Burying Data, Chapter 214

OK, I'll admit the following story ain't all that surprising unless your head has been firmly planted in the sand for the past several years. That being said, I'm sure glad somebody reported it...

"There is growing criticism of Big Pharma for failing to disclose results of clinical studies; especially studies that provide information about the safety or effectiveness of medicines being taken by consumers.

Take the case of GSK and two trials of Valtrex vs Famvir, in genital herpes.

The trials finished in 1998, but the were only published last month.

The lead researcher for the studies complained she was never given a satisfactory explanation, and noted the drugmaker responsible for the delay also owns the medicine that fared poorly.

"I was given all sorts of reasons," said Anna Wald, a professor of medicine at the University of Washington, whose work comparing the two drugs was recently published in the journal Sexually Transmitted Diseases.

"It took years to receive any material," she said. "They should have moved faster."

…

To gain an edge, SmithKlineBeecham funded a pair of comparative studies. Such clinical trials are known as head-to-head studies, but are rarely undertaken voluntarily by drugmakers due to the expense and, in particular, the possibility that results will be unflattering. In effect, SmithKlineBeecham took a gamble in hopes of goosing sales.

There was good reason. In 1997, the drugs were in a dead heat. Valtrex sales totaled $111 million on 1.6 million prescriptions, while Famvir rang up $107 million in revenue on 1.1 million prescriptions, according to Verispan, a market-research firm.

A team of researchers led by Wald conducted the studies in 1997 and 1998, but SmithKlineBeecham never shared the results, even though Wald said she repeatedly asked for the data. As a result, Wald said she had no way of knowing SmithKlineBeecham's Famvir compared unfavorably with Valtrex.

In other words, SmithKlineBeecham lost its bet.

In 2000, Glaxo and SmithKline merged, complicating the tale. The combined company promptly sold Famvir to Novartis to satisfy anti- trust concerns. A Glaxo spokeswoman said there was no information available about how the study data were handled at that time or why the data weren't given to Wald.

By then, Glaxo's Valtrex had taken the lead. In 2001, Valtrex generated $413million in sales on 4.4million prescriptions; Famvir rang up $191million in sales on 1.5million prescriptions, according to Verispan.

After the merger, Wald said she began asking Novartis for the study data, but didn't receive anything until early last year, when the drug maker sent what she described as an "enormous box of papers." She said Novartis personnel insisted the data couldn't be located.

"There are two possible interpretations," said Wald, who is also a consultant to Novartis. "Either the data got lost as part of the transfer from one company to another. The other is that Novartis didn't want to share the data be cause it wasn't favorable (to Famvir), which might hurt the sales. I don't know which it is."

…

The Novartis spokeswoman also explained Famvir data were stored among 28,000 boxes sent by Glaxo, and that talks began with Wald in January 2003. But she couldn't explain the delay between 2003 and late 2005, when Wald finally received the data.”

Hat Tip: The always ecellent PharmaGossip.

P.S. Don't worry -- drug companies don't have to share data with researchers. Just ask this guy.

Patient Groups: Grassroots or Astroturf?

The New Scientist has an excellent article on the conflict of interest involving so-called “grassroots” patient organizations that receive drug company funding for support. I’d like to thank the reader of my site that provided me the link to the story. Long excerpts (with my emphasis) below.

"They are supposed to be grassroots organisations representing the interests of people with serious diseases. But Drummond Rennie, professor of medicine at the University of California, San Francisco, and deputy editor of the Journal of the American Medical Association, believes that some patient groups are perilously close to becoming extensions of pharmaceutical companies' marketing departments. "There's a crisis here," he contends.

Rather than grassroots, the word Rennie uses to describe such organisations is "astroturf". Originating in the black arts of politics and public relations, astroturfing is the practice of disguising an orchestrated campaign as a spontaneous upwelling of public opinion.

Other health specialists don't go as far, but they are still uneasy about the financial relationships between drug firms and prominent patient groups. "I think there are grounds to be concerned," says Joel Lexchin, who studies pharmaceutical policy at York University in Toronto, Canada. He and others point to instances in which representatives of patient groups, sometimes in close contact with corporate public relations teams, have spoken favourably about drugs at meetings or press conferences.

…

So is the charge of astroturfing fair? How much money are patient groups typically taking from pharmaceutical and medical device firms, and does this affect their behaviour? To investigate, New Scientist conducted the largest survey to date of industry donations to patient groups based in the US - the biggest single market for drugs and medical devices. As well as taking a random sample, we identified groups associated with conditions for which companies have been accused of "disease-mongering" - encouraging an expansion of the boundaries of an illness in order to boost sales of a treatment for it (see "How the groups were selected", below). Though these allegations are unproven, we decided it was important to investigate whether any patient groups have received unusually large proportions of their funding from industry.

In each case, we tried to determine the percentage of a group's total funding that came from the pharmaceutical and medical device industry in the most recent year for which figures were available. This was not always easy, as US non-profit organisations are not required by law to disclose their donors' identities. Tax returns and annual reports provided some of the information, but in most cases, obtaining a figure required the group concerned to provide it voluntarily.

The extent of industry funding varied widely (see Chart, right). In some cases the cash amounts were enormous - more than $23 million in the case of the American Heart Association, the largest organisation studied, although this accounted for just 4 per cent of its total funding. Small proportions of funding may not be cause for concern, Lexchin says, unless they go toward activities like creating biased treatment information. "It depends how the money is used." Lexchin also believes there is a need for greater transparency about where such donations are coming from, so patients can evaluate for themselves the information the groups are providing.

In total, seven groups received 20 per cent or more of their funding from pharmaceutical and medical device companies, including all four linked to the conditions over which accusations of disease-mongering have been made.

One of these groups, the Depression and Bipolar Support Alliance, said it received more than half of its 2005 funding from industry. The group did not provide an exact percentage, but combined information from its annual report and tax return reveals that 77 per cent of its revenue for 2005 came from 15 major donors, 12 of which are drug or device companies.

The Restless Legs Syndrome (RLS) Foundation, for instance, received more than $450,000 of its $1.4 million revenue in 2005 from GlaxoSmithKline (GSK) and nearly $178,000 from Boehringer Ingelheim. GSK's drug Requip was approved for the syndrome in 2005, while Boehringer Ingelheim has a drug pending FDA approval. Both drugs are intended to control the symptoms of RLS over long periods. While these symptoms can seriously disturb sleep, critics claim that their prevalence has been exaggerated by GSK and in media reports.

The extent of industry funding of the RLS Foundation is "pretty incredible", says one such critic, Steve Woloshin of Dartmouth Medical School in Hanover, New Hampshire. However, both the RLS Foundation and GSK reject accusations of disease-mongering. GSK is clear that Requip is indicated for moderate to severe RLS only, says company spokeswoman Holly Russell. "The main sense we get from patients is an enormous sense of relief," she adds. "Show me the scientific article that says that people who don't have the condition or people that have very mild RLS are flocking to take drugs," says Georgianna Bell, executive director of the RLS Foundation.

…

By contrast, groups in our survey that received no industry funding seemed to be for diseases that drug companies have little opportunity to profit by. For example, the people supported by Faces, the National Craniofacial Association, are typically treated with surgery, while the Ehlers-Danlos National Foundation is for people with a disorder of the body's connective tissue for which there is no specific treatment. The Amyotrophic Lateral Sclerosis Association received just 0.6 per cent of its $16 million budget for 2005 from pharmaceutical companies. This neurodegenerative disease is typically fatal within four years of diagnosis, and there is only one drug approved by the US Food and Drug Administration to treat it. Aventis, which manufactures the drug, provided $10,000 to the association.

The timing of donations also suggests a link to marketing interests, though donations to individual groups can vary from year to year for various reasons. Pfizer, for example, was a major donor to the RLS Foundation in 2003 and 2004. In July 2004 the firm announced that it had ceased developing its candidate RLS drug, and the following year donations to the patient group ceased.

