Friday, December 28, 2007
Sunday, December 23, 2007
What strikes me in these cases is just how little progress we are making. I've been following this stuff for the last 12 years or so, and I see a lot of exposés -- but not a lot of substantial changes that result from those exposés.
For example, if you look back to 2000-2001, you'll see that David Willman -- a reporter for the Los Angeles Times -- won the Pulitzer prize for a series of articles about corruption in the pharmaceutical industry. His articles are first-rate and are still worth reading today:
But that was seven years ago. Are we in a better position today? Maybe I'm being overly harsh, but I just don't see a lot of progress made. Big Pharma has corrupted medicine -- and especially psychiatry -- and now has its sights set on psychologists.
Friday, December 21, 2007
It now appears that there have been at least three unpublished studies regarding the health effects of Merck/Schering Plough's anticholesterol drug Zetia that point to the drug causing liver problems. Read the full article at the New York Times. Only time and a little sunshine on these studies will reveal whether this is a big story, but it is important to note that this is not particularly surprising -- on this modest blog, I have documented several incidents of data pointing to poor efficacy and/or drug risks being buried (1, 2, 3, 4, 5, 6 are just a few examples). Many other blogs, newspapers, and other sources have also documented such problems. Hiding data is an everyday occurrence. For whatever new medication is approved, the public dissemination of risks and benefits are managed by the sponsoring company and what would be the company's motivation to provide data that paint a scary picture of their new drug?
Thursday, December 20, 2007
So how common is social phobia? Some varying answers:
1. Is it 7% at any one point in time and 12% over a person’s lifetime?
2. Is it 2% at any one point in time and 6.65% over a person’s lifetime?
3. Is it 1% at any one point in time and 2% over a person’s lifetime?
These estimates are all derived from peer-reviewed epidemiological studies on the topic and it is clear that they vary greatly. Let’s think about social anxiety for a moment…
Social phobia/social anxiety disorder appeared on the mental health scene with a vengeance about a decade ago thanks in large part to a wonderful “educational” campaign by Cohn & Wolfe, a PR firm hired by SmithKlineBeecham to spread the word about this allegedly underrecognized and undertreated condition that was devastating the lives of untold tens of millions across the globe (1, 2, 3).
The 12% lifetime prevalence figure is oft-cited, but it is important to consider that credible evidence has also placed the figure as low as about 2%. Yes, I am aware that the 12% figure is from the
Perhaps someone with more energy can look through these papers (as well as the many other similar epidemiological studies that have been conducted) and take a stab at why the estimates vary so greatly. Might it have something to do with where we set the cutoff? Might it be that the more we label mere shyness as pathology, the higher our rates of social anxiety disorder? Seems that we might want to consider whether a disorder actually causes significant impairment before we call it a disorder, eh?
Social phobia is often listed as the third most common mental disorder (4, 5), but it seems we had better start asking more questions and show more skepticism before blindly accepting that this condition is running rampant.
Friday, December 14, 2007
In particular, check out the following on bipolar disorder, which must be spreading like wildfire these days:
- David Healy and Joanna LeNoury have a new paper on the influx of bipolar disorder cases. Consider it required reading. Key opinion leaders, Big Pharma, astroturf patient support groups, Brandon and the Bipolar Bear, and more. Read it now. Furious Seasons has some choice excerpts
- Furious Seasons has a whale of a post on living with "bipolar disorder." As a very bright and thoughtful man who has been diagnosed with bipolar for decades, and has lived through many an interesting experience, his discussion of bipolar is quite timely and fits nicely into the present mania of diagnosing bipolar every time somebody does not respond well to antidepressants.
- The name of the post says it all: Is early-onset bipolar disorder simply normal childhood? Read it at Psych Central. I can't resist taking one choice quote from the post (quote from psychologist John Rosemond):
- In their book and in the May 2007 issue of their newsletter, available through their website, the Papoloses recommend against using the word “no” with a bipolar child “because it will trigger a meltdown.” When they were toddlers, my children often suffered wild seizures at the sound of “no.”
The Scientific Misconduct blog has a post on the conflict between integrity and money, which somehow just keeps rearing its head on this site and others.
Mind Hacks notes an example of poor journalism regarding an alleged cure for Alzheimer's.
Peter Rost, ever the excellent self-promoter (meant as a compliment), has a website promoting his expertise as a pharmaceutical marketing consultant and expert witness. After tracking his work for a while, I am convinced -- I'd certainly hire him.
The Carlat Psychiatry Blog is just on-fire all around. No need to single out a particular post.
Pharmalot points out that Wyeth just got slapped by the FDA for a highly misleading ad about Effexor. Read the FDA letter -- this ad is well beyond a little bit misleading.
Thursday, December 13, 2007
Here's the rub. Dr. Charles Nemeroff is the presenter for this continuing medical education activity entitled Add On Atypical Antipsychotics Efficacious in Short Term for Unipolar Depression. This post concerns slides 5, 6, and 9, which reference the aforementioned ARISE-RD study, which examined the use of risperidone as an add-on to citalopram (Celexa) in treating depression. The full presentation is available for your examination.
Slide 6 reads in part:
- Global Impressions of Sexual Functioning scores improved significantly in men and women (p < .02) with RIS augmentation.
- RIS may ameliorate sexual dysfunction associated with SSRIs.
Slide 9 reads in part:
- Augmentation options for treatment-refractory depression include adjunctive atypical antipsychotics.
