Journal Editor Unapologetic Over Paxil/Seroxat Article

Dr. Mina Duncan is the editor of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), which, as she noted on Panorama is very widely read among child and adolescent psychiatrists. So, in this prestigious journal, one would expect high editorial standards.

Let’s go through what happened with study 329, which turned into a publication in JAACAP in July 2001 upon which Dr. Martin Keller (see here) was the lead author. The study was submitted (after the Journal of the American Medical Association had rejected it – good for them) to JAACAP, and Panorama nicely documented a couple of the reviewer comments. They included

Overall, results do not clearly indicate efficacy – authors need to clearly note this.

The relatively high rate of serious adverse effects was not addressed in the discussion.

Given the high placebo response rate… are (these drugs) an acceptable first-line therapy for depressed teenagers?

Remember that journals receive manuscripts, and then send them to be reviewed by researchers in the field as to their quality. These reviews are generally taken very seriously when considering what changes should be made to a paper and whether the manuscript will be published.

Yet, the paper was not only accepted and published in JAACAP, but the editor seems to have ignored the suggestions of the individuals who reviewed the paper. These issues mentioned in the review were obviously not addressed – feel free to read the actual journal article and you can see that the efficacy of paroxetine was pimped well beyond what the data showed and the safety data were also painted to show a picture contrary to the study’s own data. Again, please feel free to read my earlier post regarding the study’s data versus how such data were reported and interpreted in the journal article.

Read this carefully – we all make mistakes. When someone points out that a mistake was made, it is natural to become defensive – that’s okay. However, several years after the fact, one should be able to admit fault and learn from one’s errors; at least that is my opinion.

Dr. Duncan was asked if she regretted allowing Keller et al.’s Paxil/Seroxat study to be published – her response was less that I hoped for:

I don’t have any regrets about publishing [the study] at all – it generated all sorts of useful discussion which is the purpose of a scholarly journal.

Let’s follow this train of logic. If a study is either particularly poorly done or misinterprets its own data to a large extent, then there will be an outcry of researchers and critics who will point out the numerous flaws that occurred. This could, of course, be interpreted as “useful discussion,” which I suppose is what Duncan meant happened in the case of this article. After all, there were several letters to the editor that expressed their frustration with the study and how Keller et al interpreted their data. So, according to my interpretation of Duncan’s logic, we should publish studies with as many flaws as possible so that we can “usefully discuss” them.

Of further interest, Jon Jureidini and Anne Tonkin had a letter published in JAACAP in May 2003. In their letter they stated

…a study that did not show significant improvement on either of two primary outcome measures is reported as demonstrating efficacy (p. 514).

The tone of their letter was perhaps a bit catty as it discussed how Keller et al seem to have spun their interpretation well out of line with the actual study data. I can, however, hardly blame them for their snippiness. Another nugget from their letter:

We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process (p. 514).

Thank you to Jureidini and Tonkin for their contribution to the “useful discussion” – indeed, their comments were likely the most useful of all that were contributed to the discussion. I give credit to Duncan for publishing their letter. I would be more impressed if she was willing to state that there were some problems with the editorial process in the case of this article, but I suppose you can’t win them all.

Disclaimer: I watched Panorama and took copious notes. I believe all quotes are accurate but please let me know if you think I transcribed something incorrectly.

Update (1/29/08): My apologies. I should have typed Mina Dulcan, not Mina Duncan. Sorry for the misspellings.

BPS: Getting Stranger and Stranger...

Newspeak has returned and this time a drug company had nothing to do with it. To my great disappointment, the British Psychological Society (BPS) has moved into a realm which is well past bizarre.

I’ve posted previously about Lisa Blakemore Brown, who is currently under investigation by the BPS regarding her fitness to practice psychology. The evidence against her has been described as entirely without merit by some who have seen it. For more on the evidence, go here and look at the comments.

Aubrey Blumsohn asked to be present at Blakemore Brown’s upcoming hearing in front of the BPS. What transpires next is something that would have been entirely fitting of 1984. In fact, I’m now motivated to re-read 1984 in order to better appreciate Orwell’s genius and prescient sense of what was to come.

Blumsohn was informed that the hearings were private (i.e., no guests such as himself allowed) in order to “protect Ms. Blakemore-Brown’s privacy.” To address this, Blumsohn received explicit permission from Blakemore Brown to attend the hearing. No matter, he was then denied permission to attend the hearing by the Chair of the Fitness to Practice Committee, who refused to provide a reason for denying his petition.

To really appreciate the utter insanity of an organization that unfortunately claims to represent psychology, you really must read the entire transcript of the correspondence between Blumsohn and the BPS on this matter. You will be floored. If you, like me, are a psychological researcher, practitioner and/or teacher, then I don’t know how you cannot feel ashamed that the psychologists in the UK are accountable to the BPS. And the BPS is accountable to…?

Lilly Takes A Shot

According to Reuters, Lilly's earnings fell for 4th quarter 2006 and it is also issuing guidance that its earnings may be lower than expected this year.

Eli Lilly and Co. (LLY.N: Quote, Profile, Research) said on Wednesday fourth quarter earnings fell, hurt by a charge for a settlement with users of its Zyprexa schizophrenia drug, and it forecast 2007 earnings at the low end of Wall Street estimates.

--SNIP--

Global Zyprexa revenue rose 12 percent to $1.16 billion, in large part because of price hikes. The company said U.S. demand remained flat for the pill, whose use has been crimped by concerns over weight gains that can increase risk of diabetes.

--SNIP--

Cymbalta sales leaped 85 percent to $424 million, amid soaring demand in the United States and introductions of the drug in more overseas markets. [Must be that catchy Depression Hurts campaign that miseladingly suggests Cymbalta lowers pain in depression]

And to think that there are still some relatively large lawsuits looming over Zyprexa. Ouch.

Keller, Bad Science, and Seroxat/Paxil

I will focus on Dr. Martin Keller and some seriously poor science in this post. Panorama did an excellent job of profiling Keller’s role in helping to promote paroxetine (known as Paxil in the USA and Seroxat in the UK). Note this is a lengthy post and that the bold section headings should help you find your way.

Who is Martin Keller? He is chair of psychiatry at Brown University. According to his curriculum vita, he has over 300 scientific publications. People take his opinions seriously. He is what is known as a key opinion leader or thought leader in academia and by the drug industry. What does that mean? Well, on videotape (see the Panorama episode from 1-29-07), Keller said:

You’re respected for being an honorable person and therefore when you give an opinion about something, people tend to listen and say – These individuals gave their opinions; it’s worth considering.

Keller and Study 329: GlaxoSmithKline conducted a study, numbered 329, in which it examined the efficacy and safety of paroxetine versus placebo in the treatment of adolescent depression. Keller was the lead author on the article (J American Academy of Child and Adolescent Psychiatry, 2001, 762-772) which appeared regarding the results of this study.

Text of Article vs. the Actual Data: We’re going to now examine what the text of the article said versus what the data from the study said.

Article: Paroxetine is generally well-tolerated and effective for major depression in adolescents (p. 762).

Data on effectiveness: On the primary outcome variables (Hamilton Rating Scale for Depression [HAM-D] mean change and HAM-D final score < 8 and/or improved by 50% or more), paroxetine was not statistically superior to placebo. On four of eight measures, paroxetine was superior to placebo. Note, however, that its superiority was always by a small to moderate (at best) margin. On the whole, the most accurate take is that paroxetine was either no better or slightly better than a placebo.

Data on safety: Emotional lability occurred in 6 of 93 participants on paroxetine compared to 1 of 87 on placebo. Hostility occurred in 7 of 93 patients on paroxetine compared to 0 of 87 on placebo. In fact, on paroxetine, 7 patients were hospitalized due to adverse events, including 2 from emotional lability, 2 due to aggression, 2 with worsening depression, and 1 with manic-like symptoms. This compares to 1 patient who had lability in the placebo group, but apparently not to the point that it required hospitalization. A total of 10 people had serious psychiatric adverse events on paroxetine compared to one on placebo.

What exactly were emotional lability and hostility? To quote James McCafferty, a GSK employee who helped work on Study 329, “the term emotional lability was catch all term for ‘suicidal ideation and gestures’. The hostility term captures behavioral problems, most related to parental and school confrontations.” According to Dr. David Healy, who certainly has much inside knowledge of raw data and company documents (background here), hostility counted for “homicidal acts, homicidal ideation and aggressive events.”

Suicidality is now lability and overt aggression is now hostility. Sounds much nicer that way.

Conveniently defining depression: On page 770 of the study report, the authors opined that “…our study demonstrates that treatment with paroxetine results in clinically relevant improvement in depression scores.” The only measures that showed an advantage for paroxetine were either based on some arbitrary cutoff (and the researchers could of course opt for whatever cutoff yielded the results they wanted) or were not actually valid measures of depression. The only measures that were significant were either a global measure of improvement, which paints an optimistic view of treatment outcome, or were cherry-picked single items from longer questionnaires.

Also, think about the following for a moment. A single question on any questionnaire or interview is obviously not going to broadly cover symptoms of depression. A single question cannot cover the many facets of depression. Implying that a single question on an interview which shows an advantage for paroxetine shows that paroxetine is superior in treating depression is utterly invalid. Such logic is akin to finding that a patient with the flu reports coughing less often on a medication compared to placebo, so the medication is then declared superior to placebo for managing flu despite the medication not working better on any of the many other symptoms that comprise influenza.

Whitewashing safety data: It gets even more bizarre. Remember those 10 people who had serious adverse psychiatric events while taking paroxetine? Well, the researchers concluded that none of the adverse psychiatric events were caused by paroxetine. Interestingly, the one person who became “labile” on placebo – that event was attributed to placebo. In this magical study, a drug cannot make you suicidal but a placebo can. In a later document, Keller and colleagues said that “acute psychosocial stressors, medication noncompliance, and/or untreated comorbid disorders were judged by the investigators to account for the adverse effects in all 10 patients.” This sounds to me as if the investigators had concluded beforehand that paroxetine is incapable of making participants worse and they just had to drum up some other explanation as to why these serious events were occurring. David Healy has also discussed this fallacious assumption that drugs cannot cause harm.

Did Keller Know the Study Data? I’ll paraphrase briefly from Panorama, which had a video of Keller discussing the study and his role in examining and analyzing its data. He said he had reviewed data analytic tables, but then he mentioned soon after that on some printouts there were “item numbers and variable numbers and they don’t even have words on them – I tend not to look at those. I do better with words than symbols. [emphasis mine].”

Ghosted: According to Panorama (and documents I’ve obtained), the paper was written by a ghostwriter. Keller’s response to the ghostwriter after he saw the paper? “You did a superb job with this. Thank you very much. It is excellent. Enclosed are some rather minor changes from me, Neal, and Mike. [emphasis mine].” And let’s remember that Keller apparently did not wish to bother with looking at numbers. It would also appear that he did not want to bother much with the words based upon those numbers.

Third Party Technique: This is a tried and true trick – get several leading academics to stamp their names on a study manuscript and suddenly it appears like the study was closely supervised in every aspect, from data collection to data analysis, to study writeup, by independent academics. Thus, it is not GlaxoSmithKline telling you that their product is great, it is “independent researchers” from such bastions of academia as Brown University, the University of Pittsburgh, and University of Texas Southwester Medical Center and the University of Texas Medical Branch at Galveston which are stamping approval of the product. More on this in future posts.