Meanwhile, concerns about the safety of psychiatric drugs in children, which reached new heights in 2004, have hit the Child and Adolescent Bipolar Foundation hard. Its donations from industry fell from about 40 per cent of its total revenue in 2004 to 20 per cent in 2006. "Pharmaceutical companies are not as willing to support us because of increased scrutiny around psychiatric treatments in children," says Susan Resko, the foundation's executive director. As a consequence, she has had to lay off more than half of her staff.

…

Information on the websites of some groups in our survey raises further questions. For example, the treatment section of the Depression and Bipolar Support Alliance's site was developed with an "educational grant" from Neuronetics, a company which gave at least $10,000 and possibly as much as $150,000 to the alliance in 2005. One page describes transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS) which both aim to treat mood disorders by stimulating neural activity. Neuronetics makes equipment for TMS, which has not yet been approved as a treatment. Nevertheless, the site provides web links and telephone numbers for Neuronetics and Cyberonics, a VNS equipment maker that donated between $150,000 and $500,000 to the alliance in 2005."

Read the whole story here.

My View: I am certain that it nearly always starts innocuously. A group that wants to support people with condition X starts humbly, scraping scarce resources together in a truly grassroots effort. Then company Y notices that this group needs some money, and we all know what people, as individuals or groups, will often do for money. It is my belief that most of these patient groups truly believe they are not influenced by drug company funding, but when perusing their websites, it is hard to believe this is true. Influence can be completely subconscious. I’ll write more on the Depression and Bipolar Support Alliance soon. Link to another very good story on the Requip/Restless Legs issue here.

Finally, a Debate!

My post on Depakote for mania has drawn in a comment from a person who is in obvious disagreement. I just want to refer folks to the following link, where you can chime in with your comments. Please throw in your two cents.

Restless Legs or Tireless Marketing: Requip

Health Care Renewal has a G-R-E-A-T post about disase mongering related to restless legs syndrome.

To summarize, GlaxoSmithKline sees a market for restless legs syndrome. Unfortunately for them, the vast majority of people in American don't see a need for treatment. Enter the Restless Legs Syndrome Foundation (largely funded by GSK, of course) and a few key opinion leaders in the form of physicians willing to extol the virtues of this great medication, Requip, likely in exchange for some cash. The results, if you've paid attention to this blog or similar sites, are entirely predictable. A market is created and the cash flows nicely for GSK. Of course, whether restless legs syndrome is an actual issue of significance or not is irrelevant because it's about the dash for cash, not treating patients.

Also add to your required reading list an excellent article on restless legs and disease mongering published in PLoS Medicine by Woloshin & Schwartz. In fact, let's just call this required reading. A quote from their article that sums it up nicely and simply:

"Helping sick people get treatment is a good thing. Convincing healthy people that they are sick is not. Sick people stand to benefit from treatment, but healthy people may only get hurt: they get labeled “sick,” may become anxious about their condition, and, if they are treated, may experience side effects that overwhelm any potential benefit."

You should also check out Health Care Renewal's great post below:
Health Care Renewal: Conflicts of Interest and the Marketing of Requip

Jane Pauley: Unwitting Spokesperson for Lilly?

Apparently Jane Pauely though her story might be run under mental health issues, not infomercials for Lilly and others. How low will they go? From the Smoking Gun:

"OCTOBER 25--Claiming that The New York Times duped her into granting an interview for what turned out to be a drug company-funded advertising supplement, Jane Pauley has sued the newspaper for fraud. In a lawsuit filed Tuesday in U.S. District Court, the 55-year-old broadcaster charges that she believed that the Times interview was for a news article on mental health issues, but that the story (accompanied by a full-page photo) ran in an October 2005 "special advertising supplement" promoting psychotherapeutic drugs sold by Eli Lilly and other pharmaceutical firms. Pauley, who in September 2004 disclosed her battle with bipolar disorder, alleges that the Times "duped" her into lending her name to its advertising gambit, according to the lawsuit, an excerpt of which you'll find below. After going public about her bipolar disorder, the lawsuit notes, Pauley has worked with several mental health advocacy groups, including the National Mental Health Association. Pauley's lawsuit seeks unspecified damages from the newspaper and DeWitt Publishing, which helped arrange the advertorial"

Link here. Hat tip: PsychCentral.

Big Pharma Tries to Sway the Election

Campaign contributions -- talk about return on investment! PharmaGossip has a link to a story, which is excerpted briefly below:

The Wall Street Journal on Wednesday examined how pharmaceutical companies are "pouring millions of dollars" into congressional campaigns in close races, "giving some Republicans a financial edge."

According to the Journal, "with a Democratic victory increasing likely, few recent elections have been so critical" for pharmaceutical companies, in large part because Democrats have promised to revise the Medicare prescription drug benefit to "take away most of the advantages it handed to pharmaceutical companies."

My View: Conventional wisdom has it that Republicans are cozier with Big Pharma than Dems. This may be true, but it ain't like Dems have a track record of NOT sucking up to Big Pharma. Just ask Al Gore -- see links here and here. Don't get me wrong, I'd rather see the Dems in office than the current group of plunderers, but let's not get too excited that Dems will make any serious attempt to reform the practices of Big Pharma.

Link to PharmaGossip's post here.

First Sperm Count, Now...

Does Prozac cause aggression? Research addressed this question in hamsters and below is a teaser of what they found...

"When hamsters tussle, the altercation might be one animal's attempt to establish social dominance over the other. Or, maybe it's the Prozac.

A new study indicates adolescent hamsters become more aggressive after receiving low doses of fluoxetine, the generic name for Prozac. Researchers say the findings could shed light on reported increases in aggression among young people who take antidepressants..."

Granted, this was done on hamsters, not humans. Nonetheless, it's worth reading.

Full story here at Seed Magazine (article by Meryl Rothstein).

Preventive Psychopharmacology? YIKES

Here are a few choice snippets from a Bioethics Forum post by Jerald Block...

"When does research into a preventive treatment become unethical? In many areas of medicine this is a familiar question; the ethics around immunizations is solidly grounded in such thought. However, in psychiatry, wholly preventive psychopharmacologic treatments have been unusual.

Unfortunately, such research is fraught with ethical dangers. In a recent study by McGlashan et al., “Randomized, Double-Blind Trial of Olanzapine Versus Placebo in Patients Prodromally Symptomatic for Psychosis,” it seems psychiatry may have crossed into ethically questionable territory..."

--SNIP--

"In McGlashan's study, the 14 authors cooperated under a Merck and NIMH grant and conducted their research in four clinical sites in the United States and Canada. The study examined whether olanzapine (Zyprexa) could be used in patients that appeared to be “prodromal” for schizophrenia to prevent or delay the onset of the disease. Just as some people feel tired or irritable a day or two before getting a cold, the psychosis that is the hallmark of schizophrenia is usually preceded by a motley set of other symptoms: changes in personality such as increased anger, anxiety, restlessness, moodiness, apathy, social withdrawal, odd behavior, paranoia, and/or declining school performance are often seen by the patients, friends, and family. Retrospectively, when diagnosing schizophrenia, these sorts of "prodromal" changes are frequently seen for several months before patients actually become psychotic. Unfortunately, the prodromal symptoms are also remarkably common, diffuse, and unspecific, especially when one considers that the patient is usually young – adolescence is a period of life that is normally marked by tumultuous changes in personality.

McGlashan’s team screened subjects for their study using a set of symptoms thought to be associated with the schizophrenia prodrome. They tried to select patients who were not yet psychotic but who seemed at high risk for developing schizophrenia. They then randomized their sample, giving olanzapine to one group and placebo to the other. They treated each group for one year and then observed them for another year.

Many patients dropped out of the study, and the findings were inconclusive. However, the data seemed to suggest that olanzapine might delay the onset of psychosis in those patients that are schizophrenic.

Regardless of the actual findings, though, the study never should have been performed. That it was poses a major challenge to the integrity of the controls that ensure research remains ethical.