-Controlled studies: short term efficacy with OLZ, ARI, RIS [risperidone]
In fact, here is what the lead author (Mark Rapaport) of the ARISE-RD study had to say about its results in a letter to the editor (currently in press):
The paper repeatedly states in Abstract, Methods and in Discussion that continuation of risperidone augmentation therapy was not more beneficial than placebo, and hence the working hypothesis was disproven...Compare and contrast: Nemeroff's presentation indicates that the study was a controlled trial showing that risperidone was more effective than placebo. The lead author admits that the study was a "negative finding" and that risperidone was "not more beneficial than placebo."
I would like to thank the reviewers and the editors of Neuropsychopharmacology for having the courage to allow us to publish this negative finding.
To summarize, Nemeroff did the following:
- Claimed that a peer-reviewed study showed risperidone improved sexual functioning, when the effects of treatment on sexual functioning were not even mentioned in the paper.
- Claimed that the study showed risperidone to demonstrate efficacy over placebo, which it in fact did not.
Wednesday, December 12, 2007
Read the article based on the committee's findings here. It's very good reading. They make a long list of recommendations, 24 to be exact, including highlights such as...
- External funds (i.e., drug money) should not be a part of APA's core budget
- Exhibitors at APA conventions should not pimp their wares in bizarre manners (see the American Psychiatric Association convention for examples of marketing gone awry)
- APA should consider not allowing continuing education credits for industry-sponsored courses
- No drug pens or other branded material on display where psychologists work
- Psychologists should not accept gifts from corporations (including meals)
APA will not heed the recommendations of their task force, at least not many of the important ones. Should psychologists attain prescription privileges in more states over the next 10 or 2o years, drug companies will throw their money at psychologists in the following ways (and then some)...
- Gifts, small and large
- Sponsoring continuing marketing, er, education
- Funding APA directly
- "Unrestricted" research grants
- Psychologist-to-psychologist marketing. Paying psychologists to "educate" other psychologists about medication.
- Having psychologists rubber stamp their name on ghostwritten, pro-industry "research" pieces
Prediction 2. APA and the various state psychological associations will not restrict CE credits based on who funds them. There is already grumbling about a lot of what passes for continuing education of psychologists being nothing more than fluff, puffery, or a feel-good session. That being the case, there will be many who will be drawn to the allure (however fake it may be) of science surrounding drug company-sponsored continuing education. Of course, some psychologists already receive pharma-funded continuing ed, but there is much room for drug companies to move into "educating" psychologists about their products.
Prediction 3. Psychologists will become more involved in drug research. Some people have stated, I believe quite naively, that if psychologists become more involved in drug research, they will clean it up. Um, what makes psychologists more capable of cleaning up the dirty research system (1, 2) than the current body of medical researchers. Seems like a rather arrogant belief to think that psychologists will clean up a system of biased clinical research just because they are psychologists. Psychologists will also be involved in signing their names onto puff pro-drug pieces.
I could be wrong. APA could take a stand. But APA has dedicated many resources to getting psychologists on-board as prescribers. Just read through APA press releases and see their enthusiasm (1, 2). So don't make a bet on it. For psychology to make the moves suggested by the Task Force, there will have to be a very vocal group of psychologists who constantly harrangue the leadership of APA into taking a firm stand. I'd suggest they start up a blog, get in the ears of reporters, and do anything they can to draw attention to their very legitimate concerns. I realize that prescription privileges for psychologists and being corrupted by pharmaceutical marketing are not necessarily one and the same. Only time will tell if psychology will be more strongly influenced by science or by marketing.
Friday, December 07, 2007
I have been intrigued with the Hooked blog from Dr. Howard Brody. I had the good fortune of running across the site a few months ago, but I have been doing a poor job of reading it regularly until recently.
Read this post about "intellectual bias" and flacking for Pharma. Also check out this winner of a post regarding academic physicians trying to "ride the tiger" of Big Pharma while still maintaining strong ethical boundaries.
It is about to be added to my blogroll. Good work, Dr. Brody!
Thursday, December 06, 2007
Dr. Stuart Montgomery, Imperial College School of Medicine, University of London and author of the [depression] monotherapy study, said: These study results are remarkable -- all of the doses of SEROQUEL XR examined provided improvements in MDD and GAD symptoms. Results from further studies that are still ongoing will add to our understanding of SEROQUEL XR in these conditions.What is remarkable is not that 'Quell had a slight advantage over placebo but that an "independent" academic psychiatrist is willing to pimp Seroquel so blatantly. It would appear that Dr. Montgomery is aware of who is putting butter on his bread. Finding a modest to perhaps moderate advantage for a drug over a placebo in treating depression and/or anxiety is far from remarkable, given that there are dozens of drugs and psychotherapies that have demonstrated similar or better efficacy. Then again, it is remarkable that Seroquel is related to increased risk of diabetes (1, 2, 3, 4), which is likely not the case for competing depression treatments. Of course, since the movement has now started to treat depression with antipsychotics (1, 2), perhaps we will see many people with depression moving toward an increased risk of diabetes. It might be worth noting that on the MADRS, which was the measure of depression reported in the press release, one question is regarding eating -- the more you eat, the better your score. So an antipsychotic linked to weight gain is set to do well in that those who eat a lot will score better on this item, which is then taken as a sign that they are less depressed.
I've been tracking the Seroquel for everything bandwagon for some time now (1, 2, 3, 4) and I can't wait to see where this is headed next.
Part 2. The Academic Salesperson. As Krusty the Klown might say, "I heartily endorse this event and/or product"...
