Treatment Guidelines and GSK's Open Disclosure

Last week, I noted that a recently published article had found that studies favoring GSK's "mood stabilizer" Lamictal tended to get published in medical journals while articles reaching less favorable conclusions tended to remained unpublished. I wrote that "GSK worked the system expertly and it paid off." A reader commented that he thought my characterization of GSK as hiding negative data on Lamictal was inaccurate. I appreciate his well-written critical comments, which are linked here and are partially reproduced below:

Acute Depression - All of the acute depression studies (there were 5 not 3 as you reported) were presented at scientific meetings over the years and were recently published in Bipolar Disorders (Calabrese et al. 2008). Why so long to publish? The paper was rejected twice and took 3 years to get accepted because journal reviewers did not find the data of interest.

I responded via comment that, if his history is accurate, then the reviewers should be flogged. He added that GSK had provided negative Lamictal data to numerous authors who wrote review articles on Lamictal. In some cases, this appears to be true. However, in at least one notable case, either GSK failed to provide the data or the authors completely ignored the negative data. The data here appeared in a 2004 "academic highlight" (i.e., lowlight) in the Journal of Clinical Psychiatry. Of relevance, the article was funded by an "unrestricted educational grant" from GSK. The article bashes antidepressant treatment in bipolar as unsupported by evidence. Then the expert panel of authors/key opinion leaders put together their guidelines for treating bipolar disorder.

The article begins by discussing bipolar depression. Lithium is discussed first and receives a positive review. Then comes Lamictal, GSK's mood stabilizer. They discuss, in detail, the positive results from Calabrese et al. The authors then discuss some positive long-term findings for lamotrigine before moving on to olanzapine and olanzapine/fluoxetine. They conclude that lithium and Lamictal have the best evidence for treating bipolar depression as can be seen here:

Category 1 evidence is the best evidence, so hooray for lamotrigine/Lamictal! But what don't they discuss in their "expert" review of the data? How about two negative studies -- SCA40910 (completed in 2002) and SCAB2001 (completed in 1997) -- GSK titles of studies that both showed negative results for Lamictal in treating depression in bipolar disorder. A reader tracked these down and sent them -- you can find them if you head to GSK's clinical trial registry. Given that these "International Consensus Guidelines" were published in February of 2004, you'd think the authors would have included data from both of GSK's unpublished studies unless:
A. They didn't know about their existence (and why would they unless GSK told them)
B. They knew about them but opted to not include them in this "expert review"

Given that a GSK employee has told me how open and honest GSK has been with their data, I'd be interested in seeing his response as to which of the above he believes took place. Keep in mind that the Journal of Clinical Psychiatry, in which this so-called "academic highlight" appeared is a very widely read journal. According to Google Scholar, this piece has been cited 46 times, many of which have doubtlessly recycled the inaccurate claim that Lamictal is an effective treatment for acute bipolar depression.

The same pattern as usual: Company conducts research, selectively publishes positive results, funds "educational" pieces such as "academic highlights" to paint an overly rosy picture of treatment effectiveness and/or safety, and physicians, based upon the "evidence base" delude themselves into thinking that they are writing prescriptions based on the best scientific data.

Lamictal: Break Out the Shovel

GlaxoSmithKline, manufacturer of lamotrigine (Lamictal), the antiepileptic drug used widely for bipolar disorder, happily hid clinical trial results which found Lamictal was no better than a placebo. Given recent findings about how often pharmaceutical companies selectively push positive results to publication in medical journals while suppressing negative results, this can hardly be considered a surprise. It is nonetheless instructive to examine how the published data on Lamictal paint a much rosier picture of the drug's efficacy compared to unpublished data.

Nassir Ghaemi, a psychiatrist at Tufts University Medical Center, dug through GSK's online database of information, and found that several negative Lamictal studies (studies which failed to show a benefit for Lamictal over placebo on the primary outcome measure) were quietly residing on the site. Why did GSK post such information on their site? Not out of the goodness of their hearts; rather, because they were forced to post data about clinical trial outcomes as a result of a legal agreement. Here's what Ghaemi found in GSK's database:

Acute mania: Two studies compared lithium, Lamictal, and placebo. Both found that Lamictal did not beat a placebo. Neither study was published.

