"Current Psychiatry": Now Binging on Industry Cash for CME

Current Psychiatry is a controlled circulation "throwaway" journal that comes to all psychiatrists free of charge. It's well-written, often useful, but editorially it has unfortunately become a mouthpiece for the promotional aims of its advertisers. Recently a few examples attracted my attention. 

1. This CME Supplement was packaged with the November 2010 issue. It is called “Effective Strategies for Patients With Complex Depression in Psychiatric Practice." It's supported by AstraZeneca, maker of Seroquel, and the supplement's three articles are well-masked ads for the use of Seroquel in treatment-resistant depression. There are lots of subtle promotional strategies here, but check out especially pages 10 and 11. Here, you find a paragraph on atypicals pretending that they all have the same side effects (the crucially hidden point is that Seroquel causes more weight gain and sedation than most other atypicals). On the next page, they are no longer shy about delineating side effects of specific drugs--each of which is a competitor of Seroquel. File under: "Sin of Omission".

2. Another promotional CME Supplement was published in October 2010, and is entitled  "Differential Diagnosis and Therapeutic Management of Schizoaffective Disorder." It is supported by Janssen, the maker of Invega, which was recently the first medication FDA approved for--you guessed it--schizoaffective disorder. I haven't read it yet, but this is a de facto  advertisement simply by virtue of the choice of topic. Janssen makes the only approved product for schizoaffective disorder, and in order to advertise it, they paid off Current Psychiatry to write a huge article about the disorder. It doesn't need to be "biased;" it just needs to be focused on a topic that is of inherent commercial benefit to the supporter. In my opinion, this violates the ACCME Standards of Commercial Support. 

3. Finally, in the current issue, there is this article (not a CME article) introducing Lurasidone (Latuda), the latest FDA approved antipsychotic. The authors have no disclosures, which is surprising, because the article is a glowing endorsement of Latuda. The relentlessly advertorial flavor begins with the opening tag-line ("A new atypical antipsychotic offers once-daily dosing and is well tolerated and considered weight neutral") and reaches a fever pitch at "Table 2", which claims that Latuda stimulates certain brain receptors (true) and therefore improves cognition (false).

I don't know what's going on with Current Psychiatry lately. Each of its CME supplements (and even some of its non-CME articles) are so commercially biased that it would take an army of Carlat clones to keep up with lodging formal complaints with ACCME. Anyone up to the task?  

Was the CAFE study manipulated by AstraZeneca? Maybe Not.

In Monday's post, I summarized Carl Elliott's recent article in Mother Jones, in which he argues that Dan Markingson's suicide may have been related to the fact that he was enrolled in an AstraZeneca study comparing AZ's Seroquel with two other medications. Like most clinical trials, this study put limits on what medications doctors could give their study patients. These limits are required to discover how effective a drug is for a particular condition. Otherwise, patients in research studies might be taking all kinds of miscellaneous treatments, and you wouldn't know if their improvements were due to the study drug or something else.

The crucial question here is whether this study, called the CAFE trial, was, in fact, designed to answer a valid scientific question, such as: Which of three antipsychotics is most effective? Or was it a rigged study, designed to ensure that Seroquel would look good compared to Zyprexa and Risperdal, purely in order to drive sales? It would obviously be unethical to recruit seriously ill patients into a bogus trial if it was concocted as a marketing strategy.

As Dr. Barney Carroll mentioned in a response to Monday's post, the interesting thing about the CAFE trial is that several of the major investigators were also involved in the CATIE trial. The CATIE trial was of a similar design and involved schizophrenic patients who were randomly assigned to double blind treatment with different antipsychotics. But the CATIE trial was funded by the NIMH rather than by any particular drug company. Therefore, we assume that design decisions were made relatively free of drug company input.

The results of the NIMH-funded CATIE trial were different from the AZ-funded CAFE trial--quite different. The main outcome measure for both studies was the percentage of patients who discontinued the drug. In the CAFE trial, the 12-month discontinuation rates for Zyprexa, Seroquel, and Risperdal were 68.4%, 70.9%, and 71.4%, respectively. In the CATIE trial, the18-month discontinuation rates (the 12-month rates were not reported) were 64%, 74%, and 82% for the same three drugs (two other drugs were also tested in CATIE). In the CATIE trial Zyprexa did much better than Seroquel, but it did not do better in CAFE--which seems odd considering both studies used the same methodology.