Here are some other Stuart Montgomery quotes from press releases:
"Agomelatine is an interesting and potentially very valuable antidepressant that is effective in both moderate and severe depression", says Professor Stuart Montgomery from the Imperial College School of Medicine in London. "The new agent has a unique mode of action, improves sleep without affecting daytime alertness and its efficacy is not compromised by sexual side effects, tolerability problems or discontinuation symptoms.Escitalopram (Lexapro)
"These results are important because they show we have a treatment at our disposal which is effective without sacrificing the good side-effect profile obviously preferred by patients," commented study author Professor Stuart A. Montgomery, Imperial College School of Medicine, London, United Kingdom. "The ideal combination for any first line treatment is good efficacy and good tolerability - this study shows that escitalopram has all the potency of the non selective SNRIs combined with the good tolerability of the conventional SSRIs," he concluded.Lexapro (again)
“This consistent advantage really came out as a surprise,” marvelled Prof Montgomery. “These are shocking data that no one was expecting”. He added: “At that stage we already knew that there was something special about the drug”.One more piece on Dr. Montgomery may be of interest to readers (via The Guardian ):
Finally, Prof Montgomery mentioned results coming from further studies that he referred to as “staggering” – these were decisive in establishing Lexapro’s long term effectiveness in treating both GAD and SAD.
A leading figure in the world of psychiatry gave a pharmaceutical company advice on how to get its new drug approved while he was sitting on the committee which was deciding the licence application.Read the whole article and see what you think.
An internal memorandum from Pfizer, the world's largest drug company, says Stuart Montgomery would be happy to become a paid adviser and declare an interest to the Committee on the Safety of Medicines (CSM) once the drug, an antidepressant to rival Prozac, had been through the licensing process.
When Dr. Montgomery or other key opinion leaders with similar conflicts of interest speak, we are supposed to view them as independent expert researchers whose enthusiastic product endorsements are based purely based on science. The manner in which every drug company trot out eager academic spokespeople is a sign that academic medicine has become rotten to the core.
Tuesday, December 04, 2007
I couldn’t talk about it because it was proprietary.In other words, GSK owned the data, so he could not mention the negative information unless he had their permission. In my humble opinion, this gives the impression of Emslie not being a scientist, but rather a sock puppet for the drug industry. Back to the X065 study. Why wouldn't Emslie, lead author of the study insist that the suicide attempt data be included in the X065 study publication? NIMH theoretically owned the data, as they funded the study, so why wouldn't they make sure to publish such important information? It's one thing to exclude data from two patients on Prozac who had, say, treatment-emergent flatulence, but it is quite another to exclude data on a much more troubling treatment-emergent event such as suicide attempts.
I'm not the first to notice this issue. It was previously mentioned by Jonathan Leo in a letter to the editor in Psychiatric Times. When I see this incidence of hiding suicide data and I think about NIMH's poor attempts at journalism regarding the SSRI-suicide issue, it raises my suspicions regarding whose agenda is being served at the agency.
Whose Opinion Matters? Also of note, yet frequently not mentioned by the SSRI's are terrific for kids crowd is that depression measures completed by the children and adolescents in this study showed no significant improvement versus a placebo. This has nearly always been the case in studies examining SSRIs for child and adolescent depression. Measures rated by clinicians have occasionally found an advantage for SSRIs in youth depression, yet almost never have such effects extended to the youths' perceptions of their depression. Call me crazy, but if we're going to say a treatment is effective for depression, yet the people who are depressed say it does not relieve their depression, shouldn't that raise some suspicion? The authors, however, try to squirm out of this difficult position with the following sentences:
Furthermore, self-reported depressive symptom measurements also showed improvement in both groups, but the between-group differences were not significant. However, given the wide variability of initial child self-reports, these findings are difficult to interpret.Oh, I get it. When a significant advantage is shown on a measure rated by clinicians, it is not difficult to interpret, but when a drug is not shown more effective than a placebo, well, who knows what that might mean? A very nice attempt at obfuscation on the part of the authors. You'd think this was a drug company funded study -- it hid negative data and obfuscated negative findings -- yet the good old NIMH, with our tax dollars, was behind this work.
But worry not, my friends, the study X065 conclusion, as published in the flagship journal of psychiatry (Archives of General Psychiatry) reads as follows:
These data indicate that fluoxetine 20 mg/d is safe and effective in children and adolescents.Back to Graham Emslie. He admits to helping to keep GSK's secret that Paxil was not an effective treatment for youth depression and he was the lead investigator on a study in which two suicide attempts appear to have been deep-sixed. His interpretations of research regarding Effexor for (you guessed it) youth depression also seem overly positive, and it seems that he helped to keep data on Effexor for youth depression buried for several years. But, worry not, according to his website, he is "is known internationally for his work in the treatment of pediatric depression." Indeed. I'm comforted to know that we can expect this high caliber of work from high-ranking academic psychiatrists.
Thursday, November 29, 2007
Regarding your comment that "...it takes time, effort, and using one's training in mental health," that just speaks to how the mental health profession (particularly psychiatry), despite its stated interest in improving the lives of patients, is too focused on the immediate effect on a patient's behavior than in long-term outcomes. As a psychiatrist, I am sometimes appalled at how my colleagues focus on the short-term benefit afforded by an unproven medication and ignore any consideration of the long-term side effects or, more importantly, other ways that the patient may learn to change his/her behavior for the better.Amen, brother.
We have indeed been hijacked by drugs. I wouldn't entirely blame the drug companies, though, because psychiatrists have every right not to use meds in this way. It's just that our profession's knee-jerk reaction to a psychiatric symptom is to medicate, and not to help a person through his/her struggle in a more compassionate and productive way.