Keller’s Background… It is relatively well-known that Keller makes much money from his consulting and research arrangements with drug companies. In fact, several years ago, it was documented that Keller pulled in over $500,000 in a single year through these lucrative deals. When looking at how he stuck his name on a study he did not write, endorsing conclusions that were clearly far from the actual study data, can one seriously believe that Keller operated as an independent researcher? Can you believe that this is an isolated incident?

See, for example, Keller’s involvement in a study examining the effects of Risperdal (risperidone) for the treatment of depression. This study was presented a number of times, and he never appeared as an author of any of the presentations. Yet when the study was published, his name appeared as an author. The real kicker was that he allegedly helped to design the study, according to the published article. If he had played a major role in the study, he would have been acknowledged earlier (via being listed as a presentation author), so he apparently helped design the study after it was completed, which is obviously a major feat! The whole story is here. Why put his name on the paper? So that readers would believe more strongly in the study due to his big name status.

In addition, Keller wrote about how Effexor reduces episodes of depression in the long-term though he clearly misinterpreted the study’s findings. To be fair, many other researchers have made the same mistake in believing that SSRI’s reduce depression. To quote an earlier post:

In other words, because SSRIs and similar drugs (e.g., Effexor) have withdrawal symptoms that sometimes lead to depression, it looks like they are effective in preventing depression because people often get worse shortly after stopping their medication. The drug companies (Wyeth, in the case of Effexor) would like you to believe that this means antidepressants protect you from re-experiencing depression once you get better, that they are a good long-term treatment. A more accurate statement is that antidepressants protect you from their own substantial withdrawal symptoms until you stop taking them.

Again, Keller is way off from the study data.

Keller on Camera: Keller’s response to being asked about the increased suicidality among participants taking paroxetine in Study 329 was interesting:

None of these attempts led to suicide and very few of them led to hospitalization.

Well then I suppose a huge increase in suicidal thoughts and gestures is okay, then? This is the commentary of an “opinion leader” – if statements such as the above shape opinions among practicing psychiatrists, then we really are in trouble.

Next: Well, consider this post just the start regarding Paxil/Seroxat. The way the data were pimped by GSK merits more discussion as does more discussion of allegedly detached academics and their role in this debacle.

Seroquel For Everything Update: Anorexia

A reader recently made the following comment about Zyprexa

Rumor has it that zyprexa is now going to be marketed for anorexic hyperglycemics....

I assume that this was sarcastic -- I got a chuckle from it, though I think the reader meant hypoclycemics. In any case, a study was recently published (Powers et al; International Journal of Eating Disorders) in which quetiapine (Seroquel) was used to treat people with anorexia. Mind you, this was an uncontrolled study, so the improvements in depression and other symptoms may well just be placebo effects. Here are the authors' conclusions, as seen in the study abstract:

Quetiapine was well-tolerated and patients had significant improvements in several subscales of the PANSS as well as decreases in measures of anxiety and depression.

Hey, it's just a matter of time before we can perhaps all benefit from some Seroquel in the water supply, right? I wonder how many reprints AstraZeneca has purchased of this ever so rigorous study to disseminate to physicians and to discuss at those (in)famous doctor dinners. Background here and here.

Paxil/Seroxat: WOW

I just completed watching the Panorama investigation that aired yesterday on BBC. I ever so highly recommend it. You can check it out here. This lifts the curtains on the usual sets of lies, and does an excellent job of exposing how allegedly independent researchers served as puppets for GlaxoSmithKline. I will write more about it soon. Nice to see some good investigative journalism.

Seroquel for Everything: Update

You’ve surely seen me point out earlier that I’m more than slightly concerned with the proliferation of Seroquel (quetiapine) to treat virtually everything. What started out as an antipsychotic medication has spread into bipolar (with the help of some tricky statistics, naturally), then into being investigated for alcohol abuse, bipolar in preschoolers (assuming, of course, such a disorder actually exists!), generalized anxiety disorder, and now…

Fear of Public Speaking. Yep, Furious Seasons has just documented that the good folks at AstraZeneca are now aiming for people who are socially anxious. Hey, next time I’m feeling nervous prior to a conference presentation, I’ll make sure to pop one of these bad boys. Give me a break.

I can sense a fear of public speaking “disease awareness” campaign being planned at AstraZeneca’s corporate office as I type…

Seroxat Update

A nice little tidbit from PharmaGossip on the latest in the Paxil (US) / Seroxat (UK) fiasco

This is the story of how Britain's biggest drug company deliberately misled doctors into prescribing Seroxat, which it couldn't prove actually worked for teenagers. Not only that, one of its own clinical trials indicated that they were six times more likely to become suicidal after taking it.

Link here. I've got to get to the link to watch Panorama online. Should be eye-opening.

Becoming the Blakemore Brown Sounding Board

A few days ago, I posted regarding the case of Lisa Blakemore Brown, a psychologist who has run into trouble from the British Psychological Society. Since that time, the post has generated several comments (11 at the time of this posting, to be exact).

I will quote just a couple of choice snippets from them before encouraging you to check out the post and read the comments yourself. Feel free to add your two cents to the mix as well.

I have had the priviledge of reading all of the case documents and all of the transcripts of this fitness to practice "enquiry". I can assure you that none of the allegations have anything whatever to do with Lisa's diagnostic skills, her professionalism in terms of patient care, her competence as a professional, vaccine damage, Aliens or anything of the sort. The transcripts are quite simply appalling. The British Psychological Society is naturally not very keen on the idea that they should be made public. – Aubrey Blumsohn

Everyone has a RIGHT to question, and a RIGHT to search for answers, we were born with that facility built in as part of our survival instinct. That includes Lisa Blakemore Brown. – Paula

I too have read the transcripts of this so called "trial", and as Aubrey states they have nothing to do with patients or clinical practice. A single unsupportable complaint arose from a patient who was said to have been "coached" by a certain support group, and did not have anything to do with her skills. I hope the tranbscripts [sic] are placed in the public domain as soon as possible. – PM

Lisa and I are guilty of challenging a part of the belief systems of these professions and it is clear that the BPS are prepared to stoop to any underhand methods and to disregard the principles of due process, in order to seek to discredit Lisa and to thereby discredit her invaluable work on
behalf of families with autistic children. They must not be allowed to succeed. – Charles Pragnell

There are several other interesting comments, including one that takes a view quite different than the consensus of those whom I quoted above. Go here to check them out and go here to check out the story’s background in more detail.

Paxil/Seroxat -- Will it Ever End?

The AHRP blog has a great post on how academics sold out in the case of Paxil/Seroxat. The story includes the text of a likewise great piece from the British Medical Journal on the same topic. On at least one of the Paxil studies authored by "independent" academics, the suicidality of participants magically turned into "lability" and serious aggressive behavior turned into "hostility." The study authors simply renamed the adverse events to sound more tolerable -- I'd certainly rather be "labile" than suicidal, wouldn't you? Here's a link to the abstract of said study so you can see the names of the authors who let this slip by them. Sadly, these are some of the big names in child psychiatry.

A snippet from the AHRP post:

According to Joe Collier, Panorama shows how GSK had: "written up" the pediatric Paxil trial for publication; "bought and manipulated (apparently willingly) opinion formers; worked to promote the product for use in children (although it was not, and never has been, licensed for such use);" and how the information about the safety and efficacy of Paxil was distorted in letters to prescribers, in advice to their sales force, and in messages to the media.

The Panorama story on BBC running January 29th is likely to be big...

Neuronetics Swings... AND MISSES!

Neuronetics' transcranial magnetic stimulation was rejected by the FDA's advisory panel today. For a couple of stories on the panel's discussion and recommendation, try here and here.

According to one report:

The majority of the panel—made up of an engineer, several psychiatrists and neurologists, and a statistician—had no problem with rTMS's risks. There are almost none. The biggest worry with it is that it might accidentally spark a seizure, but that did not happen even once out of the 155 patients treated. The problem was that Neuronetics couldn't prove any benefit. Treated patients got a little better, but so did those patients that underwent a sham treatment.

According to another source:

But the panel was generally unimpressed with the company's data, which showed a slight statistical advantage in depression symptoms over dummy therapy after six weeks of treatment. Several panelists expressed dismay that patients showed no improvement on some depression scales and only minor improvement on ones that showed a difference.

"The panel seems to be in consensus that the primary analysis did not establish efficacy," said Thomas Brott, the committee's chairman.

"Perhaps a reasonable person could question whether there has been an effect at all," said Brott, a neurologist from Mayo Medical School in Jacksonville, Fla.

The panel did not formally recommend to FDA whether or not the machine should be approved. But the agency scientists suggested at a public hearing that they were also uneasy with the company's results.

Ann Costello, an FDA medical reviewer, questioned whether the mixed evidence of effectiveness in Neuronetics' studies contained "any clinically relevant information."

Peter Lurie, deputy director of Public Citizen's Health Research Group, told the panel that Neuronetics did not show that its device was substantially equal to ECT, a standard that many medical devices must meet for FDA approval. He focused on the fact that patients actively treated with the machine showed mild improvement on only one of three depression scales.

"The magnitude of the finding is trivial from a clinical point of view," he said in an interview.

Maybe the FDA panel learned something from the VNS approval (here and here)?

For-Profit Research Update

I recently wrote about a psychiatrist, Dr. Andrew Cutler, who made misleading statements regarding the BOLDER I study. I ran across a little clip that mentioned more about his research venture:

Still, some junior faculty members are now abandoning academia to get into the drug-study business. Dr. Andrew Cutler, a psychiatrist, left the faculty at the University of Chicago to join the Psychiatric Institute of Florida in Orlando, a private practice with a research business. Then last year, he formed his own company, Coordinated Research of Florida, to perform drug studies full time.

Without a patient base to draw from for studies, Cutler found other ways to recruit subjects, including serving as a nursing home consultant.

"I will strategically pick a nursing home that has a large population that meets the criteria for a study," he said. "If there is a large community practice in town, I may work out a referral arrangement, or make them a co-investigator, and the arrangement is that they would be providing the patients."

Interesting. If I understand this right (and I'm not sure that I do), then he goes to local nursing homes, chums with the people in charge, then gets them to help recruit their residents as participants in drug studies from which both he and the nursing home administrators who get listed as "investigators" stand to make some cash. This is not necessarily bad, but it shows that the reach of clinical research teams, funded solely by industry, is fairly wide. Making money from enrolling your own residents in a research trial must certainly raise some conflicts of interest for nursing home administrators and physicians.

The Big Day for Neuronetics

An FDA advisory panel will be reviewing Neuronetics' transcranial magnetic stimulation device today. Their recommendation will likely be followed by the FDA in either approving the treatment for depression or not. As soon as I see anything regarding the panel's decision, I'll let you know.

A Little Help?

I've made a couple updates to the site template today. I'm trying to catch on to the whole Web 2.0 thing and make it much easier for readers to send my posts to sites like Reddit, Digg, etc. Unfortunately, my skills in this area are obviously limited. If someone wants to help out, feel free to email me -- link in the sidebar. Thanks.

Likewise, if anyone has comments about switching to the new version of Blogger, please email me or feel free to post them. I'm debating if I should make the switch sooner or later.