Acute bipolar depression: Three studies were conducted. All three showed negative results. Two were not published. On one study, there was a positive result for Lamictal on a secondary outcome measure, and the results of the study were written to emphasize the positive outcomes, as in stating "Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression."

Rapid cycling bipolar: Two studies were completed; both were negative on the primary outcome. However, one study showed favorable outcomes for Lamictal on several secondary measures. The obviously negative study was not published while the study that showed a number of benefits for Lamictal was published.

Prophylaxis (Prevention of future episodes): Two studies were conducted, both of which showed that patients on Lamictal went longer between episodes than did placebo patients. Both studies were published.

Well, I'm shocked, shocked, that GSK would simply bury a slew of negative data on their product. Who woulda thunk it? So what does this mean for Lamictal? Dr. Ghaemi was interviewed by Dr. Daniel Carlat (of Carlat Psychiatry Blog and the Carlat Psychiatry Report). There were many pieces of Ghaemi's interview that were interesting (see February 2008 issue of Carlat Psychiatry report; sorry, no link available), but the most interesting piece was:

Carlat: My understanding is that you wrote up your discovery of the negative Lamictal data and submitted the paper to some journals. What has been the response?

Ghaemi: I first submitted to JAMA because I knews they were sympathetic to this kind of critique. Their reaction was, "We already publish many papers like this; this is old news; there is nothing new here." They recommended that I send it to a psychiatric journal. So then I sent it to the American Journal of Psychiatry, but they rejected it as well, saying that they were doubtful that this type of negative publication bias was common among other companies marketing medications for bipolar disorder.

Carlat: Do you think there is much suppressed negative data about other drugs?

Ghaemi: It's very hard to get this information. Companies are not required to disclose it. And if they do publish it, they will sometimes delay publication for two or three years, and then publish it in an obscure journal that it less likely to be read.

Ghaemi also did some digging on other drugs used for bipolar disorder and found that negative studies for Seroquel and Abilify were also lurking in the unpublished zone. However, it appears that Lamictal is the worst offender of the bunch. Is it just me, or is anyone else getting flashbacks to GSK's handling of suicide data regarding its antidepressant Paxil?

Thanks to an anonymous reader for helping to track down relevant information on this and an upcoming post on this topic. The forthcoming post will deal with the misleading scientific literature on Lamictal. Key opinion leaders will likely be mentioned. The usual stuff, just on a different drug and plugging in the names of other academics who apparently deemed it acceptable to mislead their fellow physicians about the efficacy of lamotrigine. GSK worked the system expertly and it paid off.

S. Nassir Ghaemi, Arshia A. Shitzadi, Megan Filkowski (2008). Publication bias and the pharmaceutical industry: The case of lamotrigine for bipolar disorder Medscape Journal of Medicine, 10 (9), 211-211

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.

Bipolar Overawareness Week Starts With a Bang

As I mentioned last week, Bipolar Overawareness Week begins today.  There is a little bit of media coverage about the latest study from Zimmerman et al. which found that bipolar disorder was being rampantly overdiagnosed in at least one sample.  If you missed my discussion of the study and its implications, feel free to check it out.  

Furious Seasons noted that the Providence Journal has a story in which leading psychiatry researchers Michael Thase and Gary Sachs agreed that bipolar is indeed being overdiagnosed.  I was surprised that they so quickly jumped on the Bipolar Overawareness bandwagon. Welcome aboard, gents!  I have to admit I was shocked to see that Sachs gave the study any credibility given that he recently expressed uncertainty as to whether there was overdiagnosis of bipolar in children (where the rate of bipolar diagnosis has increased much faster than in adults) and has previously written about the underdiagnosis of bipolar disorder in adults.

National Public Radio also has a brief audio bit on the story.  

Philip Dawdy also chronicles his own experience of being diagnosed with bipolar disorder, a diagnosis that from his account seems questionable at best.  A very interesting story.

Bipolar Overawareness Week Starts on Monday

It appears that the massive bipolar awareness campaigns from NAMI and various drug companies have paid off big time. The conclusions of a new study by Mark Zimmerman and colleagues in the Journal of Clinical Psychiatry state, in part:

However, our results suggest that overdiagnosis of bipolar disorder is as much, if not more, of a problem than underdiagnosis.

