Pfizer: Who Needs New Drugs

...when you can just market existing drugs for new indications? I heard on NPR Marketplace earlier that Pfizer's current strategy is to focus on getting their current product line marketed for more indications rather than developing newer meds. Does this kind of admission bother anyone?

PharmaGossip has written about this issue on occasion (such as here), pointing out that there is only so long that the drug industry can run around in circles. Research money needs to start going toward developing new meds that add a significant benefit beyond existing products rather than creating me-too's or new drug classes that actually add little to existing treatments.

Remember, when you hear PhRMA waxing poetic about how much money is spent on R & D, a large chunk of that money is going to conduct studies showing that existing product X is roughly as effective as drugs A, B, C, and/or D in treating condition Y. That is the kind of research that generally does little to improve patient outcomes.

Is Neuronetics Hiring?

According to some, Neuronetics, manufacturer of transcranial magnetic stimulation devices to treat depression, is looking to boost its sales force. I've previously commented that TMS is in a bit of a bind at FDA currently (the suspense of the impending approval decision must be killing them) and that Neuronetics does a good job of monitoring any posts relevant to their product.

Even More Suicide Attempts in Clinical Trials with Paroxetine…

The full title of the article published in BMC Psychiatry is “Even More Suicide Attempts in Clinical Trials with Paroxetine Randomised Against Placebo.” The authors are Aursnes, Tvete, Gaasemyr, & Natvig. They performed a Bayesian analysis (a form of statistical analysis) on whether paroxetine (Paxil/Seroxat) is related to an increase in suicides in clinical trials. Here’s what they had to say, starting with some background:

“Last year we wrote a paper ‘Suicide attempts in clinical trials with paroxetine randomised against placebo’ [1] that hit the front pages of newspapers worldwide [2,3]. Our publication demonstrated an increased intensity of suicide attempts per year when using paroxetine compared to placebo, and caused GlaxoSmithKline (GSK) to come up with a comment [4]. Since then GSK has provided additional data to the American Food and Drug Administration (FDA), as the agency required new documentation on paroxetine. This also resulted in a Briefing Document from GSK [5] in which they admit that there is an increased risk for suicide attempts associated with paroxetine.”

Then the authors mentioned that, in the current study, “We analyzed the data GSK presented in their latest report by the same Bayesian approach used by us in our article. We included only the double blind, parallel design studies with patients randomized to either paroxetine or placebo, as recognized by GSK in the Briefing Document. These 19 studies contained 3455 and 1978 patients to the treatment and placebo groups, respectively. They resulted in 11 and 1 suicide attempts, respectively, as compared to 7 and 1 in our study. The studies lasted 6 – 12 weeks, and we obtained 601 and 333 patient years in the treatment and placebo groups, respectively.”

What did they find?

“We found that the posterior probability that medication with paroxetine is associated with an increased intensity per year of a suicide attempt is 0.99 with the pessimistic prior, 0.98 with the slightly optimistic prior and 0.99 with the slightly pessimistic prior. Hence, we can be at least 98% sure that paroxetine increases suicide attempts. This is stronger evidence than the p value equal to 0.058 given in the Briefing Document [5].”

I am not a Bayesian statistician, so I can’t necessarily critique their method very well. I can tell you that these conclusions match fairly well with evidence marshaled by Healy and others that paroxetine (as well as other SSRIs) are indeed related to an increased suicide risk. Feel free to read other posts (here, here, here, and here) and their related sources. At that point, I think you will see that, based on clinical trial data, there is indeed a greater risk for suicide on SSRI than placebo.

Uh Oh Chuck They Out To Get Us Man: Stats

This is the third (and perhaps final) post in a series on a study recently published in Neuropsychopharmacology which used risperidone (Risperdal) as an add-on treatment for depression. The study had three phases, as follows:

1) Participants who had not responded to 1-3 antidepressants other than (es)citalopram (Celexa or Lexapro) for > six weeks were assigned to open-label citalopram (Celexa) treatment for 4-6 weeks

2) Patients who failed to respond to citalopram were then assigned to open label risperidone (Risperdal) augmentation (add-on) treatment for 4-6 weeks

3) Patients whose depression remitted were then assigned to 24 weeks of either risperidone + citalopram or citalopram + placebo and the differences between risperidone and placebo for depressive relapse were examined.

Let’s start with examining the differences between the trial report found on clinicaltrials.gov and the trial as published in Neuropsychopharmacology. The clinical trials report indicated that the primary outcome measures were: a) change in Montgomery-Asberg Depression Rating Scale (MADRS); b) time to relapse, as measured by Hamilton Rating Scale for Depression and Clinical Global Impression (CGI) scores.

Secondary measures include: a) Response rate, measured by at least a 50% improvement in MADRS score; b) Change in Hamilton Rating Scale for Depression (HAM-D) and c) Clinical Global Impressions (CGI) scale scores.

Now, to the journal report. Under the results for the open-label risperidone augmentation, on page 9 of the early online version of the study, it is stated that the MADRS was “the primary measure used to assess depression severity.” Nowhere are the results of the MADRS response criteria (>= 50% change in MADRS scores) reported. Where did this go? If this was a predetermined test of treatment response, shouldn’t it be reported? While means and standard deviations of the MADRS are reported, the alleged measure for treatment response is strangely missing.

It’s also unclear what happened to the CGI scores, as means and standard deviations for this instrument are not reported anywhere. It’s mentioned that scores on this measure were used as one measure of relapse, but the means and standard deviations are missing.

Under the results from the double-blind continuation phase, we can see that the rate of relapse was 53.3% for risperidone and 54.6% for placebo. The time to relapse was 102 days for risperidone augmentation and 85 days for placebo augmentation, for which the associated p-value was .52. But a post-hoc analysis found the p-value of the difference in time to relapse was p <.05. The authors state that this difference was found because they switched to a linear ranks test. I’m no expert on this test, so I can’t make a judgment, but I can say that I’m suspicious any time a p-value goes from .52 to .05 just by switching statistical tests. At the very least, an explanation in the article is in order, as it is noteworthy that just switching a statistical test made such a change in results.

Post-hoc analysis part 2. An additional post-hoc analysis was conducted using the subgroup of patients who were fully nonresponsive to citalopram monotherapy. In other words, the people who showed the poorest response to SSRI treatment were examined in separate analyses. Their median time to relapse and relapse rate were reported as significantly different, in favor of the risperidone group. The relapse rate was 56% in the risperidone group and 64% in the placebo group. The associated p­-value was reported as .05. However, I conducted my own analysis and came up with Chi-Square = .922 and a p-value of .337. It is mentioned earlier in the paper that the authors used the Cochran-Mantel-Haenzel test and this explains how the p-value shrunk drastically. Again, a post-hoc analysis was conducted which changed the results substantially, yet the authors did not discuss reasons behind these large discrepancies. What this would appear to mean is that time to relapse differed substantially more than chance depending on the site where patients received treatment. The CMH test stratified by treatment site, which I believe would then account for differences due to treatment site. If treatment response really was dependent to a significant extent on the treatment site, this bears mention in the article, but such a discussion is nowhere to be found.

Table 2. The results here are quite interesting. This refers to the double-blind section of the study in which patients who had shown symptom resolution while receiving risperidone were randomly assigned to continue risperidone or to receive placebo. On the MADRS, patients receiving risperidone, on average, gained 11.2 points (i.e., their depression worsened by 11.2 points), whereas patients on placebo gained 10.4 points. Thus, there was a slight, but certainly not significant, difference in favor of persons on placebo worsening less than persons on risperidone. On the HAM-D, patients receiving risperidone worsened by an average of 7.6 points whereas they worsened by an average of 7.9 points on placebo. Between the two measures, it is clear that on average, there was very little difference between risperidone and placebo. However (and take out your notepads, please), patients in both groups got significantly worse over time in the third phase of the study. Thus, the scenario for the average patient is that he/she sees a relatively brief improvement in symptoms while taking risperidone then returns to a period of moderate depressive symptoms. The authors do not discuss that mean scores between groups did not differ at all in the third phase of the study.

The only evidence to emerge from this study, really, is that an open-label treatment resulted in a decrease of symptoms. If Janssen really wanted to impress, they would have included an active comparator. Say, an older antipsychotic, a so-called “mood stabilizer,” or perhaps another atypical antipsychotic. Or, if not feeling daring, at least add a placebo to the mix. Based on the study results, we cannot even conclude that risperidone augmentation worked better than adding a sugar pill to SSRI treatment.

In summary, it is unknown what happened to some of the secondary outcome measures (CGI scores, MADRS response rate) and the statistical analyses used in some cases required more explanation, as their use led to a big change in interpretation of the results.

So what do we have here? I believe this is an excellent example of a study conducted for marketing purposes. I bet that many reprints of this article have been purchased by Janssen, which will be passed on by cheerleaders, er drug reps, to physicians in a ploy to market Risperdal as an adjunctive treatment for depression. Additionally, there are likely “key opinion leaders,” perhaps including some of the study authors, who are willing to stump for Risperdal as an adjunctive treatment for depression at conferences, meetings, and dinners. With this study now published in Neuropsychopharmacology, there can be little doubt that such marketing strategies now have a glimmer of scientific sparkle on their side, although upon closer examination, the scientific evidence is very weak at best. Yet too few doctors will bother to perform closer examination of the meager science behind the marketing as the atypical antipsychotics continue their march toward rebranding as “broad spectrum psychotropic agents,” as Rispserdal was referred to in this press release regarding the present study.

I encourage interested readers to also check out my earlier posts regarding the questionable authorship of the paper (possibly involving magic!) as well as the rather blatant undisclosed conflicts of interest associated with the study. This is so distressing that I think I’ll have to chill out with a couple of Quaaludes, er, earlier versions of broad spectrum psychotropic agents.

How About Another Atypical Antipsychotic?

Pfizer says NO!

"Akzo Nobel NV said its unit Organon and Pfizer Inc agreed to end their collaboration in the further development of antipsychotic drug asenapine, but this will have no effect on the planned stock market flotation of Organon.

Pfizer's decision to discontinue its participation in the asenapine development program 'is an outcome of a commercial analysis of the compound as a part of its overall portfolio,' the companies said."

Organon will continue to develop the product regardless of Pfizer's lack of collaboration. According to www.Clinicaltrials.gov, there are 19 studies that have investigated the drug or are currently recruiting patients. Looks like Organon is swinging for both bipolar and schizophrenia. However, is this compound not late to the game? The atypical market is flooded and I'm going to boldly predict that asenapine will work no better than any existing product. It's going to take a whale of a marketing effort to push this one to importance. For Organon's sake, I hope they can get a better market share with asenapine than they did with mirtazapine (Remeron).

Source.

Way More on the Fiorello Fiasco

It appears that the Fiorello story (discussed here) has wings. Check out the post at PharmaGossip for more.

Brits Jump on CUtLASS -- Finally!

Apparently, the British press has decided that a study showing equivalent efficacy between first and second generation antipsychotic meds is worthy of discussion a few weeks (about seven weeks, actually) after the publication of the study. The American media: nowhere to be found, of course, with the possible exception of the New York Times.

Over at Furious Seasons, you’ll find a good synopsis of some of the larger issues surrounding atypicals. I believe many readers will find his points of interest. Teaser below…

"This is now the third study in about a year to knockdown the prevailing orthodoxy that atypicals reduce symptoms better than first-generation antipsychotics and that the atypicals are so kinder and gentler with the side effects. I have discussed the CATIE study here and here.

All of these studies combined raise serious questions. Here are a few:

Why do pharma companies continue to charge anywhere from 8 to 20 times as much for atypicals as they do for older antipsychotics? Because they can and no one will question them on it.

Why do doctors continue to insist, in the face of compelling data, that atypicals are great? Because they can and no one will question them on it.

Why did NAMI National put out a press release and organize a teleconference for reporters soon after this Archives of General Psychiatry study called the status of atypicals into account? Because they can and no one will question them on it. And, NAMI National gets a lot of money each year from pharma companies. Any connection?

Why have these same atypicals suddenly become frontline treatments in treating bipolar disorder, despite a profound lack of independent evidence showing that these meds are good for schizophrenics and that those poor folks can barely tolerate taking them? Why would they suddenly become so "good" for bipolars? Hell, they don't even reduce re-hospitalization rates compared to only taking a mood stabilizer. Bipolars don't particularly fancy these meds, either, as I pointed out last year.

Why are we now giving them to children? Why are their parents going along for the ride?"

For much more, interested readers should take a hike over to the post at Furious Seasons.

For my take on the CUtLASS study, feel free to read here.

Seroquel Says Sorry (Sort of)

LONDON (MarketWatch) -- Anglo-Swedish drugmaker AstraZeneca PLC (AZN) Monday said it will work with the U.S. Food and Drug Administration following a warning over promotional material for antipsychotic drug Seroquel.

The FDA warning, issued on Nov. 16, stated that Seroquel sales material distributed by the company was misleading because it minimized information about certain risks contained the the drugs' labeling.

AstraZeneca said in an emailed statement that the sales material was accompanied by a copy of the FDA-approved product labeling, which includes the complete warnings and precautions.

"AstraZeneca takes FDA's letter seriously. We will work with the FDA to resolve the matter," the company said.

Seroquel, which is used to treat schizophrenia and bipolar disorder, is AstraZeneca's second best-selling drug, with sales of $2.8 billion in 2005."

Source: MarketWatch

Cyberonics Gets Nailed!

Health Care Renewal has a great post discussing Cyberonics executives cheating on stock options...

"Two top executives have exited Cyberonics, after it disclosed that its stock options problems are much broader than previously reported.

On Monday, investors bid up shares of the Houston-based medical device maker, which said Chairman and CEO Robert Cummins and Chief Financial Officer Pamela Westbrook resigned.

The duo was replaced, on an interim basis, by three people: Tony Coelho as chairman, Reese Terry Jr. as chief executive and John Riccardi as chief financial officer. George Parker was appointed as interim chief operating officer.

The personnel changes came as Cyberonics reported widespread stock option problems in a filing Friday with the U.S. Securities and Exchange Commission..."

--SNIP--

"It's funny how questionable financial practices seem to go hand-in-hand with dodgy marketing and strange science."

Indeed. Check out the full story here. No word on how this may impact Charles Nemeroff.

More Antipsychotics for Kids

In an earlier post, I mentioned that it appears that antipsychotic use among kids has risen drastically in the past few years. Well, another study (here and here) indicated that AP use among kids increased 500% from the two year period of 1993-1995 compared to 2002. Yeah, you read that correctly. Five Hundred Percent. Five-Fold. No, I'm not kidding. And their use continues to rise.

This is not based on much evidence that these meds are more effective than older meds, like lithium or older antipsychotics. Nor is the safety data particularly compelling.

NYT: Kids Taking Lots of Psych Meds...

...despite a lack of evidence that polypharmacy is a good idea.