The Blakemore Brown Case: Part One

A psychologist in the UK, Lisa Blakemore Brown, is facing all sorts of trouble. As I understand it, the British Psychological Society is in the process of examining Brown's purported fitness to practice psychology. Essentially, Blakemore Brown has taken controversial points of view regarding the relationships between vaccinations and autism as well as Munchausen's Syndrome. From my research on her case, it appears that this case is an example of a dissident being punished for offending the "wrong" people. It would appear to have little to do with her actual fitness to practice psychology. I'm not agreeing or disagreeing with her views; I am stating that she's got the right to state those views, regardless of whom is offended.

A much more in depth layout of the issues involved can be seen at the Scientific Misconduct Blog. To preview, much of this boils down to what appear to be unsubstantiated charges regarding Brown's mental state (alleged "paranoia"), which then allegedly makes her too unstable to practice psychology. I've heard rumors that there is a lot more to come in this saga. Stay tuned.

So Funny It Hurts

Everyone must immediately read PharmaGiles, the blog that details the story of a fake drug company names Phoni (among other items). It is incredible satire regarding the drug industry. My only warning is that you may laugh so hard that you need an ambulance.

BOLDER Statements

In this post, I will discuss statements of a couple academic thought leaders regarding the BOLDER I study and how these statements compare to the actual evidence.

Cutler: Dr. Andrew Cutler, one of the authors on the BOLDER I study to which I referred earlier, had some nice things to say about the study’s findings in Clinical Psychiatry News. For example, he said “It’s a landmark study.” In addition, the article paraphrased Cutler as saying, “The study used one dose each evening, and had several other unique features, he noted. Almost all previous data on treating bipolar depression focus on bipolar I patients, but this study included rapid cyclers and bipolar II patients.”

What Dr. Cutler failed to note is that Seroquel was not more effective than placebo at the end of the eight week trial for bipolar II patients. If Cutler is going to introduce bipolar II participants into the mix, then he has an obligation to mention that treatment was not significantly more effective than placebo for this group. He may have been misquoted – I don’t know – but it does read directly like PR for the drug that goes well beyond the findings of the study which he is discussing.

It is worth noting that Cutler runs a private research firm and that it can’t hurt his standing among drug companies who hire his firm to run clinical trials when he makes statements such as those mentioned above. I found it interesting that on his firm’s website, it is mentioned “We are also noted for low placebo response.” How do you get a low placebo response besides not treating participants very well? I’m not making an accusation – I am just really curious. If placebo response has to do with expectations of getting better and these expectations are influenced by how the study personnel treat participants, then what’s the deal? Maybe you can treat participants well and still quash the placebo response; I just wish I knew more about how this was done.

Calabrese: Dr. Joseph Calabrese, BOLDER I’s primary investigator, had the following to say about the study: “There was a dramatic response within eight days of beginning treatment in patients who were symptomatic with bipolar depression.” I’m not sure if “dramatic” is the right word. Looking at Figure 2 in the article, I see that after week one, placebo patients seem to have changed by 5 points on the Montgomery-Asberg Depression Rating Scale (MADRS), while those on Seroquel seem to have changed by about 9.5 points. That’s an average difference of about 4.5 points on a rating scale where the average patient had a score of about 30 coming in. So is a score of 25 (on placebo) “dramatically” different than a score of 20.5 (on medication)? Methinks that the language itself is a little dramatic. Don’t get me wrong – it’s good that the medication was better than placebo after a week. But let’s not get hyped up beyond what is reasonable.

It is troubling when academics are willing to make PR statements that go beyond the evidence and, in Cutler’s statement regarding bipolar II, are demonstrably false. Academic thought leaders are frequently featured in news articles, review articles, PR releases, and continuing medical ‘education’ events making these types of statements that go well beyond the evidence. It seems that too few professionals in the mental health arena have picked up on the fact that marketing and science have largely melded into a witches’ brew in which what is good for a product’s sales often trumps the actual data on its efficacy and safety.

Before anyone gets upset because I mentioned people’s names here, keep in mind that I’m not saying either Cutler or Calabrese is a “bad person.” I don’t know them personally. They may well conduct top-notch research and possess saintly personalities. All I am talking about here is how their remarks seem to differ from the studies that the remarks are based upon, and how such practice is widespread.

Major Hat Tip: Depression Introspection.

BOLDER Still

I’ve written before regarding the BOLDER II study, in which Seroquel was compared to placebo in the treatment of bipolar individuals experiencing depression. My main qualm was the way that the authors calculated the size of the treatment effect. Essentially, there are a couple ways to calculate the treatment effect, and they calculated the treatment effect in a manner that made the treatment effect appear much larger. For more on this, please read my earlier posts here and here.

Well, I have since gone back to the BOLDER I study, and I can see now that the same trick was in place. We’re talking about last observation carried forward effect size (the traditional method) versus mixed-model repeated measures (MMRM; the ‘new’ method) effect size here. It may sound boring and wonky, but it is the backbone of interpreting how strong of an effect was generated by the treatment. For more details, please see my earlier post.

In BOLDER II, I could at least calculate the last observation carried forward effect size in the traditional sense based on data provided in the article. In BOLDER I, this was actually not possible. To calculate the size of the treatment effect, one must examine the means and standard deviations of all groups. This information was not provided in full, as there were no standard deviations reported. Given that reporting means and standard deviations is standard practice in medical journals, this is quite odd.

So, I just decided to use the standard deviations from the BOLDER II study to see what would happen. They seemed to be fairly comparable groups. Yes, the standard deviations of the groups in the two studies are likely to be different, but since the authors didn't report them in BOLDER I, I had little other choice. For the 300 mg Seroquel group, I found an effect size of .49, which is a moderate treatment effect. The study authors in BOLDER I, using the alternative MMRM method, found a treatment effect of .67, which is moderate to large. Using their method seemed to boostthe effect size by 37%. For the 600 mg Seroquel group, I found an effect size of .52 (moderate), whereas the study authors came up with .81, which would typically represent a large treatment effect. Using the authors’ methods, the effect size apparently increased by 36%.

The authors did not bother even reporting the standard deviations or the effect sizes calculated the traditional way. Regarding similar issues being raised about BOLDER II, one of the authors replied by saying essentially that the authors thought nobody would be interested in the traditional analysis. Call me old-fashioned, but when a new statistical analysis comes on the scene that dramatically increases the apparent magnitude of treatment effects, making treatments appear more powerful just because data are analyzed in a different way, I’m suspicious. When the old method, which has been used to calculate effects for decades, is just tossed out the window as old-fashioned, one can’t help but wonder if these drug company funded statisticians are just licking their chops because through statistical maneuvering, they have figured out how to make their sponsor’s products look better.

So, when you see that the apparent effects of treatments have grown, keep in mind that you may well be staring at the effects of newfangled statistics rather than the actual treatment.

PharmaGossip: On a Roll

No, this is not really news. PharmaGossip is about as good of a blog as you can find regarding the drug industry. We already knew that. If you’ve not been paying attention lately, please check out the following recent posts:

Sex, Drugs and Quarterly Goals

Merck – Vioxx: Order in the Court!

PharmedOut Makes the WaPo

And especially: Any suggestions for the "Cutting Edge Information Pharma Marketing Library"

Furious Seasons is Off Da Hook

In a post that can only be described as “off the hook,” Philip Dawdy at Furious Seasons describes what 2007 appears to hold in terms of psychiatric treatment research. I read the same article as did Dawdy last week regarding this year's psych med research and thought, “yeah, I’ll get to that.” Well, I’m glad I never got around to it because I could not have matched what he has written. Here are some snippets from Dawdy…

“There was an interesting story last week in Psychiatric Times. It was a curtain raiser on what the reporter promises will be a big year of data for psych MDs. Lots of studies on using atypicals in kids and adolescents--I predict that these short-term studies will show limited efficacy with big weight gain in the kiddos”

—SNIP—

"And new data on one drug, Zyprexa (olanzapine), will likely be submitted to the FDA this year in anticipation of earning a pediatric indication for either schizophrenia or bipolar disorder."

Oh my. After all the problems that have cropped up around Zyprexa's use in adults, Eli Lilly is pushing to have it approved for kids? That ought to be one very interesting filing with the FDA.

—SNIP—

I am against sticking four to six year olds full of an antipsychotic, especially Seroquel. It's well known to cause weight gain in adults and creates so much cognitive slowing and the fifth of whiskey head the next morning that it is utterly unfair to give this to children.

OK, I have to stop stealing his words. Believe me – it just gets even better in his post; I only scratched the surface. In fact, it is one of the best posts I have ever read. So get going and read it in full. Warning: His post contains adult language (and appropriately so, in my humble opinion).

UK Paper on Zyprexa

Much of the writing about the Zyprexa documents has appeared in the New York Times, but the Times of London is now chiming in as well. Here's a couple of choice cuts:

In one document dated October 9, 2000, Robert Baker, a senior Lilly clinical research physician, e-mailed colleagues about a meeting of an academic advisory board he had attended in Atlanta. It had “reinforced my impression that hyperglycemia remains quite a threat for olanzapine and may merit increasing even further medical attention and marketing focus on this topic”. Dr Baker added: “[The board was] quite impressed by the magnitude of weight gain on olanzapine and implications for glucose.”

Another internal document dated October 14-15, 1998, described the risk of weight gain as a “top threat” to Zyprexa.

Link here. Background here, here, and here.

Chemical Imbalance Watch

I have ranted before about the alleged chemical imbalance in depression. Any time I've seen a commercial for any of the SSRI's, I've just shaken my head (0r banged it against the wall), as the ads love to tout how "experts" (i.e., their marketing department ?) believe that depression is caused by some sort of chemical imbalance. The evidence, as you can read here, is scant, at best, to support such an assertion.

Well, Wyeth is still on the chemical imbalance train with their knockoff of their current bestselling antidepressant Effexor, which may be gracing your pharmacy before long. The new drug is called Pristiq and Wyeth is offering up the following as part of its early PR campaign for the drug:

In the area of depression, Pristiq is expected to improve the balance of serotonin and norepinephrine as compared with serotonin reuptake inhibitors (SSRI) because of its pharmacologic profile as a dual reuptake inhibitor.

Well, whoopee! Will it work any better than antidepressants that attempt to target either norepinephrine or serotonin? Nope. Why? Because a reliable imbalance of either neurotransmitter has never been found in depression. That's right -- never. But Wyeth continues to run with the chemical imbalance program because a lot of people have been indoctrinated, through advertising or perhaps through teachers who themselves lacked much education on the topic, to buy into this whole chemical imbalance deal.

I'm not saying that biology does not impact depression. I am saying that our current level of understanding in this area is much more speculation than it is fact. I do not believe there is a single serious scientist who would stick his/her name behind the simple "chemical imbalance" theory of depression.

And the name Pristiq? It would appear that Wyeth is aiming for a close resemblance to "Pristine," which is a bit ironic given the side effect profile of Pristiq (which will likely resemble that of Effexor closely).

More on Pristiq in an interesting post at Depression Introspection.