What's the explanation here? It could be simply be a statistical variation in outcomes. Perhaps CATIE's results were wrong, and perhaps CAFE's are right. After all, this is exactly why it's important to replicate a research finding. If a finding is replicated, we are much more confident in the truth of the original results.

In this case, however, the divergent results appear more likely due to the fact that in CAFE, Zyprexa and Risperdal were dosed much lower than in CATIE. Look at the table below. Zyprexa was dosed 42% lower in CAFE, Risperdal was dosed 38% lower, while Seroquel was nearly the same in the two--only 7% lower in CAFE. Thus, on the face of it, it seems clear that the CAFE study found Seroquel to be as good as Zyprexa and Risperdal because the design ensured that Seroquel would be dosed much higher than Zyprexa and Risperdal.

Drug	AZ-funded CAFE dose	NIMH-funded CATIE dose
Zyprexa	11.7 mg	20.1 mg
Risperdal	2.4 mg	3.9 mg
Seroquel	506 mg	543 mg

But why did this happen? Was this a design manipulation ordered by AstraZeneca marketing staff in order to make sure the results were to their liking? Or was it simply a research decision made with pure motives by the scientists who ran the trial? The answer to this question makes a difference. In fact, you could argue that it makes all the difference.

This post would have ended here if I hadn't emailed these questions to the researchers who designed the CAFE study, including Dr. Joseph McEvoy, Dr. Jeffrey Lieberman, and Dr. Diana Perkins. All three of them were also involved in the CATIE trial. They reminded me of a crucial difference in the two trials, aside from the fact that one was funded by government and the other by Astra Zeneca.

The CAFE study, as should have been obvious to me by the full name ("Comparison of Atypicals in First Episode of Psychosis"), was designed with newly diagnosed patients in mind. Typically, patients with a first episode of psychosis are treated more conservatively, with lower doses of antipsychotics, as opposed to the chronic schizophrenics enrolled in the CATIE trial. So this explains why Risperdal and Zyprexa were dosed lower in CAFE than in the CATIE.

So why, you might ask, wasn't Seroquel also dosed lower? According to Dr. McEvoy, who was the co-principal investigator on both CAFE and CATIE, at that time there were no studies guiding them on Seroquel dosing in first episode patients. "Back then," he wrote me, "many argued that higher doses were needed for optimal efficacy and there was not a side effect ceiling such as risperidone has." Eventually, a study was published showing that the average Seroquel dose needed for first episode psychosis is only 268 mg/day

Dr. Lieberman, who is chair of psychiatry at Columbia University, emailed me that "Although your inferences re dosing are understandable they are entirely incorrect. The CAFE study was wholly investigator initiated and we determined the doses for each drug. There was a clear rationale for the higher quetiapine dose relative to the other drugs which I am happy to explain to you. This study design in no way was influenced adversely by industry influence."

So there you have it. If you can believe these researchers, this may have been an example of an AstraZeneca funded study without undue commercial influence. I think they are believable, and I know that Dr. Lieberman in particular has been quoted regularly in the media recently about various new drugs, and has been appropriately skeptical about their benefits over older agents.

Of course, there are other ways in which CAFE might have been rigged, which are detailed in Carl Elliott's Mother Jones article. I've asked the investigators about these allegations and will let you know if I get a response.

"Making a Killing": New Carl Elliott Article in Mother Jones

There's a fascinating article by Carl Elliott in the current issue of Mother Jones. It's called "Making a Killing," and it shows how clinical trials have become marketing exercises for the pharmaceutical industry, sometimes at the expense of patients' lives. (You can read the article here, but you will need to complete a free registrations process).

The focus is on Astra Zeneca, maker of the antipsychotic Seroquel. Elliott tells the tragic story of Dan Markingson, a young man with schizophrenia who killed himself in a particularly gruesome way in May of 2004. At the time, Markingson was enrolled in an Astra Zeneca-funded study called the CAFE study. The acronym CAFE stands for "Comparison of Atypicals in First Episode of Psychosis." As the name implies, this study randomly assigned patients to three possible antipsychotics: Seroquel, Risperdal, and Zyprexa. The bottom line result, according the abstract in the American Journal of Psychiatry, was that the three drugs were equally effective.

However, Elliott makes the case that the study was rigged in various ways by the Astra Zeneca marketers to ensure that Seroquel would, at the least, not look any worse than its competitors. While this devious tactic may not be much of a news flash, Elliott is claiming that something more insidious happened--namely, that Dan Markingson was pressured to put his life on the line for a drug company's profits.

