Leading Psychiatrist Slammed in Leading Journal

In the latest American Journal of Psychiatry appears a review of Allison Bass's book Side Effects. As many of my readers undoubtedly recall, the book details the saga of the antidepressant drug paroxetine (Paxil) and the troubled line of "research" used to support its use in children (among other points). The reviewer clearly liked the book, which is not necessarily newsworthy. What is notable is that a book review appearing in perhaps the world's leading psychiatry journal slams a leading member of the psychiatry profession. The reviewer, Dr. Spencer Eth, writes the following:

More recently, psychiatrists have been greeted in the morning with front-page newspaper exposés of huge sums being directed by these same drug companies to the physician leaders of our field. In Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial, journalist Alison Bass has written the powerful story of a leading medication, its manufacturer, and a favored psychiatrist, whose driving force was profit not treatment.

Ouch. Though not naming the psychiatrist directly, it is clearly a reference to Martin Keller, bigwig at Brown University, whose work on one particular study regarding Paxil was the subject of a lengthy prior post. For the collection of my posts related to Dr. Keller, please click here.

Back to the review...

This well-told cautionary lacks the excitement of a novel but instead informs the reader with an actual case study with the real names of psychiatrists we know. We can see exactly how corporate greed, drug-company-sponsored clinical research, and mental health care become a toxic mix that inevitably damages our patients’ well being, our colleagues’ reputations, and our profession’s good name.

It was a refreshing surprise to see Martin Keller's goose get cooked in this review. I don't mean to sound vindictive or meanspirited. Keller has done a lot of work over the course of his career, much of which likely has some redeeming value. That being said, there can be little doubt that some of his "science" is quite dubious. And for a major psychiatry journal to run anything, even a book review, that directly goes after a "key opinion leader" who appears quite culpable in performing bad science -- that's a good sign.

Internal Documents Suggest that Seroquel Data Were Not Presented Accurately

A document dated March 9, 2000 titled "BPRS meta-analysis" shows that AstraZeneca, maker of the antipsychotic drug quetiapine (Seroquel), knew fully that its drug did not relieve schizophrenia symptoms to the same extent as its older, generic competitor haloperidol (Haldol). The document provides results of a meta-analysis, a statistical analysis that combines the results of several individual studies. The authors used the Brief Psychiatric Rating Scale (BPRS) as their main measure of efficacy. The BPRS rates a variety of psychiatric symptoms relevant to schizophrenia. More details on the BPRS can be seen here. A total of ten clinical trials were included in the meta-analysis, which variously compared Seroquel to placebo, Haldol, and several other antipsychotic medications. Four trials compared Seroquel to Haldol. Several subscales of the BPRS were included in the analysis.

When examining the amount of change on the BPRS, Seroquel consistently outperformed placebo, both on the BPRS total score and on several of the BPRS subscales. However, in several analyses, Seroquel was outperformed by Haldol and by risperidone (Risperdal; Janssen's antipsychotic). The document states: "Against 'all doses' of Seroquel, each of the three significant p-values generated was in favour of Haloperidol (Total BPRS, Factor V, and Hostility Cluster). There was no evidence of significant differences between the treatments when Haloperidol was compared to high-dose Seroquel." This is a plain admission that Haldol outperformed Seroquel on several outcomes, but that high dose Seroquel yielded approximately equivalent results to Haldol. Only one trial compared risperidone to quetiapine and the results clearly favored risperidone. The document stated: "Comparisons against Risperidone using all doses of Seroquel showed significant improvements for Risperidone on total BPRS, Factor V scores, and the Hostility Cluster. Against high-dose Seroquel only, the Anxiety item, Factor I, and Mood cluster scores were also significantly in favor of Risperidone." Risperidone beat Seroquel, and did so by a wider margin when a high doses of Seroquel was used.

The author of the document, Rob Hemmings, summarizes the results in a table, which appears below. It is described as such: "The following table is an attempt to simplify the claims that could be obtained from these results. A ✔ is entered for those comparisons where we have a statistically significant benefit, be it with 'all doses' or with high dose Seroquel... A x marks those comparisons where a comparator has demonstrated significant superiority compared to Seroquel."