Monday, November 26, 2007
Great job by Dr. Daniel Carlat. Read his piece in the New York Times Magazine regarding his stint as Dr. Drug Rep, when he stumped for Wyeth's antidepressant Effexor for a cool $30k in one year. Not bad work if you can get it. It is a fascinating account of a common industry practice -- train doctors to give speeches to other doctors in which certain treatment is pushed hard. Overplay efficacy and downplay negative effects. Drug companies state, with a straight face, that this is "educating" physicians -- buying them fancy dinners and having one of their colleagues read company-produced marketing slides on their product.
Carlat's blog is also a great source of information.
The most important thing that could come from these suits in the long run is not the money that various drug companies may have to shell out in fines. No, the important piece is the information, the internal documents that I am nearly certain document numerous instances demonstrating bad science, covering up negative data, and detailing ludicrous marketing campaigns. Check out the documents on Zyprexa over at Furious Seasons and you'll get a taste for what I mean. I've written about them on a few occasions (1, 2, 3) as have others, with one monster post from Furious Seasons serving as an excellent example. If such documents from all companies who have engaged in such ethically dubious practices were to become public information, the PR hit would be enormous. Hell, the media may even wake up and run numerous stories on this issue. Imagine: 60 Minutes, Panorama, NPR, Frontline, Now, and other news programs hitting this one hard on multiple occasions. And the complicity of academic psychiatry makes the story yet more fascinating.
As I mentioned recently:
Without academics pimping these treatments well beyond what was scientifically justifiable, these medications would never have achieved such huge success, but now this rather dangerous group of medicines is used for virtually every psychiatric disorder under the sun. These uses include "bipolar disorder" in infants, ADHD, and dementia. Let's put the most vulnerable individuals on the riskiest treatments despite no clear evidence that they work particularly well. There is indeed some evidence for the efficacy of these medications in the short-term treatment of schizophrenia and bipolar disorder, and in a small number of trials, even some long-term evidence of efficacy. But their indiscriminant use across the board for virtually every condition brings great shame upon psychiatry as a profession, on Big Pharma for its slick marketing strategies (1, 2), and most especially upon academic psychiatry for its morally bankrupt role as a group of salespeople who have misrepresented scientific findings to help promote drugs (1, 2, 3, 4, 5, 6, 7, 8).But such hopes may well be fleeting. The various offending companies may just decide to settle these cases, which nearly always means that they get to keep their dirty laundry private. Here is a sad possibility mentioned by Furious Seasons:
Risperdal goes off patent in about one month--except for some extra and short-lived pediatric indications--so I'm not sure that Janssen/J&J has a huge incentive to fight Arkansas and the other states that are suing it in order to protect what is soon to be a generic product. It's likely much cheaper for the companies to settle the case (liability insurance will cover much of the cost), write an agreement in which they admit no fault and manage to deep six any documents and other evidence of bad behavior, and move onto Invega.Unfortunately, his prognostication is likely correct. Of course, if some insider at AstraZeneca, Janssen, Bristol-Myers Squibb, or Lilly (or Pfizer --though it seems Geodon has not received much legal attention) decides to leak aforementioned documents, then we're on to something. Consider this an open call to the insiders at said companies. Email me or Peter Rost or Philip Dawdy or Ed Silverman or Jack Friday (Pharmagossip). We're all currently accepting insider documents regarding such matters...
Zyprexa goes off-patent in 2011 and Seroquel is off-patent the same year as well (not sure about patents on Seroquel XR), so one wonders how much incentive those companies have to fight the state suits, or whether they will just settle the cases and move onto whatever is next for them.
Maybe I am a bit too cynical, but it wouldn't shock me if that's how things played out. After all, Lilly has already settled about $1.3 billion in lawsuits over Zyprexa. Why stop now?
Wednesday, November 21, 2007
As documented at Furious Seasons, the state of Arkansas has leveled some very serious allegations at Johnson & Johnson, manufacturer of Risperdal via its subsidiary Janssen. Furious Seasons was kind enough to post a copy of the lawsuit. Here's a partial listing of the allegations:
- J & J hid the extrapyramidal side effects of the medication through conducting scientifically bogus studies which covered up the risks of Risperdal
- J & J marketed Risperdal off-label for such conditions as ADHD, depression, anxiety, and aggression associated with dementia
- J & J falsely represented Risperdal as cheaper and more effective than older antipsychotics
- J & J did not represent their own knowledge that Risperdal is associated with weight gain
- J & J offered kickbacks to physicians to prescribe Risperdal for "non-medically necessary" uses
- Zyprexa was clearly marketed off-label for various conditions (1, 2, 3)
- It seems that Lilly was involved in hiding the risks associated with Zyprexa (1, 2)
- Bristol-Myers Squibb just settled a large lawsuit, partially regarding claims that it promoted Abilify off-label
- Take a look at a couple studies (1, 2) that were designed to encourage off-label prescription of antipsychotics as well as a "scientific review" of relevant literature on antipsychotic off-label use.
- And of course, there are several states (I've lost count of exactly how many) that are suing Lilly for its promotion of Zyprexa and its alleged concealment of risks associated with the drug.
Monday, November 19, 2007
Here's a shocking snippet from the article:
Testifying at a congressional hearing, Dr. David Graham, a prominent FDA drug safety expert, was asked if he had issues with any medications already on the market.