Elliott acknowledges that there are risks in any clinical study. When the study is trying to answer a significant scientific questions, these risks may be reasonable. But when the study is designed to boost sales of a drug, these risks are very hard to defend.

As Elliott puts it: "It is one thing to ask people to take risks for science, or the common good, or to help other people. It is another thing entirely to ask them to risk their lives for the marketing goals of AstraZeneca."

I had read the CAFE study before, but as I was preparing this post, I noticed aspects of the design that had not struck me in the past. The study may well have been manipulated in order to make Seroquel look good. In my next post I will delve into the specifics, so stay tuned.

CME Outfitters: Guilty of Pro-Seroquel Bias, According to ACCME

In ACCME's testimony before the Senate Special Committee on Aging on July 29 of this year, Dr. Murray Kopelow, the chief executive of ACCME, defended the integrity of the embattled organization in part by pointing out that they have beefed up their enforcement of anti-commercial bias policies.

He said that he has begun to give extra "scrutiny" to organizations that "receive a large amount of commercial support," and said that 10% of all ACCME providers are now on probation. But how well does ACCME actually regulate the bad apples of CME--generally speaking, those for profit MECCs who are completely dependent on commercial support for their very existence and who consistently bend the Standards of Commercial Support in order to maintain the flow of money?

In a fascinating post by Bernard Carroll on Health Care Renewal, we get a close-up view of ACCME's new commitment to enforcement, which while showing some signs of life is severely lacking in bite.

Dr. Carroll had filed a formal complaint on December 23, 2008 about a web-based round-table discussion of the use of antipsychotics in depression, which was chaired by Charles Nemeroff (the disgraced psychiatrist who resigned under pressure as chair of psychiatry at Emory after the New York Times reported that he lied to the University about payments from GlaxoSmithKline, promising officials that he would limit his earnings to the required $10,000/year from promotional talks, then going on to earn $170,000 that year alone.)

Nemeroff's program was produced by CME Outfitters and was funded by Astra Zeneca, maker of Seroquel, an antipsychotic which was recently approved for add-on treatment of depression. After its investigation, according to Dr. Carroll, the ACCME determined that the program did, indeed, violate its standards. In particular, the course was commercially biased in favor of the sponsor's treatment because it downplayed negative side effects of Seroquel while giving short shrift to alternative, safer depression treatments.

So far, so good. The monitoring system appears to be working. Or is it?

Dr. Carroll asks a series of questions that will prod ACCME to think about the logical next step.

--If this accredited CME program was corrupted by commercial bias, shouldn't the ACCME force CME Outfitters to contact all the physicians who participated in the course in order to explain to them that they were given biased medical information?

--Shouldn't the CME credit obtained through this program be revoked?

--Shouldn't CME Outfitters be required to ascertain whether patients were harmed as a result of their biased education (for example, how many patients were put on Seroquel for depression and later developed obesity, diabetes, or heart disease as a result?).

--Will ACCME publically list its sanctions against CME Outfitters and other MECCs who have aired commercially biased CME? Or are we going to have to depend on the occasional blogger to reveal these egregious cases?

These are all crucial questions, and Dr. Carroll is awaiting a reply. Aren't we all?

AstraZeneca Behaving Badly. Very, Very Badly.

Many bad things have been reported lately about Astra Zeneca’s efforts to bury negative data about Seroquel. This revolting story of data manipulation, deceit, and academics selling their opinions to the highest bidder is being covered widely. See these excellent stories in the Washington Post, the Minneapolis St. Paul Star Tribune, The St. Paul Pioneer Press, as well as incisive blogging at Clin Psych and BNET.

These days, we hear so much about drug companies behaving badly that “accusation fatigue” sets in. We’re tempted to throw up our hands and say, “All the drug companies do this, what else is new?”

Resist the temptation. Yes, Eli Lilly's behavior was wretched, and it recently pled guilty to off-label marketing of Zyprexa for treating agitation in dementia.

But AstraZeneca has truly grabbed the brass ring of subterfuge. The Seroquel documents are revealing a company-wide pattern of blatant deceit and manipulation that is astonishing, and should make any psychiatrist think twice before believing anything Astra Zeneca has to say about Seroquel, either in the past, the present, or the future.

I'll contribute to the discussion by adding yet another data point to the mix. Here is an AstraZeneca-supported CME article which appeared as a supplement to Current Psychiatry. The title is “Issues associated with the use of atypical antipsychotic medications,” and it is dated December 2008. The identified authors are Henry A. Nasrallah, Donald W. Black, Joseph F. Goldberg,
David J. Muzina, Stephen F. Pariser, but presumably the text was written by ghost-writers at Dowden media.

