Open Up Yer Wallets

Yeah, I know the economy is in very bad shape and possibly getting worse. But for the kind of fantastic investigative journalism we get from the inimitable Philip Dawdy at Furious Seasons, one really should whip out the credit card and make a donation. A summary of his good work is available, and his more recent work on Seroquel is worthy of accolades (1, 2).

Donate here.

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.

Atypical Antipsychotics for All, Oregon Chapter

Oh boy. Here we go again. A study published online ahead of print at the Journal of Clinical Psychiatry notes that among Oregon Medicaid patients who received a prescription for an atypical antipsychotic:

• 52% had a depression diagnosis
• 34% had an anxiety diagnosis
• 15% had a PTSD diagnosis

But only 15% had a schizophrenia diagnosis and 27% had a bipolar diagnosis. So... the majority of atypical scripts were written off-label. Seroquel was the most frequently prescribed atypical, followed by Zyprexa, then Risperdal.

Doses less than what are typically given to treat schizhophrenia or bipolar disorder (subtherapeutic dosing) were quite common. As in 86% of Seroquel scripts were subtherapeutic, 59% of of Risperdal scripts, and 48% of Zyprexa prescriptions. Wait, am I calling for higher doses of these drugs? That doesn't sound like me at all, right? Don't worry, I haven't lost my mind (I think).

Here's the deal. The authors suspect that a lot of these low-dose prescriptions are being written to manage agitation and as sleep aids. The authors note that there are likely less expensive/more effective medications for such conditions. Not to sound too cavalier, but one could also recommend behavioral treatment to help with sleep as well. Nah, that's crazy talk -- not enough money to be made in that.

Primary care docs were more likely than psychiatrists to dish out low-dose antipsychotics. I guess that the Viva Zyprexa marketing blitz was a success after all. Thanks to Daniel Hartung and collagues for their study, which provides another insight into the wonderful world of atypical antipsychotics as a treatment for everything imaginable. Sorry to beat a dead horse with my zillionth post about the topic of atypicals, but isn't this getting just a teeny bit out of control?


Daniel M Hartung, Jennifer P Wisdom, David A Pollack, Ann M Hamer, Dean G Haxby, Luke Middleton, Bentson H McFarland (2008). Patterns of atypical antipsychotic subtherapeutic dosing among Oregon Medicaid patients Journal of Clinical Psychiatry DOI: ej07m03658

BOLDER Update: Lilly Started It

Some of my longstanding readers probably remember that I long ago wrote about a statistical issue in the Seroquel trials for bipolar depression (known by the corny acronym BOLDER). It was just a minor issue, you know, the kind that would make a drug look about 50% more effective than a placebo depending on which type of analysis you chose to use. No biggie.

Lilly Started It: It just so happens that Philip Dawdy (who has apparently been christened as Dr. Dawdy) at Furious Seasons recently had a letter published in the Journal of Clinical Psychopharmacology on this issue of statistics. Dawdy noted that the authors' use of a statistical method known as mixed models repeated measures (MMRM) rather than the more conventional last observation carried forward (LOCF) resulted in a major inflation in effect size. As I mentioned earlier, the choice of methods to calculate the effect size (the magnitude of difference between drug and placebo) had a big impact. Dawdy aptly noted that the authors should have reported the effect sizes calculated by both methods so that readers could note how one method made Seroquel look better than did the other method. To quote Dawdy, "...the authors should also have reported the LOCF effect sizes so that the readers would have been aware of how the method impacted the findings." I was flattered to see that my blog was cited in Dawdy's letter. I heard through the grapevine that another author attempted to cite my blog in a letter to the editor, but that the journal struck the citation to my site in the final version of the published letter. If some of y'all researchers who read this blog wanna cite my site, go ahead.

I'm not saying that Seroquel was a dud, but that it did get a boost from the analysis used in the study. When the authors are playing by a new rule when it comes to calculating the differences between drug and placebo, it would make sense to report the results using both the old rules and new rules. In his response, Michael Thase of the BOLDER team responded that "It is my understanding that mixed model repeated measurement (MMRM) analysis was chosen to compute effect sizes in the BOLDER studies because it would permit direct comparison with the results of the study of the only other treatment approved for bipolar depression, the combination of olanzapine and fluoxetine (OFC). Thus, in plain and simple terms, we were attempting to facilitate an apples to apples comparison between quetiapine monotherapy and OFC." So because Lilly did it, we did it. Um, OK. But is there some kind of law against reporting the results from both the newfangled MMRM analysis and the old-fashioned LOCF analysis? Just wondering. And if Lilly started saying it was okay to market Zyprexa off-label for various conditions, would that mean all antipsychotics could be marketed off-label for all sorts of issues? (Hypothetically speaking, of course.)