"I would pay careful attention to antipsychotic medications. ... The problem with these drugs are that we know that they are being used extensively off-label in nursing homes to sedate elderly patients with dementia and other types of disorders. ...
"But the fact is, is that it increases mortality perhaps by 100 percent. It doubles mortality. So I did a back-of-the-envelope calculation on this and you have probably got 15,000 elderly people in nursing homes dying each year from the off-label use of antipsychotic medications. ...
"With every pill that gets dispensed in a nursing home, the drug company is laughing all the way to the bank."
Granted, this is a back of the envelope calculation that may be inaccurate. But nobody disputes that these medications are linked to increased odds of dying for the elderly, and someone needs to get the science writers to read the research (cited above) that these medications don't work very well. It is hard to think of a bigger scam -- works as well as a sugar pill but increases your odds of dying. The public outrage won't start until people in the media gets rid of headlines that read:
Again, the data do not support that these drugs are much more helpful than a placebo, making the headline misleading. Please incorporate the actual research findings regarding atypical antipsychotics into the story and let's try again...
Dementia relief, with a huge side effect: The off-label use of some drugs is helping elderly patients, but may be killing thousands.
Newer antipsychotic medications offer little to no benefit over placebo, and are killing thousands of elderly patients.Doctors talk about the risk-benefit ratio with various treatments, which makes sense. When a class of drugs seems to have little benefit and a high cost, both financially and in terms of side effects (including death), shouldn't we try something else? The media create the outrage and then the change occurs. What about the academic experts who have participated in studying these drugs? They should be the most aware of the small at best benefits and the high side effect burden. Yet instead, some of them are churning out tripe such as the latest study pimping Abilify for dementia. If academics are asleep at the wheel, then it is up to the media to start the outrage. I generally like this St. Pete Times article, but if even the most skeptical writers are still claiming the drugs work, it is not a good sign.
But What Else Can Be Done? It is true that elderly patients with dementia can be difficult to manage and that giving them a chemical restraint such as Zyprexa may slow a person down. But how about the following crazy idea, again taken from the St. Pete Times piece...
I see, so you can do something else besides dole out Zyprexa and its siblings like candy. But it takes time, effort, and using one's training in mental health. You'd think that psychologists and/or other mental health professionals could easily be hired as consultants to devise such plans. Of course, it is a lot easier to just attempt to sedate chemically over and over again. But are we supposed to do what is easy, even if it is not in the best interest of the patient?
There are other options, but they take time, money and effort.
At the Cobble Hill Health Center in Brooklyn, Dr. Louis Mudannayake decided to try to change the thinking at his 400-bed nursing home.
Ignoring naysayers and the doomsday predictions of senior nurses, 18 months ago he put together a team of pharmacists, social workers and recreational therapists to review every atypical prescription.
If a new roommate caused agitation, room assignments were changed. If a new aide was hit while dressing a patient, the aide was given special training on that patient's preferences and routine.
Though the nursing home's resources were initially stretched, Mudannayake said the quality of patients' lives improved. "Ultimately, I'm convinced financial expenditures will be diminished, because it's easier to manage a patient who is calm," he said.
Atypical use at Cobble Hill has been cut from about 25 percent of patients to about 10 percent, he said. Almost 40 percent of patients were taken off the drugs completely; 75 percent of those still on the drugs have had their dosage reduced.
"We instituted a cultural change. That's what's required to bring the numbers down," said Mudannayake, who said psychiatric hospitalizations did not increase as medication dropped.
"You'll always have doctors say there's nothing else to use but atypicals, and I agree there are a small minority of patients where you need to use these drugs. But not in the numbers we are using them."
Shame, Shame, Shame. In my humble opinion, this phase atypical antipsychotic mania will be associated with gigantic shame on the psychiatric profession. Just wait a few years. The amazing part is how few "leading lights" within the field have stepped up to the plate and pointed out the problems associated with these medications. When they were first released, all sorts of "key opinion leaders" happily pushed them as a huge improvement over older antipsychotics in terms of treating schizophrenia. Turns out that was mostly hype. Then the atypicals for bipolar rush hit full force, again with the help of "key opinion leaders."
Without academics pimping these treatments well beyond what was scientifically justifiable, these medications would never have achieved such huge success, but now this rather dangerous group of medicines is used for virtually every psychiatric disorder under the sun. These uses include "bipolar disorder" in infants, ADHD, and dementia. Let's put the most vulnerable individuals on the riskiest treatments despite no clear evidence that they work particularly well. There is indeed some evidence for the efficacy of these medications in the short-term treatment of schizophrenia and bipolar disorder, and in a small number of trials, even some long-term evidence of efficacy. But their indiscriminant use across the board for virtually every condition brings great shame upon psychiatry as a profession, on Big Pharma for its slick marketing strategies (1, 2), and most especially upon academic psychiatry for its morally bankrupt role as a group of salespeople who have misrepresented scientific findings to help promote drugs (1, 2, 3, 4, 5, 6, 7, 8).
Update: I forgot to publicly tip my hat to Furious Seasons, where I first saw the link to St. Pete Times piece. Philip Dawdy also added some spot-on commentary, as is the norm at Furious Seasons.
So who is this guy? Let's find out.
License. A link to his Oklahoma physician profile can be seen here. Remember, two cases of herpes transmitted to patients = three months suspension of Oklahoma medical license. I find it more than a bit confusing that his Nevada license is still active. It would appear that in the state which houses Sin City, one can have all the sex with patients that one wants and not be subject to disciplinary action. So give herpes to two patients through sex, and the consequences are having a license suspended for three months in one state and no consequences in another state. Very interesting. Perhaps his transgressions occurred in Oklahoma, so Nevada figures it is out of their jurisdiction. But, if a doctor has sex with patients in one state, I'm going to go out on a limb here and say that his license should be suspended (or, maybe, just maybe, permanently rescinded) in all states.