"Last year in the United States, about 1.6 million children and teenagers — 280,000 of them under age 10 — were given at least two psychiatric drugs in combination, according to an analysis performed by Medco Health Solutions at the request of The New York Times. More than 500,000 were prescribed at least three psychiatric drugs. More than 160,000 got at least four medications together, the analysis found.

Many psychiatrists and parents believe that such drug combinations, often referred to as drug cocktails, help. But there is virtually no scientific evidence to justify this multiplication of pills, researchers say. A few studies have shown that a combination of two drugs can be helpful in adult patients, but the evidence in children is scant. And there is no evidence at all — “zero,” “zip,” “nil,” experts said — that combining three or more drugs is appropriate or even effective in children or adults."

--SNIP--

"The use of two-medicine combinations in children is on much shakier ground. Even for single drugs, the effectiveness of some psychiatric medications in younger patients is questionable: most trials of antidepressants in depressed children, for instance, fail to show any beneficial effect. But hardly any studies have examined the safety or the effectiveness of medicine combinations in children. A 2003 review in The American Journal of Psychiatry found only six controlled trials of two-drug combinations. Four of the six failed to show any benefit; in a fifth, the improvement was offset by greater side effects.

“No one has been able to show that the benefits of these combinations outweigh the risks in children,” said Dr. Daniel J. Safer, an associate professor of psychiatry at Johns Hopkins University and an author of the 2003 review. [To read a great article by Dr. Safer regarding the influence of drug companies on research outcomes, check this out.]

If the evidence for two-drug combinations is minimal, for three-drug combinations it is nonexistent, several top experts said.

“The data is zip,” Dr. Hyman said."

The article mentions a few cases, one of which is mentioned below...

"Fate Riske, 3, of Fond du Lac, Wis., takes two antipsychotics and a sleeping medicine to control what her mother, Elizabeth Klein-Riske, said were hours-long tantrums, a desire to watch the same movies repeatedly and an insistence on eating the meat, cheese and bread in her sandwiches separately.

On a recent visit, Fate played sweetly for four hours as her parents, who both have trouble walking, sat in front of a television. Sucking on a pacifier, Fate showed off her pink dress and matching shoes.

Mrs. Klein-Riske credited the drugs for Fate’s cherubic behavior during the visit. But a few weeks on a different antipsychotic led Fate to become aggressive, talk rapidly and “run around wild, totally out of control,” said Mrs. Klein-Riske, who receives government financial and child-care assistance because her daughter is considered mentally ill.

Fate’s weight ballooned in five months to 48 pounds from 30."

So a three year old is taking two antipsychotics? Sounds kind of like the kid is acting like a three year old to me! OK, her behavior probably is worse than the average kid, but there should be more behavioral interventions before digging into the polypharmacy chest, don't you think?

Later on,

"Antidepressants are commonly paired with stimulants, but antidepressant use has declined over the last year after the F.D.A. warning about suicide risk. In their place, physicians are prescribing combinations that include antipsychotic and anticonvulsant drugs, according to Medco. From 2001 to 2005, the use of antipsychotic drugs in children and teenagers grew 73 percent, Medco found. Among girls, antipsychotic use more than doubled."

Read the whole thing here.

AstraZeneca: Slapped Over Seroquel

According to a report today, the FDA fired a warning at AZ over Seroquel, their blockbuster treatment for bipolar disorder and schizophrenia. Here's what MarketWatch had to say:

According to the warning letter posted on the FDA Web site Wednesday, the sales material "minimizes the risk of hyperglycemia and diabetes mellitus and fails to communicate important information regarding neuroleptic malignant syndrome, tardive dyskinesia and the bolded cataracts precaution."

Blumsohn Keeps Fighting...

...and Procter & Gamble keeps hiding (data, that is). To very briefly summarize, Blumsohn would like P & G to retract a misleading (at best) paper and provide the journal in which the data were published with relevant study data, yet P & G refuses to do so. As Blumsohn states in his latest post "As stated, the main purpose of this letter is to revisit your earlier refusal to allow the data provided in April to be scrutinized in an open manner. Your refusal to allow the data to be transmitted to a journal editor accompanying a properly corrected manuscript is not appropriate. A journal editor can request raw data from an author at any time, and such refusal (particularly under the circumstances of this case) would be inappropriate." Basically, the evidence indicates that the P & G data are incorrect in the published report referenced by Blumsohn. And not just off by a bit -- we're talking a drastic difference here!

In addition, the Journal of Bone and Mineral Research (where the disputed paper was published) appears to have handled the situation quite poorly, as they continue to drag their feet on retracting the manuscript (see here and here) despite a good deal of evidence (here, for example) that the manuscript was fraudulent.

Spread the word, folks! This stinks on many levels and those involved should receive as much negative publicity as possible. Hopefully, added attention will lead P & G to start behaving responsibly. Blumsohn has voluminous documentation regarding this case at his site, which I think everyone should be reading regularly. Check out his latest post for a copy of his latest letter to P & G:

Scientific Misconduct Blog: Procter & Gamble - Let's take the high road

Bribery Pays

Caught double dipping...

"The former chief pharmacist for the state Public Welfare Department, who earned extra income from sources that included two drug manufacturers, was charged Tuesday with crimes that carry potential prison time.

Steven J. Fiorello, of Palmyra, was fined more than $27,000 last year by the State Ethics Commission for using his position to get consulting work. He was arraigned Tuesday on criminal charges for the same activity.

"Pennsylvania law very clearly prohibits state officials from using their public positions for personal financial gain," said state Attorney General Tom Corbett. "Accepting illegal payments and then failing to report them is not only a conflict of interest, but also a violation of the public trust."

Fiorella was arraigned Tuesday on two felony counts of conflict of interest, which each carry a maximum five-year prison term and $10,000 fine, and misdemeanor counts of accepting honoraria and failing to disclose income on annual statements of financial interest.

--SNIP--

Fiorello, 59, served as pharmacy director for the welfare department's Office of Mental Health and Substance Abuse Services for several years. He left state government and now works in the pharmacy industry as a consultant, his lawyer said. He already paid Ethics Commission fines totaling $27,269 in April 2005.

Fiorello allegedly accepted more than $10,000 for consulting work he did and trips he took between 1998 and 2003 for various companies, including the Pfizer and Janssen drug companies, according to court papers."

Nice work if you can find it, especially if you can get away with it, which is looking increasingly doubtful for Mr. Fiorello.

Source: BusinessWeek

Reading more, I found that...

"Fiorello was employed as the Director of Pharmacy for the Pennsylvania Department of Public Welfare's Office of Mental Health, Substance and Abuse Services. As part of his responsibilities, Fiorello served on a committee that decided which drugs would be used for mental health treatment in all state hospitals - decisions which guided more than $9 million in annual drug purchases by the Commonwealth."

And a third source said that:

"According to former investigator turned whistleblower, Allan Jones, PA taxpayers are saddled with an expensive drug treatment model known as PennMap, for the treatment of mentally ill persons in state care.

"This model is part of a large pharmaceutical marketing scheme designed to infiltrate public institutions and influence treatment practices," he explains, "Pennsylvania is paying tens of millions of dollars for patented drugs that have no proven advantage over cheaper generic drugs." [See here and here for examples on this point]

As part of the overall scheme, on July 27, 2001, Tom Ridge appointed Gerald Radke, an Eli Lilly Marketing Director, to head the PA Office of Mental Health and Substance Abuse. With Radke at the helm, PA Medicaid funded sales of Lilly’s Zyprexa rose from approximately $26.5 million in 2000 to $34.2 million in 2001, and reached $39.2 million in 2003. In state hospitals, hundreds of patients had their medications switched in the absence of medical need or indication, to comply with administrative decisions."

OK, the third source is an article by Evelyn Pringle, with whom I have some credibility issues (see here), but if her story is even close to accurate, then it looks like the money given to Fiorello by drug companies was a GREAT investment. Pay him a few measly thousand dollars and suddenly atypical antipsychotics are everywhere in the PA mental health system, which is of course worth millions.

FDA: Pay Per DTC Ad Policy

Over at the PharmaMarketing Blog is a story regarding the FDA's plan to charge the drug industry $40-50k per direct to consumer television ad. Is the industry expecting something in return? Check it out here.

Atypical Antipsychotics vs. Older Meds: $$$

I have seen various estimates in the media that have generally capped out at a ten-fold increase in price for atypical antipsychotics compared to older meds. However, I'd seen figures a few years ago suggesting a much larger price gap, so I thought I'd do some digging.

Here's what I found on Walgreens.com. These are monthly costs.

Olanzapine (Zyprexa) 15mg: $554.98
Risperidone (Risperdal) 4mg: $331.09
Quetiapine (Seroquel) 500mg: $519.77
Aripiprazole (Abilify) 20mg: $518.99
Ziprasidone (Geodon) 100mg: $483.08

Compared to:
Haloperidol (Haldol) 5mg : $10.89
Perphenazine 16mg: $29.83

Looking like a lot more than a 10-fold difference in price, eh?

Now, let's add in benztropine to control for some of the side effects commonly seen on haloperidol or perphenazine.

Benztropine 2mg: $12.09

We get a total of Haldol + benztropine of $22.98 per month and perphenazine + benztropine of $41.92. Thus, the cheapest new AP (Risperdal) is eight times as pricey as perphenazine + benztropine. Most of the comparisons with Haldol suggest that the price difference, even including benztropine as an adjunctive medication, is at least 20-fold. With perphenazine + benztropine, the difference decreases to 10-13 times as expensive.

The doses I used were from gleaning doses that were used in clinical trials.

We know, however, that the atypical antipsychotics are not 10-20 times more effective than older meds; indeed, there is little reason to suspect they are much more effective at all in comparison to older meds, as can be seen here, here, here, and here.

Uh Oh Chuck They Out To Get Us Man: COI

This post (similar to a previous post) centers on a study for risperidone as an add-on to SSRI treatment for depression.

The current post focuses on the failure of some authors to disclose their conflicts of interest. When the advance online publication of the article is examined, the only author listing any financial support is lead author Mark Hyman Rapaport, who lists four grants and a chairmanship. Janssen funded the study according to an earlier abstract version of the study, so it is curious that Rapaport did not list Janssen as a financial supporter. Rapaport was not alone in his failure to disclose. Nemeroff (the last author) and Keller (fifth author) clearly had conflicting interests that should have been declared.

Let’s start with Nemeroff. He is the editor of the journal (Neuropsychopharmacology) in which this article appeared, so he should be familiar with the journal's conflict of interest policy, which states in part: “At the time of submission, each author must disclose any involvement, financial or otherwise, that might potentially bias their work. The information should be listed in the Acknowledgements that appear at the end of the manuscript and noted in the authors’ cover letter.” The policy is pretty clear – so does Nemeroff have a significant conflict of interest in this case?

In the Journal of Clinical Psychiatry Supplement 8 from 2005, the conflicts of interest section mentions that, among Nemeroff’s quite numerous funding sources, Nemeroff has received grant/research support from Janssen, is a consultant for Janssen, and is a member of the speakers bureau for (you guessed it) Janssen, which is the company marketing Risperdal. In the same supplement, which was derived from a “planning roundtable…supported by an educational grant from Janssen Medical Affairs,” Nemeroff penned a review article that reflected favorably upon risperidone, as well as some other drugs. So it’s pretty clear that there was a conflict of interest here – it’s just that editor Nemeroff did not enforce his journal’s policies upon himself. Of course, this is not the first time such behavior has occurred. You can read about a similar failure to enforce editorial policies involving Nemeroff here and here.

But wait, there’s more! Nemeroff actually violated another of his journal’s policies, the one about duplicate publication of data.

On the Neuropsychopharmacology author instructions page, right under Nemeroff’s name as editor of the journal, you can see the following: “Submission is a representation that neither the manuscript nor its data have been previously published (except in abstract) or are currently under consideration for publication.” Nemeroff, in the aforementioned 2005 Journal of Clinical Psychiatry Supplement 8 wrote no less than five paragraphs describing the risperidone add-on study’s data, which was later published in Neuropsychopharmacology. So Neuropsychopharmacology’s editorial policy is that study data should not have been published earlier except in abstract form, but Nemeroff wrote about it for much longer than an abstract in a supplement paid for by Janssen, yet felt free to flout editorial policy regarding prior publication. This, of course, comes in addition to an egregious failure to disclose conflicts of interest.

What is the penalty for such behavior, one might ask? “An accusation that an Editor…has violated the conflict of interest policy shall be referred to the ACNP Ethics Committee for consideration and investigation. The Ethics Committee shall report its findings and recommendations to the Publications Committee and Council for action… an Editor…found guilty of violating the conflict of interest policy is subject to sanction, including forfeiture of the editorship.”

Don’t worry – Nemeroff is one step ahead of the game here – he chose to resign his editorship over the previous scandal involving his pimping of vagus nerve stimulation therapy, which you can feel free to read about here. No, Nemeroff did not state that he was leaving the editor position as a result of the VNS debacle, but the timing seems to reflect more than a coincidence.

To summarize briefly, Nemeroff had a blatant conflict of interest which he did not declare. He is also the editor of the journal in which the article appeared where he did not disclose the COI. In addition, he ignored his journal’s prohibition on prior publication of data. As the editor, he should obviously know much better. Indeed, it is difficult to believe that this was an oversight. It appears that Nemeroff was playing the role of marketer for risperidone as opposed to carrying out his duties as an editor.

How about Martin Keller? In that same 2005 supplement of the Journal of Clinical Psychiatry mentioned above, Keller is listed as having received honoraria from Janssen and as being an advisory board member for Janssen. Keep in mind that whatever work he conducted at the “planning roundtable” upon which the supplement was based was also funded by Janssen. Yet no mention of any financial support from Janssen is provided in the Neuropsychopharmacology article.

Apparently, perhaps due to Nemeroff’s earlier brush with the spotlight regarding his marketing of VNS therapy in the journal in which he edits [an article in which blatant conflicts of interest were not disclosed], the authors thought better of the conflict of interest issue. A corrigendum (correction) is displayed in the November print edition of Neuropsychopharmacology that lists disclosures for Nemeroff, Keller, and Rapaport. But if you are obtaining the article through online access (which is likely true for most people), then you won’t find the correction because it is not included in the pages of the article. Eventually the correction will be picked up on Medline, but many readers will not notice it.

Add the failure to disclose conflicts of interest to the shifting authorship line mentioned earlier and you can see why I am feeling a little skeptical. Of course, given some of Nemeroff’s past ethical issues (here and here), this is not entirely surprising. The last chapter in this tale, regarding the risperidone augmentation study’s data analysis will be told shortly.

Required Reading on Mifepristone (RU-486)

Health Care Renewal has a supremely excellent tale in the mifepristone saga that you simply must read.

Teaser...