Stats: Thase goes on to note that there is some research suggesting that MMRM does not overinflate effect sizes; rather, LOCF underestimates them. I know a bit about stats, but I'm not a statistician. Basically, the differences between the methods boil down to how data is handled for persons who dropped out of a study. The best solution is to try to track down study dropouts and assess how they are functioning, rather than having a statistical model guess at their sense of mental well-being, but this requires extra effort and time, and is sometimes not possible. Basically, the LOCF model makes some assumptions that are quirky at best, while MMRM seems to handle missing data better in many situations. All that being said, in many trials where a drug beats placebo, MMRM appears to generate effect sizes that are higher than LOCF, which then leads us to a question "Geez, have we been underestimating the effects of drugs by 50%?" -- um, that seems a little hard to swallow. I'm not quite ready to buy into that.

Furious Seasons is On Fire

Furious Seasons suffers from a chronic case of excellence, but standing out even more than usual were a quartet of posts today that should be read by all:

• DSM-V Authors Tied to Pharma (hardly surprising, but interesting)
• Beatdowns in Texas Mental Hospitals. In the land of TMAP, disgusting behavior is apparently quite widespread.
• Is Bipolar Disorder Overdiagnosed? Nah, of course not.
  
• Seroquel for Depression -- Start the Countdown. Another chapter in the Seroquel for Everything saga about to be put into print. Lock up the women and children, since they'll be the first to be 'Quelled.
  

Bipolar Child Key Opinion Leader: I Get Money

As reported on the Wall Street Journal Health Blog, Dr. Melissa DelBello's tight financial ties to AstraZeneca are again under scrutiny. This should come as no surprise to my readers, as I noted in March that, in 2003-2004, DelBello had been the recipient of $180,000 from AstraZeneca (makers of Seroquel). I gleaned this information from results of an investigation by Senator Charles Grassley. The WSJ Health Blog noted that Grassley's investigation has continued, revealing that:

DelBello, who also has received NIH grants, also reported $100,000 in outside income between 2005 and 2007. But when Grassley asked AstraZeneca directly, the total value of its payments to DelBello during those three years came to $238,000.

So she claimed initially that she received $100k from 2005-2007, but she actually pulled in $238k from a single company and who knows how much from other outside entities. In fact, it is clear that DelBello has received funding from several other corporate interests. To quote her disclosure from a continuing medical education exercise:

Dr. DelBello has disclosed the following relevant financial relationships: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, and Pfizer: Consultant; AstraZeneca, GlaxoSmithKline, Pfizer: Speakers’ Bureau; and Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Johnson and Johnson, Pfizer, and Shire: Research Support Recipient.

But wait, there's more! According to Grassley's investigation, DelBello has also established a company for "personal financial purposes." The company is called MSZ Associates and AstraZeneca put $60,000 in the coffers of the company. The address of MSZ Associates, according to Grassley, is the University of Cincinnati Department of Psychiatry (where DelBello works).

Again, as I've said earlier, I don't know Dr. DelBello, but from this information, I do indeed feel comfortable nominating her for a Golden Goblet Award. For background, read here and here. PharmaGossip's interesting visual representation of the situation can be seen here.

This is how one sets out to become a key opinion leader. DelBello quite likely has a mortgage and bills to pay, but is this confluence of commercial and academic interests really the best we can do for our patients?

Being a key opinion leader has one pleasant side effect: You Gets Mad Money.

(Warning: Video contains adult language)

"Not Much Money," KOLs, and Child Bipolar Disorder

Intro. A few months ago, I wrote about key opinion leaders (KOLs) in psychiatry arguing that we shouldn't be making such a big deal about their payments from drug companies. After all, they were just receiving chump change. At the time, my motivation was spurred by a great piece in the New York Times on the issue of physicians receiving payments from drug companies. Physicians are often paid to become "key opinion leaders," aka salespeople. Often possessing academic positions, these KOLs give speeches to fellow physicians in which they extol the virtues of a drug in exchange for cash. Of course, physicians might be leery if a sales representative was discussing the latest wonder drug, so using an "independent" physician uses a basic marketing trick, the third-party technique, in order to give the marketing message a veneer of credibility. For the past few years, KOLs have been lighting up the upscale restaurant scene across the nation, discussing the benefits of atypical antipsychotic (er, broad spectrum psychotropic) treatment for a wide variety of ills. From schizophrenia to bipolar disorder to anxiety to well, pretty much anything you can imagine, antipsychotics are the treatment du jour.