Ultimately, you can most accurately think of the author as being AstraZeneca itself.
The article begins by trying to distract attention from the metabolic side effects of Seroquel by blaming the patients rather than the drug:

While the incidence of both obesity and diabetes is soaring among the general population, these conditions are more prevalent in patients with schizophrenia, even those who have no history of antipsychotic drug use.7 Prevalence rates for both diabetes and obesity are approximately 1.5 to 2 times higher in people with schizophrenia and other affective disorders than in the general population.4… Thus, it is difficult to predict which patients will be affected and the precise role drug treatment might play in this process.

The argument here is that these patients get fat because there are schizophrenic, not because they use Seroquel or similar obesity-promoting drugs.

Of course, AZ is forced to reference the well-known official statement co-published by the American Diabetic Association and the American Psychiatric Association which implicated Seroquel and other atypicals as causing weight gain and diabetes:

The ADA/APA statement ranked clozapine and olanzapine as being associated with the greatest risk of weight gain, diabetes, and dyslipidemia.4 Risperidone and quetiapine were put into an intermediate risk category for weight gain, while aripiprazole and ziprasidone were, at the time, too new to categorize. More recent data have shown ziprasidone and aripiprazole to be relatively weight-neutral.8

But check out how they go on to back-track, creating an alternative reality in which people are supposedly questioning this data:

However, the consensus statement must be interpreted with caution. Criticism has been leveled at the report from many corners, including the Division of Neuropharmacological Drug Products of the FDA, which argued that insufficient data were available to appropriately “rank” obesity/diabetes risks for the atypical antipsychotic agents.18

The criticism they are referring to was a one page letter from the FDA, but it had nothing to do with weight gain. The letter cautioned that actual data connecting the atypicals to diabetes was minimal, and that more studies needed to be done to better characterize the relative ranking of each drug in terms of the potential to cause diabetes. But the FDA officials were clear that some drugs cause more weight gain than others: “The ADA correctly points out that SGAs have different weight gain liabilities.” Obesity, of course, is one of the main risk factors for diabetes—so you do the math.

Finally, the authors return to their main theme—insulting schizophrenics:

Other authors pointed out that efficacy considerations of these drugs are a critical and overlooked component of the discussion and that the data used to compare the agents did not adequately control for key lifestyle factors such as overreliance on “junk food.”19,20

That’s right—the problem isn’t Seroquel; the problem is that crazy people are junk food junkies!

Here is my modest proposal. Because of these documents, Astra Zeneca’s credibility is officially out the window. They should not be allowed to be involved in any medical education event. They should be banned from hiring promotional speakers and from supporting CME. AstraZeneca has lied to the medical community once too often.

The Seroquel Deception Documents

As I covered in my last post, AstraZeneca is in the midst of a Disney World sized headache in Orlando, where a federal judge is sifting through various allegations regarding the safety risks of the antipsychotic Seroquel. That headache has now become a blinding migraine, because the judge ordered many of the disclosure documents unsealed, and as predicted, we all now have a front-row seat at data manipulation at its finest.

There's too much to comment on so I'm happy to report that the extremely clever anonymous blogger at Clinical Psychology and Psychiatry has already done much of the heavy lifting for us. You must immediately go to this post to see how the pharmaceutical industry actually works.

Apparently, back in 2000, the marketing and scientific honchos at AZ knew about the results of an internal meta-analysis showing that Seroquel is less effective than both Risperdal and that ancient antipsychotic Haldol. Rather than alerting physicians to this critical piece of data, they had one of their hired guns issue the following statement in a press release: "Almost 50 years later, however, many patients are still taking these medications [such as Haldol], even though more effective treatments like Seroquel exist."

Yes, this is one of those nausea moments, for physicians, for the unsuspecting public, and especially for AZ investors, who are watching their stock's inexorable tumble down, down, down.

Of Seroquel, Sex, and Secret Documents

Seroquel (generic name, quetiapine) is an atypical antipsychotic that made a tidy $4.4 billion for AstraZeneca last year. Seroquel’s golden goose status is based on a string of FDA approvals for schizophrenia, mania in bipolar disorder, and more recently, depression in bipolar disorder. In addition, it is commonly used off-label for insomnia, and the company is applying for FDA approval for the treatment of generalized anxiety disorder.