Say what? Well, if you've been following the mental health world, you may have noted that bipolar disorder is the new plague -- it is apparently spreading like wildfire. David Healy wrote an excellent article in PLoS Medicine in 2006 which has been validated by Zimmerman et al.'s latest study. Healy wrote in part:

One of the most famous direct-to-consumer television adverts for a drug begins with a vibrant woman dancing late into the night. A background voice says, “Your doctor probably never sees you when you feel like this.” The advert cuts to a shrunken and glum figure, and the voiceover now says, “This is who your doctor usually sees.” Cutting again to the woman, in active shopping mode, clutching bags with the latest brand names, we hear: “That's why so many people with bipolar disorder are being treated for depression and not getting any better—because depression is only half the story.” We see the woman again depressed, looking at bills that have arrived in the post before switching to seeing her again energetically painting her apartment. “That fast- talking, energetic, quick tempered, overdoing it, up-all-night you,” says the voiceover, “probably never shows up at the doctor's office, right?”

No drugs are mentioned. But viewers are encouraged to log onto www.bipolarawareness.com, which takes them to a Web site called “Bipolar Help Center,” sponsored by Lilly Pharmaceuticals, the makers of olanzapine (Zyprexa). The Web site contains a “mood disorder questionnaire” (http:/​/​www.bipolarhelpcenter.com/​resources/​mdq.jsp). In the television advert, we see our heroine logging onto www.bipolarawareness.com and finding this questionnaire. The voice encourages the viewer to follow her example: “Take the test you can take to your doctor, it can change your life….getting a correct diagnosis is the first step in treating bipolar disorder. Help your doctor to help you.”

This advert markets bipolar disorder. The advert can be read as a genuine attempt to alert people who may be suffering from one of the most debilitating and serious psychiatric diseases—manic-depressive illness. Alternatively, the advert can be read as an example of what has been termed disease mongering. Whichever it is, it will reach beyond those suffering from a mood disorder to others who will as a consequence be more likely to see aspects of their personal experiences in a new way that will lead to medical consultations and in a way that will shape the outcome of those consultations. Adverts that encourage “mood watching” risk transforming variations from an emotional even keel into potential indicators of latent or actual bipolar disorder. This advert appeared in 2002 shortly after Lilly's antipsychotic olanzapine had received a license for treating mania. The company was also running trials aimed at establishing olanzapine as a “mood stabilizer,” one of which was recently published.

Here's part of an Abilify for bipolar ad...




Back to the Zimmerman study. The researchers interviewed 700 patients with the Structured Clinical Interview for DSM-IV (SCID). Keep in mind that the SCID is not a conservative measure. When patients receive an unstructured interview, they tend to receive fewer diagnoses than when they are interviewed with the SCID, which makes sense because the SCID sticks to asking detailed questions about DSM-IV symptoms, whereas most interviews ask questions about a variety of topics, and don't go into nearly as much depth regarding one's DSM-specific symptoms.

These 700 patients were also asked if they had been diagnosed as bipolar by a healthcare professional. 145 of the 700 patients included in the study indicated they had been diagnosed as bipolar. Then it gets interesting...

Of the 145 patients diagnosed as bipolar prior to being interviewed for the present study, only 63 (43.4%) were labeled as having bipolar disorder according to the SCID. Remember, the SCID tends to generate more diagnoses than a typical clinical interview, so it's not like the SCID is generally insensitive to picking up on DSM-IV disorders. The researchers even took the liberty of diagnosing many patients who did not officially meet bipolar I or bipolar II diagnostic standards as having bipolar NOS (not otherwise specified); about 25% of those diagnosed with bipolar according to the SCID were labeled as having bipolar NOS. In other words, the authors of the study went out of their way to be quite inclusive, to label some cases that did not quite meet DSM-IV criteria for bipolar as bipolar NOS. So one cannot reasonably state that they were being too restrictive with how they made their bipolar diagnoses.

To put it straight: Over half of the patients coming into the study with a bipolar diagnosis were not labeled as bipolar in the present study when given a thorough diagnostic interview.

