Seroquel, Haldol, and The Full Court Media Press

I was very pleased to have been acknowledged in a recent story in the St. Paul Pioneer Press. The reporter, Jeremy Olson, wrote the following in his story:

An Internet psychiatry blog first raised questions March 2 about the research Schulz presented at the APA conference and why it lacked any of the company's findings."It raises troubling questions when an independent academic author presents results that are in direct opposition to the underlying data," wrote the blogger, an anonymous academic.

He didn't cite my blog by name -- the unwieldy long name which I stupidly chose for the site may be responsible for that -- but I'm nonetheless grateful that my site was acknowledged for its work on this story. He is referencing my post in which I noted that a University of Minnesota psychiatry professor (Charles Schulz) had stated in a press release that Seroquel was "more effective" than Haldol. This was based upon his analysis of data comparing Seroquel to the much older antipsychotic drug Haldol in the treatment of schizophrenia. Yet an internal AstraZeneca analysis found that Haldol was actually more effective than Seroquel. Both the Pioneer Press and the Star Tribune, the two big papers in the Minneapolis-St. Paul area ran stories on the controversy.

When asked about his lavishing of praise on Seroquel in the press release, the Pioneer Press said:

In an interview with the Pioneer Press last week, Schulz defended his research and presentation of Seroquel as accurate and ethical. However, he acknowledged the corporate press release from his APA presentation might have exaggerated in calling Seroquel "significantly superior."

"You know," he said, "I can't disagree with that."

Schulz said the following in the Star Tribune:

In an interview this week, Schulz said the pharmaceutical company never shared its doubts about Seroquel, which went on to become a blockbuster, with annual sales of $4.5 billion today. "I don't recall anybody calling up and saying, oh my goodness, we have this problem," he said. At the same time, Schulz acknowledged that his own study did not really show that Seroquel was more effective than the older drug. "That's a bit of a misunderstanding," he said. "I think the overall message is that it works about the same."

Thanks to a helpful reader, I was able to track down what appears to be Schulz's presentation from 2000. It says "...quetiapine was clearly statistically significantly superior to placebo as well as to haloperidol..." This appears to contradict his statement that Haldol and Seroquel "work about the same." Again, the data from Schulz's presentation don't match AstraZeneca's internal analysis. Schulz is obviously backing away from his earlier praise for Seroquel, for which he deserves some credit. The problem was that Schulz, along with a laundry list of researchers in psychiatry were caught in a tidal wave of unbridled enthusiasm for the atypical antipsychotics, first as wonder drugs for schizophrenia, then as the Next Big Thing in bipolar, then moving into the world of depression and anxiety disorders in the absence of decent supportive evidence.

Interesting sidenote: While Schulz was presenting on the wonders of Seroquel, he was likely quite unaware that AstraZeneca has conducted a study (Study 15) which had found that Seroquel compared unfavorably to Haldol in preventing psychotic relapse among patients with schizophrenia who began the study in full or partial symptom remisison. Furious Seasons has some additional reporting on this study. It is a near certainty that Schulz was not informed about this study's results, as this could have changed his lofty opinion of Seroquel. This points to the problem of researchers relying on data collected by drug companies -- how are researchers to know they are receiving all of the data?

Note to key opinion leaders: If you don't realize it by now, you are pawns. You are being used to place an academic veneer on the marketing of drugs. The drugs that you are marketing as major breakthroughs typically offer little to no benefit over existing treatment and may cause a slew of nasty side effects. Decide if you want to be a scientist or a marketer. Don't try to do both at the same time, because the odds are pretty good that your scientific credentials will end up being tarnished. Just ask this guy. Now that the media are paying much closer attention to the conflicted interests and skewed science that sadly underlie much of psychiatry these days, it would be a good idea to maintain appearances.

Seroquel, Weight Gain, And the Pursuit of GAD and Depression Indications

Jim Edwards at BNET dug through the Seroquel documents and found many instances of AZ employees noting that Seroquel causes weight gain. Yet the company seemed bent on keeping this information hidden. As I mentioned last week, this sure seems a lot like Zyprexa redux, except with more sex scandals and perhaps more buried data. I suggest that everyone head over to BNET and see the details.