..."Looking at the new report, one sees in the Acknowledgements that the first author was supported by Corcept. One also sees that a co-author, E. Ronald de Kloet, failed to disclose his relationship to the company: he is a member of Corcept’s scientific advisory board and, unless he has sold any, the owner of 60,000 shares of Corcept stock. One also sees that this basic science article is careful to follow the company’s marketing message and branding language on the putative efficacy of mifepristone for PMD. For instance, it states, “The glucocorticoid receptor antagonist mifepristone has been shown to rapidly and effectively ameliorate symptoms of psychotic major depression.” These basic scientists also stated, “recent clinical studies have shown that the glucocorticoid-receptor (GR) antagonist mifepristone relieves symptoms of psychotic depression after a remarkably brief treatment period of 4 or 8 days.” None of the cited studies shows anything of the sort. We then read, “… similarly to its clinical efficacy, mifepristone’s effects on adult neurogenesis are rapid and positive, and may therefore be important for its mechanism of action.”

What is the deal with "similarly to its clinical efficacy" -- there is no proven clinical efficacy. The post goes on to discuss how the article makes for great marketing copy (which was likely its intent all along). A basic scientist can play marketing waterboy as well as the clinical trials folks!

Link to the excellent HC Renewal post here. More on mifepristone here and here.

Seroquel Clinical Trials Update

Over at Furious Seasons, you’ll find an excellent post about the clinical trial mania (pardon the bad pun) regarding Seroquel. Basically, Philip Dawdy went to the government’s clinical trials site and saw what was happening with Seroquel trials. The drug industry always talks about how much money it spends on research and development, yet if this is what counts as R & D, it is no wonder many people are not swayed by the industry that R & D consistently yields great new medications. Why develop new meds when you can just market existing drugs ad nauseum. Here are some of the trials that he found…

"Quetiapine (Seroquel) Maintenance Treatment in Early Onset Bipolar Spectrum Disorders" in 12 to 20 year olds

Quetiapine Fumarate (SEROQUEL) Compared to Placebo in the Treatment of Children & Adolescents With Bipolar I Mania" in 10 to 17 year olds

Quetiapine for Mania In Preschool Children 4 to 6 Years of Age With Bipolar Disorder" from the fine folks at Harvard Medical School

"Safety & Efficacy Study of Quetiapine Fumarate (SEROQUEL®) vs. Placebo in Generalized Anxiety Disorder"

"Quetiapine Augmentation for Treatment-Resistant PTSD"

I’d write more, but I’m not one to steal Dawdy’s well-deserved thunder on this one. Please read his full post. You’ll be glad you did. Since we’re talking about Seroquel, anyone want a sponsored editorial with that?

Are Patients Really Getting Better?

Currently, Lamictal is undergoing phase III trials as an add-on treatment for schizophrenia. Here’s what a recent review had to say about research done to this point on lamotrigine as an add-on treatment…

“We found five relevant trials (total n=537), but no usable data on service outcomes, general functioning, behaviour, engagement with services, satisfaction with treatment or economic outcomes. Overall, reporting of data was poor. Those data we were able to use suggested that equal proportions of people allocated lamotrigine or placebo had no global response (n=208, 1 RCT, RR 1.06 CI 0.73 to 1.54). There was no significant difference between groups in the proportions of people whose mental state did not improve (n=297, 3 RCT, RR 1.26 CI 0.81 to 1.97). There was, however, a significant reduction in the PANSS total scores (n=67, 2 RCT, WMD -16.88 CI -8.57 to -25.18, p=0.0001), positive symptom sub-scale scores (n=65, 2 RCTs, WMD -5.10 CI -8.86 to -1.34) and negative symptom sub-scale scores (n=67, 2 RCTs, WMD -5.25, CI -7.07 to -3.43). Most cognitive measures showed no differences (n=329, 2 RCTs, RR not attaining BACS composite score of 0.5 1.10 CI 0.59 to 2.04).”

So the PANSS shows change, which is good, but on the other hand there was no usable data on a number of important variables. This brings up the issue of what is clinically relevant – what is the relationship between PANSS scores and real-life patient functioning? I’m not claiming to have the answer. If PANSS scores are changing yet mental state (however it was measured) is not also improving, what's going on? The question is important – if we have nothing but a single measure indicating improvement, does this mean a drug really benefits patients? Alan Kazdin discussed this point much more brilliantly than I could in an article in the American Psychologist recently. What made this of particular concern to me was the fact that no usable data were reported, across five trials, on a variety of other aspects of patient functioning – was this just a lack of curiosity on the part of investigators or were data suppressed? I’ve not dug deeply on this one, but it is a question worth thinking about.

What a BAD Piece in the New York Times

Op-ed contributor Andrew Solomon’s words are in quotes and italics followed by my thoughts. I would have liked to post all of his piece, but I don’t think the NYT would approve (copyright issues), so I’ll try to be selective.

“Depression is the leading cause of disability worldwide, according to the World Health Organization. It costs more in treatment and lost productivity than anything but heart disease.”

So far, so good

“Despite medical advances in the last 20 years that have greatly improved our ability to help those who suffer from depression, we lack an effective system for administering care.”

I wonder which medical advances he is speaking of. Maybe SSRI’s? Or Effexor? Or Cymbalta? In any case, there is no evidence that these new treatments have brought more than perhaps a minimal advantage over treatments which existed prior to 1986 (see here and here).

“Only a very small percentage of depressives who seek help receive appropriate treatment for their condition. Research often stalls short of being translated into useful medicine. Depressives continue to be stigmatized, which makes their lives even more difficult and lonely.”

Um, I think that if Mr. Solomon is so concerned about people with depression avoiding stigmatization, he may want to stop referring to them as “depressives,” as the term indicates that he is defining people with a label, and a rather negative one at that. I can assure you that nobody who is dealing with depression wants to be called a ‘depressive.’

“These problems are similar to those cancer patients once faced, and the best way to address them might be similar as well. We need a network of depression centers, much like the cancer centers established in the 1970s.”

--SNIP--

“Following this model, the National Institute of Mental Health should coordinate and subsidize a national network of depression centers, ideally based at research universities with good hospitals and departments devoted to the subject.”

--SNIP--

“Among the thousands of depressed people I have met with, the majority have sought treatment but feel that they are not getting good care. Many of them have been prescribed antidepressants by family doctors who lack training in psychiatry and have conducted only cursory interviews before rendering their diagnoses. Antidepressants vary in their chemistry and effects; and human brains vary as much as human minds. To treat the most complicated organ in the body appropriately demands considerable expertise.”

Apparently Mr. Solomon has never heard of psychotherapy. In case he’s wondering, it has a pretty good track record with ‘depressives,’ better than the meds he seems to be touting.

--SNIP--

“(Full disclosure: my father is the chief executive of a pharmaceutical company that manufactures antidepressants.)”

Well, that clears things up a bit on my end.

--SNIP--

“Before the cancer centers came around, cancer was as taboo as depression is now. But as antibiotics and vaccines for other illnesses lengthened life expectancy, cancer became more pervasive and less shameful. Depression, too, is becoming more widespread and more frequently diagnosed. Depression and bipolar illness will affect some 20 percent of Americans during their lives, and yet the stigma endures. People often come up to me after lectures to whisper about their affliction, as though everyone else in the room weren’t grappling with precisely the same thing.

It is neither wise nor feasible for a large proportion of the population to be trying to keep a secret. A national network that helped to medicalize depression in the public imagination would reduce sufferers’ shame. The very waiting rooms of depression centers would provide incontrovertible proof of the ubiquity of the illness and ease the isolation of sufferers. Within the centers, patients would find themselves the focus of an elite community of insight and support.”

Yeah, we should medicalize it! Call it a disease! I can see it now: someone is going to say just like a person with diabetes needs insulin, ‘depressives’ need serotonin. Oh, wait, that’s been done. It’s played – there is clearly no reliable biological marker for depression, but selling depression as a “disease” sure sells those pills – just ask Mr. Solomon’s father, the drug company executive (Forest Labs)!

“…As it is established that these mental illnesses are not character defects, but instead can be characterized in terms of brain symptoms, the false distinctions between them and cancer or heart disease will become impossible to sustain…”

“We’ve made stellar progress in treating mental illness since the Prozac revolution but there is a catastrophic divide between research and practice. We must come up with a seamless way to support scientific progress and to administer the treatments we have, in order ultimately to alleviate as much suffering as possible.”

Indeed, if we are going to fix the gap between science and practice, I’d suggest 1) how about less polypharmacy (doling out a bunch of meds simultaneously), which has a very meager evidence base, and 2) how about psychotherapy first and maybe meds if psychotherapy does not work.

Mr. Solomon is clearly far out of touch with the evidence base, yet he writes books and is featured in the New York Times. That makes me feel like a “depressive.” Full text of his writing here, but it will not be available free online for long. His book has received rave reviews, though I’ve not read it, and I want to be clear that my comments only apply to his writing in the NYT today.

One more thing: "Prozac Revolution" -- did Mr. Solomon read Listening to Prozac one too many times?

Corcept: What Did I Tell You?

Don't let it be said that I didn't warn you. Finding a positive result for Corlux (mifepristone) without having to bend reality too greatly would probably help the company. If two trials failed, though, why would the current trial succeed?

SEC Filing Below...

Item 3.01 Notice of Delisting or Failure to Satisfy a Continued Listing Rule or Standard; Transfer of Listing.

Nasdaq has notified Corcept Therapeutics Incorporated that the Company is not in compliance with continuous listing standards for inclusion on the Nasdaq Global Market because (i) pursuant to Nasdaq Marketplace Rule 4450(a)(5), the Company’s price per share for its Common Stock had closed below the minimum $1.00 per share requirement for 30 consecutive business days, and (ii) pursuant to Marketplace Rule 4450(a)(3), the Company’s stockholders’ equity reported on its Form 10-Q for the period ending September 30, 2006 did not comply with the minimum $10 million requirement.

The Nasdaq notifications were provided in two letters dated November 10, 2006. On November 16, 2006 the Nasdaq staff determined pursuant to Marketplace Rule 4814(b) to adjust the period of time required for Corcept to disclose the receipt of the two letters to no later than the close of business on November 22, 2006.

Pursuant to Marketplace Rule 4450(e)(2), the company has a 180 day grace period to regain compliance with Nasdaq’s minimum bid price requirement. In order to regain compliance, the bid price of the Company’s common stock must close at $1.00 or more per share for a minimum of 10 consecutive business days anytime before May 9, 2007.

Nasdaq has advised the Company that under Marketplace Rule 4803, the Company has until December 4, 2006 to provide Nasdaq a specific plan to achieve and sustain compliance with the minimum stockholders’ equity standard.

Uh Oh Chuck They Out to Get Us Man: Authorship

If nothing else, the continuing stories regarding Nemeroff and company give me a chance to recite some excellent Public Enemy lyrics in post titles.

But seriously, the problems continue to stack up. In an article published online in Neuropsychopharmacology, a journal at which Nemeroff is the editor, the following occurred:
1) A sizable authorship switch
2) Failure to disclose conflicts of interest
3) Bobbing and weaving on data analyses

This centers on a study for risperdone as an add-on to SSRI treatment for depression. The study had three phases, as follows:
1) Participants who had not responded to 1-3 antidepressants other than (es)citalopram (Celexa or Lexapro) for > six weeks were assigned to open-label citalopram (Celexa) treatment for 4-6 weeks
2) Patients who failed to respond to citalopram were then assigned to open label risperidone (Risperdal) augmentation (add-on) treatment for 4-6 weeks
3) Patients whose depression remitted were then assigned to 24 weeks of either risperidone + citalopram or citalopram + placebo and the differences between risperidone and placebo for depressive relapse were examined.

This post focuses solely on an authorship switch. In 2004, results from this study were presented in abstract form. In this form, the authors read as follows:
Nemeroff, Gharabawi, Canuso, Mahmoud, Loescher, Turkoz, Rapaport, Gharabawi. You might think that there were two different Gharabawis, but they were both listed as George M Gharabawi, so he’s either the 2nd or 8th author – someone made an obvious typo here.

Who’s on the final published manuscript in Neuropsychopharmacology? In order: Rapaport, Gharabawi, Canuso, Mahmoud, Keller, Bossie, Turkoz, Lasser, Loescher, Bouhours, Dunbar, Nemeroff.

As if by magic, Nemeroff goes from first to last author. Rapaport moves from seventh author to first, Turkoz gets bumped down a couple spots. Keller appeared out of thin air. What did he do to get on the study? Keller is credited with “study concept and design,” which I would deem impossible since, if he really conceived and designed the study, he would have appeared as an author on the earlier abstract. Yet he is listed fourth on the list of people who designed the study. He is also credited, along with all of the authors, with “analysis and interpretation of the data” and critical revision of the manuscript for “important intellectual content.” Is it possible that he did a great job of helping to revise the manuscript? I suppose, but it seems there were plenty of other people who were also involved with the writing of the paper. Note that Keller was not credited with “drafting of the manuscript.” So Keller did not recruit participants, provided no administrative support, did not provide statistical expertise, and did not draft the manuscript, but apparently helped design the study after it was completed! Very impressive indeed.

But wait there’s more! In a press release, it is stated that “Dr. Mark Hyman Rapaport was the study’s principal investigator. Co-principal investigators were Charles B. Nemeroff, Ph.D., M.D. and Martin B. Keller, M.D.” So Keller, who played no major role in designing in the study or running patients was a co-principal investigator. Remember, he would have been listed as an author on the initial abstract describing the study results if he helped design the study.

What am I implying? There’s no doubt that Keller is a big name in psychiatry. He has, according to his CV from August of 2006, over 300 journal publications to go with dozens of book chapters. So it certainly adds credibility to the study to tack him on as an author. As for Nemeroff moving from 1st to last, that’s interesting. My thought is that with an authorship list of 12, nobody is going to remember authors 6-11, so tacking him on as last author makes the name stand out more. Just speculation on my part. And Rapaport making the jump from last to first? Well, I think that, again, we’re talking about name recognition here. Rapaport is likewise a pretty big name. Now, mind you, I’m not implying at all that Rapaport did not have a major role; indeed, the author contributions section of the paper indicates that he did quite a bit of work on the project and he absolutely appears to deserve first author credit.

There are varying standards for the ordering of authorship. In some disciplines, it just goes in descending order (which makes the most sense) – he/she who contributed most gets first authorship while he/she who contributed least gets last authorship. In others, the lab supervisor, who may have done very little on the study, gets last authorship or sometimes first authorship. In any case, the first author and the last stick out most in memory and I’m sure it doesn’t hurt to throw in a bigwig like Keller in the middle of the mix. I’m guessing it would have been better publicity to move Keller higher on the list, but there’s only so much credit a guy can receive for apparently doing magic (designing the study after it was completed) and making comments on the manuscript. Of course, inappropriate authorship is widespread, so these results come as no surprise.

More on other issues with the study later. I assure you that the authorship switch is the least of the study’s problems.

Over at Health Care Renewal...

As my readers know, I'm a big fan of Health Care Renewal. I've linked to several of their stories and I'll post a teaser of another good one here...

"The report documented nearly $36 million in illegal Medicare and Medicaid payments for procedures on hundreds of patients, in ex change for payments of $5.7 million to physicians since 2002 in ex change for sending their heart patients to UMDNJ's University Hospital.' Unfortunately, this scheme reached well into all levels of the hospital and University Central Administration, who were complicit first in forming and expediting this illegal plan, and later in covering it up,' said Stern in his report, who said the illegal activity 'persists to this day…”

Sound interesting? Check out the link to the full story here.