Naysayers. Of course, the "bipolar spectrum" club will unite to say that this article is junky. I read an email from a psychiatrist who stated that the study was flawed because the DSM-IV model of diagnosing bipolar is wrong; it is too restrictive. But since the current researchers went past official DSM-IV criteria to make some of their bipolar diagnoses, I'm not sure that is a very valid concern. But similar points will be raised over and over again. Those in favor of expanding the boundaries of bipolar disorder will insist that all this study showed was that the DSM needs change; it needs to broaden its definition of bipolar disorder. Those who were diagnosed as having bipolar disorder but were not labeled as such according to a thorough interview based on the DSM -- those people had "subthreshold" bipolar disorder, which will be labeled as an "underdiagnosed and undertreated" condition that needs to be remedied through more Awareness Days and the like. Doubt me? A group of researchers recently stated that "subthreshold bipolar disorder" was not receiving the treatment it needed, a claim they later retracted when it was pointed out that there was not a single shred of evidence to suggest that such a "condition" received any benefit from treatment with mood stabilizers or antipsychotics.

Why did bipolar become so hip? Mark Zimmerman, lead author of the present study is no pharma hater. By that, I'm not suggesting that he's in bed with pharma either; I'm just saying that he has no axe to grind. So how did he interpret his team's findings?

The impact of marketing efforts and publicity probably also plays a role. Direct-to-consumer advertisements that refer individuals to screening questionnaires can result in patients suggesting to their treaters that they have bipolar disorder. We have seen evidence of this in our practice...

We hypothesize that the increased availability of medications that have been approved for the treatment of bipolar disorder might be influencing clinicians who are unsure whether or not a patient has bipolar disorder or borderline personality disorder to err on the side of diagnosing the disorder that is medication responsive. The bias is reinforced by the marketing message of pharmaceutical companies to physicians that has emphasized the literature on the delayed recognition and underrecognition of bipolar disorder, and may be sensitizing clinicians to avoid missing the diagnosis of bipolar disorder. The campaign against underrecognition, which is also illustrated in the titles of published articles in peer-reviewed journals, has probably resulted in some anxious, agitated, and/or irritable depressed patients who complain of insomnia and "racing thoughts" being misdiagnosed with bipolar disorder.

News flash, folks. Remember, documents seem to indicate that Lilly was pushing Zyprexa in primary care to treat watered down cases of... bipolar disorder. Cases that would not pass DSM-IV muster, but, if you stretched the diagnostic boundaries quite a bit, BAM, you've got bipolar disorder.

The Last Psychiatrist has also been duly keeping tabs on the bipolar epidemic (1, 2, 3) and I recommend reading his posts on the topic. To quote from one of them:

Yes, but even though the world agrees the symptoms are the same, the consequences of each label is very different, right? The epidemiology, the prognosis-- the meds?

But the real difference is the societal implications. Getting a diagnosis changes the way you relate to the world, and the world relates to you. The label changes your identity and how you think.

Don't agree? Try killing someone and using "pervasive ADHD" as a defense. Get it?

We pretend that psychiatry is an emerging science, and hide behind a feigned ignorance ("we don't know everything, but we're making progress!") And so no one has to take responsibility, or even admit, that psychiatry is changing the evolution of humanity, right in front of our eyes, with nothing more than words.

Right. We relabel conditions and act as if we just figured out the laws of relativity. It's not ADHD or conduct disorder or borderline personality or anger management issues or just, life sucks for you right now and you're having a difficult time adjusting to life's difficulties -- it's... bipolar disorder! Look at the progress we've made! But where is the data showing that these people who are being newly christened as bipolar are actually doing any better due to their new label and their new course of treatment? Doesn't giving someone a bipolar label impact that person? I'd probably feel differently about life if a medical authority labeled me as bipolar.

So I propose that we start a Bipolar Overawareness Week, complete with a website linking to a questionnaire that makes statements like:

• Do you know that your symptoms are probably not indicative of bipolar disorder?
• Ask your doctor if you've been misdiagnosed with bipolar.
• Find out if you are unnecessarily taking Zyprexa today.
  

Let's see if we can get the National Alliance for the Mentally Ill on board. Surely they want to make sure that patients receive the proper diagnosis. Surely drug companies, with their interest in good science and good medical practice, want to help out as well, since they want to make sure that their drugs are prescribed properly.