SSRIs and Osteoporosis

Fresh from the Archives of Internal Medicine, a study by Richards and colleagues has indicated that daily SSRI usage is associated with an increased risk of falling and lower bone density, among others. Here are the results as stated in the abstract (I’ve not read the full study):

Daily SSRI use was reported by 137 subjects. After adjustment for many potential covariates, daily SSRI use was associated with substantially increased risk of incident clinical fragility fracture (hazard rate, 2.1; 95% confidence interval, 1.3-3.4). Daily SSRI use was also associated with increased odds of falling (odds ratio, 2.2; 95% confidence interval, 1.4-3.5), lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine. These effects were dose dependent and were similar for those who reported taking SSRIs at baseline and at 5 years' follow-up.

Significant sexual side effects, suicide (here and here) and now this? It’s not adding up very nicely for SSRIs. If you are at risk for bone problems, may I suggest Actonel? With such strong research backing it, you can’t beat Actonel for your osteoporosis-related needs (as you can see here and here).

Effexor For Life

In a study that parallels an earlier study (and accompanying post – Lexapro for Life), Dr. Martin Keller (presumably a primary investigator on this study) found that long-term venlafaxine (Effexor) use reduces risk for depression. In fact, he said,

these data showed that venlafaxine extended release can help prevent new episodes of depression -- providing an option to the millions of adult patients with depression who have experienced a disappointing setback or who are still seeking symptom relief.

Please note that I have text of a document from PR Newswire indicating that he made the above statement, but I don’t have a link to the text.

His comments are not all that different than those of Dr. Susan Kornstein, who was quoted as saying the following about the long-term effects of Lexapro:

These findings indicate the importance of maintenance therapy for patients with recurrent major depressive disorder beyond four to six months of improvement, even if a patient’s depressive symptoms appear to be resolved

This study: The Effexor results have not been published to my knowledge, but from what I gather from the study description, this study examined people who were on Effexor and received some sort of therapeutic response while taking it. Then, some of them kept taking Effexor and some were assigned to take a placebo (of course, not knowing they were switched to placebo). Those who took Effexor were significantly less likely to experience a recurrence of their depressive symptoms compared to those on placebo. So, apparently, you should be on Effexor forever. As noted above, Keller (and in a similar study, Kornstein) say this means that you should stay on your meds long-term because they prevent depression.

Withdrawal from Effexor: Just like Kornstein, Keller has absolutely misinterpreted the evidence. For example, in one small study, discontinuation of venlafaxine was associated with adverse events in 78% of patients compared to 22% of patients who stopped taking a placebo. Another, larger study found, similarly, that Effexor was related to increased rates of discontinuation symptoms compared to placebo. There are frequent reports to a national medication hotline in the UK regarding discontinuation symptoms when patients stop taking Effexor. In addition, there are also case reports of experiencing shock-like sensations during venlafaxine withdrawal. For a brief read on these shock-like sensations, check out this brief read in the British Medical Journal. In addition, it is now known that for paroxetine (Paxil), another antidepressant, healthy (not depressed) volunteers at times experienced depression upon ceasing taking their medication. Given the similar mechanism of action between Effexor and Paxil, one would expect a similar result for Effexor.

A quote from Dr. David Healy helps to summarize this fundamental manipulation of evidence by drug companies (and their allied “independent” academics):

It is clear now that the companies must have known that a certain proportion of these patients re-randomised to placebo, who subsequently complained of depressive and anxiety symptoms, will have been suffering from withdrawal problems. These withdrawal problems however appear to have been used as a basis for claiming that continued SSRI intake had a prophylactic effect against nervous and depressive problems. Based on such studies companies sought and have received licences to make these claims regarding prophylaxis.

In other words, because SSRIs and similar drugs (e.g., Effexor) have withdrawal symptoms that sometimes lead to depression, it looks like they are effective in preventing depression because people often get worse shortly after stopping their medication. The drug companies (Wyeth, in the case of Effexor) would like you to believe that this means antidepressants protect you from re-experiencing depression once you get better, that they are a good long-term treatment. A more accurate statement is that antidepressants protect you from their own substantial withdrawal symptoms until you stop taking them.

See No Withdrawal, Mention No Withdrawal: I do not say this as a personal affront to Keller, Kornstein, or any other academic who has made public statements regarding the long-term efficacy of antidepressants, but it seems odd that anyone, particularly anyone with research credentials, could ignore the solid evidence that there are substantial withdrawal symptoms associated with antidepressants. Many researchers apparently continue to toe the line of the drug companies that “it’s the depression, not the drug” that causes depression to return.

The Current Verdict on Long-Term Outcomes: Depression is indeed a nasty condition that often returns after it is successfully treated or after it just vanishes due to the passage of time. So yes, we should treat it. However, let’s keep in mind that antidepressants are barely more effective than a placebo in the short-term and, as we see here, can lead to problems in the long-term, where one can either choose to stay, for years, on an antidepressant (perhaps indefinitely) or have a good chance of risking some heinous withdrawal effects. Psychotherapy is much better in the long-run for depression, but it still does not positively impact many people. Like it or not, psychotherapy for depression has the best (though limited) success rate, perhaps due solely to its lack of causing withdrawal effects, or at least causing them at a much lower rate than meds.

Great Rant on Abilify Advertising

Intueri has a great rant on Abilify advertising appearing on the sides of pay phones. Read it and you too may feel the urge to say You Go Girl!

Infant Depression & Anxiety More Prevalent

...according to the headline of a "news" story at a Boston TV station.

A growing number of hospitals and universities are now offering mental health therapy. Experts believe that if they can address these issues early, they can avoid bigger problems later in the child's life.

And by 'early,' they mean as early as one year old.

Psychologist Douglas Goldsmith says "even by the first birthday, some of the research is saying we should be able to start to see signs of more serious social disorders."

Well, Dr. Goldsmith, I'd love to become more familiar with such research. I actually don't think there is any research of any decent quality addressing anxiety and/or depression in children prior to their first birthdays. If any of y'all have access to such research, please address it in my direction. I'd especially be interested in research that shows that interventions with pre-one year olds helps children avoid "bigger problems" later on.

Hat Tip: Depression Introspection.

Zyprexa Inquiry Expands

Alex Berenson of the New York Times has another in what may be an endless stream of stories regarding olanzapine and its questionable (at best) marketing practices. I’ll start by quoting from his latest piece:

Illinois and Vermont are now part of a coordinated five-state civil investigation into the way Lilly promoted Zyprexa, a treatment for schizophrenia and bipolar disorder. The states are investigating whether Lilly tried to hide Zyprexa’s risk of causing weight gain and other risks associated with diabetes and whether the company promoted Zyprexa for use in patients who do not have schizophrenia or bipolar disorder.

Federal laws prohibit such so-called “off label” marketing, although doctors may prescribe any drug for any disease that they believe the drug will help.

The orders on Thursday and yesterday are the first formal demands for Lilly documents from state attorneys and they indicate an escalation of the investigation, according to Ms. Hagan and Julie Brill, who is an assistant attorney general in Vermont.

For background on this story, please feel free to see such posts as this, this, this, and this. Make sure to also check out the AHRP site for much information on the Zyprexa case.

Greed and Cancer Docs

This is rich, bloody rich. I'll just let Bloomberg do the talking:

Cancer doctors must disclose all financial ties to investment firms, said a leading U.S. physician group seeking to stop the leak of insider information on clinical drug trials.

The American Society of Clinical Oncology described the new policy, the most strict of any medical group, in a Jan. 20 article in the Journal of Clinical Oncology. The Alexandria, Virginia-based professional organization has more than 23,000 members worldwide.

Cancer physicians must disclose all consulting or advisory arrangements they have with either investment or commercial interests, the policy says. Investment firms cultivate doctors with lucrative consulting arrangements, and traders can use their inside knowledge to buy and sell stocks of companies developing new therapies before the information becomes public.

--SNIP--

The policy was crafted in response to reports about the growing practice of physicians consulting for Wall Street firms about confidential drug research, typically for $300 to $500 an hour, the authors wrote. The practice was described in an August 2005 investigative report by The Seattle Times, and it later attracted scrutiny from Senator Charles Grassley, Republican of Iowa, and the U.S. Securities and Exchange Commission.

The Times found 26 cases in which doctors leaked critical information about ongoing drug research to investment firms, despite signing confidentiality contracts with sponsors of drug trials.

--SNIP--

Peter Eisenberg, a prominent cancer physician in Marin County, California, said the newly strengthened ethics policy for cancer doctors was a ``necessary step.'' He said the advice will help physicians who want to do the right thing, yet, ``for those who aren't scrupulous, no policy will suffice.''

Eisenberg said he stopped his $600 an hour consulting with Wall Street firms after reading the Seattle Times report about how investors elicit inside information from doctors. The Jan. 20 journal article cited instances where analysts have posed as fellow doctors or patients in order to elicit information from doctors.

``They know how to get the information, and basically, I don't know how to keep it to myself, so I decided to stop,'' Eisenberg said of working with investment firms.

So, basically, many oncologists involved with research trials are sneakily disclosing research findings so that investment firms can either buy or sell shares of drug developing firms. Pretty sleazy, eh?

Why this is even worse than it looks: Many physicians are breaking confidentiality agreements because they are getting paid quite a handsome sum. But when research results show that a drug is ineffective and/or dangerous (think SSRIs for child/adolescent depression, for example), research docs do not disclose the negative information to the people who actually need to know these results -- patients. This leaves tens of thousands of people taking medication that is dangerous and/or ineffective. So, to summarize, if they get paid off, many docs will break their confidentiality agreements with drug companies, yet when trial results show that a drug is not a good treatment option, nearly all research doctors will hide behind their confidentiality agreements and let people suffer. This does not exactly engender faith in the academic-pharmaceutical complex, does it?

Many thanks to an anonymous reader for the link.

Arkansas Antipsychotic Update

Dr. X did some digging and found a couple of resources that shed more light on the apparent overdrugging of child and adolescent inmates at an Arkansas prison facility run by Cornell Companies at the time of the incidents.

Check this out:

An internal affairs unit report studied “forced psychotropic medications/chemical restraints” over a 45-day period beginning Sept. 1. Video surveillance of injection procedures was part of the investigation.

A log showed 22 juveniles had been given 52 injections of Thorazine and Benadryl as chemical restraints. But a separate incident report showed 16 injections were not recorded on the log and a total of 25 juveniles received injections. There were signed physician orders for injections in only 11 of the 25 cases.

--SNIP--

Though not allowed as discipline, the report concluded that medication was used as a disciplinary tool.

Nice. REAL Nice. Thanks to Dr. X for the update. I only posted some of the lowlights. Feel free to check out the links to read more.

Thanks for Your Support

The results are in for the 2006 Medical Blog Awards. While I did not win in the category of Best New Blog, I thank all who voted for my site. It was an honor to receive quite a few votes and to be listed next to some excellent sites. For results, please go here. Congrats to all winners, especially to the NHS Blog Doctor, who won in three categories.

Antipsychotics Will 'Correct 'You

A youth correctional facility in Arkansas had some problems in the fairly recent past. What kind of problems?

Well, the private firm that was formerly contracted to run the facility, Cornell Companies, "was fired last year for inappropriately injecting children with antipsychotic medications" according to an AP report.

Nice. Now the State of Arkansas has hired another private firm, G4S Youth Services of Virginia, which will assume control of the facility in a few days. I couldn't find any further information on this, but it certainly jumped out at me.