The questions above suggest four reasons why the study is so disturbing.

How likely is it that the disease will manifest? Psychiatrists are not yet able to accurately predict who will manifest schizophrenia. The psychological testing instrument the authors used in the study had a large false positive rate. In prior studies, 46% to 80% of those tentatively labeled "prodromal" never developed schizophrenia after up to two years of observation – they were false positives. In McGlashan's experiment, 16 of 29 subjects (55%) who were given placebo failed to progress to schizophrenia over the two years they were examined. Thus around half of those treated with olanzapine were getting the neuroleptic for a disease they, too, did not have.

How likely is it that the treatment will create significant side effects or complications? During the period of the study, olanzapine was known to be associated with several serious complications. Specifically, one should worry that, after one year of exposure at doses ranging from 5 mg to 15 mg, patients would develop metabolic syndrome or, possibly, diabetes. Also, at the time the study went to IRB, olanzapine was known to be strongly associated with large weight gains. Indeed, McGlashan's paper showed those subjects getting olanzapine gained, on average, about 19 pounds over the placebo group. Finally, olanzapine, like all neuroleptics, can significantly alter a patient's personality and/or sleep. At the doses received, personality and sleep changes would be the rule, not the exception.

How severe are those complications? Metabolic syndrome and associated diseases, like diabetes, have significant morbidity associated with them. With regards to weight gain, there is well-established morbidity and mortality risks correlated to obesity. Finally, it is unclear how the quality of one’s life will be affected during and after one year of getting daily neuroleptic. Forming and solidifying new relationships occupies much of the time in adolescence and young adulthood. As neuroleptics affect cognition and emotionality, we might expect olanzapine to influence one's ability to build relationships, for better or worse.

How long will such complications impair the patient? The median age of the subjects was 16 years. One subject was remarkably young – 12 years old. Given their young age and the chronic nature of all the complication discussed above, we might anticipate they would have a large impact over the patient's life..."

--SNIP--

"Finally, one should note that the study could affect many more people than the 31 patients immediately involved. When you have a trial with so many distinguished investigators from elite institutions appearing in a top-notch psychiatric journal, it sends the message to those reading it: prescribing neuroleptics for similar patients is alright. The article implies that treating a troubled adolescent with a neuroleptic for a year for symptoms that are suggestive of schizophrenia's prodromal syndrome is entirely ethical. I believe we have established no such thing and that such research may legitimate what is, at present, bad practice..."

Full story here.

Post on Evidence Based Psychotherapies for Kids Updated

If you're interested, just follow the link.

Here's to Your Brain

This is great news to start off your weekend!

"Researchers found that moderate amounts of alcohol – amounts equivalent to a couple of drinks a day for a human – improved the memories of laboratory rats.

Such a finding may have implications for serious neurodegenerative diseases like Alzheimer's, said Matthew During, the study's senior author and a professor of molecular virology, immunology and cancer genetics at Ohio State University .

“There is some evidence suggesting that mild to moderate alcohol consumption can protect against diseases like Alzheimer's in humans,” said During. “But it's not apparent how this happens.”

He and his colleague, Margaret Kalev-Zylinska, a postdoctoral researcher at the University of Auckland, in New Zealand, uncovered a neuronal mechanism that may help explain the link between alcohol and improved memory.

“We saw a noticeable change on the surface of certain neurons in rats that were given alcohol,” During said. “This change may have something to do with the positive effects of alcohol on memory.”

The researchers presented their findings at the annual Society for Neuroscience conference in Atlanta.

...

The researchers measured the rats' blood-alcohol levels three times throughout the study. Toward the end of the study, they subjected the rats to two different memory tasks.

For the first task, the rats were given several minutes to examine two identical, square plastic objects. After a certain amount of time, a researcher replaced one of the objects with a new, round object made of glass. The researchers measured the amount of time that each rat spent checking out the new object – an indication that the animal recognizes it as a new object.

Rats given low doses of alcohol spent about three times longer examining the new object than did rats on the alcohol-free diet. Rats given the high dose of alcohol spent equivalent amounts of time checking out both objects, suggesting that they were unable to differentiate the old object from the new one.

For the second task rats were placed in a box with two chambers separated by a door. One chamber was well-lit, while the adjacent chamber was dark. After placing a rat in the well-lit chamber and then lifting the door, the researchers timed how quickly the rats entered the dark chamber (rats are nocturnal, and naturally prefer dark spaces.) Once inside the dark chamber, the rat received a mild electric shock to its feet.

The researchers repeated this same experiment 24 hours later, and kept track of how long it took the animal to enter the dark chamber. Many of the animals re-entered the dark area, yet the rats given alcohol waited anywhere from 2.5 to 4.5 times longer to enter the dark chamber than did the animals given the alcohol-free diet.

“The results suggest that both doses of alcohol moderately improved the animals' ability to remember this negative event, since they seemed hesitant to go into the dark area,” During said. “It also suggests that high levels of alcohol can reinforce bad memories. [D'OH!]

“People who drink to forget bad memories may actually be doing the opposite by reinforcing the neural circuits that control negative emotional memory,” he continued.

At the end of the study, the researchers analyzed brain and liver tissue from each animal.

They found that low levels of alcohol increased the expression of a particular receptor, NR1, on the surface of neurons in a region of the brain, the hippocampus, that plays a role in memory. Researchers think that NR1 plays a role in memory and learning.

...

“These experiments suggest that the effect of alcohol works through the NR1 receptor, at least where memory and learning are concerned,” During said.

“We didn't see any toxic effects of low-level alcohol consumption on the brain or the liver,” During said. “It didn't damage neurons nor did it cause liver damage during the short study. But the higher dose of alcohol damaged both.”

Link here. Hat tip to Robert Karl Stonjek.

Is AstraZeneca in Trouble Over Seroquel?

PharmaGossip has a post indicating that AZ may indeed be facing trouble for its big moneymaker. I wonder if AZ should start stashing away briefcases full of Benjamins for lawsuits since Zyprexa cost Lilly over $700 million in lawsuits last year.

Link to PharmaGossip's post here.

The Doctor is More Important than the Pill

In a very cool study, Kevin McKay, Zac Imel, and Bruce Wampold analyzed data from the famous NIMH Treatment of Depression Collaborative Research Program. Is it the pill or the person prescribing it responsible for patient improvement? Let's find out...

Data from 112 patients were analyzed using a technique called hierarchical linear modeling. The results: The amount of improvement in depression scores (both self-reported on the BDI and based on the HAM-D interview) indicated greater effects for the psychiatrist than the medication or placebo itself. There was still a modest treatment effect after controlling for the effect of the psychiatrist, but the psychiatrist had at least as large of an effect (larger but not statistically significantly larger).

The graph in the right corner indicates improvement on the BDI. Zero equals average improvement on the BDI. As you can see, some psychiatrists' patients improved quite a bit and some performed miserably. Yet the same medication or placebo was being given.

Their quote to close the article: "Based on these findings it can be concluded that the person of the psychiatrist makes a difference in the response to antidepressant medication. Therefore the health care community would be wise to consider the psychiatrist not only as a provider of treatment but also as a means of treatment (pg. 290)."

My View: This is a striking finding that the doctor, as a person, is as important if not more so than the treatment being given. Too bad most psychiatry programs dedicate little training to the development of clinical skills!

Link to the abstract here.

Do "Evidence Based" Psychotherapies Work Best for Youth?

Yeah, I know I’ve spent a lot of space discussing psychiatry but this post deals with psychological treatments for youth. The new issue of American Psychologist contains a meta-analysis by Weisz, Jensen-Doss, and Hawley, comparing so-called evidence based treatments to usual community care. Evidence based treatments (EBTs) are those that have been shown efficacious in comparison to some sort of control group, even a control as unimpressive as a group of individuals who receive no treatment. So the claim to fame of many alleged evidence based treatments is that they are better than nothing.