Hat Tip: Furious Seasons.

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.
  

In the Name of Science and Charity

Philip Dawdy at Furious Seasons has noted that Eli Lilly released a short report in which they describe the funding they provided to a variety of organizations. All in the name of science and charity, of course. Beneficiaries of Lilly's largess include:

• The American Psychiatric Association
• Massachusetts General Hospital's Psychiatry Department
• National Alliance for the Mentally Ill
  
• Medscape
• American Academy of Child and Adolescent Psychiatry
• Center for Medical Knowledge
• Continuing Medical Education, LLC
  
• Institute for Continuing Healthcare Education
• Johns Hopkins University School of Medicine
• Postgraduate Institute for Medicine
• University of California -- Irvine

These were just some of the big recipients. The report itself is well worth checking out. One will note that Lilly is kindly funding a lot of "education" about fibromyalgia just as they try to move Cymbalta for all things pain-related. The amount of "education" regarding bipolar disorder is also instructive. Um, Viva Zyprexa?

Read some of the details at Furious Seasons and read Lilly's report as well. To Lilly's credit, at least they are making an attempt at disclosure; their industry colleagues are more than welcome to follow suit. Remember that the figures from Lilly's report are from the first quarter of 2008 only.

Genetic Testing for Bipolar: Are You Kidding Me?

Academics Dr. John Kelsoe and Kurt May have fired the warning shot: Genetic testing for mental disorders is on its way. Like much else in the mental health field, I fear that marketing may yet again trump science. Kelsoe and May's new test is out and it claims it can assess the risk for bipolar disorder (sort of) for a fee of $399.

Both Furious Seasons and Daniel Carlat have already opined wisely on the topic. The first issue is the science behind such testing -- if the science does not support the validity of the test in determining if someone actually has a mental disorder, then the test is a sham. So what does the science say? According to an article in Science, one genetic variant used in the test was associated with a tripling of risk for bipolar disorder. The catch: The variant was only found in 3% of individuals with bipolar disorder and 1% of the people without bipolar disorder. A genetic variant that is only possessed by 3% of people with bipolar can hardly be considered as widely useful. A combination of five variants in another study was found in 15% of individuals with bipolar disorder compared to 5% if those without the condition. As I understand it, the current test, as put forth by Kelsoe and May through the company Psynomics, tests for a combination of the previously mentioned variants. Again, the set of variants they are using are not very common even among people with bipolar disorder. So even if you are bipolar, the odds are high that this test would not label you as such. In the world of testing, this is called low sensitivity, which means that a test is nothing to cheer about.

Additionally, according to the Science piece, other researchers were unable to replicate Kelsoe's findings, making the test yet more questionable.

The thing about bipolar disorder is that it can be diagnosed by (drum roll please)... interviewing a patient thoroughly! That's right, a well-trained interviewer can simply ask questions to determine whether an individual has bipolar disorder. Imagine that. There is often a hullabaloo made over patients with bipolar disorder being initially misdiagnosed as depressed -- the way to solve this problem is not to perform a fairly useless genetic test, but rather to actually spend time with patients, perform a thorough assessment, and listen to them. How's that for a wild idea? If your response is: "But there's no time to actually talk with the patients," then no cookie for you! It is likely true that many people later diagnosed with bipolar were initially seen in primary care settings for a brief appointment, in which they were diagnosed as depressed (the underlying bipolar piece was missed). Again, giving a scientifically dubious test because "Gee, it's based on genetics so it has to be accurate" rather than training physicians to improve interviewing skills will only worsen the problem.

When I have more time emerges, I will post again on the topic. This idea of genetic testing for mental disorders certainly needs much more attention. When academics go into marketing, strange things can happen, as I have documented here on many occasions.

Link-O-Rama, Early March Edition

A few pieces of interesting news...

• Dr. Daniel Carlat has been busy. He aptly notes that Pristiq is an Effexor copycat that apparently provides no special benefits over soon to be generic venlafaxine. Hey, didn't I just write a piece or two about Effexor? In addition, Carlat continues to hammer the corrupting, I er, continuing medical education industry. He also documents the use of deceptive "surveys" to market antipsychotics. Excellent work -- keep it up! Dr. Grohol at PsychCentral pointed out another set of potential problems with the surveys.
  