Occupational Therapy for Dementia...

Holy Toldeo! A study published in the BMJ today (Graff et al.) showed a gigantic effect of cognitive-behavioral occupational therapy for mild to moderate dementia patients. I've not seen any type of intervention for any condition yield such a huge effect in quite some time. Essentially, as a result of the intervention caregivers saw themselves as much more competent, and dementia patients’ functioning levels were much, much higher in the treatment group compared to the control group. The PDF is up on the BMJ site and is worth a read.

We Should TALK to People With Dementia?

A recent review (Ayalon et al., in Archives of Internal Medicine) indicated that neuropsychiatric symptoms of dementia can be treated effectively with psychological interventions. A couple caveats are in order: a) the review was based on a very small number of trials b) we are probably not generally talking about large symptom reductions for most people. Let's keep in mind that the use of either typical or atypical antipsychotics in dementia are linked to untimely side effects, like death to name one. That, and antipsychotic medications are not particularly effective in treating symptoms. So, I'm all in favor of behavior therapy -- relieves symptoms to an extent and doesn't cause death -- how can you top that?

Atypical Antipsychotic Results (Guess)

Another study (White et al in the latest Schizophrenia Research) comparing first and second generation antipsychotics, this time in elderly patients with severe (poor outcome) schizophrenia, found that there was no difference in their ability to impact positive or negative symptoms over time. This goes hand in hand with other trials (like this and this) that have failed to differentiate the two classes in terms of efficacy. Yes, I am aware that older antipsychotics induce tardive dyskinesia and other horrendous effects, but the new meds are not exactly a walk in the park when it comes to safety!

Lexapro For Life?

Here’s a summary from a study which appears in the Journal of Clinical Psychiatry in November (courtesy of PsychCentral).

“Between 2000 and 2003, researchers evaluated approximately 200 participants at 28 centers in the United States who had responded positively to eight weeks of treatment with one of four different SSRIs: fluoxetine, sertraline, paroxetine or citalopram. This was followed by four months of treatment with escitalopram. These participants were then randomly assigned to fixed-dose treatment with 10 or 20 mg of escitalopram or placebo for one year.

“Patients who were switched to placebo showed a significantly higher rate of depression recurrence (65 percent), compared to those who stayed on escitalopram (27 percent),” said Kornstein. “This was true even though the patients showed a full resolution of their depression at the start of maintenance treatment.” The medication was found to be safe and well tolerated throughout the study, she said.

“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,” she said.

This work was funded by Forest Research Institute.”

Your first impression may be: Lexapro (escitalopram) for life! Let’s look at the flip side of the coin, shall we?

First, discontinuing medication for one group and putting them on placebo is going to set up an increased rate of depression due to discontinuation/withdrawal from the medication.

Second, and more importantly, a meta-analysis by De Maat, Dekker, Schoevers, & de Jonghe regarding long-term treatment outcomes for psychotherapy and medication found that the longer term relapse rate for medication was 57% compared to 24% for psychotherapy. In the studies they examined, both medication and psychotherapy were provided in the short-term, then discontinued, and the long-term results were then analyzed.

I suppose it may be true that if you continue people on medication for a longer time, they may maintain lower symptom levels. But, when the medication is taken away, look what happens – likely, it’s relapse.

So is it cost-effective to keep people on so-called maintenance medication therapy indefinitely as compared to providing psychotherapy, which provides superior long-term results without the need for maintenance treatment? I think the answer is an obvious no.

In addition, there is precious little evidence regarding the long-term effects of antidepressants, as can be seen in an interesting article here. Despite the widespread long-term use of antidepressants, surprisingly little is known about their impact and what happens upon discontinuation of long-term treatment.

To summarize: We know antidepressants fare much worse than psychotherapy when both treatments are provided short-term then discontinued and outcomes are examined over the long-term. We don’t know the long-term effects of keeping people on indefinite maintenance pharmacotherapy. I have a feeling some people will make a big deal about Kornstein’s findings; please refer them to this post.

Advertorial Update...

I've been informed that the Seroquel "sponsored editorial" also appeared in the July issue of the Journal of Clinical Psychiatry. Granted, JCP has recently published articles which either did not report data fully or used highly suspect statistical analyses so I suppose I shouldn't be surprised that the editorial board would allow commercial editorials. The recent call-out in JCP for more research on atypical antipsychotics for anxiety also fits nicely with the sponsored editorial, doesn't it?

Hat tip to the anonymous reader for informing me about the July sponsored editorial.

Someone's Betting on Corcept

I just saw a brief headline that...

"Corcept Therapeutics announces $3 mln private equity financing Co announces that it has entered into a definitive agreement with certain accredited investors for the private placement of 3 mln shares of its common stock at a price of $1.00 per share. Pursuant to the agreement, the investors, who are led by Paperboy Ventures, have irrevocably committed to purchase the shares."

There are only three logical explanations:
1) These people are looking for a tax write-off when Corcept collapses due to the poor performance of its Corlux (mifepristone/RU-486) product in treating psychotic depression. When the FDA determined the drug is not approvable, they’ll drop a tax bracket or two.
2) These investors have been snowed by someone; they don't know what they're doing. They haven't read posts such as this, this, and this. They don't know that the efficacy of Corlux is nothing to write home about, as it appears to help little with depression and not particularly greatly with psychotic symptoms either.
3) They know something that I don't. Maybe the FDA, circa vagus nerve stimulation, is going to approve Corlux regardless of its actual efficacy.

Seroquel for Everything! (Except Weight Loss)

In Indiana, a recent story regarding Seroquel (which, as I've posted earlier, AstraZeneca is trying to get marketed for anxiety)...

"A Lowell couple is suing pharmaceutical giant AstraZeneca in federal court for failing to disclose the true dangers of its popular anti-psychotic drug Seroquel...

--SNIP--

"The lawsuit, filed last week in U.S. District Court in Hammond, says Randall Waugaman developed "diabetes and/or diabetes-related injuries" while taking the prescription drug.

Jim Minnick, a spokesman for AstraZeneca, declined to comment on the Waugaman's case, but said in general the company is disputing the claims in the swell of litigation filed in federal courts across the country.

"The safety of patients who use our medications is our highest priority," Minnick said Tuesday. "(Seroquel) is a safe and effective medication when used as directed as a prescribed medication."

Seroquel was approved by the U.S. Food and Drug Administration in 1997. A promotional news release says Seroquel is the most popular "atypical antipsychotic" prescribed drug in the United States, with global sales of almost $2.8 billion last year."

--SNIP--

Like many other litigants, the Waugamans claim that AstraZeneca covered up the results of its own studies on the drug that found it also could affect weight gain and hyperglycemia, potentially causing diabetes."

Well, well, well. Although it's fairly clear that Seorquel isn't a diabetes/weight gain inducer to the extent of Zyprexa, there is indeed evidence that Seroquel is often not good for one's weight (as can be seen here and here, among several others). Add this to additional lawsuits regarding the safety and marketing of Seroquel, and it makes one wonder if Seroquel will continue to be a cash cow.

A Reader Poll...

What do CPP readers do for a living? Pick ONE.
	Drug/Device Company Employee
	Mental Health Professional in Clinical Practice
	Researcher
	Journalist/Blogger
	Lawyer
	Student
	I just read blogs all day long -- no job
	Other
Free polls from Pollhost.com

Sponsored Editorial?

In the October Journal of Clinical Psychiatry appears a “sponsored editorial.” Last time I checked, editorials often reflected the informed opinions of the editorial board or perhaps a knowledgeable guest. But, no, this editorial reflects the opinion of AstraZeneca, maker of Seroquel.

You can see what it looks like to the right. How far do we want to blur the line between marketing and science? If the claims made in this advertorial are true, then perhaps someone should write them up in more detail and submit an article on the topic, rather than giving the hint that the editorial board approves of this non peer-reviewed message. Maybe the editors of the Journal of Clinical Psychiatry no longer have standards or maybe it was an oversight. In any case, it is well beyond the standards of acceptable scientific journal editing to allow an advertisement to be labeled as an editorial.

Drug Firms Will NOT be Bullied...

... says US Deputy Health Secretary Alex Azar! From the Guardian...

"The White House is lobbying British ministers to allow the world's main drug companies unrestricted access to the NHS as part of a package of free market reforms for the service. The US government is positioning itself behind the giant pharmaceutical firms, predominantly based in America, which have been piling pressure on the body that approves drugs for use in hospitals and for prescription by GPs. The drug companies claim that they are being held back by the National Institute for Clinical Excellence and have separately lobbied for it to be reformed. In a surprising intervention, the US deputy health secretary, Alex Azar, forced the issue in London yesterday, ahead of talks with officials following a trip to the US last week by the health secretary, Patricia Hewitt. He said attempts to use rationing mechanisms such as Nice to cut soaring drugs bills would stifle innovation - an argument that is constantly made by the pharmaceutical industry. Allowing all new drugs to be used in the NHS would result in the companies "fighting it out" on price, Mr Azar said, which would drive the drug bill down.
He made it clear that he was also in favour of the drug companies being allowed to advertise directly to patients. At the moment they may only advertise to doctors.

He also wanted to share the US experience of offering private insurance packages to people on Medicare - the healthcare scheme provided by the government to the poor and elderly. It might be possible for the UK government to consider something similar, he suggested, so that everyone could choose either a basic healthcare deal or top it up themselves if they wanted to pay for more than the state could afford.

--SNIP--

"How are we making sure that we don't take steps on cost containment that are short-sighted and prevent the investment in long-term biomedical research and development and innovation, so that when my kids are senior citizens we have the next generation and next, next, next generation of drugs?"

"The White House arguments will increase the mounting pressure on Nice, which is regularly castigated by patient groups and drug companies when it rejects a new medicine from use in the NHS on cost grounds."

--SNIP--

""In all of our systems it is so easy to make the decision to cut costs today by going after drug prices, and to not focus on what will be the impact on long-term innovation," he [Azar] said.

My View: Yeah, I am sure that the Brits would LOVE a Medicare boondoggle like ours! There is no doubt that seniors across the UK are begging for an Americanized system of health care.

Then Azar has the audacity to say that these "market reforms" will cause price competition? Find me one iota of evidence to support such a baldfaced lie. The American government decided, nah, we don't need to negotiate prices -- we'll pay whatever y'all good folks in the drug industry would like us to pay. Despite all the free market rhetoric, this is the kind of thing that would make Adam Smith turn over in his grave! In a free market, prices are determined through negotiation, not by fiat.

Arguably, my favorite statement from Azar was the time-honored scare tactic of, to paraphrase, "if drug prices drop, how will they ever have enough money to conduct research to develop new products?" I'd buy that if three things were true:
1) If drug company research was devoted to truly discovering new drugs, rather than copycat me-too meds that add no benefit to patients
2) If drug company research was NOT frequently devoted to conducting trials that simply showed an additional indication for an existing drug in an already crowded market. Risperidone for depression is an example of such (more on that later) -- how many drug treatments do we really need for depression? Or, how about Seroquel for anxiety?
3) If drug company cash was not devoted so highly to marketing as opposed to research

Oh, and as for the new drugs save lives argument, please see this excellent post at the incomparable Pharma Marketing Blog.

Assay Sensitivity or Efficacy?

I was sure glad to see David Healy mentioning the concept of “assay sensitivity” in his latest article. I discussed his article earlier regarding issues of safety. Now it's time to move on to efficacy. A few years ago, I remember Donald Klein mentioning that some trials that failed to show superiority of medication over placebo were not failed trials; they simply lacked “assay sensitivity.” So apparently the trials that showed superiority of medication were sufficiently sensitive and trials which did not show superiority lacked sensitivity. To me, this sounded a lot more like a way to justify the generally meager to moderate (at best) effects of antidepressants over placebo rather than a realistic scientific appraisal of the evidence.

Here’s what Healy says: “… many, including the regulators who approve the drugs on the basis of such trials, regard antidepressant trials as assay systems aimed at demonstrating a treatment signal from which a presumption of efficacy can be drawn, rather [than] as efficacy trials… If these trials are simply assay systems, it can be reasonable to discount and leave unpublished evidence from failed trials in which an active treatment fails to distinguish from placebo, on the basis that the trial lacked assay sensitivity... Alternatively, if we regard antidepressant trials as efficacy trials then both those demonstrating a treatment effect and those not demonstrating a treatment effect should be thrown into the meta-analytic hopper, and if this is done the degree of superiority of active treatment may be little more than 5%, or a mean of 2 points on the Hamilton Rating Scale for Depression scores, or no greater than it was shown to be in paediatric antidepressant trials (Khan et al., 2000; Kirsch et al, 2002).”

Counting trials as “assays” is ridiculous. Patently absurd, in fact. To do so is to endorse the idea that only one’s successes count. This is akin to boxer A fighting boxer B 10 times. In 7 fights, boxer A and boxer B fight to a draw – the judges cannot reach a decision. In two fights, boxer A wins by knockout and in a third, boxer A wins via a split decision of the judges. We would logically conclude that boxer A is a bit better than boxer B, but is clearly not superior by a large margin. However, under the “assay sensitivity rule,” we’d only count the times when boxer A won, and conclude that he is a far superior fighter than boxer B, which is clearly a mockery of the evidence based on their ten bouts.

In fact, a meta-analysis reached the same conclusion – that including only studies with “assay sensitivity” results in biased conclusions. In fact, the authors state, “Unless evidence is gathered to support the hypothesis that using the AS method reduces bias [of which there is none currently], meta-analysts should make quality judgments that are based on study methods, and that are independent of outcome.”

This essentially means that existing meta-analyses of antidepressant efficacy are biased, because, with the exception of the few meta-analyses that included unpublished studies, meta-analyses have relied on only published studies (which, almost by definition, yielded at least some significant advantage for the drug).

More from Healy:
“From the RCT data cited above, it appears that when people improve during antidepressant trials, 80-90% of the response can be attributed to the natural history of the disorder, or to the effect of seeking help, or to the benefit of any lifestyle advice or problem-solving offered by the clinician, or to what has been called countertransference or related aspects of the therapeutic encounter.”

I believe what Dr. Healy is referring to is what we in psychology call the “common factors,” including the therapeutic relationship. I recall that 80-82% of the antidepressant effect was accounted for by placebo in Kirsch’s work, and that when one looks at active placebos (placebos with side effects similar to antidepressants, which then keeps participants blind to their treatment condition more consistently), the number gets closer to 90% or above. Moncrieff, Wessely, & Hardy conducted a meta-analysis on the active placebo topic that bears this out.

So if the active effect of the drug (i.e., the effect we can attribute to the drug over placebo and other factors) is very small, what should we do?