A debate has raged for about 15 years over whether these EBTs are better than what is actually being done by mental health practitioners in the community. Weisz and colleagues, to make a long story short, basically found a small difference (effect size of d = .30 at endpoint and d = .38 at followup) favoring EBTs over usual care. Through moderator analyses, they ruled out different amounts of treatment received as explaining the difference (i.e., the EBT group didn’t just turn out superior because they received more sessions). They also generally ruled out another few potential extraneous variables.

The most interesting moderating variable to me was that when the EBT was delivered/supervised by the developer of the therapy, the advantage was d = .33, but when the EBT was not delivered/supervised by the developer of the therapy, the advantage was a paltry d = .09.

My View: As the authors pointed out aptly, it was pretty unclear what “community treatment” meant in most studies. On one hand, there is a very well described EBT, and on the other is whatever clinicians are doing. This makes it very difficult to pin down why this small advantage exists for EBT, as all that is known is that it is being compared to some mishmash of various techniques. I also wonder if therapists in community care being overwhelmed with patients (high caseloads) may have something to do with their lesser performance.

Then again, it may all just be that therapists trained to do EBT are aware that it is supposed to be superior and just work harder since they know that they are under a microscope, so to speak. There are not many psychologists who would take the time to design a therapy then not attempt to make sure it is being implemented to its fullest when it is being compared to an alternative treatment. The therapists giving the EBT are aware that there is some pressure to achieve results. I would think this makes them work harder because they feel a great sense of accountability whereas in usual practice, there may not be as great a sense of accountability on day to day basis. I’m not saying that your typical clinician does not at all feel accountable, but that there is not as much pressure on her or him to achieve results as measured on a variety of questionnaires. This got a little longer than I expected – sorry about that. Please comment to add your two cents on the topic.

Update: I noticed that some of the "usual clinical care" conditions to which these EBTs were compared were pretty bogus. Many of them were case management only controls. The EBT therapists generally got extra training and supervision whereas the usual care therapists were on their own. So what we can take away from this is that well-trained therapists with small caseloads and tons of supervision do better than some combination of case management and/or overloaded therapists performing treatment without supervision. Hopefully the EBT crowd will see the results for what they are instead of proudly (but wrongly) proclaiming superiority over a legitimate alternative form of treatment. I'm pretty sure that non-EBT psychotherapies administered with the same advantages EBT had in terms of training, supervision, and low caseloads would also prevail in a contest with bogus therapy.

Link to American Psychologist website here.

Prozac Lowers Sperm Count?

I'll quote briefly from a Times Online story on the possible effects of Prozac on sperm count...

"A case report on two patients taking the most common class of antidepressants, which includes the market leaders Seroxat [Paxil] and Prozac, has revealed a possible adverse effect on both the concentration and swimming ability of sperm.

Doctors at the Cornell Medical Centre, in New York, who were treating the two men for infertility, found that when the patients stopped taking selective serotonin reuptake inhibitors (SSRIs), their fertility problems disappeared, only to resume when they restarted antidepressants.

The first patient was taking citalopram, known as Cipramil in Britain. The second was on sertraline, which is sold as Lustral in Britain. The second patient then switched to a different SSRI, venlafaxine or Effexor. Again, his sperm count dipped, only to climb again when he came off the drug.

The implications of the study are limited by the very small number of patients, but similar effects have been reported in a another dozen patients. A clinical trial has begun of 30 men taking sertraline.

Peter Schlegel, who presented the research yesterday at the American Society for Reproductive Medicine conference, in New Orleans, said: “The patients had normal sperm counts and motility before medication. On the medication they have severe deterioration of both. The same patients going on and off medication had the same pattern. It shows a strong association.”

Impotence and delayed ejaculation are common side-effects of the drugs, and Dr Schlegel believes that the drugs may be preventing sperm from getting into semen.

Allan Pacey, senior lecturer in andrology at the University of Sheffield, said: “There does seem to be a major correlation. Maybe this is an unknown side effect of these drugs that is only just coming to light.”

The researchers warned patients taking SSRIs not to abandon their use of the drugs over concerns for their sperm count, as sudden changes in treatment may worsen psychiatric conditions.

SSRIs are the most commonly prescribed antidepressants in Britain, and are taken by between two and three million people."

My View: Remember when SSRI's were first released -- there was nary a mention of any sexual side effects. Well, we now know that SSRI's are very frequently associated with sexual side effects, as can be seen here, here, and here. There's even a push by some to use SSRI's as a treatment for premature ejaculation. The current data are based on a very small sample. My bet, however, is that larger studies will show similar results. We'll see...

Hat tip: Mike Tintner

Depakote for Mania: Small Beans

In the latest Journal of Clinical Psychiatry, there is a trial of divalproex (Depakote ER) for mania. These patients were all hospitalized, so we’re talking about a relatively severe group of patients. The 21-day study used the following measures: Mania Rating Scale (MRS), Manic Syndrome Scale (MSS), and Behavior and Ideations Scale (BIS). The authors noted that there was a statistically significant difference found between Depakote and placebo on all three measures.

But wait, how much of an effect are we talking about? Did Depakote outshine placebo by a large margin? One is left wondering about this point, as the authors did not report the effect size of the difference between groups. I calculated the effect sizes (d) and here is what I found for each measure: MRS: .229; MSS: .233; BIS: .235. Remember that the generally used criteria are d = .2 (small), d = .5 (medium), d = .8 (large). According to conventional standards, then, we’re talking small beans here. An advantage for Depakote that was very small in size. Depakote also resulted in a significant increase in body weight (1.8 kg) compared to placebo (.5 kg). 1.8 kg in three weeks? Keep gaining weight at that rate over a year and you’re looking at Zyprexa!

The authors acknowledged no ghostwriters, but considering that four of the authors work for Abbott (the maker of Depakote), I suppose they didn’t need to hire out to find a friendly writer. How else do you explain that there is no discussion of the wimpy gains in comparison to placebo? Ahhhh, when industry and science collide...

Alzheimer's: Weed or Aricept?

Granted, the study was conducted on rats, but still...

"Marijuana has strong anti-inflammatory effects, and many researchers believe that there is a compelling link between chronic inflammation and the progression of Alzheimer's, said Gary Wenk, a study co-author and a professor of psychology at Ohio State University.

“Inflammation in the brain is part of aging,” Wenk said. “It happens to almost all of us as we age. But in some cases, this inflammation gets out of hand and causes serious damage.”

Treatment with a synthetic compound similar to marijuana reduced inflammation in older rats in addition to making the animals “smarter,” said Wenk, who is also a professor of neuroscience and molecular virology, immunology and medical genetics.

“The compound substantially improved the memories of the older rats,” he said. “These animals were able to hold on to key details of a specific task. Untreated older rats, on the other hand, were not.”

The researchers presented their findings October 18 in Atlanta at the annual Society for Neuroscience meeting.

Evidence suggests that people who regularly smoked marijuana in the 1960s and 1970s rarely develop Alzheimer's disease, said Wenk, adding that researchers are eager to develop a drug with the anti-inflammatory properties of marijuana, but without the drug's psychoactive effects.

...

“The compound significantly improved the older rats' memories,” Wenk said. “They found the platform faster, suggesting that they were less apt to forget key information for this task. It's a pretty good prediction of how a human would respond to this drug.”

Younger rats treated with the compound found the escape platform faster than non-treated younger rats did. However, the difference wasn't as remarkable as that of the older group, possibly due to the lack of age-related changes in the brains of the younger rats.

“Older rats have impaired spatial memory, due to the effect of aging on the brain,” Wenk said.

Wenk conducted this work with Ohio State colleagues Yannick Marchalant and Francesca Cerbai, both postdoctoral researchers in psychology, and Holly Brothers, a graduate student in psychology."

My View: Hey, the effects can't be much less than current so-called memory enhancing drugs! Smoke 'em if you got 'em??

Link to full story here.

Cymbalta: Flooding the Market

Lilly has been busy pushing duloxetine (Cymbalta) via its "depression hurts" ad campaign as well as (I suspect) drug reps "educating" doctors about its wonders.