Daily Zyprexa Post

Noting that earlier Zyprexa lawsuits have included gag orders (i.e., we pay you off and you shut up!), a quote in an excellent post I ran across went like this:

So there you have it. My point, if any? Gag orders protecting the guilty should not be permitted as part of any civil settlement. Prohibit it by law, and we won't have to put up with this nonsense. If civil litigation is supposed to be a mechanism for protecting the public, it will work best if it includes public airing of the relevant facts and evidence. An outcome in which a few of the people who were injured get compensated, at the cost of keeping the truth from everybody else, is not in the public interest, and it should never be allowed to happen.

Good point. Every time we have a lawsuit, there is the potential for docs to become public. That’s how David Healy got access to files indicating that SSRI manufacturers were cooking the books on the suicide numbers to make placebo look more dangerous than it actually was. Yet in many cases, the documents vanish and hidden information about the safety and/or efficacy (or lack thereof) is again relegated to the company archives.

Billy LOVES the Free Market

We’re going to play a neat game. It’s called ‘Free Market’ Billy Tauzin versus ‘I Hate Competition’ Billy Tauzin. You can pick the winner at the end.

The drug industry loves to discuss the free market and its wonders. Billy Tauzin is the president of PhRMA, the leading drug industry trade group and former Louisiana Congressman. For a brief yet entertaining story on how Billy ended up as PhRMA president, see this column in Slate.

The following are quotes from Billy Tauzin, excerpted from a speech titled Free Market Health Care Solutions Are Best for Patients at something called an American Legislative Exchange Council Annual Dinner in San Fransico, CA. I added the color highlights.

Tonight, I salute you for your dedication to the fundamental principle that free-market based solutions work best for preserving our liberties and building a strong country, strong states and strong communities.

—SNIP—

The strength and success of America’s pharmaceutical research industry, I am proud to say, is just one example of what we work for when we fight for free-markets, reducing government interference in the economy and for fostering of an economic environment that promotes opportunity and innovation.

—SNIP—

But while we marvel at the promise of these new health care technologies and medicines, we should also not lose sight of the fact that patients are the ultimate beneficiaries of this revolution.

—SNIP—

We must work together to make sure that the healthcare market remains free because the best, most efficient and cost-effective solutions will come from a free market.

—SNIP—

And, if you want to work for free-market solutions to the problem of access to medicines, we also are there to work with you and support you.

—SNIP—

The free-market in health care helped save my life.

Okay, you get the point – Billy loves the free market and the free market in health care saves lives. And those good folks in PhRMA (e.g., essentially all major developers of medications) are all in favor of the free market.

News Flash -- PhRMA does NOT believe in the free market: While PhRMA likes when the market works in their favor, they also believe in circumventing that same market when it comes to competition. When drugs are slated to come off-patent, which would allow generic version of the drug to be made, PhRMA members have increasingly turned to buying off the competition. That’s right; they simply pay the generic manufacturer to not make a generic version of the patented drug, so that the consumer can continue to pay a hefty price for the drug which is still under patent. Ain’t that a nice deal? Here’s a quote from a recent AP story regarding this practice:

“Sadly, the incentive to enter in such pernicious pay-for-delay settlements are substantial,” FTC commissioner Jon Leibowitz told lawmakers.

In a typical settlement, the payment is still less than the potential loss in sales to a brand-name company once a generic competitor enters the market, said Michael Wroblewski, of Consumers Union. And the generic manufacturer makes more from the payment that it would from actually selling its version of a drug, he said.

But wait, Billy had this to say about pay-for-delay arrangements:

“Courts and experts have stated unequivocally that settlement of litigation should be encouraged and that settlement of patent litigation can benefit consumers. Blanket prohibitions on certain types of settlements could force both sides to spend valuable resources litigating their patent dispute to judgment,” said former Rep. Billy Tauzin, R-La., president and chief executive of the Pharmaceutical Research and Manufacturers of America.

What does he mean? Well, the makers of the patented drugs nearly always try to stretch out their patents through a variety of complicated legal maneuverings. So he’s saying that these pay-to-delay arrangements help to defray PhRMA member legal costs. Well, then, by all means, keep doing what you’re doing – we certainly wouldn’t want a drug company to have to hire an attorney to try to stretch out a patent. Between stretching patent expirations and fighting in court to keep their internal documents that likely reveal questionable marketing practices (or worse) secret, these poor drug companies must be drowning in legal fees. Cry me a river.

On one hand Billy loves the free market. On the other hand, Billy hates competition, which, incidentally is the foundation of the free market! Billy is likewise not a fan of Americans importing drugs from Canada; after all, they would also be a source of competition. Adam Smith must be rolling over in his grave.

Background on this story can be found here and here.

Shadow Statisticians

An interesting new study is available in PLoS Medicine (Gotzsche et al., 2007). Due to the open access of all PLoS articles, you can read it in full for free and I encourage all of you to do so.

In this study, the authors examined 44 trials supported by industry. They examined whether there were contributors listed on the original study protocol (submitted prior to the start of a study) who did not appear on the final published manuscript, which was of course published after the completion of the trial. They found evidence for ghost authorship in 75% of cases. In almost all ghost-suspected cases, the protocol listed that a company statistician would help interpret the data, yet the statistician in question was not listed as an author on the publication.

Why does this matter? This is important because when you are reading an article, you are expecting that the listed authors were responsible for the study design, data collection, data analysis, interpretation, and writing of the paper. Look at the following example:

A paper is listed as having “Independent” Academic Author X, Company Statistician Y, and “Independent” Academic Author Z. It concludes that a drug is highly effective and very safe. Given that it has a company statistician, do you trust its results entirely? Well, if the company statistician is removed, leaving only two “independent” academic authors, then the potential influence of the statistician is removed from plain sight. We are thus more apt to assume the analyses were done objectively, not with an eye toward cherry picking data to show positive results.

To quote from the PLoS article, “[Ghostwriting] might happen because the study ‘looks’ more credible if the true authors (for example, company employees or freelance medical writers) are not revealed.”

But wait, there’s more: The 75% figure is almost certainly an underestimate. Why? Because this study could not detect the presence of ghostwriters – it is rare for a company to mention in a study protocol that a ghostwriter will be used to write a draft of the study manuscript for publication. So how often are ghostwriters used? Healy estimated that among psychiatry papers, perhaps 50% are ghostwritten. If we look at papers that were written up by professional medical writers and/or used company statisticians yet failed to acknowledge them properly in the final manuscript, we are clearly looking at an exceedingly high percentage of papers!

Conclusion: To be clear, a company statistician may conduct analyses properly and a medical writer may write a manuscript that accurately and fairly represents the study’s data as well as the research design’s strengths and limitations. Yet there have been many cases where the statistics in industry-supported studies have been dodgy (for example, here and here) and in which a medical writer has written a draft that is clearly overly optimistic (such as this and this) regarding a treatment.

Analyzing data in a “friendly” manner to a product is just another way in which industry-supported science has largely merged with marketing. I don’t believe that hiding the identities of people who analyzed the data and of the hired gun(s) who wrote the manuscript can be viewed in any other way.

Great Comment on Lilly's Comments

An anonymous reader made a comment suggesting that Lilly may either be losing their minds or that they have reached strange new heights in their attempt to protect Zyprexa. Maybe they need a safe, gentle psychotropic such as Zyprexa to ease their concerns. Anyway, the quote is below, with my added color highlighting and replacing Arthur with Joseph:

Arthur [correction] Joseph Heller could no better than:

"Eli Lilly, in email messages to the BMJ, states that it is pursuing action because 'these individuals have violated a federal court order by leaking the documents' and that it has not released its internal documents publicly because the company 'has no intention of violating that order by releasing documents ourselves.'"

A judge can only require that individuals other than a company do not make a company's proprietary documents public. A company itself can make any and all of its internal memos public at any time. This is a idiotic as a battered wife claiming that a restraining order on her husband also means that she cannot approach within 300 yards of herself.

Some of the people at Lilly were once deemed to be pretty sharp. Either they need something like Zyprexa, or they're blowing deliberate nonsense at the BMJ about an issue that has already made it onto Page One of the Grey Lady.

Neither scenario makes Eli Lilly look all that good.

Sharp witted comments are always welcome -- keep 'em coming!

The Latest On the Zyprexa Docs

From around the blogosphere, here’s what a few folks are saying about the latest Zyprexa developments. Below are quotes from various sites. Some may be reordered and I also provided only snippets. Go to the original posts for more. Any color highlighting is my addition, while italics are from the original authors.

Site: Measuring Up.

I thought I’d seen it all. But Judge Jack B. Weinstein, the presiding justice in the case against Eli Lilly and its hot selling antipsychotic drug, Zyprexa, showed me I hadn’t…

So how does he react? The judge tells this same lawyer that he needs to provide a list of every single recipient who received the “stolen” documents and collect all copies. On top of this, Judge Weinstein ordered that each of these 14 recipients communicate this injunction to everyone else who has since made copies, posted them to a web site or facilitated in the distribution of any information taken from the documents...

What planet is this judge from? It’s simply hilarious that this highly respected individual believes he can control the flow of this information after it has spread virally to thousands or points across the Internet. I’m not sure if he understands what the Internet is (or isn’t for that matter), but by executing this order, it has also made Eli Lilly look extremely foolish in the process. My guess is that most of the individuals who continue to distribute this information have absolutely nothing to do with Eli Lilly’s litigation and are probably passing on interesting fodder like this simply because of their interest in health related issues. Will he prosecute every ordinary citizen (including me) who has passed on the information at hand?

The genie is out of the bottle and no one can put him back. Legal issues aside, it’s time for Eli Lilly to focus on saving its reputation and come clean now.

Site: Health Care Renewal.

I cannot comment on the legal merits of the argument that the Eli Lilly memos about Zyprexa should not have been published.

It does seem to me that any effort to restrict discussion of the case by parties not involved in the case would be a serious general affront to free speech.

Furthermore, to make the best possible medical decisions for individual patients, the patients and their health care professionals need the best possible evidence about the benefits and harms of therapy. Thus, patients, health care professionals, and ultimately the public have a need to know about the benefits and harms of medications like Zyprexa, and about any attempts to suppress or manipulate such evidence by interested parties, particularly the medications' manufacturers.

Although I can appreciate Eli Lilly's interest in having a fair day in court, the company's attempts to corral documents that put its managers in an unflattering light do not enhance trust in how the company is run.

Site: More Health Care Renewal.

The latest issue of the British Medical Journal featured a news article by Jeanne Lenzer about how Lilly has tried to suppress publication of the internal memos on which the Times based its series. [Lenzer J. Drug company tries to suppress internal memos. Brit Med J 2007; 334: 59. ] [BMJ quotes follow]

After the injunction was granted to Eli Lilly the documents rapidly disappeared from the internet. The company was given access to Dr Egilman's [a leaker of said documents] computers for three days for 'forensic examination'; and Mr Reinert said that Eli Lilly has indicated that it wants to seek 'all possible sanctions' against Dr Egilman. The consequences, Mr Reinert said, 'could be very severe' and could conceivably extend to compensatory damages and time in jail.

Mr Gottstein said that Eli Lilly has also warned him of possible 'disciplinary action at the bar.'

Eli Lilly, in email messages to the BMJ, states that it is pursuing action because 'these individuals have violated a federal court order by leaking the documents' and that it has not released its internal documents publicly because the company 'has no intention of violating that order by releasing documents ourselves.'