The table demonstrates that according to an analysis by AstraZeneca employees, Seroquel is only shown to outperform placebo, whereas Seroquel is shown to demonstrate poorer efficacy than several other medications.

Under the heading "Conclusions," the document states, in part:

In terms of generating positive claims for Seroquel, these analyses seem somewhat disappointing. Although some trends in favour of Seroquel were observed in the Factor I and Mood cluster items, there was no evidence in these analyses of a significant benefit for using Seroquel over any of the active agents assessed."

The internal analysis clearly indicates that, based on several clinical trials, Seroquel offered no benefits over the competition in terms of reducing schizophrenia symptoms. Indeed, other drugs tended to outperform Seroquel.

How Can These Data be Managed? Shortly after the internal meta-analysis was completed, AstraZeneca employees discussed how to handle the negative results. An AstraZeneca publications manager, John Tumas, wrote in an email

The data don't look good. I don't know how we can get a paper out of this. My guess is that we all (including Schulz) saw the good stuff, ie the meta-analysis of responder rates that showed we were superior to placebo and haloperidol and then thought further analyses would be supportive and that a paper was in order. What seems to be the case is that we were only highlighting the good stuff and that our own analysis support the "view out there" that we are less effective than haloperidol and our competitors.

It would appear that an earlier analysis provided positive results which did not hold up during the internal meta-analysis. "Schulz" almost certainly refers to Dr. Charles Schulz, a psychiatrist at the University of Minnesota. In a press release from the year 2000, Dr. Schulz was quoted:

I hope that our findings help physicians better understand the dramatic benefits of newer medications like SEROQUEL because, if they do, we may be able to help ensure patients receive these medications first. The data suggest that SEROQUEL is an effective first- choice antipsychotic.

This press release was based on Schulz's presentation at the American Psychiatric Association convention in May 2000. The email from John Tumas discussed earlier noted that a group at AstraZeneca needed to meet soon "because Schulz needs to get a draft ready for APA and he needs any additional analyses we can give him well before then." It is unclear if Schulz ever received the analyses that showed Seroquel was less effective than Haldol. Regardless, in the press release, he was also quoted as saying: "Almost 50 years later, however, many patients are still taking these medications [such as Haldol], even though more effective treatments like Seroquel exist." While he was stumping for Seroquel in a press release, AstraZeneca's internal data painted a completely different picture.

Schulz, in his role as primary author, would typically be expected to demonstrate a solid understanding of the data underlying his presentation. It raises troubling questions when an independent academic author presents results that are in direct opposition to the underlying data. Such issues have been mentioned previously on this site.

The documents regarding Seroquel are available at Furious Seasons. Reporting on other facets of the documents can be found at the St. Petersburg Times, Bloomberg, New York Times, and the Wall Street Journal.

The Budget Crisis, Universities, and Key Opinion Leaders

Everyone knows that state budgets across the United States are in a crunch. All state-supported universities are looking for sources of income outside of taxpayer funds. As state legislatures look to cut money, many state universities are in for a big budget hit. So if the state is going to pony up less money, how can a university survive...?

Perhaps by seeking to entice industry funding. Set up a few clinical trials and see what happens. There is nothing inherently wrong about university faculty working on industry-sponsored research. In an ideal world, all goes according to plan and all benefit from such collaboration. Universities love industry collaboration because it brings in good money. Researchers like to collaborate with industry for some altruistic motives, such as receiving funding to work on investigating treatments that might hopefully bring about better lives for people struggling with various ailments. Because receiving funding makes the university
administration happy, it also makes life at a university medical center much more pleasant for those who bring in the bucks.

But how do things really work? Sometimes, they go well. But there are also nondisclosure agreements, in which an "independent" academic researcher gives away any right to discuss the data from clinical trials that he/she is working on unless approval is given by industry. As Graham Emslie, key opinion leader in the field of child psychiatry, can attest to, there are certainly many cases where negative results were found for a drug, but the negative data were buried to avoid any untoward publicity. Academics often farm out their writing of joint work with industry to ghostwriters who spin the final product to pimp a product rather than accurately describe the results. As regular readers know, this is just the tip of the iceberg.