The drug’s approval for bipolar depression was particularly valuable, because it opened the door to off-label use in garden variety, unipolar depression—a much bigger market than bipolar depression. The problem is that the “BOLDER” studies, which formed the basis for FDA approval, had a glaring weakness. The patients who were enrolled were very different from the patients we see in clinical practice. The BOLDER studies excluded patients with:

--Current depression lasing longer than 12 months
--Substance use within 12 months
--Any other recently treated psychiatric disorders
--Suicidal ideation

In addition, any patients who had tried and not responded to two previous trials of antidepressants were not eligible for the study. This restriction is especially problematic, because by the time most real patients get the diagnosis of bipolar depression, they have already been on many rounds of antidepressants.

Thus, Seroquel is approved for a very special and unusual kind of depressed bipolar patient—someone who is who is unlikely to be seen by practicing psychiatrists. The patients I see are sicker and much more complex; prescribing Seroquel for them may or may not make them better, but is all but certain to cause significant weight gain, rendering them more vulnerable to heart disease and diabetes.

Which is all a very long-winded introduction to the latest scandal-in-the-making from AstraZeneca. As covered in BusinessWeek, and the Furious Seasons blog, AstraZeneca is being sued by thousands of patients who allege that the company hid information about Seroquel’s risk of weight gain and diabetes. 6,000 claims have been consolidated into a single case before a federal court in Orlando Florida.

Reams of documents have been shipped in by AstraZeneca related to the case, but none have been disclosed yet, because no actual trial has commenced. It is possible that in order to avoid disclosure of embarrassing documents, the company will settle the case and prevent a trial. But the news agency Bloomberg has filed a motion to force these documents to be unsealed, citing “the public's right of access to judicial documents."

Presumably, these documents will be just as damaging as the leaked Zyprexa documents which showed that Lilly’s “Viva Zyprexa” campaign deliberately encouraged primary care doctors to prescribe Zyprexa for unapproved uses.

Maybe more damaging, actually, because at least the Lilly documents did not involve a senior company scientist having sex with a company funded researcher and a ghostwriter. That’s right, folks—according to one publically available court document, the company’s lead research director, Wayne Macfadden, was getting awfully busy with women who did Seroquel research and wrote up the BOLDER results.

The document alleges that Macfadden's relationships with the women were "relevant and highly probative evidence of one high level AstraZeneca employee's determination to exploit his sexual relationships with these women in order to elevate Seroquel's status in the prescribing medical community through supposedly 'independent' publications of Seroquel safety and efficacy data….Moreover, the mere existence of these relationships calls into question the integrity of the scientific work product of those involved."

We don’t know if all these allegations are true, although Macfadden has already admitted to the dalliances.

At this point, AstraZeneca needs to do the right thing, which is to unseal the secret documents. Only then will the company be able to clear its name.

Current Psychiatry CME: Looks like an Ad, Smells like an Ad...Yep, It's an Ad

In Dr. Goldberg’s response to my “Guess the CME Sponsor” parlor game, he is defending the accuracy and balance of his article. However, I never questioned the accuracy of the Current Psychiatry supplement.

The supplement is both accurate and is a veiled advertisement for the use of Seroquel in the treatment of bipolar depression.

Commercial bias and accuracy of content make excellent bedfellows, because accurate and academic presentations of material give the articles exactly the aura of legitimacy that the sponsor is purchasing.

The Current Psychiatry supplement was entitled “Diagnosing and Managing Psychotic and Mood Disorders,” which is an extremely broad topic. There are hundreds of approaches one might use in covering the topic.

For example, one could focus specifically on depression with psychotic features, in which you’d emphasize the overall superiority of ECT, while also covering a variety of combinations of antidepressants and antipsychotics.

You could focus on treating mood problems as they arise in schizophrenia, most commonly depression and suicidal ideation. Such an article (here is one example) would focus primarily on antidepressants.

You could focus on treating psychosis in patients with risk factors for cardiovascular disease, in which case you would talk about Abilify over and over again, as happened in this recent CME supplement sponsored by Bristol-Myers Squibb, and published by the Journal of Clinical Psychiatry.

You could focus on the treatment of acute mania, in which case you’d pretty much have to give equal airtime to all the atypicals and the mood stabilizers.

But, in 3 of the 4 cases presented, Dr. Goldberg and colleagues chose to focus their attention on the treatment of acute bipolar depression. It just so happens that Seroquel is one of two treatments FDA-approved for bipolar depression. It just so happens that AstraZeneca funded the supplement.