"I don't make much." One KOL in the wonderful world of atypicals has been Melissa DelBello. In particular, her specialty is children with bipolar disorder. I've previously stated my beef with the child bipolar paradigm and I'll discuss a couple of my contentions a bit later in the post. DelBello has been involved in research regarding the treatment of child bipolar disorder (not saying I necessarily agree with the term; just using it because she used it). As a KOL, DelBello has given talks supported by AstraZeneca, manufacturer of Seroquel. As for her reimbursement for such talks, she said "Trust me. I don't make much."

Here is what a little investigation from Senator Charles Grassley uncovered regarding DelBello's definition of "not much" money.

Here is where it gets interesting. After Dr. DelBello released her study, Astra Zeneca began hiring her to give several sponsored talks. Another doctor told The New York Times he was persuaded to start prescribing drugs [Page: S10722] such as Seroquel after listening to Dr. DelBello. But when the reporter from the New York Times asked Dr. DelBello how much money she got from Astra Zeneca, she told the paper: ``Trust me. I don't make much.''

Well, I decided to find out how much, and I went directly to the University of Cincinnati who, by the way, has been extremely cooperative, helpful, and responsive. Soon I figured out just how much ``not that much'' money is. Dr. DelBello's study, which helped put Seroquel on the map, was published in 2002. That next year, she got more money than she has ever received from the pharmaceutical companies--at least that is what the documents that I have say.

In 2003, Astra Zeneca alone paid her a little over $100,000 for lectures, consulting fees, travel expenses, and service on advisory boards. In 2004, Astra Zeneca paid her over $80,000 for the same services.

So, if I have this correct, $180k over two years is "not much money." Hey, this is quite similar to a response from another moonlighting entrepreneur with a license to practice medicine. To quote from the New York Times...

The psychiatrist receiving the most from drug companies was Dr. Annette M. Smick, who lives outside Rochester, Minn., and was paid more than $689,000 by drug makers from 1998 to 2004. At one point Dr. Smick was doing so many sponsored talks that “it was hard for me to find time to see patients in my clinical practice,” she said.

“I was providing an educational benefit, and I like teaching,” Dr. Smick said.

Right. The companies provide you with the slides and the key marketing points, and you call yourself an "educator." Um, doesn't that actually make you a marketer? And the clincher: Who has time for patients in clinical practice when you are off stumping for the hot drug of the week?

The KOL-Pharma Marriage: For all I know, Dr. DelBello is a great human being. I disagree with her a great deal on the child bipolar thing, but there are certainly many very bright and reasonable people who see things differently than myself. Personally, I have difficulty seeing the child bipolar bandwagon as anything other than a massive campaign to re-brand a broad spectrum of unruly behavior under one heading that can be used to call out for antipsychotic treatment. Researchers in the area of child bipolar perceive that scientific progress is being made because they have "discovered" a condition that affects millions of youth. Big Pharma loves it because, conveniently, they can treat this newfound condition with their cash cow atypical antipsychotics. And the marriage between child bipolar researchers and Big Pharma becomes even tighter through the well-paying speaking gigs in which KOLs pimp atypicals as the treatment for child bipolar, a condition that was considered quite rare until KOLs and Pharma "educated" us about this "neglected and undertreated serious medical condition."

Taking large payments then writing them off as "not much" just adds another brick to the wall of conflicted interests that dominates medicine these days. The physician-marketer (aka KOL) can perhaps take great pride in the rate of treatment for child bipolar expanding by perhaps 4000% of late. In fact, the spread of atypical antipsychotics for children, the elderly, and everyone else is such good news that I think KOLs should be up for some sort of marketing award. Go Team Seroquel! Viva Zyprexa! Rock on Geodon Crew! Gimme an I-N-V-E-G-A! Pimp that Abilify!

Believe it or not, I'm not against industry-academic collaboration. But I am against industry-academic corruption. When there are no checks and balances on a system, one should not be surprised when it is subverted by a combination of power and money. When academics turn into industry spokespeople, or become information launderers, or become medal winners in the conflict of interest department, why on Earth should we simply trust them as if they had no skin in the game?