It added, 'We intend to try the remaining cases in court—not in the news media.' [end of BMJ quote]

This is a chilling development. It seems to me that patients, physicians, and the public ought to know whether Lilly marketed Zyprexa honestly, or whether it sought to deceive, and particularly whether it sought to suppress or manipulate data from trials on patients who thought that the information about them was to be used for the advancement of science, not commercial marketing purposes.

Lilly, of course, has a right to explain its actions, and defend itself from any allegations about its conduct.

But for a drug company to threaten whistle-blowers with "very severe" sanctions, including jail time, in a case like this does not exactly inspire confidence in their commitment to transparency, or to putting the welfare of patients, particularly patients in drug trials, ahead of marketing concerns.

Site: Electronic Frontier Foundation. No quotes here. Contents from some of the legal docs are provided here. If you’re really serious about this case, this is a great resource. It’s the site from whence the above picture came.

Zyprexa Play by Play

The New York Times has issued a play by play account of what has happened with those now famous Zyprexa documents. How the documents got released and by whom are contained therein.

In a manner more eloquent that I put it earlier...

On his TortsProf blog (snipurl.com/Torts), William G. Childs, an assistant professor at Western New England School of Law in Springfield, Mass., put it this way in a headline: “Judge Tries to Unring Bell Hanging Around Neck of Horse Already Out of Barn Being Carried on Ship That Has Sailed.”

Yeah, good point. Another ruling on access to said Zyprexa docs is expected on January 16th.

Breakin'

I'll likely be away from the blog for a few days. I also may take a few days to reply to emails and comments.

The Actonel Saga Continues

Dr. Aubrey Blumsohn continues his battle with Procter & Gamble. The short story is that Procter & Gamble appears to have cooked the data regarding its osteoporosis drug Actonel. Blumsohn was one of the authors on the Actonel work and when he made the audacious move to ask if he could see the data upon which his study was based, his request was rejected on multiple occasions. The documentation on his site is in-depth and if you have time to look around, I believe you will come to the conclusion, like Blumsohn did, that P & G indeed screwed with the data, which was one good reason for P & G to hide the data from the academics who are listed as the study authors.

Blumsohn is seeking to publicize the actual study data, yet P & G continues to play games. They are sticking with their line that the data are "proprietary," meaning that they want to stand by their apparently fraudulent analyses of the data and keep Blumsohn from re-analyzing the data for presentation and/or publication.

Please see his latest post and just dig around on his site for a while. You'll be amazed. If only all academics who were under the employ of drug companies kept such thorough documentation and were willing to take a stand.

Instead, we have many academics such as Graham Emslie, who openly admits that he withheld study data because it was negative to a sponsor. In a sense, I view Emslie somewhat positively for having the courage to say something. However, his remarks came after he sat on the negative data for years and there was no damage to be done since the sponsor, under intense pressure, appears to have released the previously suppressed data.

Australia Issues Slap on Wrist

A pharmaceutical trade group, Medicines Australia, has lightly punished some of its own.

The authority [Meedicines Australia] received 27 new complaints in 2005-06, with 11 found to be breaches and seven left unresolved. A third of the complaints were made by health care professionals, while a similar number were lodged by pharmaceutical companies about their competitors.

The allegations range from false advertising and claims about drug effectiveness to lavish entertainment of doctors.

The authority fined the pharmaceutical industry a total of $260,000 and ordered several companies to withdraw advertising from magazines.

Baxter Healthcare was banned from taking doctors on any more "educational" cruises.

Source.

Here's a quote from the Medicines Australia report:

In discussing the education provided at the function, the Committee expressed concern that no formal invitation had been provided for the meeting nor any formal agenda, which would have added weight to the justification that the primary purpose of the evening meeting was educational. Members considered it unfortunate that in the absence of any formal invitation or agenda, Baxter had had to ask several doctors, including the presenter, to provide testimonials to the Committee. This did not reflect well upon the industry.

Yeah, kinda hard to be eduational when it is apparent that there was no plan to educate prior to the event. If you went to class on a boat in which there was no planned agenda to teach you anything, that may actually be considered less than educational!

Just the Zyprexa Facts, Ma'am

Not the lies from the blogosphere (like this and this) and the New York Times. Taking a page directly from Wal-Mart, Lilly has now set up a website called Zyprexafacts.com. This strikes me as a bit of a desperate PR move by Lilly.

What’s on the site?

Well, on a few occasions, it makes statements like: “Illnesses that affect the brain, such as schizophrenia and bipolar disorder, are thought to be caused by certain chemicals in the brain being out of balance.” Please. There may well be brain issues in people with various “mental illnesses,” but this whole ‘chemical imbalance’ thing is 95% marketing, 5% science. Find a serious scientist who will step up to the mic and tell us about the definitive chemical imbalance that causes bipolar, schizophrenia, or much of anything else in the mental disorder world.

Check THIS out:

News reports claim that Lilly encouraged doctors to prescribe Zyprexa to children and elderly populations for non-approved uses. Is this true?

Lilly is committed to following the highest ethical standards and to promoting our medications only for approved uses.

However, it is important that the public understands physicians can and do prescribe medications outside the labeled uses. We believe that the final word on treatment and medication choices is well-placed in the hands of treating physicians who are best qualified to make the most informed decisions in prescribing medications for their patients.

It is important for doctors to be aware of information about medications, so they have the best available clinical data to help them make informed decisions when choosing a treatment for patients.

The statement that the final word on treatment rests with treating physicians is used repeatedly on the site. Obviously physicians write the prescriptions, but Lilly is helping to make doctors “aware of information” about medications (i.e., Zyprexa) to help them make “informed decisions” in prescribing medications (i.e., Zyprexa) for their patients (who may or may not have bipolar or schizophrenia).

You really should check out their Zyprexafacts site. It’s a laugh a minute. Remember that Lilly was able to push Prozac through the FDA based on the most meager evidence imaginable (Please see Breggin’s Talking Back to Prozac or Healy’s Let Them Eat Prozac – some of you might be having a cow that I’m citing Breggin, but his bit on how Prozac was approved is spot on), yet Lilly described Prozac as having an unprecedented amount of empirical support. We're not dealing with a company that has a history of honesty about its meds.

One more thing. Healy has also uncovered evidence suggesting that Zyprexa may be associated with suicidality. Perhaps Lilly can cover that on their website next.

Hat Tip: HealthCareVox.

Check Out the Health Wonk Review...

... and much more at Health Care Renewal. The HW Review has links to a number of interesting posts from various healthcare blogs.

There is also a great post regarding the head of the Massachusettes Biotechnology Council who has been convicted of obstructing justice, yet continues to serve in his executive role.

Also check out the post regarding William McGuire, the incredibly rich former CEO of United Health. I'll quote the snippet that made me want to wretch:

She says his income gives him extra credibility in health-policy debates because it shows his success. 'He needs to be compensated appropriately so that his business model has believability in the market,' says Ms. Mundinger [board member of United Health], who is dean of the nursing school at Columbia University.

Yeah, people wouldn't take McGuire seriously if he was not stocking away hundreds of millions in salary and stock options. These people live in a world so different than 99.5% of the population that we can't possibly understand them, and they, likewise, can't possibly understand us. Which would be fine, except that it is these detached from reality New Rockefeller Health Care Executive Robber Barons along with the legislators in their pockets who are determining the policies and costs of health care that affect everybody. Scared?

Metabolic Syndrome and SSRIs

A recent study (Raeder et al., Dec 2006, Journal of Clinical Psychiatry) indicated that SSRIs were associated with abnominal obesity and elevated cholesterol levels. There was a nonsignificant trend indicating that SSRIs may be associated with increased incidence of diabetes.

Which SSRIs? Citalopram (Celexa) was not associated with any of the risk factors studies, while paroxetine (Paxil) made out quite poorly. Due to a lack of large numbers of subjects on fluoxetine (Prozac), fluvoxamine (Luvox) or sertraline (Zoloft), people on these drugs were treated as one group, which was associated with increased abdominal obesity and elevated cholesterol.

Antipsychotics: Unsurprisingly, antipsychotic use was also associated with obesity and other health problems.

The authors suggest that SSRI-treated patients be monitored closely for the metabolic syndrome, which is a major risk factor for heart disease and diabetes. Sounds like a good idea.

My View on SSRIs: I’m not saying that SSRIs absolutely don’t work – they work a little bit better than a placebo. And placebo works pretty well, so you’re prescribing a nice-sized placebo effect with an SSRI.

Yet the cost is an elevated risk for suicide as well as potentially the risk for metabolic syndrome (though some research has indicated that SSRIs may actually improve metabolic health). The sexual side effects are also notable for many. The long-term outcomes with SSRIs appear poor.

One Drug For Another...

A recent study (Tiihonene et al., Am J Psychiatry 2007) compared aripiprazole (Abilify), methylphenidate (Ritalin) and placebo in the treatment of amphetamine addiction.

Here are the study results (quoting from the abstract):

Patients allocated to aripiprazole had significantly more amphetamine-positive urine samples than patients in the placebo group (odds ratio=3.77, 95% CI=1.55-9.18), whereas patients who received methylphenidate had significantly fewer amphetamine-positive urine samples than patients who had received placebo (odds ratio=0.46, 95% CI=0.26-0.81).

My problem with the abstract: The abstract concludes with a positive statement about methylphenidate, but says nothing about the drastic ineffectiveness of aripiprazole. I’ve not read the article, so I cannot say anything about what its actual text. I can say, however, that when a drug is related to drastically worse outcomes than placebo, as was the case for Abilify, then I think a statement should be put into the abstract’s conclusion about this finding. This is related to one of psychiatry’s big problems – focus on the positive (sometimes in a distorted manner), and ignore the negative. I’ll have to get the full text and look further.

Abilify’s performance: Why would people taking Abilify be so much more likely to use amphetamines compared to people taking placebo? Well, if I’m big into amphetamines and somebody puts me on a drug that includes sedation, akasthisia (extreme agitation), tremor, restlessness, and potential extrapyramidal symptoms (movement disorder) as side effects, I can see how someone who likes amphetamines might be tempted to jump back into the amphetamine habit.

Methylphenidate’s performance: Using a minor stimulant such as Ritalin makes some sense in that you’re following the same logic as replacing heroin with methadone. Replace a more dangerous habit with a less dangerous one. Ritalin might help some folks get the stimulant effect they’re looking for without the dangers of (meth)amphetamine use. However, there’s no free ride – there are likely some issues with long-term use of methylphenidate as well, though I’d rather be a regular Ritalin user than a so-called “Meth Head.”

One Quote Says It All

Dr. Graham Emslie, who has participated in a number of psychiatric drug trials for children, appeared in a brief interview clip on an Austin TV station’s investigation into SSRI use among children. Emslie was contracted by GlaxoSmithKline as an investigator in a study examining the effects of paroxetine (Paxil) on child/adolescent depression. As such, he was aware that data showed that Paxil was no more effective than a placebo, but (and here’s the killer quote):

I couldn’t talk about it because it was proprietary.