Healy opines as follows:

"But what should happen if the combined non-drug components contribute four times more of the eventual response to treatment in standard cases than does the active drug? If the money and culture are to follow the evidence in this scenario, where should they go? One possibility is to modify the APA statement to say that psychiatrists rather than antidepressants can save lives. For example, we might expect lives to be saved in the case of clinical practice, informed
by the evidence, that restricts antidepressant use to cases in which it is clear that the condition has not resolved of its own accord, efforts at problem-solving have not led to a resolution, and hazards such as suicide arising from the severity of the condition have shifted the risk–benefit ratio in favour of a closely monitored drug intervention with informed patients, rather than non-intervention. Aside from the scientific and clinical merits of this position, there is a political case for reading the data this way, in that if there is no evidence that antidepressants pose risks [which is of course untrue but is often stated by "opinion leaders"] and if antidepressants rather than physicians save lives [likewise untrue but believed by many], then in a brave new world in which healthcare is being segmented, it is not difficult to foresee a future in which depression screening and treatment might be undertaken by non-medical personnel."

If I'm understanding him correctly, then I don't think he could be more correct. The psychiatrist him/herself accounts for a significant part of treatment outcome. Poor interpersonal skills? Can't form solid relationships with your patients? My bet is that your outcomes are poor, regardless of the pharmacological regimens you employ. In both psychotherapy and pharmacotherapy, the therapist/physician influences outcome regardless of the treatment provided. Instead of focusing on the type of antidepressant, which we know does not make much of a difference in influencing outcomes, we should be figuring out what therapist behaviors and/or personality traits are related to good outcomes -- there's more action there than sifting through a bunch of antidepressants which yield little benefit over a placebo in any case.

But figuring out what types of therapists are effective does not reward shareholders and is thus research that will take decades to conduct (who's going to fund it?), while clinical trials of medication will plug along in a direction where we can be assured that the sponsor's desired outcomes will be found (except when the pesky government gets involved in research, such as with CUtLASS 1) while patients in the real world benefit little to not at all from these trial results. Creating yet more drugs which serve to benefit shareholders, corporate executives, and allied academic researchers yet fail to yield any benefit to patients over existing regimens -- The cycle continues.

Academic Stalking?

David Healy has a very interesting little site (within his main site) discussing the "academic stalking" behavior of some of his colleagues. It is worth reading here. It gets into issues with James Coyne, who has been Healy's most outspoken critic, and it sets an excellent defense regarding the serious questions about Healy's reputation that Coyne has raised. In my reading of both Coyne's criticisms and Healy's defense, I find Healy does an excellent job.

To quote from Healy, the general theme of this page is to describe how: "One of the consequences of taking a stand on an academic issue that has commercial implications seems to be ongoing academic harassment or stalking." And you wonder why I remain anonymous!

Anyone with an interest in antidepressants and the commercial influence on their study should give it a read.

Mifepristone (RU-486): Move The Goalposts Wider

Note: Some articles I mention below are without an abstract, so they received no link. The latest drama on mifepristone (RU-486, Corcept Therapeutics) continues to play out. DeBattista and Belanoff published a review (Trends in Endocrinology and Metabolism) discussing the great potential (in their eyes) for mifepristone in treating depression and possibly other conditions. Of course, let’s keep in mind that DeBattista owns shares in Corcept and is a consultant for them as well while Belanoff is the CEO of Corcept, so of course the review was park marketing, part science.

Robert Rubin and Bernard Carroll in a letter to the editor pointed out aptly that DeBattista and Belanoff’s review “makes exaggerated claims of efficacy.” They added that among the studies cited as proving evidence for mifepristone’s efficacy:
*One did not report a statistically significant benefit on any outcome measure
*Another “contained no statistical analyses of drug benefit whatsoever. The weak trend toward efficacy was created by alteration of the scoring method of a key rating scale (the Brief Psychiatric Rating Scale or BPRS). Had this scale been scored in accordance with its original psychometric validation, the results would have been even weaker than they were portrayed: only five, rather than 12, of 19 subjects who received high-dosage mifepristone would have shown a 50% reduction in the Positive Symptom Subscale (PSS) of the BPRS.
*The third study claimed a marginal benefit of mifepristone over placebo in producing a 50% reduction of scores on the PSS (p = 0.046). However, the statistical analysis failed to use Yates’ correction in computing the chi-square result. When the proper statistical test is used, or when the alternative Fisher exact test is used, then the result is clearly nonsignificant (p = 0.10). In addition, by analysis of variance the authors failed to find a significant main effect of mifepristone on any outcome measure of psychotic symptoms (with respect to the PSS) or general psychopathology (with respect to the BPRS) or depressive symptoms. The other two cited studies have appeared only in abstract form.

DeBattista and Belanoff, in their rather weak response, point out that one of the studies published only in abstract form is now in press and that it found significant results on the BPRS (as measured by a 30% reduction in scores) and several secondary measures. More on that study in a minute. They then point out that two small studies examining mifepristone which were criticized for failing to achieve statistically significant results by Carroll and Rubin yielded large effect sizes. I assume they mean pre-post effect sizes, meaning effect sizes that were not compared to placebo, as one of the studies did not use a placebo control. I’m not generally impressed when two small studies find large effects (not in comparison to a placebo) which do not carry over to larger studies. Note that DeBattista and Belanoff did not refute the points made about manipulating a rating scale to find a significant result or failing to use the proper correction for a statistical test, which also then pushed nonsignificant results to becoming significant. However, DeBattista and Belanoff make an excellent point when they state that “The first step with mifepristone is to demonstrate with greater confidence that the drug has a clinical effect.” Great point! That particular sentence sounds like a retreat from their earlier statements about mifepristone’s efficacy.

Now, as for that larger study on mifepristone for psychotic depression, which is now in press in Biological Psychiatry. DeBattista and Belanoff are the first two of eight total authors. The standard used to define response was a 30% reduction in BPRS scores. With a sample of 105 taking mifepristone and 116 taking placebo, the categorical analysis using Cochran-Mantel-Haenszel tests was barely significant (p = .041). Means and standard deviations were not reported for the BPRS, so who knows what happened in terms of effect size, but I’d bet it was not impressive. The results were more impressive for the Positive Symptom Subscale of the BPRS (p = .006), but it is again hard to calculate effect size without means and standard deviations.

The authors move on to reporting scores on a subgroup who had somewhat elevated Positive Symptom Scale Scores, and in this case means and SD’s are reported and it looks like about a .50 effect size favoring medication. How did this subgroup do on their overall BPRS score? Good question, because for this subgroup, only one measure (the aforementioned PSS) was reported. Apparently the patients with lower Positive Symptom Scores are not worthy of a subgroup analysis, likely because such an analysis would have shown unimpressive results.

The authors then move to another subgroup, 42 patients selected because they were “chronologically, the patients enrolled in the latter part of the study” and were being examined as part of an FDA analysis. This group showed the largest effects, according to my rudimentary analysis. It seems a little ridiculous to just report on the last 42 patients enrolled in the study. Why not report on the first 42? Oh, right, because when a group of 221 patients is enrolled, one draws a more valid conclusion from looking at the overall group rather than reporting on a random subset. Hello?? Maybe this is an attempt to send a message to the FDA – I’m not sure.

Now let’s move to the two biggest catches. One, there was no significant effect on depression (as measured by the Hamilton Depression Rating Scale). Let’s keep in mind that the patients had psychotic depression, which means treating the depressive symptoms might be nice.

The biggest catch was that everyone was allowed to take concomitant medication as their physician deemed appropriate. So the study really compared a mishmash of drugs plus mifepristone to a mishmash of drugs plus placebo. Not exactly the type of tightly controlled efficacy trial upon which one can make many conclusions. Especially considering that the authors reported little about which drugs were prescribed to which patients and how this may have influenced outcomes.

So, in the end, the study showed very little. More points to Rubin and Carroll. Methinks we need more people in psychiatry who are willing to throw the BS flag when they see products being overhyped.

I will say one good thing about the DeBattista et al study. The following quote was great: “The discovery of psychotropics to date has rested on serendipity and repetition of drugs with similar pharmacological profiles.” Unfortunately for them (as Corcept shareholders), the data do not support that their unique drug works any better than a me-too drug, and it is still unclear if mifepristone is much better than a sugar pill.

Link to an earlier post involving Carroll and Rubin here. Keep up the good work fellas.

New Drugs Save Lives (wink wink)

Wow, does Pharma Marketing Blog have a great post today! PhRMA and related industry groups have been complaining that the UK doesn't approve drugs fast enough, which is of course causing untold suffering and death.

You have to see Pharma Marketing's post here to appreciate the negative correlation between a nation's frequency of using new drugs and its average lifespan. I am fully aware that correlation does not imply causation, but the post really does indicate that Big Pharma's claim that delays in approving drugs is likely not a serious problem at all.

Antidepressants and Suicide in Clinical Trials: Update

David Healy’s interesting article in Advances in Psychiatric Treatment entitled “The Antidepressant Tale: figures signifying nothing?” deserves some attention. There are two main points, one relating to the safety of antidepressants and another relating to efficacy.

Let’s start with safety. Suicide is a rare event and, as such, is difficult to predict with much statistical certainty. Thus, antidepressant trials lack the statistical power to show differences in suicidal acts between antidepressant and placebo. While clinical trial data have rather consistently shown an increased relative risk for suicide and suicidality on antidepressants versus placebo, the absolute risk remains low, thus resulting in differences that are not statistically significant.

So do we say, “oh well, it’s not less than 5% likely than the differences between antidepressant and placebo are due to chance alone, so prescribe all the drugs you want?” Apparently many think so. Do we need to be 95% sure that a drug is related to significantly more suicides before we do something about it?

Healy starts off discussing an analysis conducted by Lilly which showed the relative risk for suicidal acts on fluoxetine was nearly twice that of such acts on placebo but that the difference was not statistically significant (due to the general rarity of such acts overall):

“The analysis gave the relative risk of suicidal acts for patients taking fluoxetine
compared with placebo as 1.9 (95% CI 0.2–16.0). This led Beasley et al to state ‘Analysis of the incidence of suicidal acts (suicidal attempts and completions) revealed no statistically significant differences in the act rates between fluoxetine-treated and placebo treated patients’. And the conclusion they drew from this lack of significance was that ‘Data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients’ (Beasley et al, 1991)…

Using this analysis, if we return to the Beasley et al (1991) paper it is clear, that although the statement ‘the analysis of the incidence of suicidal acts revealed no statistically significant differences in the act rates between fluoxetine treated and placebo treated
patients’ is supportable, it should not lead to the conclusion that ‘data from these trials do not show that fluoxetine is associated with an increased risk of suicidal acts or emergence of substantial suicidal thoughts among depressed patients’.”

What Healy fails to mention here is some of his own work, which I found disappointing. For example, in the Beasley meta-analysis, it was later found out that “no mention was made that benzodiazepines had been coprescribed in the clinical trial program in order to minimize the agitation that Lilly had recognized fluoxetine could cause[32] … no reference was made to the 5% of patients who dropped out for anxiety and agitation. This drop-out rate, which is statistically significantly greater than for placebo, holds true for other SSRIs as well.” (Healy 2003 in Psychotherapy & Psychosomatics). So with coadministration of benzodiazepines to control agitation and removing the people who dropped for agitation and anxiety (perhaps the most likely to be suicidal), the results are not statistically significant but certainly point much more toward suicidality on fluoxetine than placebo.

Later, Khan et al (2003 in American Journal of Psychiatry) examined the rates of suicides in SSRIs, active comparators, and placebo and found a relative risk of 1.4 (95% CI .56-3.62) in favor of greater suicide on SSRIs and, when including all antidpressants found a RR of 1.62 (95% CI .66-4.02). Let’s keep in mind that the above issues with the coadministration of benzo’s applied in many of these studies, as well as some studies (though it’s unclear how many) counting suicides on placebo washout (when all participants were receiving placebo – nobody was taking antidepressants) as placebo suicides, which biases the data in favor of drugs appearing safe. See links on inappropriately attributing suicide/suicidality to placebo here and here. So even with the deck stacked in favor of showing drug safety, there is still an enhanced suicide/suicidality risk associated with antidepressants compared to placebo. Curious, eh? Perhaps if the deck was not stacked, this difference would have actually achieved the magic p-value of .05 or less.

But wait, there’s more. Next Healy discusses another Khan et al meta-analysis (2002 in Journal of Affective Disorders). Here’s what Healy said in his most recent article:

“One of the most striking instances of the unwillingness to think that signals might offer evidence of a hazard posed by a therapy came from Khan et al in a 2002 review of deaths by suicide of adults participating in clinical trials of fluoxetine, paroxetine, sertraline,
clomipramine, fluvoxamine, clonazepam and venlafaxine for obsessive–compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder or panic disorder. From this dataset, they concluded: ‘We found that suicide risk among patients with anxiety disorders is higher than in the general population by a factor of 10 or more. Such a finding was unexpected... The sample of patients selected was considered at minimal risk of suicide’ (Khan et al, 2002). Anxiety disorders, they suggested, posed a risk of suicide. In fact, this dataset on 12 914 patients taking active treatment and 3875 patients taking placebo reported 11 suicides in the active treatment groups and no suicides in the placebo groups. The data on suicidal acts were incomplete but combined data for suicidal acts and suicides show a relative risk of 1.65
for active treatment over placebo. It takes a prior judgement that antidepressants could not trigger suicide to interpret such data as evidence for the suicide risk posed by anxiety disorders rather than by the antidepressants used to treat them (p.322).”

But wait, there’s still more. According to the most comprehensive meta-analysis on the subject, the relative risk of suicidality on SSRIs is 2.93 versus placebo (Fergusson et al., 2005 in BMJ). And, to quote more from Healy:

“In December 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) published a report on antidepressants and suicide (Committee on Safety of Medicines Expert Group on the Safety of Selective Serotonin Reuptake Inhibitors, 2004). This
gave data for suicides in adult placebo-controlled trials of sertraline, citalopram, escitalopram, fluvoxamine, venlafaxine and mirtazapine from which the relative risk of completed suicide on active treatments compared with placebo emerged as 2.42. The relative risk for suicidal acts on active treatment was 2.37 compared with placebo and the relative risk for the combination of both suicides and suicidal acts compared with placebo was 2.38. These values of 2.37 and 2.38 are statistically significant but have not led to clear warnings.”

So depending on the meta-analysis that is examined, there is sometimes statistical significance, but there is always a strong trend for a relative risk of about two or greater for suicidal acts or actual suicides on drug compared to placebo. This occurs despite some studies inappropriately assigning suicidality or suicide to placebo when it occurred during a placebo washout period, when the placebo was not being compared to the medication, and that benzodiazepines were coadministered in many of the original studies.

Healy goes on to point out that we may in fact be entirely too enamored with conventional significant testing in many cases. In the case of safety, I agree with him. Differences in rare events may be difficult to detect statistically, but when the heavy bulk of the evidence falls clearly on one side of the equation indicative of iatrogenic effects of a treatment, it is essential that we pay attention to this evidence.

I’ll post separately on the other issue mentioned by Healy regarding efficacy since this post is already long enough.