• Furious Seasons puts forth Ye Olde Pimp Slappe on antidepressant use in bipolar disorder with a side dish of I Told You So. He has indeed questioned the use of antidepressants in bipolar disorder and the latest data continue to question the utility and safety of such practices. Philip Dawdy notes accurately that he is the only person in the USA to host the infamousZyprexa documents online. He also broke a number of excellent stories on said documents. All for the salary of zero dollars. So why not send him some money? He's doing a fundraiser currently. You can donate here. Hey, I'd like to rake in some donations for myself. I think I provide a somewhat valuable service, and my day job doesn't exactly make me rich. But when Dawdy is doing such work much more productively than myself and he doesn't even have a day job (file under journalism in crisis), I think he deserves your financial consideration, not I. So if you ever had the kindhearted intention of sending me cash to support my work, send your money to Philip Dawdy.
  
• Health Care Renewal is chronically excellent, as y'all know already. Recent stories include a fat conflict of interest involving the head of the Obesity Society, yet another chapter in the sordid University of Medicine and Dentistry of New Jersey affair, and a take on the baseless lawsuit from HipSaver.
• Speaking of HipSaver, Aubrey Blumsohn has also written eloquently on this case, which I hope receives scrutiny from many sources. He also reports unfavorably about the sham investigation of GSK. Bob Fiddaman and Seroxat Secrets were similarly unimpressed.
• Peter Rost is on the job market.
• As usual, Pharmalot and PharmaGossip have continued to provide all the news that's fit to print. Of particular interest to my readers (I think) was the marketing of Abilify. Perhaps yet more interesting, the 6th episode of RX -- Sex, Drugs, and Quarterly Goals is up. Everyone should check out all six episodes. I'm hooked.
• Pharma Giles has been generating his usual brand of dead-on satire. I was particularly amused by his take on the most recent Kirsch antidepressant meta-analysis.
• In "who cares?" news, bifeprunox is apparently dead in the water. Better hope that Pristiq sells in droves, Wyeth...

As for myself, I have at least one piece in the works involving a key opinion leader and cash. Stay tuned.

Why I Love the Discussion Section

A recent study in the Journal of Clinical Psychopharmacology found that aripiprazole (Abilify) offered no benefit over placebo in treating biploar depression. Well, at least that's what the results showed, but the discussion section told a bit of a different story. At the end of eight weeks, Abilify failed to beat placebo on either the Montgomery-Asberg Depression Rating Scale or the Clinical Global Impressions -- Bipolar Severity of Illness Scale.

It is rare that an industry-sponsored article reports negative results and it would be nigh-impossible to find a published industry-sponsored study that failed to put a happy spin on the negative results. Sure, the results were negative in this study, but if the dosing was different, the treatment could have worked. There's always a loophole, some possibility that results would have been dandy if something were different. Check this out:

It is possible that the dosing regimen used in the current studies may have been too high for this patient group, or that titration was too rapid. Specifically, the unexpectedly high rates of discontinuation caused by any reason or because of AEs suggest that the aripiprazole starting dose (10 mg/d) may have been too high and that the dose titration (weekly adjustments in 5-mg increments according to clinical response and tolerability) may have been too rapid...

However, because preliminary data indicate that aripiprazole may have a potential value as adjunctive therapy in patients with bipolar depression, future studies that focus on the use of aripiprazole as adjunctive therapy using a better-tolerated dosing schedule with a more conservative escalation may be of greater value for the treatment of patients with bipolar depression...

And my favorite part...

Although the improvements in MADRS total scores in the current aripiprazole studies did not separate statistically significantly from placebo at end point, the significant effects observed with aripiprazole monotherapy within the first 6 weeks are clinically meaningful and similar to the effects seen with olanzapine monotherapy and lamotrigine monotherapy in patients with bipolar depression.