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.

Atypical Antipsychotics for the Elderly: A Booming Business

A recent report in the St. Petersburg Times has indicated that between 20-26% of atypical antipsychotic prescriptions are for elderly people. The drugs are typically given in order to help calm patients. This is interesting because the data supporting their efficacy is very weak (1, 2, 3). While the article in the Times is interesting and discusses the problems with the drugs in terms of side effects, it, along with other media coverage with which I am familiar, is missing a major point: Atypical antipsychotics show minimal effects over the benefit given by a placebo. They are also linked to an increased risk of death. So you are increasing the odds of your patients dying, but you are, according to clinical trial research, providing minimal clinical benefit.

Here's a shocking snippet from the article:

Testifying at a congressional hearing, Dr. David Graham, a prominent FDA drug safety expert, was asked if he had issues with any medications already on the market.

"I would pay careful attention to antipsychotic medications. ... The problem with these drugs are that we know that they are being used extensively off-label in nursing homes to sedate elderly patients with dementia and other types of disorders. ...

"But the fact is, is that it increases mortality perhaps by 100 percent. It doubles mortality. So I did a back-of-the-envelope calculation on this and you have probably got 15,000 elderly people in nursing homes dying each year from the off-label use of antipsychotic medications. ...

"With every pill that gets dispensed in a nursing home, the drug company is laughing all the way to the bank."

Granted, this is a back of the envelope calculation that may be inaccurate. But nobody disputes that these medications are linked to increased odds of dying for the elderly, and someone needs to get the science writers to read the research (cited above) that these medications don't work very well. It is hard to think of a bigger scam -- works as well as a sugar pill but increases your odds of dying. The public outrage won't start until people in the media gets rid of headlines that read:

Dementia relief, with a huge side effect: The off-label use of some drugs is helping elderly patients, but may be killing thousands.

Again, the data do not support that these drugs are much more helpful than a placebo, making the headline misleading. Please incorporate the actual research findings regarding atypical antipsychotics into the story and let's try again...

Newer antipsychotic medications offer little to no benefit over placebo, and are killing thousands of elderly patients.

Doctors talk about the risk-benefit ratio with various treatments, which makes sense. When a class of drugs seems to have little benefit and a high cost, both financially and in terms of side effects (including death), shouldn't we try something else? The media create the outrage and then the change occurs. What about the academic experts who have participated in studying these drugs? They should be the most aware of the small at best benefits and the high side effect burden. Yet instead, some of them are churning out tripe such as the latest study pimping Abilify for dementia. If academics are asleep at the wheel, then it is up to the media to start the outrage. I generally like this St. Pete Times article, but if even the most skeptical writers are still claiming the drugs work, it is not a good sign.

But What Else Can Be Done? It is true that elderly patients with dementia can be difficult to manage and that giving them a chemical restraint such as Zyprexa may slow a person down. But how about the following crazy idea, again taken from the St. Pete Times piece...

There are other options, but they take time, money and effort.

At the Cobble Hill Health Center in Brooklyn, Dr. Louis Mudannayake decided to try to change the thinking at his 400-bed nursing home.

Ignoring naysayers and the doomsday predictions of senior nurses, 18 months ago he put together a team of pharmacists, social workers and recreational therapists to review every atypical prescription.

If a new roommate caused agitation, room assignments were changed. If a new aide was hit while dressing a patient, the aide was given special training on that patient's preferences and routine.

Though the nursing home's resources were initially stretched, Mudannayake said the quality of patients' lives improved. "Ultimately, I'm convinced financial expenditures will be diminished, because it's easier to manage a patient who is calm," he said.

Atypical use at Cobble Hill has been cut from about 25 percent of patients to about 10 percent, he said. Almost 40 percent of patients were taken off the drugs completely; 75 percent of those still on the drugs have had their dosage reduced.

"We instituted a cultural change. That's what's required to bring the numbers down," said Mudannayake, who said psychiatric hospitalizations did not increase as medication dropped.

"You'll always have doctors say there's nothing else to use but atypicals, and I agree there are a small minority of patients where you need to use these drugs. But not in the numbers we are using them."

I see, so you can do something else besides dole out Zyprexa and its siblings like candy. But it takes time, effort, and using one's training in mental health. You'd think that psychologists and/or other mental health professionals could easily be hired as consultants to devise such plans. Of course, it is a lot easier to just attempt to sedate chemically over and over again. But are we supposed to do what is easy, even if it is not in the best interest of the patient?