I did a brief literature search via PubMed to see what all the hype was about. I found one study that compared paroxetine to duloxetine which found no significant benefit for duloxetine over paroxetine. Link here. I couldn't find anything else comparing it to another medication. Seems like its modest benefits are similar to the rest of its competitors, many of which can be purchased much more inexpensively in generic form.

Then there is the issue of flooding journals with highly similar studies. For example, one study examined the effects of duloxetine on males versus females -- link here. Another examined the effects of duloxetine on Whites versus Blacks -- link here. But wait, there's more -- an article comparing Whites to Hispanics -- link here. All of these include overlapping authors. Do these really warrant separate publications? Couldn't these data, which I bet are from the same database, have been published in one article? None of these articles indicated that gender or race was related to safety or outcomes, so this seems like an obvious attempt to plaster journals with references to duloxetine so that an air of scientific credibility can surround it, resulting in higher prescription rates. When marketing and science collide, duck and cover. Apparently this strategy is working well for Lilly, as Cymablta sales are soaring. In the absence of evidence, just flood journals with unimportant findings in droves and watch the cash flow increase.

Forest: All Eggs in Two Psychiatric Baskets

More from Bloomberg: “Forest Laboratories Inc. said fiscal second-quarter profit increased 18 percent on demand for its two biggest-selling medicines.

Net income for the quarter ended Sept. 30 rose to $241.1 million, or 75 cents a share, from $204.9 million, or 59 cents, a year earlier, reflecting sales of the Lexapro antidepressant and Namenda for Alzheimer's disease, New York-based Forest said today in a statement. The profit beat analysts' estimates.

Sales jumped 12 percent for Lexapro and 26 percent for Namenda, and the two drugs accounted for 80 percent of Forest's revenue for the quarter, the company said. Forest is developing and licensing new drugs to reduce its reliance on Lexapro and Namenda.

``The issue for Forest is, can the company sustain this kind of growth?'' said Timothy Chiang, an analyst at FTN Midwest Securities Corp. in New York, in a telephone interview today. ``Certainly, the company's results were better than my forecasts, but I still have a longer-term view on the stock.'' Chiang rates Forest shares ``neutral'' and doesn't own any.

Second-quarter revenue for Forest increased 15 percent to $847 million from $736.5 million a year earlier. Sales of Lexapro climbed to $522.7 million, while Namenda reached $155.6 million…

“Forest won a federal court ruling in July protecting Lexapro, which it started selling in 2002, from generic competition from Teva Pharmaceutical Industries Ltd., based in Petah Tikva, Israel.

While Teva can't copy Lexapro before 2012, Teva has started selling a generic form of Zoloft, an antidepressant made by New York-based Pfizer Inc., and some drug-industry analysts have said the generic might cut into how many new patients buy Lexapro.

``We have not seen any meaningful change in prescribing patterns for Lexapro at this point,'' Goodman said.

Forest licensed Lexapro from Copenhagen-based H. Lundbeck A/S and acquired rights to Namenda from the Merz Group, based in Frankfurt am Main, Germany. Namenda's patents begin expiring in 2010, and Forest may face generic competition for the drug as early as 2011, Chiang said.

``Around 2011, 2012, the company could be dealing with a cliff, falling off a cliff, in terms of its revenue base,'' Chiang said. ``They're working hard to put together a late-stage pipeline.''

Hey, how about making another SSRI? There are just not enough of those on the market. Or, better yet, try a dual norepinephrine/serotonin reuptake inhibitor and market it very aggressively. That apparently worked for Cymbalta – just ask Lilly. It seems like Forest is overly dependent on these two psych meds, and I would think that given Namenda’s very modest benefits, there couldn’t be more too much more growth for it. Then again, there are many products that offer few benefits which end up being widely used. Take Neurontin, for example.

Link to Bloomberg post here.

Lilly: Cymbalta and Zyprexa are Cash Cows

According to Bloomberg, “Eli Lilly & Co.'s third-quarter profit rose 10 percent as sales of its Cymbalta antidepressant almost doubled. Net income rose to $873.6 million, or 80 cents a share, from $794.4 million, or 73 cents, a year earlier, the company said in a statement on PR Newswire… The result beat analyst estimates.”

Revenue from Cymbalta, up 91 percent to $348.6 million, benefited after Lilly reorganized its sales force to focus on the market for depression drugs. Cymbalta ``continues to show exceptionally strong growth in 2006, and new prescription levels are currently more than 40 percent above late 2005 levels,'' Ryan wrote in an Oct. 4 report to investors.

Lilly also said that sales of the Zyprexa schizophrenia drug, which declined 5 percent in 2005, had stabilized. Sales of Zyprexa rose 4.8 percent to $1.08 billion, the first increase recorded for the drug in at least six quarters. In 2005, the drug provided about 29 percent of the company's total sales.

Zyprexa benefited from ``pricing increases that are offsetting double-digit prescription declines,'' said Chris Shibutani, a JP Morgan Securities analyst in New York, in an Oct. 11 report to investors.

In July, the state of Mississippi joined three other states suing Lilly over Zyprexa, saying the drugmaker fraudulently touted Zyprexa for unapproved uses, including for children, and hid the drug's potential hazards, including excessive weight gain and an increased risk of diabetes.

Lilly has agreed to settle about 8,000 personal injury complaints related to the drug for $700 million in 2005 and faces more than 4,000 additional claims.”

Must be all that evidence piling up indicating that Cymbalta is much more safe and effective than other antidepressants? Perhaps I should post on the evidence regarding this hot-selling medication. I can see why Lilly keeps jacking up the price of Zyprexa. With all of the lawsuits, it has to be pretty pricey to justify its existence!

Link to Bloomberg article here.

Credible Source (?) on Paxil

I was reading through Evelyn Pringle's latest article on GlaxoSmithKline, which I will excerpt in a moment. It struck me that she may also have a significant conflict of interest here, but some points bear mentioning nonetheless.

Much of the piece focused on Paxil.

" Glaxo's latest escapade was revealed on October 5, 2006, when Bloomberg News reported that Glaxo conducted a recall of Paxil CR, a selective serotonin reuptake inhibitor antidepressant, last month because some of the pills may lack an active ingredient, but that the company did not warn patients who may be taking the useless pills.

Doctors told Bloomberg that patients who either abruptly stop taking Paxil or get inactive pills, can face the risk of suicidal thoughts, shooting pains and flu like symptoms.

The Paxil CR pills are the highest dose sold, and can cause severe withdrawal symptoms, according to Dr Stephen Ellen, a psychiatrist from the University of Massachusetts Medical School in Worcester. "If it is true that patients might have gotten dummy pills without knowing it, it is outrageous," he said.

According to Glaxo, the FDA knew about the problem and approved the limited recall plan, but FDA spokeswoman, Susan Cruzan, told Bloomberg that she did not know the details of the September Paxil CR recall.

This incident is even more outrageous because back on March 4, 2005, the government cited Glaxo for the exact same wrongdoing when the FDA and the Department of Justice initiated the seizure of Paxil CR tablets after Glaxo failed to meet the standards laid out by the FDA to ensure product safety, strength, quality and purity.

Among the violations noted then by the FDA, was the finding that the tablets could split apart and patients could receive a portion of the tablets that lacks any active ingredient, or alternatively a portion that contains active ingredient and does not have the intended controlled-release effect."

So Glaxo was selling an unknown amount of Paxil without the active ingredient and not letting anyone know that they were, in fact , receiving placebo. Oops! Granted, Paxil ain't much more effective than a placebo, but the withdrawal effects are certainly a concern, especially when people don't know they are withdrawing.

What I don't like about this piece is the frequent mentions of the Baum Hedlund law firm. Maybe the folks at this firm really are tireless consumer advocates -- I have no idea. But it does read as a bit of an infomercial for the firm. I suppose that makes sense in the context that the end of the article states "Written as part of the Paxil Litigation Monthly Round-Up, Sponsored by Baum Hedlund's Pharmaceutical Antidepressant Litigation Department."