Of course, the “it just so happens” part is the core of the problem. There was nothing random about it. The authors knew exactly who was funding the supplement, and they chose to highlight the advantages of Seroquel because of this.

If you take great care in choosing the topic, you can always find one that will inevitably highlight the sponsor’s product. This is fine, as long as it is clear to the readers that it is a promotional activity. For example, on the Seroquel.com website, there is plenty of accurate information about the advantages of Seroquel for bipolar disorder, including a case study similar to the cases presented in this supplement. This is an excellent source of information for those interested in learning about patients for whom Seroquel is helpful. But it’s an advertisement, festooned with Seroquel logos. It is transparent, and it is honest.

The Current Psychiatry supplement is neither transparent nor honest, because it holds itself out as being accredited Category 1 CME. ACCME criteria are explicit that accredited CME cannot be crafted in order to endorse the sponsor’s product. Specifically, this supplement violates Standard 5.1 of the ACCME’s Standards for Commercial Support, which states: “The content or format of a CME activity or its related materials must promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.”

This is the point in the debate where defenders of commercial CME will argue that this not conflict of interest, but rather “convergence” of interests. AstraZeneca gains by showcasing Seroquel, and the physicians gain by learning about a good treatment. But this is called advertisement and promotion, not CME. If the Current Psychiatry supplement had been preceded by the statement, "The following is a product advertisement funded by AstraZeneca," there would be no controversy about it at all.

Getting the ACCME seal of approval is supposed to mean something. It means that the educators have one single agenda in mind: helping physicians sort through the complexities of diagnosis and treatment in order to do the right thing by their patients. The Current Psychiatry supplement, however, was written with two agendas: educating practitioners and selling Seroquel.

Dr. Joseph Goldberg Responds to our Critique of Current Psychiatry CME Supplement

Note: I just received this e-mail from Dr. Joseph Goldberg, in response to our recent critique of this AstraZeneca funded supplement of the journal Current Psychiatry. With Dr. Goldberg's permission, I am printing his letter below in its entirety. I'll comment on it when I get a chance, most likely early next week.

Dear Dr. Carlat,

Your distillation of our comments in the case presentations of our recent Current Psychiatry supplement implies that the authors' goal was to motivate clinicians to diagnose more bipolar disorder and then use a medication manufactured by the sponsor of the CME. For the sake of fair balance to your readers, you might mention our findings published elsewhere that community practitioners fail to utilize DSM-IV criteria when diagnosing bipolar disorder, and consequently over-diagnose it in as many as 2 of 3 patients with mood instability and substance abuse (Goldberg et al., J Clin Psychiatry 69: 1751-1757, 2008); in such over-diagnosed patients, mood stabilizers appear far over-used to the exclusion of rigorous substance abuse treatment. But in patients WITH DSM-IV bipolar disorder, suicide risk is significantly higher, and use of unstudied drugs or medications with negative data may lead to disastrous outcomes.

Part of our goal in these case discussions was to review the differential diagnosis of bipolar disorder. Psychiatric medications work better when the diagnosis is correct, but often fail when it is not. Your comments fail to discuss the importance of correct diagnosis, differential diagnosis, and evidence-based (i.e., well-studied) therapeutics, as expressed in our supplement.

When a diagnosis of bipolar disorder IS correct, unfortunately, few medications have robust effects. In the case of bipolar depression, for example, the controlled trial literature has far more negative than positive studies (e.g., antidepressants + mood stabilizers are no better than mood stabilizers alone [Sachs et al., NEJM 2007; 356: 1711-1722); aripiprazole is no better than placebo (Thase et al., J Clin Psychopharm 2008; 28: 13-20); lamotrigine has 4 negative placebo-controlled studies (Calabrese et al., Bipolar Disord 2008; 10: 3; 10: 323-333)). For better or worse, quetiapine and Symbiax are the only psychotropics that have demonstrated efficacy for acute bipolar depression. The academic community would greatly welcome CME-sponsorship by more organizations, but most studied agents are now either off-patent (e.g., lithium, divalproex, lamotrigine), lack FDA indications due to negative findings (e.g., divalproex for maintenance; oxcarbazepine for acute mania (Wagner et al., Am J Psychiatry 163: 1179-1186, 2006); topiramate for acute mania (Kushner et al., Bipolar Disord 8: 15-27, 2006); or lack any data (e.g., ziprasidone or risperidone for bipolar maintenance). Our case discussion reflects this literature, but yours does not. Readers deserve a more fair-balanced critique of our summary than the one you provide.