Shame, Shame, Shame. In my humble opinion, this phase atypical antipsychotic mania will be associated with gigantic shame on the psychiatric profession. Just wait a few years. The amazing part is how few "leading lights" within the field have stepped up to the plate and pointed out the problems associated with these medications. When they were first released, all sorts of "key opinion leaders" happily pushed them as a huge improvement over older antipsychotics in terms of treating schizophrenia. Turns out that was mostly hype. Then the atypicals for bipolar rush hit full force, again with the help of "key opinion leaders."

Without academics pimping these treatments well beyond what was scientifically justifiable, these medications would never have achieved such huge success, but now this rather dangerous group of medicines is used for virtually every psychiatric disorder under the sun. These uses include "bipolar disorder" in infants, ADHD, and dementia. Let's put the most vulnerable individuals on the riskiest treatments despite no clear evidence that they work particularly well. There is indeed some evidence for the efficacy of these medications in the short-term treatment of schizophrenia and bipolar disorder, and in a small number of trials, even some long-term evidence of efficacy. But their indiscriminant use across the board for virtually every condition brings great shame upon psychiatry as a profession, on Big Pharma for its slick marketing strategies (1, 2), and most especially upon academic psychiatry for its morally bankrupt role as a group of salespeople who have misrepresented scientific findings to help promote drugs (1, 2, 3, 4, 5, 6, 7, 8).

Update: I forgot to publicly tip my hat to Furious Seasons, where I first saw the link to St. Pete Times piece. Philip Dawdy also added some spot-on commentary, as is the norm at Furious Seasons.

Son of Risperdal Beats Seroquel

Janssen, manufacturer of Invega (son of Risperdal) funded a study comparing Invega, Seroquel, and placebo in the treatment of schizophrenia. Results were as follows:

"After two weeks, those on Invega had a greater reduction in symptoms as measured by a standard test called Positive and Negative Syndrome Scale for Schizophrenia, or Panss. The test measures symptoms such as disorganized thoughts and uncontrolled hostility. The score for Invega patients declined 23.4 points, 17.1 points for Seroquel and 15 points for placebo, according to J&J."

By the way, note the rather paltry advantage of Seroquel in comparison with placebo. These results fit nicely into a pattern. A study published in the American Journal of Psychiatry in 2006 found that clearly, the best predictor of which antipsychotic would be shown superior in a head-to-head comparison was who funded the study. Also feel free to examine their table in which they point out the biases in these various comparative studies.

Pharma claims to spend bazillions of dollars on research -- but these studies aren't research in the classic sense, which is a scientific endeavor undertaken to gain knowledge. These are exercises in marketing -- set up a study with some sort of bias favoring your drug, then hurry and rush out the drug reps with low cut blouses and fistfuls of reprints of studies showing your drug is superior to the competition. Then, the competition retaliates by setting up a study in which their drug is set up to win due to some sort of biased design. And the cycle goes on and on and on. Pharma then counts these "studies" as research expenditures and waxes on about their dedication to developing lifesaving medications. As if these studies done purely for marketing purposes have anything to do with developing lifesaving medications.

Background on Invega:

• The Creativity Crisis Continues
• Invega: Can You Say 'Patent Extender'?

The Zyprexa Whitewash

Furious Seasons has another tidbit from the Zyprexa documents. It involves the terms "diabetes" and "whitewash." You can read the internal Lilly document yourself at Furious Seasons and decide for yourself.

If you've been living in a cave for the past 10 months or so, here are some other features regarding the infamous Zyprexa documents:

• Zyprexa: Off-Label Promotion?
• Demented Marketing of Zyprexa?
• Zyprexa: The New Mood Stabilizer and Downplaying Risks
• Zyprexa: Off-Label Marketing Part 2

And then there is Abilify. Read Brandweek NRX's piece here. Oh, and Seroquel? Read here and here. The lawsuits will keep coming, and there will be large payouts. I'm not a fan of suing the pants off everyone, but if there is no other way to fight off-label marketing and other dubious promotion tactics, then so be it.

Amateur Sleuthing

The Wiki Scanner story is simply irresistible. Pharmalot let us know that AstraZeneca had changed the Wikipedia entry for Seroquel (story via the Times of London). Read more at Wired and Forbes. But, why wait around for a journalist to break the story when you can do it yourself? The Wiki Scanner site is a wonderful tool for amateur sleuths such as myself. Wanna see which companies made changes to Wikipedia entries? Here's just one example: Edelman PR made a change to the Wikipedia for Celecoxib (Celebrex) and for Viagra.