As y'all know, I'm not in the antidepressant fan club, as evidenced by posts such as this, this, this, and this. It just seems that this particular article comes across as a bit too much in favor of lawsuits. I suppose her counterargument may be that there are few other avenues to pursue recourse and convince manufacturers to change poor practices given that the FDA is toothless. If that were her response, I would have no rebuttal.

All that being said, I could find nothing that really contradicted the original report at Bloomberg, which can be found here.

BusinessWeek Chimes In

BusinessWeek has a brief story on the influence of gifts on prescribing practices. Link here. Hat tip to PharmaGossip.

Put Your Creativity to Work

Want to work for a drug company?

Over at the Scientific Misconduct site, a small group of us are having a good time putting our creative powers to work. What would YOU do as a drug company interested in advancing profits, I mean, science?

Check it out here and add to the comments on the linked page. If you don't enjoy this, take it as a bad sign.

More Unimpressive Results for Atypical Antipsychotics

The Journal of Clinical Psychiatry (October 2006) has an article comparing haloperidol (Haldol), risperidone (Risperdal), and olanzapine (Zyprexa) in treating first-episode psychosis. This is a great design because patients were medication-naïve – they had not taken antipsychotic meds before.

The results: On all outcome measures, there was no significant difference between medications. They were equally effective. For side effects, haloperidol caused more extrapyramidal side effects and both risperdal and olanzapine caused more weight gain (especially olanzapine). Again, patients on the vastly more expensive second generation antipsychotics essentially fare no better than patients on the older medication. Don’t take this as a ringing endorsement of older meds – medications that cause heinous extrapyramidal side effects among a host of other unpleasant effects are certainly a mixed blessing.

I’ve posted extensively about second generation antipsychotics. Feel free to read about them here, here, here, here and here.

Zoloft for PMS: Impressive Statistical Gymnastics

As the trend continues toward medicalizing (diagnosing and treating) increasingly more aspects of human mental functioning, it should come as no surprise that the latest issue of the Journal of Clinical Psychiatry features a study examining the use of sertraline (Zoloft) in treating PMS.

The study concluded that “intermittent, luteal phase dosing with low doses of sertraline is an effective treatment for PMS (p. 1630).” It appeared that lower doses of the medication (25 mg) were actually as effective or more effective than higher doses (50 mg). They also tested a couple other dosing schedules, finding all to be somewhat effective.

One problem I noted (but the authors generally did not) is that the effects are all in the small to moderate range. The Quality of Life Enjoyment and Satisfaction Questionnaire yielded virtually no change on drug compared to placebo, but I would think a quality of life measure should be an important part of the study. After all, if PMS is such a huge problem, then surely a treatment that impacts PMS would notably improve quality of life? Hmmm…

There was a huge statistical problem in this study as well. The authors used 12 measures to assess outcome and also used two different dosages of the drug (25 versus 50 mg). They also used three dosing schedules – luteal phase, at symptom onset, and continuous. This created 72 comparisons of drug versus placebo. Of these 72 comparisons, I counted 36 that were statistically significant. That means that half of the comparisons found no significant advantage for medication. But wait, it gets more fishy…

Despite making 72 comparisons, the authors employ their own unique definition of statistical significance. Instead of using the p-value of .05 or less as their cutoff, they opt for p < .08 on some measures, which is generally not accepted in the scientific community. So, if we factor in these seven p < .08 results, we are left with only 29 of 72 comparisons showing a significant (p < .05) advantage over placebo. When making so many comparisons, one expects to find some differences based on chance alone (Type I error in statistical jargon). However, the authors made no adjustments for multiple comparisons. This, friends, is data dredging.

It is a time-honored strategy – use a lot of outcome measures and a variety of dosing schedules so that your drug, which seems to have only a mild effect, will come up as statistically significantly superior to placebo on some measures, which will allow you to fill up a few pages discussing its efficacy.

Ghostwriter Watch: “The authors also wish to acknowledge Edward Schweizer, M.D., Paladin Consulting Group, New York, N.Y., for assistance in the preparation of the manuscript. (p. 1631).” I don’t know a lot about Dr. Schweizer, but I am assuming his consulting firm was paid by Pfizer and wrote quite a bit of the paper. Let me know if I’m wrong. Good deal: Pfizer pays for the study (this is acknowledged in the article), conducts a variety of statistical gymnastics through its analysis, then pays a ghostwriter to write a good chunk of the manuscript.

MHRA: It Just Keeps Coming

Aubrey Blumsohn has more interesting items on the MHRA over at his blog. I don't have time to summarize his posts now except to say that they pack his usual punch. As he says, if you're not outraged, you're not paying attention.

Check his site out here.

Coming Soon...

Either later today or tomorrow, I should be able to post my reviews on some articles from the October Journal of Clinical Psychiatry. After briefly perusing some of the articles, I can assure you that I have issues with more than one of these studies and will be sharing these critiques with you soon.

Generic Risperidone Coming Soon?

PharmaGossip has a post indicating that generic risperidone may be coming to market in 2007. This could really throw a wrench into plans to continually spread the use of these overrated medications with a whole litany of patients. Perhaps there will be a PR blitz to demonize risperidone in order to keep patients on the more expensive drugs. We'll see.

Check out the post here.

Conflicted Conflict of Interest Policy at Stanford

Check out the update on Stanford's allegedly "tough" conflict of interest policy over at Health Care Renewal...

Health Care Renewal: The American Medical News Reports Stanford's New Conflict of Interest Policy in a Vacuum

Yet Another Poor Showing for Atypical Antipsychotics

The New England Journal of Medicine published another study from the CATIE group, this time testing second generation (aka SGA or “atypical”) antipsychotic medications on patients with Alzheimer’s Disease.

Let’s start off by quoting the authors’ conclusion from the abstract: “Adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer’s disease.”

Olanzapine (Zyprexa), risperidone (Risperdal), and quetiapine (Seroquel) showed no significant advantage as a group (combining the three medications into one group) over placebo in efficacy on the primary outcome measure, the Clinical Global Impressions Improvement Scale. 32% of patients on olanzapine were rated as having at least minimal improvement compared to 26% for quetiapine, 29% for risperidone, and 21% for placebo. When comparing olanzapine to placebo, the difference is statistically significant (barely, with p = .05). The authors did not report effect size differences, but across the CGI-I, Neuropsychiatric Inventory, and Brief Psychiatric Rating Scale, they appear to all be in about the .25-ish range (according to my mental calculations based on reported means and standard deviations), suggesting very modest improvement for drug versus placebo.

Another important measure was discontinuation of treatment. Overall, there was not a significant difference between placebo and medication on how frequently treatment was discontinued by clinicians.

How about safety? Over 12 weeks, 11% of both the olanzapine and risperidone groups gained over 7% of their body weight, compared to 3% of placebo patients. All medications resulted in significantly greater increase in body mass index compared to placebo. Both olanzapine and risperidone were significantly more likely to cause extrapyramidal symptoms compared to placebo. Remember that one reason SGAs were supposedly superior to older antipsychotic meds was because SGAs would cause extrapyramidal symptoms at a very low rate. Hmmm...

Thank you NIMH for funding this study! The bad news continues to flow about second generation antipsychotics. Link to the study abstract here. Feel free to read more about atypical antipsychotics here, here, here, and here.

War, What is it Good For... Part 2

I’ve now read through the latest Iraq mortality study. The methods were quite similar to the study published in 2004 and seem solid. I’ll admit I’m not an expert in epidemiological methods, but my limited knowledge of cluster sampling jives well with what they did. A more informed discussion of the 2004 article’s methods, with rebuttals to many criticisms, can be found here. I would imagine that the same potential criticisms and comments would apply in the present study.

Some of you may wonder – why is this even being discussed on a Clinical Psychology and Psychiatry site? Maybe because people dying in droves is much more important than anything currently happening in psychology or psychiatry. I suggest all of you pay attention to this study and watch what the media does with it.