In other words, Emslie had an agreement with GSK that he would not share their trial data without GSK's permission, even when it showed that Paxil was no more effective than a placebo and related to poorer safety outcomes than placebo. This is what I have been beating the drum about repeatedly…

Of note, on his webpage, it is stated that Emslie "is known internationally for his work in the treatment of pediatric depression." Perhaps he should also be known as an academic who is willing to suppress results unfavorable to his corporate sponsors. Of course, Emslie should not be singled out; at least he had the courage to be interviewed. There are many other who have agreed to keep unfavorable data hidden.

Academics have increasingly become puppets of the drug industry. If you can’t share the negative results of your study, you are acting as a puppet. A well-paid puppet, but a puppet nonetheless. Science supposedly involves the disclosure of all of your data. Especially in the case of medicine, when scientific data are buried, people suffer and die needlessly. If anyone wants a good example of why industry and academia need to get out of their shared bed, this is it.

Thanks to AHRP for the link to the video and thanks to K-EYE TV in Austin, TX for running the story. Direct link to the video here.

SSRIs and the Zyprexa Docs

The AHRP blog is smoking hot with posts on SSRIs and the latest developments regarding the Zyprexa documents, which Lilly is still desperately trying to control.

There are links to several YouTube videos on SSRIs. I’ll be watching them in the near future – they sound tantalizing.

Roll on over to the AHRP site and check it out for yourself.

PharmedOut

On occasion, lawsuits bring great good to the people. PharmedOut is one such example. At this new site, you can see such jewels as:

• The Zyprexa drug rep video.
  
• Links to abstracts and articles on how the drug industry influences prescribing practices.
• A nice list of links to excellent websites covering said topics

Justice Alert: This program was funded as part of the settlement between Warner-Lambert (a division of Pfizer) and the attorneys general of all states and Washington DC. What settlement? The one regarding the blatantly misleading advertising for Neurontin.

If you are a blogger or journalist, please see if you can give PharmedOut a spot of coverage.

One of Those Feel-Good Stories

The Guardian has a neat story today about people with schizophrenia and depression who appear to benefit from playing soccer (football).

An Italian psychiatrist is obtaining startling results with patients suffering from schizophrenia and depression by enlisting them in a competitive football team. Mauro Raffaeli trains his players, many of whom cannot work and are on psychiatric medication, twice a week on a pitch on the outskirts of Rome.

Of the 80 who have passed through the ranks since the team formed in 1993, over half have cut down their drug intake, but more importantly, more than half have returned to work. "Drugs you can often never get rid of, but reintegrating into society is as important," he said.

Obviously, this is not tightly controlled research. But it does back my intuitive sense and observations as well as some research (the research is only relevant to people with depression) indicating that physical activity is good for one’s mental health. In this case, I think the combination of physical activity with teamwork helps to provide a sense of meaning – hey, I’m part of a team! People are counting on me. Et cetera.

I’m all for more creative interventions for schizophrenia and/or depression. The drugs and psychotherapy that are currently provided are unfortunately not getting the job done, so it’s nice to see someone trying something unconventional that is likely to not result in many adverse effects.

Check it out at the Guardian.

The Creativity Crisis Continues

I’ve mentioned this theme earlier. PharmaGossip and Merrill Goozner, among others have been banging this drum for much longer than I. The problem is that, on one hand pharmaceutical companies bemoan the allegedly huge costs of research and development. On the other hand, there have been a lack of innovative developments.

For example, the FDA has now approved Invega as a treatment for schizophrenia. The active ingredient?

“Although the drug contains an active substance never before approved by the FDA, that substance is an active metabolite of an old drug, the atypical antipsychotic Risperdal (risperidone), which is marketed for treating schizophrenia.”

Who developed Invega? Janssen, which also developed and markets Risperdal. Not coincidentally, Risperdal will soon be going off-patent. So, as generic competition swoops in, Janssen wants to keep its patients on its high-cost med, which, of course, is now switching from Risperdal to Invega.

Are there likely to be clinical advantages for Invega over Risperdal? Nope. It’s too similar to Risperdal to expect any notable differences. So, scientifically, it would have of course made better sense to develop something different, but this ain’t about science or benefiting patients…

Post Spree Blues

After going on a binge of posts yesterday, I've got a several more pressing issues to tackle today. So I refer y'all to the PharmaMarketing Blog and to Health Care Renewal, two sites where things have been moving and shaking with very interesting topics.

In addition, don't shirk your duty to vote for the Best of 2006 Medical Blog Awards, especially the best new medical blog award!

Zyprexa: $500 Million in Lawsuits

Lilly has agreed to shell out a half billion dollars to settle legal claims brought by those who claimed to be harmed by Zyprexa. There are 1200 more claims that will head to court in April, so the $$ to be paid out will nearly certainly increase. To nobody's surprise, Lilly has described the lawsuits as "baseless." Just like the last batch of "baseless" lawsuits that were settled for $700 million, I'm sure!

Source.

Selling Zyprexa

PharmaGossip has a great link to a video, purportedly of a Lilly drug rep discussing how he sold Zyprexa to docs. You should check out the full video, but I’ll provide two rough quotes from the video below:

1. Just drink a glass of water before a meal and another glass after the meal. That will counteract the weight gain with Zyprexa.

2. Statistics are like prisoners – torture them long enough and they’ll tell you whatever you want to hear.

NASW and Janssen: Strange Bedfellows

The National Association of Social Workers is coming under some serious heat from a group of its members. Why? Here’s the letter from the opposition group.

“On October 6, 2006, the National Association of Social Workers (NASW) sent to its Specialty Practice Sections on mental health and private practice an emailed “Invitation to Join The National Adherence Initiative for Schizophrenia.” An article in the November issue of NASW News also announces and describes the initiative.

The brief text in the email asked social workers to consider enrolling “in a nationwide data collection effort.” It stated: “Partial adherence is a significant problem in the treatment of schizophrenia … and can affect up to 75% of patients.” It invited participants to “identify up to 10 clients with schizophrenia that you feel are at risk for partial adherence.”

The last line of the text informed that this initiative “is sponsored by Janssen, L.P. in partnership with NASW.” The pharmaceutical company Janssen, a subsidiary of Johnson & Johnson, markets Risperdal (risperidone), an antipsychotic drug that grossed $2.3 billion in US sales in 2005. Social workers who enrolled received a packet from Janssen, with the “study instrument,” that spoke of nothing but the importance of drug treatment adherence for schizophrenia.”

Say what? Oh, it gets even more juicy.

“Treatment compliance is an old issue in schizophrenia care. Everyone in this field knows that antipsychotic drugs’ unpleasant effects make them extremely undesirable to patients. The Janssen initiative closely follows the government-sponsored CATIE studies’ findings that three quarters of patients on atypical antipsychotics such as Janssen’s Risperdal—falsely touted for a decade as vast improvements over older drugs—stop taking their prescribed medication because of “inefficacy, intolerable adverse effects, or other reasons.”

The study instrument mailed to social workers consists of eight “yes/no” questions, each describing a “deficit” in patients that would put them “at risk” of “partial adherence.” In our view, no information not already well known from dozens of previous studies on adherence to neuroleptic treatment, including the $45 million CATIE studies on nearly 1,500 patients, is likely to come from this Janssen-NASW study. The adherence initiative repeats that “partial adherence” is a significant problem in the treatment of schizophrenia—but the more significant problem lies rather with the drugs’ now well established ineffectiveness and adverse effects.

Why would Janssen be doing this? Pay close attention…

“Janssen’s exclusive patent to market oral risperidone will expire in 2007, and the company stands to lose significant revenue as cheaper generic versions come to market. Janssen is therefore now emphasizing the long-acting injectable version of risperidone, which it markets as Risperdal Consta—on which it still holds patent for several more years (and which sells for more than the oral version). The history of antipsychotic drug use shows that one notion, and one notion only, has ever justified using long acting injectable antipsychotics: adherence (compliance). In this light must Janssen’s “adherence initiative” be more fully appreciated.”

It appears that Janssen initiated contact with NASW on this matter and they allegedly made a contribution to the NASW foundation in return for this collaboration.

What was Janssen going to do with this information? I don’t know, but I’ll speculate they wanted to get patients to try out a Janssen product like Risperdal Consta or Invega (their “new” antipsychotic that is essentially a clone of Risperdal). I don’t know what the next steps will be – hopefully the social workers will respect patient confidentiality and not just start handing out names and contact information to “researchers.”

To summarize: Janssen gets a wild hair and contacts NASW, which agrees to participate in this “research” campaign to “help” patients, possibly in exchange for a donation from Janssen. There is little scientific knowledge to be gained from such a study, but Janssen gets to push its Risperdal Consta and/or Invega on what could be a large group of patients. Unfortunately, I’ve not been able to track down the full text of the email, but I’ll work on it and I’ll follow up the story as it develops.

Thanks to Writhe Safely for covering the story. Note that her site is not for those who are offended notably by profanity.

I NEED my Quell, Man!

Over at Furious Seasons, there is a great post about the possibility that for some, Seroquel might be addictive. Apparently, prison inmates are crushing and snorting Seroquel, or "Quell" as it's known in the clink. Ironic, given that Seroquel is being investigated as a treatment for addiction.

There have been a couple of documented cases of significant problems resulting from Seroquel withdrawal. Of note, there is very little research on any symptoms that may emerge as a result of discontinuing antipsychotic medication, especially for atypical antipsychotics. If nobody bothers to study the topic, then how would we ever know if "Quell" and perhaps some of its brethren cause nasty withdrawal effects? Of course, there's no money to be made by studying something as unsexy as withdrawal effects, so it probably won't be done.

There's much more over at Furious Seasons.

Newspeak Update:

There is yet another article in the New York Times on Zyprexa today. It is not flattering. To make a long and sad story short, a patient gained a lot of weight on Zyprexa (80 pounds over five years) and died of a heart attack. Granted, who knows if the Zyprexa was responsible for the weight gain and subsequent death, but it raises suspicions.

The part of the article I’ll focus on is the language used by Lilly in its response. As I’ve alluded to in a prior post, Lilly has trotted out Newspeak, or Maximum PR, to defend its drug. One of their statements regarding the latest incident was “Zyprexa is a lifesaving drug.”

Does Zyprexa save lives? As a class of drugs, atypical antipsychotics, of which Zyprexa is a member relate to a higher death rate compared to placebo for elderly patients with dementia. In schizophrenia, compared to clozapine, Zyprexa is associated with more suicide attempts. I am not familiar with any research showing that Zyprexa relates to fewer suicide attempts than any other treatment or less suicide than a placebo. Please inform me of any studies to the contrary – I could have missed something.

Enough about suicide. We know that Zyprexa can cause diabetes and we know that diabetes is not good for one’s health and life expectancy. Now, the clincher from the New York Times story today: “[Lilly’s] own clinical trials show the drug causes 16 percent of the patients who take Zyprexa to gain more than 66 pounds after a year.”

Yeah, that’s a lifesaver.

Hat Tip: Furious Seasons.

Time to Vote

Voting has begun and continues through Sunday January 14th. Your votes count as half and a panel of medical bloggers' votes count for half.

THE MEDICAL BLOG AWARDS OF 2006!

I have been nominated for best new medical blog and I'd appreciate your support. Head over to Medgadget and vote.