OK, so the argument is that while treatment did not work at the end of 8 weeks, the effects after 6 weeks were really super-duper impressive. Gimme a break. The authors did not present the actual numbers on the MADRS (the primary manner in which depression was assessed); rather, the data were presented in figures. Um, isn't science supposed to be based on numbers -- shouldn't they be provided in the text of the paper? At 6 weeks, the difference in scores between Abilify and placebo looks to be a little more than 2 points on the MADRS, a rating scale that spans from 0 to 60. And if a drug makes a person 2 points better relative to placebo, then the findings are "clinically meaningful"? Keep lowering that bar, fellas. While the discussion reaches out to rescue the reputation of Abilify, it does (to be fair), also point out on a couple occasions that Abilify was not particularly efficacious at the end of 8 weeks and was related to a worse safety/tolerability profile than placebo. In fact, relative to some other studies I've dissed regarding their sunny presentation of unimpressive results (like this one), the current Abilify article is a model of fair discussion.

Side note: Akathisia was reported by about a quarter of patients taking Abilify. The funny thing about akathisia is that it is not well-defined in this study or in many others. Is it a problem with movements, mental tension, something else, or what? It would seem important to know, given that Abilify apparently causes akathisia in droves. Do a Pubmed search for aripiprazole and akathisia and you'll see what I mean. A couple descriptions of akathisia follow:

• Increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable
• On the first day of treatment he reacted with marked anxiety and weepiness, on the second day felt so terrible with such marked panic at night that the medication was cancelled
• Another: A movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot and crossing and uncrossing the legs while sitting. People with akathisia are unable to sit or keep still, complain of restlessness, fidget, rock from foot to foot, and pace.

Mood Stablizers and Suicide

As reported on Pharmalot and Furious Seasons, the antiepileptic/"mood stabilizer" class of drugs has been stuck with a suicide warning by the FDA. Granted, the FDA wasn't exactly quick to come to their conclusion -- these drugs have been on the market for quite some time, but better late than never. Others have noted similar concerns prior to the FDA's interest in the topic. Hey, does this remind anyone else of the SSRI-suicide story (1, 2, 3, 4, 5, 6, 7, 8)?

But wait a minute, aren't these supposed to be "life saving" medications? Wait, I can hear it coming now... Drug Wonks and others with similar views will be complaining that because the FDA is irresponsibly "fearmongering," people will stop taking their life saving medications and masses of suicide will ensue.

Bipolar Explosion, Spot-On Parody, and Other Highlights

A number of great posts have emerged across the wonderful world of health blogs as of late.

In particular, check out the following on bipolar disorder, which must be spreading like wildfire these days:

• David Healy and Joanna LeNoury have a new paper on the influx of bipolar disorder cases. Consider it required reading. Key opinion leaders, Big Pharma, astroturf patient support groups, Brandon and the Bipolar Bear, and more. Read it now. Furious Seasons has some choice excerpts
  
• Furious Seasons has a whale of a post on living with "bipolar disorder." As a very bright and thoughtful man who has been diagnosed with bipolar for decades, and has lived through many an interesting experience, his discussion of bipolar is quite timely and fits nicely into the present mania of diagnosing bipolar every time somebody does not respond well to antidepressants.
• The name of the post says it all: Is early-onset bipolar disorder simply normal childhood? Read it at Psych Central. I can't resist taking one choice quote from the post (quote from psychologist John Rosemond):
  
• In their book and in the May 2007 issue of their newsletter, available through their website, the Papoloses recommend against using the word “no” with a bipolar child “because it will trigger a meltdown.” When they were toddlers, my children often suffered wild seizures at the sound of “no.”

On the topic of disease mongering, the best parody I've yet seen may have just been penned by the incredible Pharma Giles. The Pharma Giles take on the Montel Williams fiasco is also a great laugh.

The Scientific Misconduct blog has a post on the conflict between integrity and money, which somehow just keeps rearing its head on this site and others.

Mind Hacks notes an example of poor journalism regarding an alleged cure for Alzheimer's.

Peter Rost, ever the excellent self-promoter (meant as a compliment), has a website promoting his expertise as a pharmaceutical marketing consultant and expert witness. After tracking his work for a while, I am convinced -- I'd certainly hire him.

The Carlat Psychiatry Blog is just on-fire all around. No need to single out a particular post.

Pharmalot points out that Wyeth just got slapped by the FDA for a highly misleading ad about Effexor. Read the FDA letter -- this ad is well beyond a little bit misleading.