If academics are willing to be oversee industry-sponsored research, have substantial input into writing the final presentation of the results, and actually review the data from these joint ventures with industry, then academic-industry collaboration can be fruitful. However, if academics are simply used to recruit patients for clinical trials, stamp their names on papers consisting of data with which they are entirely unfamiliar, and are complicit in hiding negative data, then the current sad state of affairs will continue unabated.

Given the current financial situation, universities will be encouraging faculty very strongly to get external funding for their work, and we can only hope that academics will behave responsibly when such collaborations occur.

Academics, Atypicals, and Marketing

Ahhhh, there is nothing like the sweet smell of investigative journalism in the morning. Robert Farley published a whale of an excellent piece on how atypical antispychotics were marketed in the St. Petersburg Times on Saturday. I will discuss some of the tasty tidbits from the article, but you'd be a fool to not read the entire article yourself.

Farley notes that the manufacturers of atypical antipsychotics needed to spread the word that their drugs worked better than older antipsychotics. The one slight problem was that there was not any solid evidence (except when looking at biased studies) showing that the new drugs were superior. So if the companies could not advertise this point directly, they needed to enlist third parties to say it for them. In other words, it was time for some information laundering. In what has become the standard operating procedure for the field, "independent" academics were enlisted to make recommendations that the new drugs were better than the old drugs.

So hire a few academics as consultants, fly them off to a "consensus conference," and have them generate treatment guidelines. Would the guidelines be biased? Well, yeah, but that's pretty much the point -- science be damned, it's about market share, baby. Like the Texas Medication Algorithm Project (TMAP), which helped to propel the atypicals to first-line treatment (and second-line, for that matter), and other TMAP clones across the nation. Throw in a few studies of the effectiveness of TMAP, then misinterpret their results, and BAM, you've now established (based on little to no credible evidence) that atypical antipsychotics are the new wonder drugs. And with the wind at your back, hey, why not see if you can market these drugs for everything? After all, you've got the support of the "independent" academic community...

Also see Psych Central's take on the story.

Seroquel for Everything and Academic Spokespeople

Part 1. Seroquel for Depression and Anxiety. AstraZeneca is slowly rolling out the PR for Seroquel as a treatment for depression and generalized anxiety disorder. At something called the 7th International Forum on Mood and Anxiety Disorders, AstraZeneca (via academic frontman Stuart Montgomery) has trotted out data from their latest clinical trials which purportedly show that Seroquel beat placebo for depression and GAD. Here's a quote from the detached, independent, non-conflicted academic author, Stuart Montgomery...

Dr. Stuart Montgomery, Imperial College School of Medicine, University of London and author of the [depression] monotherapy study, said: These study results are remarkable -- all of the doses of SEROQUEL XR examined provided improvements in MDD and GAD symptoms. Results from further studies that are still ongoing will add to our understanding of SEROQUEL XR in these conditions.

What is remarkable is not that 'Quell had a slight advantage over placebo but that an "independent" academic psychiatrist is willing to pimp Seroquel so blatantly. It would appear that Dr. Montgomery is aware of who is putting butter on his bread. Finding a modest to perhaps moderate advantage for a drug over a placebo in treating depression and/or anxiety is far from remarkable, given that there are dozens of drugs and psychotherapies that have demonstrated similar or better efficacy. Then again, it is remarkable that Seroquel is related to increased risk of diabetes (1, 2, 3, 4), which is likely not the case for competing depression treatments. Of course, since the movement has now started to treat depression with antipsychotics (1, 2), perhaps we will see many people with depression moving toward an increased risk of diabetes. It might be worth noting that on the MADRS, which was the measure of depression reported in the press release, one question is regarding eating -- the more you eat, the better your score. So an antipsychotic linked to weight gain is set to do well in that those who eat a lot will score better on this item, which is then taken as a sign that they are less depressed.