Guidelines Were Meant to be Broken

According to Bloomberg:

Companies that belong to the International Federation of Pharmaceutical Manufacturers & Associations must adhere to a revised code of ethics that bars them from giving doctors money or other gifts that might influence drug choices, such as paying for trips to golf resorts or luxury hotels. The code, updated Jan. 1 for the first time in a decade, applies to the group's 26 member companies, including Pfizer Inc., and hundreds of other drugmakers that belong to its 46 industry associations.

``What we're trying to do is prevent as many of the activities as possible that have not helped the reputation of the industry,'' IFPMA Director General Harvey E. Bale said in a telephone interview. ``We need to make sure the product is the best product for the patient and it's not influenced by gifts and it's not influenced by hospitality or vacations.''

SNIP

The IFPMA's new code limits companies to gifts that are work-related and of modest value, such as stethoscopes or medical dictionaries.

SNIP

Also covered in the IFPMA's revised code are the locations of medical and scientific meetings. These events shouldn't be held in ``renowned or extravagant venues'' and the hospitality shouldn't exceed what doctors would normally be willing for pay themselves, according to the code.

My View: Lipstick on a pig. If Lilly can claim with a straight face that Zyprexa does not cause diabetes, then I'm fairly sure any drug company can just redefine "extravagant,""work related," and "modest value" to suit their needs. The major medical conferences will still be largely supported through drug company funding and academics will still receive lavish salaries for working on drug company sponsored experimercials. There are still misleading journal ads, direct to consumer ads, and drug reps spinning off all sorts of half-truths (at best).

Hat Tip: Anonymous Reader and PharmaGossip.

Antipsychotic Newspeak

Not nearly enough space has been devoted on this site or others to discussing how manufacturers of antipsychotic medications have used euphemisms to gloss over the side effects of their products. No, euphemism is too weak. It’s much closer to Newspeak. If you’ve forgotten, Newspeak was the language used in Orwell’s classic ‘1984.’

Part 1: Zyprexa. Consider this. Lilly referred to Zyprexa (olanzapine) as a “safe, gentle psychotropic” in an attempt to lure more doctors into prescribing it for a broader variety of problems. I suppose they could have also said: “Zyprexa, It’s not just for psychosis anymore,” but that would not have been nearly as sexy. Lilly also recently said that there is “no scientific evidence establishing that Zyprexa causes diabetes.” As one of my readers pointed out in an email, that claim is reminiscent of Bill Clinton stating that that oral sex does not constitute “sexual relations.”

Here are some results from research regarding Zyprexa and diabetes. In one study, patients assigned to take olanzapine had a much higher rate of diabetes one year after starting medication compared to those talking Haldol. In another study, bipolar patients receiving either three months of meds or three filled prescriptions of meds had a much higher rate of diabetes on Zyprexa (as well as other atypical antipsychotics) compared to those receiving older, conventional antipsychotics. Another study also found elevated diabetes incidence with atypical antipsychotics compared to those who used Haldol. I could go on for much more space citing more and more studies linking Zyprexa to poor safety outcomes. You can also do it yourself. Go to PubMed. Type in “olanzapine and diabetes” (without quotes) into the search term box and look at the plethora of studies that demonstrate that Zyprexa causes diabetes. You don’t need a Ph.D. or M.D. to interpret many of the study abstracts. Go ahead, look for yourself, then reconcile your findings with the statement that Zyprexa does not cause diabetes.

Part 2: Risperdal. In a recent press release, Risperdal (risperidone) was referred to as a “broad spectrum psychotropic agent” thrice. Gee, that sure sounds better than “atypical antipsychotic,” right? It’s a clever marketing ploy as the term “broad spectrum” suggests that, wow, this med helps to alleviate a whole bunch of symptoms! Well, does it? I wrote at length about a recent study where Risperdal was used to treat depression. There was very little evidence that it actually helped alleviate symptoms of depression, as the only evidence that Risperdal may be effective came in a phase of the study that did not utilize any sort of placebo control. When the placebo was implemented, Risperdal did very little in comparison.

Does risperidone have evidence as a long-term treatment for bipolar disorder? Nope. There is some evidence for Risperdal in the short-term treatment of mania, though it is no more effective than (much less expensive) Haldol. There is certainly evidence that it has greater efficacy than placebo but it is not more effective than older meds in treating schizophrenia. There is no well-designed study addressing the use of Risperdal for anxiety and one placebo-controlled study showed that Risperdal was not effective in reducing cocaine cravings.

So, despite being labeled as a “broad spectrum psychotropic agent,” Risperdal only shows evidence of treating schizophrenia and short-term evidence of treating mania. That ain’t “broad spectrum” by any reasonable definition.

Zyprexa is a safe, gentle psychotropic and Risperdal is a broad spectrum psychotropic agent – psychiatry's Newspeak.

Paid to Take Meds?

From the Belfast Telegraph:

Mentally ill patients are being paid by the NHS to take their drugs in a radical experiment to improve compliance.

Four patients suffering from schizophrenia are receiving between £5 and £15 each time they have a "depot" injection - a long acting drug which is normally given once a month.

The payments handed out by the Newham Centre for Mental Health in east London have dramatically improved the patients' adherence to treatment and reduced the time they spend in hospital suffering relapses, and problems with neighbours and the police.

SNIP

The four patients in the study were cared for by an assertive outreach team and had a history of stopping their medication and getting into trouble. That changed when they were paid, with three of the four needing no hospital admissions, compared with between 80 and 362 days in the previous two years.

However, a survey of 150 team managers of assertive outreach teams revealed widespread distaste for the approach. Three-quarters said they objected to payments on ethical grounds - some objected because of the impact on NHS budgets.

It beats forced medication but still seems a bit on the odd side.

Zyprexa: Cat is Out of the Bag

One has to hand it to Lilly for using its lawyers to intimidate those who would dare to post its internal docs regarding the misleading and likely illegal marketing of Zyprexa. Over at the Alliance for Human Research Protection, Lilly’s tactics are documented for all who are interested. See these two posts (here and here) in particular. You can also check out the Zyprexakills website (little dramatic in the title, but it does grab one’s attention) for more.

This also jives with some of the buzz I’ve picked up from others who claim to have been intimidated by Lilly's attorneys. It would appear that Lilly is issuing injunctions to block anyone from displaying the documents. Lilly appears to have successfully scared many folks in that many links where the Lilly documents could be downloaded have vanished. Nice work fellas -- very Mussolini-like.

Nice, but too little too late. It is clear that many people have obtained the documents (one site indicated that at least 20-something people had downloaded the docs just from its site prior to the link being pulled). The temporary injunction protecting the documents expires today, though I would not be surprised if some other sort of legal protection was extended. Though Lilly is trying its best, the truth about Zyprexa’s misleading marketing and the coverup of its ill effects will be exposed. The New York Times got the ball rolling (here and here) and I don’t think that Lilly can stuff the cat back in the bag.

Oh, and if you are one of the aforementioned attorneys, don't bother injuncting me. There's nothing on this site that even suggests I have allegedly "improperly obtained" documents regarding Lilly, nor will you find any link to the documents here.

Will Dems Bring Change?

Bloomberg has a good article on some Democrats’ plans to change drug-friendly legislation and what might stop such reforms from occurring, from which I’ll quote:

Industry leaders including Jim Greenwood, the president of the Washington-based Biotechnology Industry Organization, say they expect the House to pass a change to the 2003 Medicare legislation that would let the federal government directly negotiate prices for the 22.5 million elderly and disabled citizens enrolled in the drug plan.

SNIP

It can take 60 votes in the Senate to consider legislation, and Democrats will have only a 51-49 majority; even if a measure got to Bush, he would probably veto it, Greenwood says. Overturning a veto requires two-thirds majorities in both chambers.

SNIP

Kennedy, 74, and the outgoing chairman of his committee, Wyoming Republican Senator Michael Enzi, 62, are working on a bill that places additional requirements on companies and the Food and Drug Administration for the advertising and monitoring of new drugs. And lawmakers including North Dakota Senator Byron Dorgan, 64, will push to let Americans buy cheaper medicines from Canada.

Lawmakers are also trying to design a process to allow FDA clearance of the first generic versions of major biotech drugs. Generic medicines often sell for about a third the price of brand-name products.

SNIP

``We are looking at supporting policy makers who share similar philosophies on access to quality health care,'' says Pfizer spokesman Jack Cox. Greenwood and Johnson say their groups and members are reaching out to more Democrats, and they expect industry political giving to shift.

``The Democrats want to leverage their power to generate some PAC donations from a very wealthy industry,'' Tufts University's Berry says. ``With one hand they're going to spank the industry, and with another hand they're going to hold their hands palms up.''

My View:Pay close attention to the last two paragraphs. Some Dems, like Waxman, are not likely to be bought off. Others are not so likely to resist the cash. Additionally, though the Decider in Chief does not like to use his veto very often, look for him to slap down any legislation that disses his pals in the drug industry. There may be some token reforms, but nothing meaningful is likely at this point.

Hat tip to PharmaGossip.

Atypical Antipsychotics: The Word is Spreading

PharmaGossip has a link to a good review regarding how atypical antipsychotics stack up to their much cheaper generic competitors. Suffice to say the review is not flattering, though I'd say it's more positive toward the atypical meds than is deserved.

Of course, I've been ranting about these overpriced, under-effective, and dangerous meds since the inception of this site in September 2006. We'll see when the results of research will be able to override the drug reps, infomercials, er, continuing medical "education", misleading journal supplements, and the like; in other words, how much research must be published showing the atypicals are overrated before prescribing practices change and serious resources are placed into researching better medications for psychosis?

More on the Seroquel BOLDERs

Dawdy over at Furious Seasons has corresponded with Dr. Michael Thase (see the entire post regarding the correspondence here), the lead author on the BOLDER II study, which I discussed earlier. My main complaint was that the study generated its effect sizes (the statistical measure of how large of an effect was generated by treatment) in an unconventional manner. They used a method called mixed model repeated measures analysis (MMRM). Let’s not get into the statistical details too deeply, suffice to say that this is not the conventional method for generating effect sizes.

One of Thase’s responses to questions regarding the effect size calculation was that MMRM is becoming “rapidly adopted as the method of choice for clinical trial data sets” – however, I have not seen it used to the extent that I’d call it the “method of choice.”

The main issue remains: the apparent magnitude of the effect of Seroquel on depressive symptoms increased by 50% when MMRM was used. That makes the treatment look more effective than when the more conventional method is used. Thase responded that “we did not report effect sizes using the [traditional] LOCF method largely because we didn't anticipate that someone would actually want to see them” – why wouldn’t people want to see them – given that the MMRM method inflated the apparent effect of the treatment by 50%, this is certainly news worth reporting in the article!

Mind you, the interpretation of effect sizes has always been based on traditional methods – we have no idea if the interpretation of effect sizes based on MMRM is accurate. I can buy into using MMRM as a method of testing statistical significance (was the treatment more effective than a placebo) but not into using MMRM to generate effect sizes (how much more effective was the treatment than a placebo). When a change of 50% can be seen in the magnitude of treatment depending on the type of analysis used, it is controversial and requires further explanation.

Thase has done a lot of good work and this post should not be taken as a personal attack on him. Indeed, I was glad to see him respond to Dawdy -- that is a good sign of collegiality and openness and he is commended for responding. I strongly disagree with the way data were presented and I don’t buy Thase’s argument that the traditional analysis was just not interesting enough to publish.