I'm far too short on time to continue this exercise, but I encourage all of you to hit the Wiki Scanner site and see what you can find.

Quellin' in the Joint

I'm never sure how Ed at Pharmalot is able to keep up on literally everything drug-industry related, such as the recent story regarding the use of psychotropic medications in Vermont prisons. The latest story that I picked up from his site included estimates of 40 and 46 percent of the Vermont prison population being on some form of psychotropic medication. If either of those are close to correct, then I'm pretty sure we have a problem. In one Vermont prison, 20% of inmates were on Seroquel.

Perhaps that is not surprising in light of earlier research that Seroquel (or "Quell" as it is known in some correctional circles) is crushed and snorted in prisons and that some folks find it quite difficult to stop taking the medication. There have been other case reports indicating difficulties in patients discontinuing the Quell (1, 2 ). It was also reported (though it is unclear to what extent this is true) that some inmates request Seroquel because it gives them "a buzz."

And I thought Seroquel was just another "safe, gentle psychotropic..."

Seroquel for Everything: Off-Label Marketing?

Peter Rost has a trio of documents on his site regarding potential off-label marketing of Seroquel. As you may recall, I promised to track the Seroquel lawsuit saga that I am fairly certain will continue to unfold. Why the lawsuits? Partially due to allegations of off-label marketing. The latest chapter, from Rost's site, is that AZ appears to have sent out a letter to sales representatives asking them to inform doctors about "medical education" events. As you probably know by now, "medical education" is quite often drug company-speak for "advertising." (1, 2, 3 ).

These "medical education" events were available via VHS, DVD, or webcast for doctors to view at their convenience. One event discussed Seroquel use in the young and the elderly, while another focused on Seroquel for bipolar depression prior to Seroquel receiving FDA approval for such an indication. Is that naughty? Yes. Is it illegal off-label marketing? I'm no lawyer, but I bet not.

Why? Well, the medical education was not provided by AZ. No, it was provided through a third party (i3 CME ), which was "supported" by AZ. i3 CME then found some key opinion leaders to provide "education" to their physician peers. The marketing message is laundered through i3 CME so that AZ can say, "We weren't marketing anything off-label -- we're not responsible for what i3 CME did with the program -- i3 CME is independent!"

Yeah, right. Should i3 CME wish to stay in business, they're going to make sure to get pro-AZ speakers and design a program that paints Seroquel in a good light. My favorite part is this snippet from the letter from the AZ CME director to sales reps.

AstraZeneca supported an independent educational activity on October 8, 2006 in the areas of "psychosis and dementia."

So if AZ supported an "independent" educational activity, doesn't that make the activity, um, not independent? Give me a break. For more on the Seroquel for everything saga, please read prior posts here and here.

Antipsychotics for Kids Update

I posted hastily earlier regarding a story in the Edmonton Journal on a survey of Canadian child psychiatrists. The article previously cited was based on a paper in the June issue of the Canadian Journal of Psychiatry. This survey investigated the frequency of prescription of newer antipsychotic medications for patients under 18 years of age.

As part of the survey, psychiatrists were asked for which disorders they prescribed atypical antipsychotic medications. Among those who prescribed atypicals (Risperdal, Zyprexa, Seroquel, etc.), here's the percentage who reported prescribing them for various conditions

• 81.8% bipolar (Go Team Biederman?)
• 30% depression
• 25.9% eating disorders
  
• 51.2% ADHD
• 74.7% poor frustration tolerance
• 35.9% insomnia
• 89.4% pervasive developmental disorder
• 51.2% oppositional defiant disorder
• 59.4% conduct disorder

The list goes on, but the above interested me the most. Apparently, the child bipolar paradigm is winning favor in Canada (as it obviously is here in the U.S.), and there are a variety of (how do I say this nicely?) not well-supported prescribing practices occurring. I'd add a rant, but the numbers speak for themselves. It's not clear precisely how often the medications are being prescribed, but it is clear they are fairly common. The survey further noted that 12% of these prescriptions were for children under age nine. Read the full-text of the study here.

Subthreshold Bipolar: Media Blitz and Lilly

I posted in lengthy form yesterday about the newly legitimated "subthreshold" bipolar disorder (hereafter referred to as SBD) that 2.4% of Americans allegedly will develop during their lifetime. The press releases and "news" stories have predictably followed. Let's start with something called Medical Condition News. Prepare for some bad journalism...