-- Joseph Goldberg MD,
Assoc. Clin. Professor of Psychiatry, Mount Sinai School of Medicine;
Deputy Editor, Current Psychiatry

Current Psychiatry: Guess the CME Sponsor!

Yes, it’s time for your favorite game show, Guess the CME Sponsor.

Today, we have a special treat for you, a supplement from Current Psychiatry, entitled “Diagnosing and Managing Psychotic and Mood Disorders.” It is accessible online here.

The rules of this game are simple: No peeking to see which drug company has paid for the preparation of the supplement (so skip page 2).

Let’s start, shall we?

This supplement is composed of four case studies. As we know from past experience, medical education communication companies (MECCs) increasingly use case studies to communicate a marketing message in CME. Medscape did this so blatantly once that BusinessWeek published an article about it.

Both Medscape and Dowden Health Media (publisher of Current Psychiatry) love to use cases because they offer so many avenues for promoting the sponsor’s drug. There are usually three phases of promotion:

Phase 1: The case begins with a patient doing poorly on medications. This “bad” medication regimen is strategically chosen by the MECC to cast competitors in a poor light.

Phase 2: The “faculty” members (most or all of whom are consultants or speakers for the sponsoring drug company) then discuss the case, ostensibly in order to come up with ideas for how to improve the patient’s treatment. Here, the MECC can choose to highlight themes to accentuate advantages of the sponsor’s drug and shortcomings of competitors.

Phase 3: Finally, there is a dramatic denouement, in which the faculty decides on a better medication regimen. Obviously, MECCs will ensure that the rescue regimen incorporates the sponsor’s drug. If they are good at gaming this system, they will try not to make this blatantly obvious. As we’ll see below, Dowden Health Media has a lot to learn about subtlety.


Case 1: Treatment-resistant psychosis and schizophrenia

1. Initial unsuccessful medication regimen: Risperdal Consta, haloperidol decanoate, valproic acid.

2. Faculty discussion:
--Is the patient’s diagnosis of schizophrenia accurate? The faculty decides that the patient may actually have either schizoaffective disorder or bipolar disorder.
--They discuss the bad side effects of first generation antipsychotics, such as EPS.

3. Rescue medications: Start clozapine, stop haloperidol, and increase Risperdal Consta.

Comment: Janssen’s Risperdal Consta jumps out at us, because the rescue regimen involves increasing the dose as well as starting clozapine. However, it would be hard to imagine Janssen being happy about a case in which a patient starts by doing poorly on their medication. The faculty dwells on disadvantages of older antipsychotics, seemingly in order to lay the groundwork for the promotion of one of the atypicals, but at this point, we don’t know which one they will favor. Clozapine is available as a generic, so is not sponsorable. At this point, the only thing we can be fairly certain of is that Janssen is not the sponsor of the supplement.

Case 2: Psychosis with bipolar mania

1. Initial unsuccessful regimen: Risperdal and valproic acid; Risperdal was stopped because it wasn’t working, the patient was switched to Zyprexa, which helped a bit but caused 18 pounds of weight gain in one month.

2. Faculty discussion:
--The patient was initially misdiagnosed with ADHD and depression, but actually had bipolar disorder; initial use of stimulants may have precipitated a manic episode. (The message here is: “Diagnose more bipolar disorder.” This is a common industry CME tactic, in which experts harp on how the diagnosis for which the sponsor makes a drug is often missed. After all, the sponsor can’t make money unless the condition is liberally diagnosed.)
--Zyprexa is bad. To quote Dr. Pariser: “Olanzapine is a very effective atypical antipsychotic, but weight gain is a major concern for many patients receiving this drug as well as clozapine. I have observed that many patients who gain weight tend to go off the medication, and those who do may not always admit that they are nonadherent.”

3. Rescue regimen: Lamictal, topiramate, and an un-named medication that Dr. Goldberg coyly describes in these terms: “another atypical antipsychotic with a somewhat lower risk of metabolic side effects, relative to olanzapine, as well as an indication for treating bipolar depression to help lower the risk of suicide in this high-risk patient.” Which medication might Dr. Goldberg be referring to? Well, there are only two FDA-approved medications for bipolar depression: Symbyax (Zyprexa combined with Prozac), and Seroquel. Since he specifies that the best choice would not be Zyprexa, he must be referring to Seroquel.

Comment: The sponsor sure ain’t Eli Lilly. Any MECC that would take CME money from Lilly and then feature a case in which Zyprexa caused an astonishing 18 pounds of weight gain in one month would never see another dime from Lilly again.