Imprisonment of Study Participants. That's what the FDA found in their investigation of Dr. Linden. One woman wished to participate in a study in Linden's inpatient facility. She agreed to participate in a study and then changed her mind. She was not allowed to discontinue the study for four days, and only after the involvement of an attorney. What part of "you can discontinue the study at any time" did Linden fail to comprehend?
Patients Without Consent. Two patients did not sign informed consent forms to participate in studies. This is a gigantic no-no. Participants absolutely must provide consent to participate in studies, particularly when they involve taking medications. On six additional occasions, participants signed the incorrect consent form.
Unlicensed Hospital Stays. In one study, patients were placed in an unlicensed hospital for at least two weeks. The study protocol called for patients to be placed in a licensed hospital. Oops.
Drug Dosing. Patients were given incorrect doses of study medication on multiple occasions in one study. I'll quote the FDA report regarding drug dosing in another study:
The amount of study drugs dispensed to, and returned by, subjects 002, 005, 008, 015, and 020 cannot be determined.Adverse Events? What Adverse Events? Two participants who were placed under emergency inpatient detention during their participation in studies -- their extreme mental instability was not reported as a serious adverse event. Seem to me like it would be rather important to report all serious adverse events that occur in a study. Unless, of course, one was either sloppy or wanted to bury negative data.
And there is more, believe it or not. The FDA investigation only examined two trials. All of the above problems and more based on two studies. Impressive. And then he collects data which is the foundation of the "science" that supports various medications.
Who Would Hire This Guy? Well, let's see. According to his research webpage, he has done clinical trial research for the following:
- Bristol-Myers Squibb
- Boehringer Ingelheim
- Eli Lilly
- Johnson & Johnson
- I 3 Research
- INC Research
- PPD Development
- Rho Inc.
- Bipolar Disorder
...is also recognized as a leader in his community and he is a member of several Speakers Bureaus including: Wyeth Pharmaceuticals, Pfizer Pharmaceuticals, Bristol Myers Squibb and others.Time For Bad Jokes. I can't help myself. Here are a couple of quotes from his site.
Our P.I. is Actively Involved in TrialsYes, he has a very hand-on approach. Wink-wink. Also feel free to insert your own punchline. One more...
David E. Linden, M.D., our Principal Investigator, is actively involved in the research we conduct. As a result, you directly benefit from his years of experience and expertise.
Dr. Linden has an extensive and prestigious portfolio in Clinical Psychiatry.Again, I'll leave the punchline to you. It would appear that drug companies have rather lax standards regarding their investigators, would it not? It would seem that imprisoning your patients, having sex with them, playing all sorts of sloppy with data, and other misdeeds would disqualify a person from engaging in clinical trial research. I understand that there will be occasional data errors in research; one can never rule out human error and I accept that. But this is well past slight mistakes due to occasionally poor oversight. And is this what we would like our "science" to based on?
I've written about a similar situation (minus the sex/herpes part) in an earlier post. After reading this post and my prior post, as well as the links contained in both posts, does it not make one wonder the extent to which psychiatric drug research is based on sloppy and/or fraudulent data? I'm not throwing out a number here. I really have no idea. Perhaps these are rare occurrences. But given that FDA oversight of research is close to nonexistent, much of what happens in research is essentially done on the honor system. Unfortunately, it appears that there is enough dishonor in the current honor system to strongly suggest that we need a lot more oversight.
Thursday, November 15, 2007
Two upcoming stories will both titillate and enrage.
1) How a certain company hid risks of a medication. And I have the documentation to prove it. Of course, "independent" academics make a special appearance.
2) A researcher with an impressive record. It is unlikely that any researcher has given sexually transmitted diseases to more patients than this person. Holding patients captive? Yes. Running clinical trial sites that provide strange data? Yes. And more.
All coming, hopefully soon, from your humble correspondent. Readers, please continue to send tips.
In the meantime, several blogs have been absolutely ablaze lately, including the following. Do yourself a favor and check them out.
Drugs like Vioxx, Oxycontin and possibly Avandia have all recently been launched onto an unsuspecting public in the quest for billion dollar profits, and have gone on to harm tens of thousands, even though there is evidence to suggest that the companies behind them had a pretty good inkling of the potentially lethal hazards and side-effects from data they chose to selectively ignore during trials.Slam dunk. I'd also add the atypical antipsychotics into the mix as well. Take a look at recent data regarding their performance in dementia, for example (1, 2). Shockingly poor. And who is accountable when these medications are marketed to bury risks and make false statements regarding a drug's efficacy? Apparently, nobody. Sure, a fine may be levied, but that's just a drop in the bucket. You don't think accountants and lawyers are busy figuring out, as I type, how much money can be lost in lawsuits versus how much can be made from B.S. marketing campaigns that overstate benefits and hide risks? It's all a risk-benefit calculation: How much financial risk do we take by hiding data versus how much can we benefit from aggressively marketing the product?
People have needlessly suffered or died, at best because of complacency and at worst because of corporate greed, and as a result public trust in the pharmaceutical industry has never been lower. And because of public mistrust, the regulatory environment has become so tight that it is now much harder to launch new medicines of any sort – a situation which is a constant cause of whining by the pharma CEOs who are, ironically, ultimately responsible for creating the hostile regulatory climate in the first place!