War, What it it Good For?

The Les Roberts/Gilbert Burnham team is stirring up trouble again, shining a light on the number of Iraqi deaths attributable to the American (aka “Coalition of the Willing”) invasion. Their number: 655,000 Iraqi deaths above what would have been expected prior to the war. This differs substantially from Our Great Leader’s estimate of “about 30,000, more or less,” mentioned by Bush in December 2005.

I’ve not yet seen the study, as it is due to hit the Lancet website on Thursday. I’m going to be all over it, examining its methodology and discussing it in more depth. I am very familiar with this group’s first study, which estimated (at the low end) that about 98,000 Iraqis died in about the first year post-invasion. Why a low estimate? Because they came to that number by excluding Falluja from the analysis. They figured that so many people had died in Falluja that including it would bias their sample. Including Falluja would have brought their figures to about 200,000 dead.

The researchers reportedly used cluster sampling again in the new study, which is the same method used in the prior study. It is the appropriate method when investigating such topics as this. In the first (and I’m guessing also in the latest) study, they randomly selected a number of clusters/areas to visit, then were randomly assigned to neighborhoods in these areas through random numbers entered into their GPS systems. They went to the 30 nearest houses and knocked on doors, collecting data regarding deaths prior to the invasion (starting 1/1/2002 until the start of the invasion) and post-invasion. They requested death certificates (to confirm the report of death) from a relatively small number of families, and these certificates were provided over 80% of the time. In the new study, they were reportedly provided over 90% of the time when requested. You may ask why they did not request death certificates from everyone – consider that it may be considered disrespectful and could result in danger to the researchers to ask for confirmation of household deaths.

A test of the American media is coming. Will it dare report these figures? If it does, can they resist the temptation to include accompanying commentary from a Republican blowhard who moans about how this study is "just politics," is "biased," and just an attempt by liberals to "embolden the enemy"? When the war was relatively popular in 2004, the media did not linger long on Roberts et al.’s findings, preferring to refer to other sources (such as www.iraqbodycount.net) for its reports of total Iraqi dead. Would the American people support a war in which an estimated 650,000 Iraqis have lost their lives? Granted, many of the deaths are due to insurgent and sectarian violence. But remember that such groups were not killing people prior to the invasion. Saddam was one bad apple, but even he likely could not have dreamed of replicating this type of chaos and killing.

Summaries of the study available here and here.

Update: The new study just posted on the Lancet's site. More upcoming, hopefully soon...

Osteoporosis Training -- Sign up Now!

From the Department of Irony?

I saw that Dr. Richard Eastell, from the bone metabolism unit at Sheffield University, would be chairing a session on osteoporosis. Another chapter in the Procter & Gamble saga, I wonder? Eastell was taped saying that he was concerned that putting pressure on P & G to show its trial data to researchers who were ostensibly running the trial (including Eastell and Aubrey Blumsohn) would result in the university losing a valuable financial partnership. Others have made more of these comments than have I – the comments don’t sound good, but in themselves, they are far short of incriminating. Basically, they just made him sound like a research dean who cared more about money than science – which I suspect is likely true of many deans. In these days of cutting state support for education, deans who bring in more $$$ from the drug industry at the expense of integrity are probably the norm rather than the exception at many research universities.

There were some other revelations that disturbed me more about Eastell's conduct, such as the following excerpt from a British paper. The context, as mentioned previously, was regarding P & G expecting Blumsohn and Eastell to affix their names to a paper, though they had not seen the raw data on which it was based...

"No self-respecting scientist could ever be expected to publish findings based on data to which they do not have free and full access," Dr Blumsohn wrote.

But in December 2004, in a letter to Dr Blumsohn, Professor Eastell said that, under guidelines from the US Pharmaceutical Research and Manufacturers of America (PhRMA), "there is not access to the data...".

He added: "The approach we have taken for this manuscript of working closely with the statisticians to identify the best approach to analyse the data is an example of best practice." He said that if Dr Blumsohn wanted to be a co-author of the paper he would have to sign an author's agreement stating he was in "full agreement" with the work." Full text of that article is here.

An example of best practice? Where would it be considered best practice for researchers to write manuscripts based on data they have not seen? Planet PhRMA?? Give me a break! Granted, it happens all the time in psychiatry and all over medicine, but it sure as hell does not match any reasonable scientist's definition of "best practice."

Eastell was later investigated (with no charges sticking) for some irregularities (financial in nature) that can be read about here.

In the end, Eastell is now running a rather expensive event in the name of osteoporosis training. If you’d like to register, just follow the link here. I think I'd rather attend an Eastell seminar titled something like: "Ghostwriting for the 21st Century" -- that would be worth a steep registration fee. How much the seminar will overlap with P & G talking points has yet to be determined but a high degree of overlap is expected. Should any of you attend the seminar, let me know...

For much, much more background on this saga, you really need to go to Aubrey Blumsohn’s blog. Or check out the Slate article for a good start. You could also read this if you'd like.

Update:
I noticed the following quote on the website which advertises this event:
"This course is suitable for pharmaceutical industry personnel from clinical through to marketing disciplines."

You are encouraged to insert your own punchlines here (or in the comments page). I assume that this meets or exceeds PhRMA guidelines.

Eastell may be the nicest man on the planet. He may even be the most ethical gentleman in all of the UK. I'm just pointing out that this chain of events could be construed as strange and reflective of the quite powerful influence of industry in science.

Who’s Conducting Your Meta-Analysis?

The BMJ just published a rather fascinating comparison of meta-analyses published through the Cochrane Collaboration (which seems generally free of industry influence) and those published by authors who reportedly received funding from drug companies. The authors limited their comparison to those that compared the same two drugs in the treatment of any disease to assure a close apples-to-apples comparison. For example, a Cochrane review of Drug X versus Drug Y for Disease Z would be compared to drug company supported review of Drug X versus Drug Y for Disease Z.

8 pairs of reviews compared Cochrane reviews to industry-supported reviews. The findings: Cochrane reviews were of higher quality than industry supported reviews (p < .01), They also more often stated the search methods used to find studies (p = .06), searched comprehensively (p = .06), avoided bias in the selection of studies (p = .03), reported criteria for assessing the validity of the studies (p = .03), used appropriate criteria in assessing the studies (p < .01), described methods of concealment of allocation (p = .02), and described excluded patients (p = .03), and they used more sources to identify studies (p = .02)... One of the industry supported reviews had no conclusion, as it referred to physiological characteristics of the drug. The other seven reviews supported by industry all recommended the experimental drug without reservations, compared with none of the Cochrane reviews (p < .01).

There is more in the article worth reading. Check out the full text here. It is currently an online only article that I imagine will be published soon in the print version. My respect for the BMJ continues to grow, as it appears to publish many more articles that probe into some of the unseemly practices in medicine than its counterparts, though the Lancet, JAMA, and New England Journal of Medicine all publish good work on these topics on occasion.

Bottom line: Industry engages in selective publication of trials, then they summarize the research by selectively including trials and making recommendations for treatment that are not supported by evidence. Not surprising, but it is more evidence of corruption.

Switching From an Atypical to a Conventional Antipsychotic – Who Dares?

At this point, there have been many studies that have examined the effects of switching patients with schizophrenia from conventional/first-generation antipsychotic medications (FGA) to newer antipsychotic/second-generation antipsychotic meds (SGA). These studies have usually examined patients whose symptoms were poorly controlled on FGA but improved on SGA. The results typically indicate some improvement, which is often used as an argument to pimp SGAs.

Taking this argument a step further, a recent study in the Journal of Psychiatric Research examined schizophrenia patients who were stable (not doing extremely poorly, but seemingly not functioning very well either) on their FGA meds. They were switched to olanzapine (Zyprexa) or risperidone (Risperdal), both SGAs, and they showed improvement in their symptoms over a 22-week time period (some of which involved tapering from old to new meds – 12 weeks on treatment with the new medication alone). Ok, great. So switch everyone to SGAs, right?