Welcome to Furious Seasons

I've added another member to my links today. The Furious Seasons site covers a lot of ground, but often discusses issues similar to those mentioned on this site. Well-written, thoughtful, and interesting. Too bad there are not more mental health-related sites like his. -SIGH-

Seroquel for Anxiety? Say What??

According to Bloomberg, AstraZeneca is going to do the following: "[CEO] Brennan said he planned to grow sales of top drugs like Seroquel, by expanding its use into generalized anxiety and bipolar disorder, and by introducing a once-a-day version of the pill."

Say what? GAD is one of the more treatable mental illnesses around. It response quite well to psychotherapy (with CBT being the most studied intervention, but other psychotherapeutic interventions also appear efficacious) though residual symptoms are often present. Giving someone a heavy duty medication such as an atypical antipsychotic? I don't think so!

I can see it now. The wheels are in motion. A review in a recent (September) issue of the Journal of Clinical Psychiatry states that "The efficacy of these agents [atypical antipsychotics] in various anxiety conditions needs to be further investigated with large, well-designed comparison studies." This may surprise you, but most of the authors had significant financial ties to AstraZeneca.

The buzz is starting. Follow up with a couple short-term trials showing greater reduction in anxiety than a placebo (though perhaps not by a large margin) and then make sure that the paid speakers discuss it at fancy dinners and that the trials find their way into prescribers' inboxes. Don't worry -- Seroquel won't be compared to an SSRI and certainly not to psychotherapy in an AZ-sponsored trial -- we wouldn't want to compare it to treatments with greater efficacy and/or fewer side effects! It's a rather predictable formula.

Of course tranquilizing medications such as antipsychotics reduce anxiety. It's just that there are much better treatment options available. What a great example of trying to expand the market for an existing drug! Profit over patient welfare.

Hat tip: Furious Seasons.

Quote of the Week

From the New England Journal of Medicine (Nov 9, 2006):

Allistair Wood said: "It is eye-opening to review the list of the 10 top-selling drugs and recognize how few of them show any evidence of superiority over generic drugs, even though billions of dollars are spent on them. This is truly an indictment of our prescribing practices. <sup>"

Ya think? I suppose someone needs to point out the obvious. Physicians are smart people, almost by definition, yet prescribing practices are often nonsensical. Who can really claim that advertising to consumers and physicians, providing travel junkets for physicians, and provding free merchandise and free meals for physicians and their staff (and the list goes on) does not lead to incredibly wasteful prescribing practices?</sup>

When Blumsohn Speaks...

...you should listen. If you have ever wanted to see an example of well-documented research misconduct, then you absolutely must check out his site. His latest post indicates that Procter & Gamble still remains silent and has taken no action to correct multiple publications that were based on quite selective (and hidden) data reporting. If you read through the entire list of documents on his site, I am certain that you will be stunned. It is unfortunate that this type of practice is not just an isolated fluke event.

Corcept: Still a Bad Investment

My pals over at Corcept continue to lose money. You may recall Corcept as the company that is trying desperately to get mifepristone (RU-486) approved to treat depression. The main problem has been that trial results have yielded little hope. The oft-cited (both on this site and in the psychiatric literature) Charles Nemeroff has a conflict of interest related to Corcept that you can read about here. Here's the latest on Corcept:

"(RTTNews) - Corcept Therapeutics Inc. (CORT | charts | news | PowerRating) reported a third quarter net loss of $6.4 million or $0.28 per share, compared to a net loss of $5.2 million or $0.23 per share in the same quarter of last year.

Analysts polled by First Call/Thomson Financial expected the company to report a loss of $0.28 per share.

For the nine months of 2006, the company reported a net loss of $21.0 million or $0.93 per share, compared to a net loss of $14.8 million or $0.66 per share in the year ago period. Collaboration revenue for the period was $221 thousand."

Link here.

Burying Conflicts of Interest

The good folks at Health Care Renewal have a great post, from which I will quote. The topic is pay for performance initiatives for physicians. The discussion is regarding a journal article on the topic. Quote begins here...

"Take in particular the article written by one John W Rowe MD, which was derived from the Harvey Kimball lecture Dr Rowe gave to the 2005 American Board of Internal Medicine Summer Conference. [Rowe JW. Pay-for-performance and accountability: related thems in improving health care. Ann Intern Med 2006; 145: 695-699.]

So who is Dr Rowe, and why should we heed his call for pay-for-performance, even though even he admits that current approaches have major deficiencies?

The Annals identifies Dr Rowe as being "from Columbia University, New York, New York." His address is listed as the Mailman School of Public Health there. Thus, his current position seems to be on the faculty of a well-known school of public health. Dr Rowe did mention that he has "exprience as the leader of a large academic health science center and as chief executive officer of a major health insurer." The Annals lists his "potential financial conflicts of interest" as "employment: Aetna Inc." and "stock ownership or options (other than mutual funds): Aetna Inc." Thus, he is also a part-time employee of Aetna Inc., a large health insurer and commerical managed care organization, perhaps a part-time medical director, or analyst, who holds a few shares of stock in a retirement plan? Worldly physicians, but not all Annals readers, may realize, instead, that Dr Rowe is not just a part-time mid-level employee, but is the former chief executive officer (CEO) of Aetna Inc.

However, the statement also reveals he still has a very important position with Aetna. He was has been Chairman of the Board since April 1, 2001, and still holds that position, although he plans to retire at the end of this year. In 2006, his salary was $1.1 million, his bonus was $2 million,… [and on it goes…]

You must read the full post here...

Upcoming...

Check back soon for posts on antidepressants (it never ends) and the tale of one researcher whose conflicts of interest nearly move him into Charles Nemeroff-ville. I bet that neighborhood looks like Wisteria Lane!

DTC Marketing: A Good Investigation

John Mack has done a dynamite job of investigative journalism over at the Pharma Marketing Blog. CommonHealth released a report claiming that direct to consumer advertising does not lead to patients asking their MD's for newer, more expensive medications. On its face, the claim is of course laughable, as there would be no DTC advertising if it did not influence patients to ask their doctors for expensive meds. CommonHealth then covered up their data as tightly as possible -- it makes it easier to place the appropriate spin on the study that way! Enter John Mack...

John mentions that "the trade press -- including PE [Pharmaceutical Executive] Magazine -- is spinning the study to prove a point rather than to help understand how DTC works. The point they want to prove is that DTC does not cause consumers to ask for more expensive medicines. The study proves no such thing, yet CommonHealth is aiding and abetting the misinterpretation of its study by denying us acces to their data.

"Here, we can see that there were 585 mentions of a brand name drug either by the doctor or the patient during the 440 visits recorded. True, the doctor initiated the discussion in the vast majority of cases (455 or 78% of the mentions). Yet the patient mentioned a brand name drug first in 130 cases or 22% of the mentions. That's a far greater percentage than the 1.0% to 3.9% numbers that CommonHealth focuses on in its PR campaign to make its case that DTC does not play a role in patients requesting advertised drugs.

Obviously, DTC advertising plays a huge role in raising awareness of new treatments among consumers. That role is often cited by the industry as a beneficial effect of DTC advertising. If DTC and PR, which is just another arm of DTC advertising (see "Marketing Disguised as PR"), are primarily responsible for raising awareness of drugs in the minds of consumers, then, by extension, whenever a patient mentions a drug by name in a doctor's office, that mention is due to the influence of advertising.

Despite all the obfuscation and spinning of the data, no one is really fooled. But the sad part is that there is a call out for the FDA to establish an advisory board of communication experts that will help it design better methods of communicating drug benefits and risks to consumers. This advisory board will include experts from agencies such as CommonHealth. If this study is any indication on the kinds of advice the FDA will be getting from communication experts, then I anticipate a lot of blog-worthy fodder in my future!"

Jus another reason that I recommend that you regularly visit the Pharma Marketing Blog.

How do I Love PLoS Medicine?

Let me count the ways. I have to say that PLoS Medicine seems to have their act together more than any other general medical journal regarding discussing ethical issues, though I think the others have been doing good work lately.

Anyway, PLoS has an article by a Who's Who of medical ethics reformers (Mansfield, Lexchin, Jureidini to name a few) that you should really check out. I'll quote a few choice snippets to whet your appetite...

"The US Accreditation Council for Continuing Medical Education states that “residents must learn how promotional activities can influence judgment in prescribing decisions and research activities through specific instructional activities” [5]. World Health Assembly resolution 52.19 urges member states to “integrate the rational use of drugs and information on commercial marketing strategies into training for health practitioners at all levels.” However, a recent worldwide survey of education about pharmaceutical promotion in medical and pharmacy schools found that “in most cases ‥ students devoted one half day or less to this topic during their professional training; in nearly one third of cases, medical faculties devoted only 1–2 hours” [6]. That survey also found wide variations in objectives, ranging from aiming to “increase students' ability to extract beneficial information from drug promotion” to aiming to “increase students' use of independent information sources.”

--SNIP--

"Box 2. Four Objectives for Education about Pharmaceutical and Device Promotion

All health professionals should be aided in the following ways:

• Educated explicitly about decision making and evaluation of evidence and promotion.

• Helped to understand that there is no proven method for enabling them to gain more benefit than harm from promotion.

• Helped to understand their responsibility to avoid pharmaceutical and device promotion.

• Educated explicitly about the most reliable sources of information."

My View: Ya think? Of course, we should be doing all of the above in medical education. Physicians in training also need to learn about research methods and statistics in much more detail. Medical education has clearly failed to produce physicians who understand how sloppy research designs and suspect use of statistics can make a mediocre product look good. I believe that better research training is as important as the above suggestions.

Read the whole article here. Hat tip to PharmaGossip.

Cyberonics: Abandon Ship

Every time I do a little research on vagus nerve stimulation, I find something new, yet I can nearly always count on my search to yield results showing either a) corruption, b) poor efficacy, or c) both. Guess what I found this time?

I'll just quote from Public Citizen's review of the VNS literature...

"The VNS device is implanted beneath the left clavicle in an outpatient procedure that typically costs $25,000 (including the device).[6] A lead runs to the vagus nerve and generates 30-second electrical pulses every five minutes. The device was approved in 1997 for refractory epilepsy, but Cyberonics pursued the additional indication of TRD, perhaps because the company estimated that the market for the latter was 4.4 million people in the U.S. alone. In a May 11, 2005, letter to the FDA urging the agency to not approve the device, we described the inadequacies in the data supporting the efficacy of VNS for TRD.[7] Here, we summarize those data and incorporate the entire letter by reference.

Expecting to demonstrate the efficacy of VNS over the short-term, Cyberonics conducted an appropriately designed randomized, controlled trial (Study D02 Acute Phase) of three months duration in which all TRD patients were implanted with the device, but only half had the device turned on. The other half did not have the device turned on, and so received “sham therapy. The study was a failure. On the primary outcome measure (the Hamilton Rating Scale for Depression, or HRSD), VNS showed no efficacy compared to sham therapy; the same was true for nine of ten secondary analyses.[8] This remains the best-designed study of VNS to date.

Following Study D02, the company offered sham therapy patients the chance to have their device turned on (Study D02 Long-term Phase). Predictably, the patients improved over time. This is a near-ubiquitous finding in studies of depression patients due to both the placebo effect and the tendency of patients enrolled into studies of relapsing conditions to improve over time (regression to the mean) because their condition is typically worse at the time of enrollment than at other times. In this and the follow-up to Study D02, patients were unblinded and, unlike in the acute phase of Study D02, were permitted to change concomitant therapies including other antidepressants and even electroshock therapy.

Facing rejection of their application by the FDA, the company opted to add a comparison group for Study D04, which merely compared the Study D02 Long-term Phase patients to this hastily assembled comparison group. Like Study D02 Long-term Phase, there was no blinding, concomitant therapies were permitted to change over time and the comparison patients were recruited from overlapping, but different, sites. Indeed, the authors of a published report on VNS acknowledge that the comparison arm “had not originally been intended to serve as the [control]; it was intended to describe health care costs ”[9]. A modest benefit was reported by the researchers, but only after the only (secondary) outcome that was positive in Study D02 was hand-picked to be the primary outcome for Study D04. Moreover, in an analysis mandated by the FDA, adjusting for overlapping sites and concomitant treatment produced no statistically significant finding on any primary or secondary outcome.

A weaker package of studies is difficult to imagine. Yet, inconceivably, the FDA issued an approvable letter on February 2, 2005, and approved the device on July 15, 2005, overruling an August 12, 2004, non-approvable letter the FDA had sent to the company."

There's a lot more in the full document, which you can peruse here. Suffice to say it's very shady. Of course, all of this didn't stop star academics like Charles Nemeroff from signing off on VNS therapy's alleged wonders! Though having several hundred publications under his belt, that has not stopped (perhaps it's actually encouraged) him to get involved with some chicanery related to VNS and other controversial treatments. This does not make academic psychiatry look good when "respected" big name psychiatrists pimp treatments that clearly provide little to no benefit.

Happy Two Month Anniversary to CPP!

I'd like to wish my site a happy two month anniversary. It's nice to see increasing numbers of people dropping by lately. As always, if you have stories that you believe are newsworthy, drop me an email. All correspondence will be treated as confidential.

Bipolar: It's Everywhere!

I have mentioned earlier that Big Pharma needs a new market for antipsychotics. After all, they’re generally under patent protection for a little while longer, and since there is little sign of making any new drugs which may actually improve outcomes for patients with psychiatric conditions, they are just expanding the market for existing medications. Bipolar disorder is the next big frontier, and one important part of finding a new frontier in psychiatry is to emphasize how this frontier represents an undetected epidemic. This is where a nice article from David Healy in PLoS Medicine comes in. It will be quoted at some length interspersed with my commentary…

Healy reminds us that the term “mood stabilizer” is a relatively recent phenomenon, as the term was rarely mentioned to the use of valproate (Depakote) to treat bipolar in 1995. By 2001, Healy points out that there were over 100 articles being published annually that had a subject heading of “mood stabilizer.”

“Repeated reviews make it clear that the academic psychiatric community still has not come to a consensus on what the term “mood stabilizer” means [5–7]. But this lack of consensus did not get in the way of the message that patients with bipolar disorders needed to be detected and once detected needed mood stabilizers, and perhaps should only be given these drugs and not any other psychotropic drugs [8,9].”

--SNIP—

“Bipolar disorders entered the DSM (Diagnostic and Statistical Manual of Mental Disorders) in 1980. At the time, the criteria for bipolar I disorder (classic manic-depressive illness) involved an episode of hospitalization for mania. Since then, the community based disorders bipolar II disorder, bipolar disorders NOS (not otherwise specified), and cyclothymia have emerged. With their emergence, estimates for the prevalence of bipolar disorders have risen from 0.1% of the population having bipolar I disorder (involving an episode of hospitalization for mania) [11] to 5% or more when the definition of bipolar disorders includes the aforementioned community disorders [12]. A range of academic institutions has also grown more interested in the condition.”