Pharma industry wonks talk about the “risk/benefit” of new drugs, and yet it seems that these days it’s the public who take the risks and the CEOs and shareholders who get the most benefit.
Executives hide behind the line that they cannot be aware of every little thing that goes on their companies and therefore cannot be responsible for any illegal actions of their underlings. Sorry, guys, but just what do you get paid six, seven or even eight figure "compensation packages" for? By and large, it certainly isn’t for your personalities or good looks, is it?
Howard Udell is certainly now trying to suggest that, well, sure he pleaded guilty, but only because he was the boss and not because he was actually personally responsible for any wrong-doing. Sorry, pal, that may well be true but I think the buck stops with you. If you or your fellow execs weren’t aware of any wrong-doing THEN YOU DAMN WELL SHOULD HAVE BEEN.Mr. Udell is still employed in his capacity as Chief Counsel for Purdue, Ms. Skolek points out to me.
Monday, November 12, 2007
Efficacy: Here’s what the authors said…
Apripiprazole 10 mg/day was efficacious, and safe for psychosis associated with AD, significantly improving psychotic symptoms, agitation, and clinical global impression.
Quickie stats lesson. In determining if there is a “statistically significant difference” between two groups, a large factor is the size of the sample. Just because a difference is “statistically significant” does not imply that the difference actually means anything of value. With a large sample size (as was seen in the present study), very small effects can become “statistically significant.”
Next, let's discuss the size of these treatment effects -- how helpful was Abilify? Mean change on the Neuopsychiatric Inventory – Nursing Home Version was 17.6 points for the 10 mg/day Abilify group and 13.0 points for the placebo group. With the knowledge of the mean change and the standard deviations from both groups, one can easily calculate the effect size, which indicates the magnitude of the treatment effect (i.e., did people get a little better or a lot better?). The effect size (using Cohen’s d) was .14. The general guideline is that d = .20 is a small effect, so less than small – I guess you could call it miniscule.
How about other measures used in the study? Here are a few...
- Neuropsychiatric Inventory – Nursing Home Version Psychosis subscale: Effect size = .19
- Clinical Global Impressions – Severity: Effect size = .12
- Clinical Global Impressions – Improvement: Effect size = .10
- Brief Psychiatric Rating Scale: Effect size = .15
- Cohen-Mansfield Agitation Inventory: Effect size = .17
No matter how you slice it, the effects were all very small. Let’s also do a common sense test. The Clinical Global Impressions – Improvement Scale asks one question. The wording may vary slightly across studies, but one example is:
Rate total improvement whether or not in your judgment it is due entirely to drug treatment. Compared to his/her condition at admission to the project, how much has he/she changed?
In the current Abilify study, the average advantage for people taking Abilify 10 mg/day versus placebo was 0.3 points. There are seven points on the rating scale. For example, at one point on the rating scale is minimally improved and the next point is moderately improved. So the average patient on Abilify was 0.3 points closer to moderately improved compared to minimally improved relative to someone on a placebo. Can you say ooooh, big deal?
Anyone who has taken a basic course in statistics should be either laughing or crying (your choice) at this point. What makes this particularly egregious is that the first two authors are academic researchers who absolutely must have received this lesson dozens of times during their research training, so there is no pleading ignorance on their part.
Statistical Significance: Okay, maybe this is a smaller point. But when I plug their numbers (means, SD, N) into a t-test, I find that some of the differences they labeled as statistically significant are no longer statistically significant. Yes, they used a different statistic, which was apparently useful to them, but I thought I’d at least mention that if someone chose to use a different analysis, the data may have turned out as not statistically significant. In any case, the benefits of Abilify as shown in this study are minimal at best.
Safety: Okay, so Abilify does not work very well, but at least it won’t kill you, right? 18 people died across the course of the study, including 3% of the placebo group and 7% of the Abilify 10 mg/day group. Cerebrovascular adverse events were reported for four patients in the 10/mg Abilify group and zero people in the placebo group. As has become nearly an essential disclaimer in studies these days, the authors write: “Eighteen deaths occurred during the study, none of which were considered to be related to study medication. [my emphasis]” Of course not. The study is funded by a Bristol-Myers Squibb, and the company and its “independent” academic investigators determine if the drug could have caused any deaths. The fox is policing the henhouse.
Discussion: The best part of any article is the discussion, because it is a marketing exhibit.
The results of this placebo-controlled fixed-dose study indicate that aripiprazole impacts beneficially on psychotic symptoms in institutionalized patients suffering from psychosis associated with AD; this is the first such study to report improvement in both primary and secondary outcome measures in this patient population...
Aripiprazole also produced significant improvement in other aspects of psychological and behavioral symptoms, as evident from changes in secondary outcome scores...
Thus, the results indicate that the use of aripiprazole cannot only alleviate the specific symptoms of psychosis, but can also reduce the overall psychological and behavioral burden of AD...
Interestingly, the 5 and 10 mg/day doses of aripiprazole show robust efficacy to improve the CMAI scores from baseline to endpoint, reinforcing the evidence that atypical antipsychotics are efficacious in the treatment of agitation. [Apparently “robust efficacy” means having a miniscule impact relative to placebo.]
Again, see above commentary about the extremely small extent to which Abilify “impacts beneficially” upon participants in this study.
To the authors’ credit, they mention that
Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo.