Despite all the bad news, AZ is pressing onward with its application for FDA approval for Seroquel in both generalized anxiety disorder and depression. Yikes. I broke the story earlier this week about the "scientific literature" claiming that Seroquel worked better than Haldol in the treatment of schizophrenia, yet internal company data showed Haldol as superior to Seroquel in reducing schizophrenia symptoms. Between discrepant data, the apparent hiding of negative clinical trials and trying to keep doctors distracted from data indicating that Seroquel caused weight gain, I think that Seroquel's luck may have ran out -- my bet is that the FDA won't approve the drug for depression or GAD. But I've been wrong before; the FDA did approve Abilify as an add-on treatment for depression based on pretty flimsy evidence.

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.

Seroquel Becomes Zyprexa, Part 2. But With More Sex.

I had a big post on Abilify ready to go for today, but I'll sit on it for a few days because Seroquel is the new Zyprexa, and that is the big news of the week. Well, that and Forest getting probed for allegedly marketing Celexa and Lexapro off-label for depression in kids. But more on that later. In the meantime, check out Jim Edwards' nice piece on the emerging scandal.

Back to the 'Quel. First off, a big-time round of applause for Philip Dawdy at Furious Seasons. He's been covering the unfolding Seroquel mess like a hawk, which is exactly what he did during the days of the Zyprexa documents scandal, which is still costing the admittedly criminal corporation of Lilly billions. According to legal documents, Wayne Macfadden, former U.S. Medical Director for Seroquel, admits to being engaged in sexual relationships with a British researcher at the Institute of Psychiatry (IOP) who participated in Seroquel research. Incredibly, Macfadden was also apparently entangled in a sexual relationship with a ghostwriter who wrote up results of Seroquel studies. The attorneys who are suing AstraZeneca claim that: "The IOP researcher suggested that Macfadden would punish her if she even looked at studies that were favorable to Seroquel's competitors." Better yet, Macfadden was alleged to have "promised sexual favors in exchange for intelliegence on AstraZeneca's competitors." It would seem a relevant conflict of interest to note that one was engaged in sexual relations with the Seroquel Medical Director, wouldn't it? I don't typically care about people's sex lives and am in favor of respecting people's privacy. Except when it is potentially related to poor science and/or poor care of patients.

So that's a little weird. And then... according to the Wall Street Journal, internal documents from AstraZeneca suggest that AZ hid concerns that the drug caused diabetes. Gee, that sounds like a page from the Zyprexa playbook. AZ sales reps were instructed to inform physicians that there was no causal link between Seroquel and diabetes. However, according to the WSJ, "In a 2000 position paper about the safety of Seroquel sent to Dutch regulatory authorities, an AstraZeneca doctor named Wayne Geller wrote that there was a relationship between the drug and diabetes. 'There is reasonable evidence to suggest that Seroquel therapy can cause impaired glucose regulation including diabetes melliutus in certain individuals,' Dr. Geller wrote." Expect a few more stories to appear in the mainstream press followed by AZ doling out decent chunks of change to settle lawsuits. This may kill Seroquel's chances of FDA approval for depression, generalized anxiety disorder, and the common cold (OK, I made that one up). Let's hope the documents make their way to the internet so that bloggers such as myself and Philip Dawdy can dig through and go into more depth than the mainstream press. Just like we did with Zyprexa (1, 2, 3).

Can we call this the Sex-o-quel scandal or is that too cheesy?

By the way, Furious Seasons is currently running a fundraiser. I will be making my donation today, and you should do the same if you are in favor of mental health journalism that breaks important stories and is bold enough to cover a wide variety of important issues, regardless of their level of controversy.

Seroquel Lawsuits on the Rise

Lawsuits against AstraZeneca regarding its alleged failure to disclose the risks (like diabetes) of its drug quetiapine (Seroquel) are on the rise. Apparently, more than 350 cases were filed in Delaware state court in April. I'm not entirely clear if the latest lawsuits also allege off-label marketing, which is apparently becoming something of a calling card for AZ these days. Off-label marketing has been part of other Seroquel legal actions. No wonder, as it appears that Seroquel is being investigated as a treatment for, well, everything, as I've pointed out previously (1, 2, 3, 4, 5).

More details here.

Hat Tip: Furious Seasons and Pharmalot.