Now, there is a case to be made that antipsychotics reduce symptoms in the case of acute mania (though, as I've shown earlier, it is not necessarily a very impressive effect). This, however, carves out a limited market, as acute manic states are generally short in duration. The trick, then, is to make sure that physicians and patients are convinced that they must use the medications indefinitely to prevent relapse. In other words, to profit immensely from the use of antipsychotics, people must be convinced that there is a prophylactic effect. Of course, if there really is a strong long-term positive effect for these meds, then everyone stands to benefit. Patients improve and drug companies’ bottom lines are justifiably enhanced.

Indeed, this is just what Big Pharma is attempting to do —persuade people that antipsychotic meds have an excellent long-term benefit:

“There is a growing amount of patient Web site and patient support materials that in the case of Zyprexa state that “bipolar disorder is often a lifelong illness needing lifelong treatment; symptoms come and go, but the illness stays; people feel better because the medication is working; almost everyone who stops taking the medication will get ill again and the more episodes you have, the more difficult they are to treat” [17]. Information available from Janssen (the makers of Risperdal) states “medicines are crucially important in the treatment of bipolar disorders. Studies over the past twenty years have shown beyond the shadow of doubt that people who receive the appropriate drugs are better off in the long term than those who receive no medicine” [18].

“There is, however, much less evidence than many might think to support these claims for the prophylactic drug treatment of manic-depressive illness (bipolar I). And there is almost no evidence to support such claims in the case of whatever community disorders (bipolar II, bipolar NOS, cyclothymia) are now being pulled into the manic-depressive net by the lure of bipolar disorder.

With the possible exception of lithium for bipolar I disorder, there are no randomized controlled trials to show that patients with bipolar disorders in general who receive psychotropic drugs are better in the long term than those who receive no medicine [19]. This may stem in part from difficulties in conducting trials on psychotropic drugs that last more than a few weeks in conditions as complex as manic-depressive illness. One short-term, randomized, placebo-controlled trial (in which patients were only followed for up to 48 weeks) that some see as a basis for claiming that olanzapine may be prophylactic in bipolar disorder [2] has been regarded by others as indicating that this drug produces a withdrawal-induced decompensation when stopped [20]. Even in the case of lithium, there is some dispute over what has been demonstrated [19], with the best evidence stemming from large open studies in dedicated lithium services rather than from randomized trials [21].

This evidence of benefit for one agent (lithium) and possible benefit for one more (olanzapine) must be weighed against two harms associated with use of antipsychotics: (1) a consistent body of evidence indicates that regular treatment with antipsychotics in the longer run increases mortality [22–26]; and (2) there is evidence that in placebo-controlled trials of antipsychotics submitted in application for schizophrenia licenses there is a statistically significant excess of completed suicides on active treatment [27]. A range of problems associated with antipsychotics, from increased mortality to tardive dyskinesia, never show up in the short-term trials aimed at demonstrating treatment effects in psychiatry.

But aside from these hazards, there are also grounds to question whether the treatment effects that some think have been demonstrated in bipolar disorder trials translate into therapeutic efficacy. If use of these agents based on demonstrated effects leads on to efficacy, admissions for bipolar disorder might be expected to fall, but the evidence for this is difficult to find. In North Wales before the advent of modern pharmacotherapy, patients with bipolar I disorder had on average four admissions every ten years. In contrast, against a background of a constant incidence of bipolar I disorder, and dramatic improvements in service provision, bipolar I patients show a 4-fold increase in the prevalence of admissions despite being treated with the very latest psychotropic medications [11]. This is not ordinarily what happens when treatments “work,” but quite often is what happens when treatments have effects.”

Healy goes on to point out in more detail that the risk of suicidal acts is apparently significantly higher among users of mood stabilizers…

“Two suicides (493/100,000 person- years of exposure) and eight suicide attempts (1,969/100,000 person-years of exposure) occurred in the group given an active drug (943 patients), but no suicides and two suicide attempts (1,467/100,000 person-years of exposure) occurred in the placebo group (418 patients). Based on these absolute numbers from these four trials, I have calculated … that active agents are most likely to be associated with a 2.22 times greater risk of suicidal acts than placebo (95% CI 0.5, 10.00).”

The article then points out that there is a groundswell of bipolar diagnoses among children in the United States though the question of whether this represents disease awareness or disease mongering is still open. I strongly suspect it is the latter, as bipolar disorder has generally been thought to not emerge until adolescence except in extremely rare cases. At least that was the case prior to the latest "epidemic" in psychiatry. Bipolar diagnoses, especially of children, are often based on quite subjective criteria and may reflect inaccurate reporting by parents. How far will the mania for bipolar go?

“Experts that appear willing to go so far as to accept the possibility that the first signs of bipolar disorder may be patterns of overactivity in utero [32] can only further compound these problems.”

Antipsychotics are potent sedative agents, so, as Healy points out, they will likely slow down overly active children (see trial results for antipsychotics in autism, for example) as measured on a rating scale, resulting in apparent efficacy. Who needs limit setting, boundaries, and warm but firm parenting when you can simply sedate kids with very powerful tranquilizers? I am not meaning to state that parenting and/or behavior therapy can solve the problems of all bipolar, er, overly active children. I am saying that practitioners would be wise to attempt many other treatment options prior to using these meds, whose long-term impact on children is likely to be deleterious from a health standpoint.

Please read Healy’s article here. Read a critique of his paper (which doesn’t even attempt to refute the main points of his arguments) and then read his reply here. You can also see my prior post on the future of antipsychotic meds (hint: distribute them much more widely) here.

Yet More Trouble for Newer Antipsychotics...

California's top law-enforcement official is investigating drug makers' marketing practices for blockbuster antipyschotic medications.

At least four pharmaceutical companies - AstraZeneca PLC (AZN), Eli Lilly & Co. (LLY), Bristol-Myers Squibb Co. (BMY) and Pfizer Inc. (PFE) - have disclosed in recent days they received subpoenas from the California attorney general's office seeking information about their respective antipsychotics. The drugs are approved to treat bipolar disorder and schizophrenia.

Eli Lilly, which makes Zyprexa, and AstraZeneca, maker of Seroquel, indicated that the subpoenas received in September sought information about their marketing practices for the antipsychotics, as well as the drugs' status on California's "formulary," or list of preferred drugs for a state insurance program.

Lilly of Indianapolis said in a regulatory filing Friday its subpoena was related to "our efforts to obtain and maintain Zyprexa's status on California's formulary." Also, Lilly said the subpoena concerned "remuneration of health care providers." Lilly spokesman Phil Belt said the company is cooperating with the request for information. AstraZeneca of the U.K. disclosed its subpoena in a document posted on its Web site last week…”

--SNIP--

“Newer antipsychotics have become big moneymakers for drug companies, with Zyprexa posting $4.2 billion in sales and Seroquel generating $2.76 billion last year. Abilify, a newer drug, posted sales of $912 million in 2005.”

My View: Perhaps California has grown weary of paying ridiculous prices for medications that lead to signfiicant health problems such as diabetes without having any efficacy advantage over older antipsychotic meds. It would be nice if an antipsychotic was developed that lacked the heavy side effect burden of either the first or second generation meds.

Read the full story at MarketWatch here.

Neurontin: Blast From the Past

My readers may recall mention of Neurontin a while ago. I just wanted to post a link to the full text of the great article in the Annals of Internal Medicine that exposed the shenanigans associated with Neurontin's promotion. Check it out here.

UK Pharma Flexes Its Electoral Might

PharmaGossip has a good post on how UK Pharma is trying to influence the US midterm elections through donating money to their shills, er, favored representatives. The thing that people must keep in mind is that Dems are also drug industry patsies, so don't expect any serious reform regardless of who wins.

rTMS: What's the Real Story?

Couturier reviewed rTMS for major depression via a meta-analysis, which was published in 2004. Link to her study here. Here’s a quote:

“Results: Six studies that met the inclusion criteria were identified and included in the meta-analysis. Two of these reported a significantly greater improvement in mood symptoms in the treatment versus the sham group. When combined in the meta-analysis, the overall weighted mean difference was –1.1 [on the HAM-D] (95% confidence interval –4.5 to 2.3), and the results of a test for heterogeneity were not significant (χ2 = 5.81, p = 0.33). Conclusions: This meta-analysis suggests that rapid-rate rTMS is no different from sham treatment in major depression; however, the power within these studies to detect a difference was generally low. Randomized controlled trials with sufficient power to detect a clinically meaningful difference are required.”

There were some legitimate criticisms of her method, which you can read here along with her reply. Couturier’s reply seems to have addressed the criticisms aptly.

Since that time, two studies have shown greater efficacy for rTMS over sham therapy (here and here). To my knowledge, there has not been a meta-analysis that has accounted for these new studies. The effects seemed reasonably large, though I’ve only read the abstracts at this point.

So what’s the story with rTMS? It’s pretty murky. FDA may approve it because it seems to have two studies showing efficacy yet there are a fair number of studies showing no efficacy. All told, it is going to be one controversial decision that I look forward to discussing more as it develops. I'm certain the folks at Neuronetics are crossing their fingers!

Great Video Clip

The clip here is one of the best of the best. It isn't often when TV hits one out of the park, but if you like a) drug reps b) ethics in medicine and c) Heather Locklear, then what are you waiting for?

Just TOO funny!

Hat tip to PharmaGossip for the summary of the New York Times story on drug companies providing funding for training doctors to resist the persuasive tactics of drug reps. Yes, you read that correctly. The following is a partial quote from PG's site:

"Medical schools in several states are boosting programs that teach doctors and students to challenge the sales pitches of drug companies and avoid being dazzled by them.

Big Pharma spends billions of dollars a year on marketing to doctors; sometimes throwing lavish events to seal the deal on certain medicines.

Critics say slick promotion is unduly influencing how drugs get prescribed, sometimes to the detriment of patients.

A small number of schools are now adding lectures and continuing education seminars aimed at persuading doctors to challenge claims made during sophisticated sales presentations.

But here's the kicker!

The money for some of the university programs about drug advertising comes from a $430 million legal settlement over promotion practices by Pfizer.

The company was accused of illegally paying doctors to prescribe its drug Neurontin for uses that had not been approved by the FDA. The settlement has so far awarded $11 million to 28 institutions."

Please read it all here.

More on Cyberonics

What else is going on? Of course, the discussion of questionable use of ghostwriters, buying off academic "researchers," and the like has been documented earlier. But there are other problems in the house of Cyberonics. According to an AP story,

"On multiple occasions in the last two months, Metropolitan Capital Advisors Inc. [a major shareholder] has asked you [Cyberonics] to tell us and the rest of the stockholders of Cyberonics Inc. when the 2006 annual meeting of stockholders will be held," read the letter to the board of directors. "Despite the company's professed commitment to stockholder democracy and good corporate governance, no date has yet been set despite the explicit requirements of Delaware law to the contrary."

The letter asked whether a delay in filing past financial results was the cause of silence on an annual meeting. It went on to accuse the board of dragging its feet in filing its financial statements and scheduling the meeting because "it does not believe this is the most propitious for the board to seek both to elect its hand-picked slate of directors and to oppose our efforts to elect new leadership."

The company has received two delisting notices from Nasdaq over its failure to file full-year financial results for the year ended April 28 and the quarter ended July 28. The Securities and Exchange Commission is in the midst of an informal investigation into the company's past stock option granting practices. Also, the U.S. Attorney's Office for the Southern District of New York has subpoenaed the company.

Metropolitan Capital owns about 1.8 million of Cyberonics' 25.2 million shares outstanding."

Greetings to Neuronetics!

I'm not particularly technologically inclined, but I did notice that someone using SMiller's account (according to my research, that's Stanford Miller, VP of Business Development) at Neuronetics was giving the site a look tonight. Someone at Neuronetics was previously checking my site out today based upon a Google News alert. Just thought I'd say hello.

Anyone know when Neuronetics' TMS treatment for depression will go before the FDA? It got delayed a couple weeks ago for undisclosed reasons. In any case, I'm flattered that I could get a bigwig like Mr. Stanford to check out the site. Please come back again!

Upcoming...

In the next few days, I'm going to post on transcranial magnetic stimulation for depression again as well as some bipolar disorder related stuff.

As always, if any of you have any ideas for posts, let me know...

Bow to the Mighty PharmaGossip

Big congratulations going out to one of my favorite sites of all time -- PharmaGossip. The British Medical Journal very recently featured a brief writeup of his site, which will likely boost the site's already substantial traffic. If you're not following PharmaGossip, you're not in touch with the world of pharmaceuticals.

Paxil Lawsuit Update

GlaxoSmithKline PLC has agreed to pay $63.8 million to settle a lawsuit's claims that it promoted its antidepressant drug Paxil for use by children and adolescents while withholding negative information about the medication's safety and effectiveness.

As part of the settlement, GlaxoSmithKline denies the lawsuit's claims, including that consumers paid too much for the drugs, but the world's second-largest pharmaceutical company wants to resolve the matter to avoid further litigation costs.

Read more at PharmaGossip. Read more about Paxil shenanigans here, here and here. After re-reading these posts, I want to sue them!

More on the Nemeroff Saga

Well, well, well. Another chapter in the Nemeroff saga is upon us. A brief but fabulous article in Clinical Psychiatry News (CPN) provides an excellent summary. You really should follow the link here after you read the current post. Let’s start with some background…

In July 2006, the journal Neuropsychopharmacology published an article ostensibly focusing on the purported mechanism of action for vagus nerve stimulation therapy (VNS) for treatment resistant depression. To summarize, Nemeroff was lead author of the review article (which was at least partially ghostwritten), editor of the journal in which it appeared, and a paid consultant to Cyberonics, the manufacturer of the VNS device. To top it off, all of the co-authors were also paid consultants to Cyberonics. It is tough to match that for conflicts of interest! The article contained a disclosure of funding from Cyberonics to write the article, but nothing was written indicating that all authors were paid consultants to the company.

On July 7, not wasting much time, Cyberonics issued a press release extolling the aforementioned review article as proof that VNS is a most excellent treatment for depression. Of course, Cyberonics did not bother to mention that the authors of this allegedly scientific review were all on the Cyberonics payroll! Nor did the press release (or the original article) mention that much of the article was drafted by a ghostwriter hired by Cyberonics. To ice the cake, Nemeroff is featured praising VNS in the press release. See my earlier post here for a longer rant and a few more details.

Cyberonics ordered 10,000 reprints of the Neuropsychopharmacology article. Mind you, this article was (quoting from the CPN editorial) “viewed as an infomercial because it followed the Cyberonics public relations message and branding language on the modest efficacy of VNS therapy. No mention was made of the controversy surrounding the Food and Drug Administration's approval of VNS therapy or the Senate Finance Committee's scathing report on the approval.”

Modest efficacy, you wonder? To quote the NY Times: “…in the most carefully controlled trial, a group that had the device implanted but not turned on fared nearly as well as the group being stimulated. Critics also pointed out that long-term results indicated that 30 percent of the patients reported worsening depression similar to Ms. Coram’s, creating unanswered questions about potential harm.” Nemeroff et al’s review was much more positive, stating that: “After reviewing all the available data, taken together, it is clear that VNS Therapy is a promising treatment for patients living with TRD. Given the nature of TRD, it is exceptional that the antidepressant effect of VNS Therapy has been shown to improve over time and is sustained long-term for patients with TRD.”