I've been tracking the Seroquel for everything bandwagon for some time now (1, 2, 3, 4) and I can't wait to see where this is headed next.

Part 2. The Academic Salesperson. As Krusty the Klown might say, "I heartily endorse this event and/or product"...

Here are some other Stuart Montgomery quotes from press releases:

Agomelatine

"Agomelatine is an interesting and potentially very valuable antidepressant that is effective in both moderate and severe depression", says Professor Stuart Montgomery from the Imperial College School of Medicine in London. "The new agent has a unique mode of action, improves sleep without affecting daytime alertness and its efficacy is not compromised by sexual side effects, tolerability problems or discontinuation symptoms.

Escitalopram (Lexapro)

"These results are important because they show we have a treatment at our disposal which is effective without sacrificing the good side-effect profile obviously preferred by patients," commented study author Professor Stuart A. Montgomery, Imperial College School of Medicine, London, United Kingdom. "The ideal combination for any first line treatment is good efficacy and good tolerability - this study shows that escitalopram has all the potency of the non selective SNRIs combined with the good tolerability of the conventional SSRIs," he concluded.

Lexapro (again)

“This consistent advantage really came out as a surprise,” marvelled Prof Montgomery. “These are shocking data that no one was expecting”. He added: “At that stage we already knew that there was something special about the drug”.

Finally, Prof Montgomery mentioned results coming from further studies that he referred to as “staggering” – these were decisive in establishing Lexapro’s long term effectiveness in treating both GAD and SAD.

One more piece on Dr. Montgomery may be of interest to readers (via The Guardian ):

A leading figure in the world of psychiatry gave a pharmaceutical company advice on how to get its new drug approved while he was sitting on the committee which was deciding the licence application.

An internal memorandum from Pfizer, the world's largest drug company, says Stuart Montgomery would be happy to become a paid adviser and declare an interest to the Committee on the Safety of Medicines (CSM) once the drug, an antidepressant to rival Prozac, had been through the licensing process.

Read the whole article and see what you think.

When Dr. Montgomery or other key opinion leaders with similar conflicts of interest speak, we are supposed to view them as independent expert researchers whose enthusiastic product endorsements are based purely based on science. The manner in which every drug company trot out eager academic spokespeople is a sign that academic medicine has become rotten to the core.

Teaching is For Suckers

...says the American medical school system. Health Care Renewal has an excellent post on how getting grant and/or drug company money is far and away the top priority for medical school faculty, while teaching is a much lower priority. I've likewise written about the topic previously. Read the post at HCR -- you'll be glad that you did.

Getting Paid at a Med School

Health Care Renewal has a great post about how teaching is the bottom priority at many academic medical centers where physicians are trained. Teaching physicians are paid less than public school teachers for their teaching duties in many instances, and nearly always get paid much less per hour for teaching than for research or patient care.

I've known psychologists and psychiatrists at medical centers and they often seemed nervous to me. Why? Because their salary was based on algorithms that most closely resembled a Choose Your Own Adventure book.

The base salary was close to nil, and they then had to make their salary through seeing patients and/or working on funded research. If you wanted to work on research on something unsexy (read: not funded by the government or a drug company), you were pretty much doing it for free. Hence the lack of academics working at medical centers who can conduct research that challenges the dominant paradigms of today. Teaching? Hey, just because they were teaching future psychologists and physicians doesn't mean they actually got paid for it.

Maybe that's also why academics at medical centers also tend to avoid speaking out in most cases -- they wouldn't want to get labeled as a "bad apple" who no drug company wishes to fund. Maybe that person could find some government grant money but getting blacklisted by Big Pharma does not exactly make you a top dog for getting government money.

If you follow the "correct" choices, you can make a bunch of money and become a "key opinion leader." If you choose incorrectly, well, you can become David Kern, Betty Dong, David Healy, Nancy Olivieri, Gretchen LeFever, or the like.

Read Health Care Renewal's excellent take on the situation.