Seroquel for Kids

If your child is suffering from bipolar disorder, help is available. While I think the linked advertisement is no longer on television (I don't know for sure), Massachusetts General Hospital is nonetheless enrolling patients ages 4-6 with bipolar disorder to participate in a study where they will receive quetiapine (Seroquel) to alleviate their symptoms.

I can only hope that it will be as great of a study as a similar investigation that utilized Zyprexa for adolescents with bipolar disorder. Of course, we know (because someone at Harvard said so) that children with bipolar disorder become suicidal in 75% of cases. Did I mention I have a bridge that I'm looking to sell...

Please read Intueri's post as well as my earlier post to see just how "scientific" the diagnostic process is for kids and adolescents regarding bipolar disorder.

Whose Gold Standard?

Decision Resources has recently claimed that Zyprexa will remain the “gold standard” for schizophrenia treatment. Philip Dawdy found such a finding rather odd, as neither he nor many others (including myself) had ever found Zyprexa to be the most supported schizophrenia treatment. Most research indicates that Zyprexa works roughly as well as other medications, with its slight efficacy advantages in some studies (which may be based on biased research) likely offset by its tendency to induce weight gain and diabetes. In addition, the same consulting firm has also claimed that Seroquel will become the “gold standard” for treating bipolar depression by 2010.

Well, Brandweek NRX is now reporting that Decision Resources is claiming that the yet-to-be-FDA-approved Acomplia is set to become the new (you guessed it) “gold standard” in treating obesity. Never mind the side effects of depression and anxiety. Text of the press release can be seen here.

It would appear that Decision Resources likes to bandy about the term “gold standard” quite a bit in their reports. In fact, look what happens when you combine “gold standard” with “Decision Resources” – click here.

I’m not really sure what this company actually does and I’m not going to take much time to figure it out. I just find it odd when a company keeps churning out reports labeling various treatments as being the “gold standard” in the absence of any good clinical trial evidence.

Seroquel for Everthing Update: WHAT??

AstraZeneca has reported that its trials with quetipaine (Seroquel) for generalized anxiety disorder and depression are going well, to the point that it plans on filing for FDA approval for said conditions in 2008. As you may recall, Seroquel is currently being studied as a remedy for, well, just about every mental condition (1, 2, 3, 4, 5). Here's what I'm betting is happening...

You conduct enough studies using a drug that is mildly better than a placebo, making sure to usually enroll a large sample of people. At least two of the studies will turn out to be "statistically significant" and who cares what happens in the other studies -- just don't publicize them or include them in your FDA application! If there are seven or eight studies examining Seroquel in depression currently, then we shouldn't be surprised if two of them yield somewhat better results for Seroquel. Considering that some depression rating scales rate an improved appetite as an improvement in depression, then Seroquel-induced weight gain actually counts in its favor.

Hat Tip: Furious Seasons

Antipsychotics or Anna Nicole Smith?

California House Representative Henry Waxman, in his role as chair of the Committee on Oversight and Government Reform, has requested information from Lilly and AstraZeneca regarding their marketing of antipsychotics Zyprexa and Seroquel, respectively. AZ was further asked to provide information regarding its marketing of Actiq, a narcotic lollipop (!) and Fentora, a narcotic lozenge.

Information regarding the safety and purported off-label use of drug coated stents from Boston Scientific and Johnson & Johnson was also requested.

I’d like to point out that bloggers, including Philip Dawdy, myself, and Roy Poses, have written about the shenanigans associated with Zyprexa’s marketing while the major news outlets (except the New York Times) have remained stunningly silent. Perhaps Waxman’s latest move will revive the brain dead media from the fascination with Anna Nicole Smith, Britney Spears, and other stories that are completely unworthy of journalistic attention.

What, is that a blond celebrity with her breasts becoming unhinged from her top? Zy-what? Sero-who? Ugh.

Hat Tip: Furious Seasons.

AstraZeneca: Sued Over Seroquel

Over 10,000 US patients have filed lawsuits against AstraZeneca, alleging that AZ hid dangers of its bestselling atypical antipsychotic quetiapine (Seroquel). The lawsuits allege that AZ was not forthcoming about side effects such as significant weight gain and diabetes. In addition, the lawsuits focus on Seroquel allegedly being promoted for unapproved uses, a point I have suspected (here and here) for a while on this site.