While lamotrigine and topiramate were part of the rescue regimen, they are both generic, so unsponsorable. The rescue antipsychotic was Seroquel, so after two cases, my best guess is that the sponsor is AstraZeneca, maker of Seroquel.

Case 3: Bipolar depression and anxiety

1. Initial unsuccessful regimen: Effexor XR and clonazepam

2. Faculty discussion:
--Patient was misdiagnosed with depression; actually had bipolar disorder and OCD (diagnose more bipolar!)
--It can be difficult treating bipolar disorder when combined with anxiety. But Seroquel may actually be a good choice for both! To quote Dr. Goldberg: “Given data from studies of generalized anxiety disorder and quetiapine’s ability to reduce anxiety symptoms in the context of depression, using this drug alone might be safer than augmenting with sertraline and be just as effective as the combination.”
3. Rescue regimen: Seroquel, lamotrigine, and sertraline.

Comment: Looks like the MECC is pushing Seroquel for anxiety in anticipation of a possible indication for generalized anxiety disorder. Both lamotrigine and sertraline are generic and unsponsorable.


Case 4: Depression and anxiety: Distinguishing unipolar and bipolar disorders

1. Initial unsuccessful regimen: Sertraline, then Effexor XR.

2. Faculty discussion:
--Yet another patient with bipolar disorder misdiagnosed with depression—I guess there’s an epidemic of this. Funny how the faculty neglects to cover the evidence indicating that bipolar disorder may now be over-diagnosed.

3. Rescue regimen: Seroquel and lamotrigine.

Comment: C’mon guys, Seroquel again? Would it kill you to be subtle?

Conclusion

Let’s go through the possible sponsors.

Janssen: No, because Invega was not mentioned, and in one case, Risperdal Consta was ineffective at the starting dose.

Eli Lilly: No, because Zyprexa was never used as a rescue medication, and one of the cases featured the worst example of Zyprexa-induced weight gain that I have heard of.

Pfizer: No, because Geodon is never a used as a rescue medication.

Bristol-Myers Squibb: No, because Abilify is hardly mentioned at all.

My guess is that the sponsor is AstraZeneca, because in three out of the four cases, Seroquel is the linchpin of the rescue regimen.

Now for the fun part. Go back to the supplement, turn to page 2, and you’ll find that the sponsor is………AstraZeneca, maker of Seroquel.

Winners receive a lifetime supply of Seroquel. We are not responsible for fatalities, injuries, or loss of employment due to the sedation and weight gain caused by Seroquel. Employees of AstraZeneca and Dowden Health Media are not eligible for participation in this contest.

Drug-Rep Free Zone

I've had it. As of today, I am no longer allowing drug reps into my office.

Yes, until today, I was seeing reps a few times a month for 5 minute visits in order to keep up on trends in drug company marketing techniques. But today, an Astra Zeneca rep and his district manager came in to push Seroquel for bipolar depression. They came armed with the two studies that won Seroquel its FDA approval. The studies have their limitations, but somehow these reps didn't bring these up.

Instead, what I got was a ridiculous hard sell: "Dr. Carlat, given this data, would you choose Seroquel over the other atypical antipsychotics for bipolar depression?" I asked them if Astra Zeneca had done any head-to-head studies comparing Seroquel with the others. The rep adopted a pseudo-confused look, and said, "I'm not even sure that kind of study would be ethical--would the FDA even allow you to compare an approved drug with an unapproved drug?" I pointed out that the FDA, in fact, requires that drugs be compared with placebo, the ultimate in "unapproved" drugs, and that they deem this ethical enough.

He tried another tack. "What are the symptoms of bipolar depression that you have the hardest time treating?" I said that all the symptoms are hard to treat--that, in fact, bipolar depression is a very difficult illness to treat. Out came his computer, with a slide showing that Seroquel successfully treated every one of the depressive symptoms in one study. "Now doctor, if you had a patient come into your office with suicidal ideation, and you had an agent that would help those symptoms in a week, wouldn't you want to use that agent?"

Of course I would, and there are many other agents that will work better than placebo in a week. But my rep wasn't interested in talking about the alternatives. The focus, as always, was on his product, and on his bonus.

I've printed out the National Physicians Alliance's brochure, "Why Doesn't My Doctor See Drug Reps?" and will put it in my waiting room. I'll let you know how my patients respond. For now, I'm still accepting samples (making me the most despised of doctors among drug reps, a "sample-grabber") but that will be the next to go.