The headline reads as follows: "4 percent of US adults have some form of bipolar disorder"

Sure, a newly minted disorder (SBD) that actually appears nowhere in the official diagnostic manual accounts for most of that, but whatever.

Here's how the news piece characterized SBD:

...a milder, sub-threshold bipolar disorder that involves hypomania with or without depression, otherwise classified as bipolar disorder "not otherwise specified" in the current diagnostic nomenclature of the American Psychiatric Association.

Except that SBD did not require hypomania -- SBD actually required more like half of hypomania. Note to journalists: Read the article, then write on it.

How about treatment? Here's what the article said:

However, over the previous 12 months, only 25 percent of those with bipolar disorder I, 15.4 percent with bipolar disorder II and 8.1 percent with sub-threshold bipolar disorder received appropriate medication

Remember, there is scant if any research on what appropriate medication is for bipolar II and there is not a damn bit of research attesting to medication for SBD. Remember, the article said that appropriate medication included mood stabilizers, antipsychotics, and lithium. Who cares that this is just pulled out of a hat?

Article 2
This one has appeared on a few different sites. Duck and cover.

However, only a few [who current were in an "episode"] received appropriate medication (25.0% for bipolar I, 15.4% for bipolar II, and 8.1% for subthreshold bipolar disorder). Appropriate maintenance medication for currently asymptomatic patients was even lower (17.9%, 15.6%, and 3.2%, respectively).

Again, this is suggesting that there is an appropriate medication treatment for bipolar II and SBD, when the data just ain't there. If the mainstream press jumps on this, this could be a big problem.

The Zyprexa Connection
The rich irony of this is that Lilly has been shamed by the disclosure of internal documents (like this one) showing that it pimped Zyprexa to primary care doctors for a condition similar to SBD. Apparently Lilly was just ahead of their time. Lilly must be shaking their heads -- they get negative media coverage while researchers have now just sneakily endorsed the treatment of watered-down bipolar disorder with... drugs like Zyprexa. Please read my earlier post to see how this all ties together. There was no science behind the treatment for faux bipolar when Lilly was offering it, and there is still no science behind it today.

Subthreshold Bipolar: The Giant Sucking Sound

Just how many people have bipolar disorder AND what is the deal with “subthreshold” bipolar disorder? Research in the latest Archives of General Psychiatry attempts to answer just these questions. There is some strange stuff going on in this article. Suffice to say that if you hear a giant sucking sound – it is the sound of people with bipolar II and (worse) subthreshold bipolar disorder being sucked into long-term treatment with medications that lack evidence for their conditions. Warning: This is a long post. Read on…

Regarding prevalence of bipolar disorder in the US, the authors concluded that bipolar I has a one percent lifetime prevalence while bipolar II has a 1.1% lifetime prevalence. But 2.4% of people develop, at some point in their lives, “subthreshold bipolar disorder.” I don’t have major issues with how they assessed for bipolar I or bipolar II, but what, exactly, is the deal with subthreshold BP?

Well, here is their definition. To qualify for subthreshold BP, you must have had the following symptoms more than once:

A. A distinct period of persistently elevated, expansive, or irritable mood, lasting throughout at least 4 days, that is clearly different from the usual non depressed mood.

B. During the period of mood disturbance, two (or more) of the following symptoms have persisted and have been present to a significant degree:

(1) inflated self-esteem or grandiosity
(2) decreased need for sleep (e.g., feels rested after only 3 hours of sleep)
(3) more talkative than usual or pressure to keep talking
(4) flight of ideas or subjective experience that thoughts are racing
(5) distractibility (i.e., attention too easily drawn to unimportant or irrelevant
external stimuli)
(6) increase in goal-directed activity (either socially, at work or school, or
sexually) or psychomotor agitation
(7) excessive involvement in pleasurable activities that have a high potential for
painful consequences (e.g., the person engages in unrestrained buying sprees,
sexual indiscretions, or foolish business investments)

C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic.

D. The disturbance in mood and the change in functioning are observable by others.

Let’s play mix and match with these criteria.