Some conceptual problems that are not mentioned in this study loom large. To draw any sort of conclusion regarding the effects of medication, a control group is needed, yet there was no control group in this study. For example, the inclusion of a control group that was maintained on their current medication or, better yet, told they were switching medications, but actually received their same FGA medication. One could have witnessed how they progressed in comparison to how the SGA-switch group progressed.

Or, how about a study in which one group was switched from FGA to SGA, and another group was switched from SGA to FGA. Yes, I said it. Why have there been no studies (to my knowledge) that have switched patients from SGA to FGA? I’ll tell you why. Because it is likely that they (SGA to FGA switchers) would show just as much change as those switching from FGA to SGA. SGAs are widely used enough and have existed for long enough that surely there are many people with schizophrenia who have taken SGAs only – that is, they have never taken FGAs. So switch them to FGAs in a study and see what happens. When this study is conducted, I’m prepared to eat humble pie if it does not confirm my predictions. In fact, let’s have three studies conducted independent of drug company funding and see what happens. NIMH, what do you think? In the meantime, all the hoopla about switching from FGA to SGA needs to S-T-O-P. This is easy research to conduct and I’ll be awaiting its results.

BS Watch: I’d like to mention one further concern with this study. The authors noted that there was a significant decline in Simpson-Angus scores, which assesses extrapyramidal/motor problems commonly associated with antipsychotic treatment. The authors did not report means and standard deviations for the measure, just that F(5, 204) = 4.2, p < .01. From the figure in the article, we can see (look to the top right) that the mean score on this measure dropped by a little less than .20. This mean change of less than .20 occurred on a measure that ranges from 0-40, so I think their figure may well qualify for the next issue of Misleading Charts Quarterly.

Read more about the “amazing” SGAs here, here, and here.

Update: I was likely in error regarding the Simpson-Angus scores. Though the version of the measure I have is scored on a 40 point scale, it is true that some studies use a version that I believe runs from 0-4. In any case, I stand by the graph being misleading without at the very least discussing the effect size associated with the comparisons of EPS scores.

Medicate First, Ask Questions Later?

The Washington Post had an interesting op-ed on Sunday from a child psychiatrist who is disgusted by the increasing trend to medicate child behavior that was once known as being bratty, or testing parent's limits.

I'll steal my favorite quote...

"Doctors need to take the time to understand their pediatric patients better and have the courage to deliver the bad news that sometimes a child's disruptive, aggressive and defiant behavior is due to poor parenting, not to a chemical imbalance such as bipolar disorder or ADHD."

I'll also steal another favorite:

"Parents and teachers today seem to believe that any boy who wriggles in his seat and willfully defies his teacher's rules has ADHD. Likewise, any child who has a temper tantrum is diagnosed with bipolar disorder. After all, an anger outburst is how most parents define a "mood swing."

I realize that it would be naive to assume that all, perhaps even most, childhood behavior disorders are caused by poor parenting. And by "poor parenting," I am not referring to abuse, just to a poor understanding of behavior management. But with parental attention switching to work, finances, plasma television, and other material accoutrements, it sure is easy to turn to pills rather than parenting to raise children.

Check out Dr. Roberts' full editorial in the WaPo here. Prepare for the coming epidemic of bipolar disorder in youth and adults, as I've discussed previously.

Big Pharma: Less Cash Toward Misinforming Doctors?

According to John Mack at the ever-thoughtful Pharma Marketing Blog:

“2005 marks the second consecutive year of decreased growth in commercial support of continuing medical education (CME) by the pharmaceutical industry, according to the 2005 annual report of the Accreditation Council for Continuing Medical Education (ACCME), which collects this data from accredited CME providers.”

Why would these big supporters of infomercials, er, "education" do such a thing? John thought:

“This could be in reaction to calls from the medical community that medical schools stop accepting "free gifts" from pharmaceutical companies and that grants for CME from pharma be contributed to a general fund rather than to individual physicians. We could be witnessing payback by the pharma industry.”

There’s more on his site, which I encourage you to check out here. Go directly to his post on CME here.

Links to articles and abstracts that justify my skepticism toward the accuracy of medical education provided by Big Pharma can be found here, here, and here.

Mo Pranksta Than Gangsta

This site tends to be a little serious, so I thought I would switch gears and offer readers the chance to check out the Gizoogle version of the blog. For those of you not familiar with Gizoogle, it translates sites into a Snoop Dogg version of gangsta slang.

Link is here. May contain language inappropriate for non-thug minors. You'll either fall over laughing or scratch your head in puzzlement.

CPP Manifesto

I was just sending an email and I got to ranting a little bit. I am reproducing that email here in edited and expanded format because I think it represents the manifesto of this site.

It seems to border on amazing that tens of billions have been spent on developing meds for depression, schizophrenia, anxiety, and bipolar disorder, as well as many other psychiatric conditions, yet in nearly all cases, the meds we have now are no more efficacious than meds designed 50 years ago. Spending less time on developing me-too meds would be a good start. How many atypical antipsychotics are really necessary? How many SSRIs really need to be on the market? Allocating fewer resources to marketing and more to research wouldn't hurt either.

Hopefully one or more among us can help improve upon 50 years of meager progress in psychiatric treatments. I'd add that, despite the hype, clinical/counseling psychology hasn't exactly done a great job of developing therapies that add much beyond already existing treatments. As with my prior comment about SSRIs, how many variants of cognitive-behavior therapy do we need? How many times will we compare various therapies to each other in studies to come to the underwhelming conclusion that therapy which is intended to be effective is better than therapy that is not intended to work, but essentially all therapies that are based on a credible rationale and are intended to work yield equivalent outcomes (see research from Bruce Wampold). We know that monitoring outcome more closely and regularly improves outcome in psychotherapy (see Michael Lambert et al's research if you need proof), yet few clinicians bother to monitor outcome in any systematic fashion, if they record outcome at all.

Perhaps I'll feel more optimistic later, but the current state of affairs in both psychiatry and psychotherapy seems more hype than help, with psychiatry being the greater of the two offenders. Given that psychiatry has many more financial resources to develop treatments than does psychology, one would expect that psychiatric treatments would be superior, but such has rarely proven to be the case when medications are compared to psychotherapy in head to head trials. Indeed, the opposite is often true, especially in the long-term (most notably for depression and anxiety). Yes -- I realize that meds are standard treatments for bipolar and schizophrenia, but psychotherapy has shown some promise in these areas, and neither meds nor therapy are associated with very impressive long-term outcomes for bipolar or schizophrenia. Let me state clearly that treatment often works -- I'm not pulling a Tom Cruise here -- but that there has been a pathetic amount of progress made in improving mental health outcomes in proportion to the time and money spent on research.

Shame on individuals and companies who do not contribute to improved treatment outcomes. Companies that bury or distort trial data are shameful. Hiding safety data to make drugs falsely look safe and/or inappropriately attributing adverse events to placebo (among a laundry list of poor practices) is beyond reprehensible. Academic researchers who let their industry-provided cash cloud their judgment – double dishonor on you. Yes, we all make mistakes, but when a conflict of interest is present, we should do our damndest to at least maintain an image of propriety! All mental health practitioners that do not attempt to demonstrate the effectiveness of their individual work (i.e., does treatment, as I provide it, work to alleviate symptoms and improve the quality of life of my patients) – you’re part of the problem as well. Yes, the type of patients you serve of course impacts their outcomes and your ability to measure them, but by God, you should certainly try your best to incorporate some sort of individual accountability to make sure your patients are improving at a reasonable rate. I’m not endorsing pay for performance or any other buzzwords, just suggesting strongly that clinicians pay close attention to their outcomes, since that is the bottom line reason why they have clinical jobs in the first place.

OK, I suppose I’ve officially hit “diatribe mode,” so I’ll sign off with the above as the official manifesto of the site. Please comment if you think I’m losing my marbles or if you think “right on” or somewhere in between.