So, to the aftermath we go, from the CPN piece. Drs. Bernard Carroll and Robert Rubin “sent the ACNP Council a notification of these problems on July 11, 4 days after the Cyberonics press release appeared. When, after almost a week, we got no response, we shared the information with several journalists.” What did the ACNP do in response?

“In response to the widening controversy, ACNP began damage control. Initially, ACNP proposed simply to publish a corrigendum in a future issue of the journal. In response to member feedback, ACNP then acted on the urgent need to correct the 10,000 reprints.

On July 25, the executive committee (ACNP president, past-president, and president-elect) issued a statement to members aimed at casting the events in the least unfavorable light. Their conclusion? The use of a professional writer did not amount to “ghostwriting” in this case [Hmmm -- I'm not sure in WHICH case one would find a verdict of ghostwriting according to ACNP]. No one was held accountable.

The executive committee's statement avoided any criticism of Cyberonics (which is a supporting corporation of ACNP) [Hey, someone has to pay the bills!], and Dr. Nemeroff repeatedly dismissed the problem as “a simple oversight.” [If this is an oversight, there is a disturbing trend of oversight on Nemeroff’s part, as can be seen here]

“A second wave of negative feedback from members to ACNP Council came after the executive committee's statement. Also on July 25, the New York Times cited the Cyberonics case as exemplary of how corporations use academic experts to push their products.

By Aug. 3, ACNP President Kenneth Davis issued a second communication to the membership, very different in tone from the initial executive committee statement. This message intimated that individuals would indeed be held accountable. The next day, an unflattering news item appeared in Science.

By Aug. 25, ACNP announced to members that Dr. Nemeroff was resigning his editorial position. At press time, a search for a new editor was in progress.”

--SNIP--

“Omnibus disclosure forms, which the authors said they had sent to the journal for the editors to review, often serve to obfuscate the compromised status of authors vis-à-vis specific publications. In the case of the Cyberonics-funded VNS therapy review, the only relevant disclosure that by ACNP policy should have been included in the article for readers to see was the paid Cyberonics-consultant status of the academic authors, not their many relationships with other corporations. All eight have been members of the Cyberonics Mechanism of Action Advisory Board since 2003.”

When the leaders of professional societies lose their ethical compass, individual members can exert moral suasion by speaking out.

Physicians associated with professional journals should insist that articles featuring such marketing tactics be routinely rejected. Stanford University's School of Medicine has led the way by announcing a ban on faculty members placing their names on ghostwritten articles.” [Great idea, but I wonder if they will just a) not acknowledge that their articles are ghostwritten or b) take the position that having someone else write your articles is not ghostwriting, such as the ACNP]

My View: It’s nice to see someone blowing the whistle in a widely read trade publication! Their speaking out did appear to help chase Nemeroff from his editorial position and really helped to bring a spotlight to a situation that desperately called for public notice. Indeed, I find these stories highly motivational -- vigilance can indeed yield results!

One point that bears emphasis is that the omnibus conflict of interest statements serve to better cover up relevant conflicts of interest than to clarify them. Reading many psychiatry journal articles, one sees that an author will acknowledge research funding from six companies, unrestricted grants from two or three, paid speaker status for five, and so forth. What is relevant is who paid for this particular article. I want to know if the authors were funded to conduct this study by the drug or device manufacturer, not whether the authors spoke to a group of physicians about some other product made by a different company. I’d also like to know if the authors serve on an advisory board for the company whose product they are pimping.

I agree that journals should toss out ghostwritten infomercial articles. One does not have to look far in many psychiatry journals to see junk “review” or “mechanism of action” articles that are clearly nothing more than infomercials. It’s predictable. If a new product is coming out or an existing product is trying to expand into a new indication, watch for so-called scientific journals (and especially journal supplements) to be flooded with cheap toilet paper-quality articles talking about how this treatment will help to improve outcomes for an undertreated or treatment resistant population. Given how few actual advances have been made in treating psychiatric conditions in the past few decades, readers are well advised to wait until sufficient data have been collected prior to showing anything other that skepticism toward these corporate propaganda pieces, er, review/theoretical mechanism of action articles. Carroll and Rubin are absolutely correct to call for journals to not publish them, yet they bring in revenue as either supplement fodder (as we know, supplements are generally funded by drug or device companies), or they are purchased en masse as reprints ($$$ for the journal publisher) so I am afraid that their suggestion will not be taken seriously. Another post on that topic to come sometime in the near future...

Atypical Anitpsychotics Disappoint A-G-A-I-N

McCue, Waheed, Urcuyo, Orendain, Joseph, Charles, and Hasan just published a study in the British Journal of Psychiatry suggesting that haloperidol (Haldol) may be more effective than some of the newer, dramatically more pricey antipsychotic meds. Link to abstract on journal's site here or just read below...

Background There is little information on the comparative effectiveness of second-generation antipsychotic agents.

Aims To determine if any of five second-generation antipsychotics or haloperidolis more effective in treating acutely ill patients with schizophrenia, schizoaffective disorder or schizophreniform disorder.

Method A sample of 327 newly admitted patients were randomised to open-label treatment with aripiprazole, haloperidol, olanzapine, quetiapine, risperidone or ziprasidone for a minimum of 3 weeks. Measures of effectiveness were improvement in mental status so that the patient no longer required acute in-patient care, and changes in Brief Psychiatric Rating Scale (BPRS) scores.

Results By the first measure, haloperidol (89%), olanzapine (92%) and risperidone (88%) were significantly more effective than aripiprazole (64%), quetiapine (64%) and ziprasidone (64%). Changes in BPRS ratings were not significant among treatments.

Conclusions Haloperidol, olanzapine and risperidone are superior to aripiprazole, quetiapine and ziprasidone for the acute treatment of psychosis in hospitalised patients with schizophrenia, schizoaffective disorder or schizophreniform disorder.

My View: At worst, it appears that haloperidol was as effective or more effective compared to the new meds, yet is about 1-5% of the cost. Hmmm... And it ain't like Haldol is a wonder drug. This is one of a number of recent articles that has found the second generation antipsychotic meds have been highly overrated. Feel free to check out my prior posts on the topic, including this, this, this, this, and this.

Fluoxetine and Self-Harm in Kids

In an article titled "Suicidal behaviour in youths with depression treated with new-generation antidepressants," Dubicka & Hadley, in the latest British Journal of Psychiatry found that fluoxetine was associated with greater risk for self-harm and suicidal thoughts. Not a huge risk in comparison with placebo but any increase should be of concern. Link to abstract here though it is also reproduced below...

Background Concern exists that antidepressants can cause suicidality in youths with depression.

Aims To determine the pooled risk of self-harm and suicidal behaviour from randomised trials of newer antidepressants.

Method A meta-analysis was carried out to calculate odds ratios for the combined data.

Results Self-harm or suicide-related events occurred in 71 of 1487 (4.8%) of depressed youths treated with antidepressants v. 38 of 1254 (3.0%) of those given placebo (fixed effects odds ratio 1.70, 95% CI 1.13–2.54, P=0.01). There was a trend for individual suicidal thoughts, attempts and self-harm to occur more often in youths taking antidepressants than in those given placebo, but none of these differences was statistically significant.

Conclusions Antidepressants may cause a small short-term risk of self-harm or suicidal events in children and adolescents with major depressive disorder.

Not surprising results given other research on the topic, such as this, this, this, and this.

"Educational" Materials

The following packet, New Technologies in the Treatment of Mood Disorders, available free on the DBSA website has a couple doozies that bear mention. Let’s go through them…

(a) “Scientists believe that depression and bipolar disorder are caused by an imbalance of brain chemicals, called neurotransmitters. Medications used to treat these illnesses work to change brain chemistry and correct this imbalance.”

The problem: There is, at best, scant evidence of any reliable neurotransmission deficit in depression and bipolar disorder. There may indeed be a so-called “chemical imbalance,” but research has yet to find one. Please feel free to read a highly excellent article regarding this topic here.

(b) Transcranial Magnetic Stimulation (TMS) is mentioned, which in and of itself is fine. The brochure briefly describes the treatment.

The problem: It mentions that TMS “…helps correct the existing chemical imbalance,” which would be fine if there was indeed an identifiable chemical imbalance, which there is not.

The other problem: The info packet mentions that “Production of this brochure has been made possible by a grant from Neuronetics.” Neuronetics is the big name in TMS therapy devices. Neuronetics provides a little cash and DBSA discusses their treatment as a means of alleviating a chemical imbalance to a wide audience of people who likely either have a mood disorder or know someone who does.

What’s my beef with the chemical imbalance? The more that people believe depression is caused by some sort of chemical imbalance, the more likely it is they will seek biological treatments, which in comparison to psychotherapy show roughly equal results in the short-term and much poorer results in the long-term. Likewise, psychotherapy seems to be free of the various side effects associated with biological treatments.

Here's what some will say: “You're trying to question DBSA's motives -- how dare you! Mood disorders are terrible illnesses and DBSA helps support people with these illnesses.” My response: I'm not questioning anyone's character. I'm pointing out that Neuronetics funded this packet and within the packet is an unsubstantiated claim about TMS alleviating a chemical imbalance. I think it is great that DBSA is supporting people. However, just because an organization has many noble members who wish to support people, that is not a free pass. If a noble organization is describing information inaccurately, then someone should point that out regardless of the good intentions of their membership.

Reality is Stranger than Fiction: Rozerem Ads

Over at the consistently educational and entertaining Pharma Marketing Blog, you just have to read up on Rozerem. You know, the new sleep med that is getting killed by Lunesta and Ambien. There is some just plain funny stuff about their ad campaign. The Big O and the Beaver -- who came up with these ideas?? Freud is rolling over in his grave!

Conflicts of Interest on NPR

NPR did a broadcast in September (I think) about conflicts of interest in medicine. It's worth a listen, though I don't give it my absolute highest recommendation. Panelists include Jerome Kassirer, Ezekiel Emanuel, Sanford Friedman, and Thomas Stossel. Link here. There are a group of physicians who are outspoken about conflicts of interest being a sign of mega-progress in research who view drug reps as good teachers and conflicted interests as a means of benefiting patients. Stossel is in that camp. The irony is that he talked a few times about there being no evidence indicating that conflicts of interest create problems. He must have somehow missed such evidence as this, this, this, this, and this.

COI Mentioned in Psychology

It seems that conflicts of interest are rarely discussed in psychology. Of course, this is largely because psychologists are usually not being funded by drug companies to conduct research. Nonetheless, how conflicted interests impact researchers is an inherently psychological topic. So I was pleased to see that the Association for Psychological Science Observer decided to run a brief writeup from Daniel Greenberg about COI. Excerpts below:

..."Which brings us to the recent embarrassments of the nation’s most widely circulated medical journal, the Journal of the American Medical Association (JAMA), which this year has publicly acknowledged three separate research papers in which authors failed to disclose financial ties to pharmaceutical manufacturers, as required by JAMA since 1985. In one of these papers, published February 1, nine of the 13 co-authors failed to report their financial dealings with pharmaceutical firms. In more trustful times, the omissions would have stayed in the family, but not today. The spotlighted research concluded that cessation of drug treatment for depression during pregnancy could lead to a relapse — a controversial finding of obvious interest to manufacturers of anti-depressants.

A front-page article in the July 11, 2006, Wall Street Journal, headlined “Financial Ties to Industry Cloud Major Depression Study,” poured it on, reporting that “The lead author — Lee S. Cohen, a Harvard Medical School professor and director of the perinatal and reproductive psychiatry research program at Massachusetts General Hospital — is a longtime consultant to three antidepressant makers, a paid speaker for seven of them, and has his research funded by four drug makers. None of his financial ties were reported in the study. In total, the authors failed to disclose more that 60 financial relationships with drug companies.” The authors explained that the research for their JAMA paper was financed by a federal agency, and, in their view, no conflict existed. Even so, JAMA responded, their dealings should have been disclosed when the paper was delivered. In a letter co-signed by several of his non-disclosing colleagues, lead author Cohen agreed, stating that “disclosures would have provided utmost transparency with respect to potential conflict of interest and we wholeheartedly support such a practice.”

The New York Times joined in with an editorial referring to JAMA as a “conflicted medical journal.” And writing in the Boston Globe, Jerome Kassirer, a former editor of the New England Journal of Medicine, JAMA’s leading rival, warned that “journal editors fail to ask the questions necessary to identify the conflicts.... and still recruit financially conflicted physicians to write articles and editorials that involve selective interpretation of data.” Kassirer added, “The public trust is at stake, and despite widespread publicity, editors fail to weed out writers with conflicts.” Kassirer also argued that disclosure is over-rated as an antidote to conflict. “The cure for public distrust is to employ people who have opted not to be compromised by money.”

On the opposite side of the fray is Thomas Stossel of Harvard Medical School, who frequently argues in public forums that close ties between academics and pharmaceutical companies are beneficial to health and that CoI concerns have evolved into a witch hunt. In a July 2, 2006, Washington Post article titled “What’s Wrong with Money in Science?” Stossel and a Harvard colleague, David Shaywitz, contended that many cures have evolved from “links that are now widely portrayed as dangerous, corrupting the pursuit of scientific truth and threatening the public.” And they took a swipe at public interest groups on the trail of CoI and “their boosters at JAMA.”

She also dismissed the idea of adopting severe penalties for non-disclosure, such as banishment, temporary or permanent, from the coveted pages of JAMA. Though a few journals have taken that step, DeAngelis rejected it, with an explanation from the competitive underside of big-league scientific publishing. Sanctions against transgressing authors would simply divert them to another journal, she said, a process that “cleans our house by messing others.” Collective action by journals, she said, risks anti-trust prosecution. The proper way to go, DeAngelis argued, is to refer offenders to their deans — a step that she reported taking on two occasions.

In this busy season of agitation over conflict of interest, a contender for the prize case showed up in the July issue of the journal Neuropsychopharmacology. Co-authored by eight academics, the paper favorably reported trials of an implantable electrical device for treating depression. Absent from the paper was any disclosure that the authors served as consultants to the company that makes the device, including the paper’s lead author, Charles B. Nemeroff, chairman of the Department of Psychiatry and Behavioral Sciences at the Emory University School of Medicine. In addition to that job, Nemeroff was also editor of Neuropsychopharmacology, a position he resigned following disclosure of his non-disclosure."

My View: Do I even need to state my opinion? Have you ever been to this site before? If you're interested on reading more about Dr. Nemeroff, please feel free to read earlier posts about the above incident and other interesting Nemeroff behavior here, here, here, and here.

Free Plug: I read Daniel Greenberg's previous book a few years ago (Science, Money, and Politics) and I give it high marks. If you're interested, you could purchase it here. No, I don't get a cut if you buy it.