So, if you have twice or more had a time when your mood was persistently irritable or high (A) and you didn’t need much sleep (2) and you felt pretty full of yourself (1), then you, my friend, qualify for subthreshold BPD. Or, if you, on a few occasions, were full of energy (A) and feeling much better than average (A) for, say a week, and your self-esteem was notably increased as well (1) and you got much more than usual accomplished (6) – then you also have subthreshold BPD. Let’s not forget that the second author has been saying for years that we exist on a “bipolar spectrum” with many cases of “soft bipolar” (subthreshold bipolar) being missed by unwary clinicians. Maybe he's right, but this type of definition does not give me the impression that "soft bipolar" is a big time problem.

Feel free to play more mix and match in the comment section of this post. I’m sure that most people diagnosed with subthreshold bipolar were more severely impaired than this, but these criteria are clearly too loose.

Oh, and when one goes to the comment section of the article (page 547), the authors state that their “prevalence estimate of subthreshold BPD is likely to underestimate bipolar spectrum disorder in the population”. Huh? That’s because their “definition of subthreshold BPD is still more restrictive than the definitions proposed by clinical researchers.” Oh, okay then. Because some researchers are willing to play even looser with their criteria, then we should just accept that there are a lot more people out there who have this so-called disorder.

The authors also looked at “severity of role impairment.” This analysis was based on people who had recently suffered from bipolar or subthreshold BPD. They found that among people with subthreshold BPD, 46% has “severe” role impairment, and 42% had “moderate” role impairment due to their “subthreshold mania”. Role impairment was defined as participants’ highest score of their impairment across four domains: home management, work, social life, and personal relationships. So if a participant scored no or mild impairment in three of four areas, but scored moderate on one area, then the person was counted as having moderate impairment. That’s what I call rounding up! I’d also like to see other some sort of other measure used besides this quickie disability scale. What were the real-life consequences associated with their subthreshold hypomania? That question remained unaddressed.

One other thing. On page 546, the authors state that the average number of “episodes” – either manic, depressive, hypomanic, or subthreshold hypomanic was 77.6 for those diagnosed with bipolar I, 63.6 for those diagnosed with bipolar II, and 31.8 for those diagnosed with subthreshold BPD. It strikes me that these numbers may as well have been pulled out of a hat. How the hell could somebody recall, in their life, how many “episodes” they’ve had and say, “Oh, geez, I think maybe 87.” I could be wrong, but I ain’t buying these figures.

Treatment: Warning – this is both sneaky and scary. The article goes on to essentially say that psychiatrists are much more apt to provide appropriate medical treatment for bipolar disorder than are non-psychiatrist physicians. It mentioned that those who had experienced “subthreshold” bipolar in the last year only received appropriate treatment 8.1% of the time. Earlier in the paper, appropriate treatment was defined as treatment with mood stabilizers (e.g., lithium), anticonvulsants (e.g., Depakote) and antipsychotics (e.g., Zyprexa, Seroquel, Risperdal). Rant on this to come in next paragraph -- it gets worse.

Now pay close attention. Only 3.2% of people who had a subthreshold diagnosis during their lifetime, but had not experienced an episode during the past year received “appropriate medication maintenance” treatment. WHAT?? Back up. There is scant, if any, data, saying that people with this newfangled diagnosis of “subthreshold” bipolar benefit from short-term treatment and there is not a *blanking* shred of evidence to say that people with “subthreshold” bipolar benefit from treatment with antipsychotics, mood stabilizers, or lithium in the long-term. How the hell did this section sneak through peer review? So it is now officially “appropriate” for people to receive Zyprexa or Seroquel for their “subthreshold” bipolar disorder in the long-term, even when they are experiencing no symptoms? Incredible. The paper also implies that people with bipolar II should receive constant treatment – again, where is the data to support such a recommendation. The long-term data on bipolar I treatment is also not great, but it dwarfs the data on bipolar II and “subthreshold” BP.

Funded By: The study was funded by various government agencies, the Robert Wood Johnson Foundation, and the John W Alden Trust. “Preparation of [the] article was supported by AstraZeneca.” As my astute readers know, AstraZeneca makes Seroquel, which is one of the “appropriate” treatments in this study. How does a company support the preparation of an article? Does this mean it was ghostwritten? I’m not accusing; I am just curious how a company would help to prepare an article? It would, after all, be to AZ’s benefit to suggest Seroquel was appropriate for people with “subthreshold” bipolar. Maybe I’m being too conspiratorial?

As I write this, I am thinking that I must have misinterpreted the article – there’s no way that the authors would endorse short-term and “maintenance” treatment for bipolar II and “subthreshold” bipolar given the lack of evidence. Please let me know if I misinterpreted something – I would really like to be wrong!

Hat Tip: Furious Seasons.