Right, kind of like what happened in this study, at least for the patients who took 10 mg of Abilify. I realize it may have been a chance occurrence that the Abilify 10 mg patients died at a higher rate, but when you combine minimal treatment benefit with doubling the risk of death, why the hell would anyone choose to prescribe Abilify based on results from this study?
Believe it or not, there are a couple of other points about the study that I could prattle on about, but I think the point has been made.
Journal Policies: If you wander over to the American Journal of Geriatric Psychiatry’s Instructions for Authors, you can see the following:
Provide measures of effect size liberally. Give cautions when statistical significance has doubtful clinical or practical significance.
What I have done in this post is provide the measures of effect size since the authors did not provide a single measure of effect size. Not a single one. But wait, if this paper clearly violates one of the main principles listed under “Statistic Guidelines” for the Instructions to Authors, how did it get published? Good question. And that takes me right back to my earlier posts on peer review and how the “experts” who review papers sometimes do so in a slipshod, lazy, biased, and/or incompetent fashion (1, 2, 3, 4). And the editor? Did he even skim this manuscript to see if it conformed to the guidelines of the journal?
So a paper that flouts the journal’s own policies is published, a paper in which statements regarding a product’s efficacy are far overblown. Perhaps drug reps will be disseminating this wonderful piece of science nationwide or even internationally to help get patients onto Abilify because now their marketing is based on "science." Will physicians see through this sort of ruse and laugh the reps out of the office, or will they briefly scan the abstract, conclude the drug is effective, and then whip out their prescription pads? You tell me.Last, but not least, I present a Golden Goblet Award to the academic authors of the study as well as to the coauthors at Bristol-Myers Squibb. Your ability to present teeny treatment effects as "robust" and get away with it is notable. Great work. You deserve a good cut of however many $$$ are added to BMS's coffers from unneeded prescriptions of Abilify for dementia.
Friday, November 09, 2007
The atypical antipsychotics keep taking a beating on this site (1, 2) -- lots of hype for these medications treating, um, everything, yet little supporting data.
Thursday, November 08, 2007
I have pilloried the study published in the American Journal of Psychiatry in September 2007 that purported to show that fewer SSRI prescriptions for kids in the USA was associated with an increase in the youth suicide rate for American youth. I quote from my earlier post below:
Various newspapers and websites dumbly ran with this story using descriptions such as:
Look closely at the above graphs (click to enlarge) from the article. Note that the decrease in SSRI prescriptions from 2003 to 2004 was very slight across the 0-10, 11-14, and 15-19 age groups, which is the timeframe in which suicide rates for those aged 5-19 increased notably. The larger declines in SSRI prescribing for youth occurred from 2004-2005, which happens to be when the suicide rate for those aged 15-24 appears to have decreased from 10.3 per 100,000 (see Table 9; page 28 here) to 9.8 per 100,000 (see Table 7 here). Yes, I know I am comparing data for ages 15-24 to data on ages 5-19, but I think this makes sense when one considers that the suicide rate for those 14 and under is much lower than for those aged 15-24. Actually, grouping suicide data for ages 5-19 makes little sense to me given the vast differences in suicide rate within this age group.
It is important to note that the authors of the paper did not have data from 2005, but there is nothing from the 2003-2004 U.S. SSRI prescription data cited in their paper that even suggests a relationship between decreased SSRI use in youth and an increased suicide rate, as the decrease in prescriptions was minimal. Pay close attention: The authors ran a total of zero statistical analyses to examine the relationship between SSRI prescription rates and suicide rates in the United States. That’s right, zero. So they put up a couple of figures without a single shred of statistical evidence, then claim that declining SSRI prescriptions are associated with an increase in suicide rates. Any peer reviewer who was not drunk or on a high dose of Seroquel should have noticed this gigantic flaw.
Warnings that antidepressants may increase teen suicides appear to have backfired, a new study suggests......and others. Please read my earlier post regarding idiotic media coverage of this article for details.
Suicide rates for preteens and teenagers increased sharply when the Food and Drug Administration slapped a "black box" warning on anti-depressants and doctors started writing fewer prescriptions for young people, according to federal data released Thursday
Enter NIMH: In a story datelined September 19, 2007, Jules Asher wrote a story for the NIMH website. As of today, it is still available. It mentions that
...based on mathematical models using previous years' data, the authors predicted an 18 percent increase in youth suicides between 2003 and 2005.And, as mentioned above, this prediction turned out to be incorrect. Youth suicide rates in 2005 showed little change from 2004. Perhaps the NIMH writing staff could throw that little tidbit of information into an updated version of the article? Earlier in the piece, it is mentioned that
NIMH grantees Robert Gibbons, Ph.D., University of Illinois at Chicago and J. John Mann, M.D., Columbia University, and colleagues, make a case for a possible link between changes in prescription patterns, regulatory warnings and suicide rates in the September, 2007 issue of the American Journal of Psychiatry.Again, note that they did not make much of a case in that the only statistical analysis they presented was from the Netherlands, yet they apparently believe such data generalized to the US as well. And remember that their own graphs contradict their argument and that the 2005 preliminary data on suicides also contradicts their arguments. The reason I am ranting/raving here is because I expect better from an allegedly nonpartisan organization that is dedicated to science. Why publish a story on the NIMH website pushing results from a study that is so full of holes that I could drive a fleet of Mack Trucks through it? Did the NIMH run stories publicizing findings of more credible research showing a link between SSRIs and increased suicide attempts? Nope. Kind of makes one wonder to what extent NIMH is an objective organization dedicated solely to advancing science, doesn't it?
Major hat tip to an anonymous reader who passed along the link to this wonderful article.