearly all of the authors failed to disclose their conflicts of interest. One of the authors who failed to disclose relevant conflicts was Charles Nemeroff, who was also the editor of the journal (Neuropsychopharmacology) in which the study was published, so he cannot claim ignorance of the rules. In the ARISE-RD study, Nemeroff was also republishing data he had previously published, which is a no-no. Read the linked post for more details.
Authorship. The authorship was switched around as the study went from earlier abstract form to final copy. Especially curious was the addition of key opinion leader Martin Keller to the authorship line. Why switch authors? My take is that the more big names one can slap on a study, the thicker its veneer of academic credibility. If one follows the trail of this study, one would have to believe that Keller designed the study after it was already completed – something is fishy here… Read both linked posts (1 and 2) for background.
Statistical legerdemain was at work. The authors, in an earlier report, declared the measures they would be investigating to assess the efficacy of treatment. Several of these measures were reported incompletely or not at all in the final published version of the paper. This looks a lot like burying negative data. In addition, some of their analyses seemed to yield results that could best be described as magical. Read the linked post for background on the statistical issues.
Change in Findings. I speculated earlier that their finding that risperidone warded off depression to a significantly greater extent than placebo for patients who did not respond at all to initial antidepressant treatment was bogus. Well, the authors just published a brief corrigendum in Neuropsychopharmacology in which they state that
Following the publication of this article, the authors noted that in the abstract and in the next to last paragraph of the results section, a P-value for part of one of the post hoc analyses was incorrectly reported. A significant P-value was reported for both the difference in time to relapse and for relapse rates in a subgroup of patients fully non-responsive to citalopram monotherapy. Although the P-value for time to relapse was correctly reported, the correct P-value for the comparison of relapse rates is not significant (P=0.4; CMH test). This change does not alter the major findings of the study nor any of the conclusions of the report. We appreciate the assistance of a diligent reader in identifying this error.
First off, since I noted in a prior post that their original test looked suspiciously wrong, I suppose that I may have been the diligent reader. If so, you’re kindly welcome. If it was someone else who brought it to their attention, then thanks for doing so.
What they are basically saying, to the statistically uninitiated, is that they reported that risperidone appeared to be effective for a group of people but that, in fact, their analysis was wrong. The analysis, done correctly, shows that risperidone was not effective in preventing the return of depression in persons who…
(a) initially showed no response to antidepressant treatment, and
(b) whose depression improved while taking risperidone as an add-on treatment and then
(c) took risperdone for six months
…in comparison with people who were switched to a placebo after showing improvement in symptoms (b). In other words, risperidone did not prevent relapse into depression.
In the abstract of their paper, it is stated that
Open-label risperidone augmentation substantially enhanced response in treatment-resistant patients.
Later in their paper, it is stated that
Our secondary analysis revealed that patients who were least responsive to citalopram monotherapy may be those most likely to benefit from continuation therapy with risperidone.
Great – except that this is the result they just retracted. In other words, if you showed no response at all initially to the antidepressant, then whether you were allotted to receive a placebo or Risperdal in the final study phase made no difference; you were equally likely to experience a relapse of depression. So, despite their claim to the contrary, this does, in fact, change one of their major conclusions.
Was a Stork Involved? Where do incorrect findings come from? Two sources, generally. One is from Honest Mistake-Ville. Second is from corporate headquarters. Given the large number of authors on this paper, it seems pretty odd to me that nobody would have caught the error. I have no problem with honest mistakes being made, but given the large number of other issues surrounding authorship (1, 2), failure to disclose conflicts of interest, and statistical/data reporting issues, I’m very suspicious. When you take this latest finding away, look what happens. Here are the main findings from the abstract that compare risperidone to placebo, quoted directly, edited to show the most recent correction…
Median time to relapse was 102 days with risperidone augmentation and 85 days with placebo (NS); relapse rates were 53.3% and 54.6%, respectively. In a post-hoc analysis of patients fully nonresponsive to citalopram monotherapy, median time to relapse was 97 days with risperidone augmentation and 56 with placebo (p=0.05); relapse rates were 56.1% and 64.1%, respectively
So risperidone wins on only one of four analyses in comparison to placebo. And it is the weakest analysis of the bunch, one that looks at only a subgroup of the participants, and finds that you get a little more time, on average, before you relapse, but you still have essentially the same likelihood of becoming depressed as if you had taken placebo.
When the study was published, press releases were issued that attested to the drug’s efficacy in helping patients with treatment-resistant depression. Now that the second correction has been made to the paper (the first was related to not disclosing relevant conflicts of interest), there will be no press releases correcting the earlier, overly optimistic press releases. Many physicians have likely received a copy of this study in their mailboxes, but I am certain they will not receive a follow-up notice to inform them that the results were incorrect.
This reminds me of another post that described similar problems occurring throughout the so-called scientific investigation process.
The ARISE-RD study is now officially nominated for a Golden Goblet Award. Not sure which authors merit individual nomination, though both Nemeroff (1, 2) and Keller (1, 2) have appeared multiple times on this site regarding other issues.