Here's some snippets from the latest story from Bloomberg:

AstraZeneca said in a preliminary annual report filed Feb. 1 that it knew of about 1,200 lawsuits containing the claims of about 8,000 plaintiffs. The company ``has not determined how many additional cases, if any, may have been filed,'' AstraZeneca said in the filing. The company said in May it faced 232 Seroquel suits, including those with multiple claims.

--SNIP--

Seroquel, approved for use for schizophrenia and bipolar disorder, is part of a class of newer antipsychotic drugs including Zyprexa and Johnson & Johnson's Risperdal. Seroquel passed Zyprexa last year as the top-selling atypical antipsychotic, [AZ spokesperson] Minnick said.

AstraZeneca has been sued by 9,956 individuals in U.S. courts over Seroquel, according to a Feb. 5 filing in federal court Orlando, Florida, where the lawsuits have been consolidated in a multidistrict litigation for evidence-gathering and pre- trial hearings.

This includes claims by 7,171 plaintiffs in federal courts, primarily. The claims are made in about 1,500 lawsuits, many of which have multiple plaintiffs.

The suits claim that AstraZeneca knew the risks of Seroquel and didn't warn patients in the U.S. ``until they were finally forced to do so by the FDA,'' according to a complaint filed in federal court in Massachusetts, on behalf of 997 plaintiffs.

--SNIP--

The growth in sales of the drug, from $66 million in 1998 to $2.75 billion in 2005, was spurred by ``AstraZeneca's aggressive marketing of Seroquel,'' according to these patients, whose cases have been transferred to federal court in Orlando.

The marketing ``consisted chiefly of overstating the drug's uses and benefits (including massive off-label promotion), while understating and consciously concealing its life-threatening side effects,'' their complaint said.

Lawyers representing Seroquel users have agreed to limit the claims filed to people who said they developed serious health problems after taking the drug, said attorney Paul Pennock, lead plaintiffs' counsel in the multi-district litigation.

``Everybody involved took a blood oath that we were only going to pursue cases where there was a real injury, like pancreatitis, diabetes or severe exacerbation of existing diabetes,'' said Pennock of Weitz & Luxenberg in New York. ``This was as opposed to the Zyprexa litigation where a lot of people took on all comers,'' he said.

Pennock represents more than 1,700 plaintiffs, about 67 percent of whom were prescribed the medication for off-label uses, including insomnia, depression, anxiety, post-traumatic stress disorder and Alzheimer's, he said.

I'll be keeping my eye on this one. Given that AZ has been studying Seroquel as a treatment for virtutally everything, I strongly expect they "educated" physicians about the results from these studies on conditions other than bipolar and schizophrenia (which have yielded, from what I've seen, not overly impressive results) via doctor dinners, journal article dissemination, continuing medical misinformation, er, education, and the like.

Seroquel for Everything Update: GAD

I have mentioned earlier that Seroquel is being studied as a treatment for virtually every psychiatric disorder under the sun. You can now access a very brief outline of the latest Seroquel study for generalized anxiety disorder here.

The official title: An International, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Active-Controlled Study of the Efficacy and Safety of Sustained-Release Quetiapine Fumarate (Seroquel SR™ ) in the Treatment of Generalized Anxiety Disorder (SILVER)

Virtually all big drug trials now have cute acronyms. Seroquel has used BOLDER before (here and here) and now it's SILVER. If only the academic researchers associated with these studies put as much thought and time into their work on the data analysis and writeup of these studies as the marketing teams did in coming up with the acronyms.

And how, exactly, did SILVER come from the above title? Seems like a stretch...

But wait, there's more.

Here's another study. In this one, Seroquel will be compared with placebo in the treatment of GAD in elderly folks. And still another study, this one apparently comparing Seroquel to placebo in the treatment of GAD, again. How about another one -- this one comparing Seroquel to Lexapro for GAD.

And another one -- this one apparently will put folks on Seroquel for a while, then follow those who show improvement. Some who improve will get switched to a placebo while some stay on Seroquel. If people switched to placebo show more anxiety, then AstraZeneca and its allied academics will say that Seroquel is a good long-term treatment. Of course, maybe it's just that Seroquel has withdrawal symptoms, and that is what caused the anxiety. Yes, this is all hypothetical, but it is the card that has been played time and time again for other psychiatric disorders.