Zyprexa for Teen Bipolar

Zyprexa for teen mania is great, except for the Fat Camp Factor -- from the study abstract:

The mean baseline-to-endpoint weight change was significantly greater for patients receiving olanzapine relative to patients receiving placebo (3.7 kg versus 0.3 kg), and the incidence of treatment-emergent weight gain 7% of baseline was higher for olanzapine-treated patients (41.9% versus 1.9%)

The drug did appear to be much more effective than placebo according to the abstract, but I'll have to read the article before I can weigh in on efficacy more confidently. Gaining 7% of your body weight in three weeks? Um, that ain't good. Gimme a D, Gimme an I, Gimme an A (can you see where I'm going here -- diabetes, anyone?)...

Maybe these kids should have been drinking diet soda -- that will save them from weight gain, at least that's what Lilly might tell them. There were 13 "authors" on the study -- apparently being good at recruiting patients counts as authorship, since there is no way that 13 people made a legit contribution to the study outside if recruitment is left out.

More at Furious Seasons.

Subthreshold Bipolar: Told You So!

I Said: This is one of those "you heard it here first" moments that you might read about at times on a site like Peter Rost's. On May 10 of this year, I wrote a lengthy post about an Archives of General Psychiatry article that pushed the common existence of a new form of bipolar disorder, which the authors called "subthreshold bipolar disorder." Not only was this condition relatively common -- it required treatment! I strongly encourage you to read the post. Other also chimed in wisely, including Furious Seasons, Polarcoaster, and Dr. X. Ruth introduced us to a hilarious song regarding the new diagnosis. Others were less pleased and threatened to rip myself and others new orifices.

I pointed out several notable issues with the study and its conclusions. One of my main issues of contention was as follows:

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.

They Said: The September issue of the Archives of General Psychiatry contains a correction from the authors, which reads in part:

"...the reference to inappropriate pharmacological treatment of bipolar disorder should have been restricted to bipolar disorders I and II and not included subthreshold bipolar disorder."

In other words, they were wrong to imply that subthreshold bipolar disorder required pharmacological treatment. Well, thank you very much -- I told you so. The authors also noted a couple of small errors in the some tables, and that disclosures were left out for some of the authors. In addition, I noted earlier that the authors mentioned that "preparation of [the] article was supported by AstraZeneca." The authors have now indicated that "AstraZeneca did not provide any financial or scientific support for this study."

I heartily thank the authors for making the corrections. Errors in tables are easily understandable, but I am still struck that nobody caught the subthreshold bipolar treatment issue, including the authors, the peer reviewers, and the editor. Perhaps that says something about the state of academic psychiatry or perhaps it was just an oversight. One more thank you to deliver. This one goes to Dr. Bernard Carroll, who is credited in the correction with having alerted the study authors to the problem with their statements that subthreshold bipolar required pharmacological treatment.

The Bad News: Here's the problem. News stories have already circulated indicating that subthreshold bipolar is real and requires treatment. Not a single news story will cover the latest turn in events, in which the study authors retract their conclusion that subthreshold bipolar requires drug treatment. The damage has already been done. This reminds me of a post I wrote in June where I wondered how we could amplify news such as this? A major conclusion of a study is withdrawn but who will ever know? Let's face it, not many people read the Archives of General Psychiatry (even including psychiatrists), and those that read it don't usually skim through the bottom of a page at the end of a reference section (where the current retraction was located) looking for corrections. Might journals want to post corrections in a more accessible manner? Might the so-called health media want to report on these corrections?

Subthreshold Bipolar Disorder: Update

The internet is abuzz with discussion about subthreshold bipolar disorder. There seem to be two camps forming (with some slight variations within each group).

One group is skeptical about this new disorder and not impressed with the new study which suggests SBD is not being treated appropriately.

Another group appears to believe that the newly minted SBD is legit and doubting it is a sign that you might be a "pop psych pundit." Here are some snippets and links to each camp, along with my occasional commentary [in brackets].

Skeptical posts...

• Polarcoaster said:
  

  Yes, this “subthreshold” stuff is ridiculous, but within limits, I like the idea of the bipolar spectrum because it makes people aware of things that actually are bipolar symptoms but aren’t necessarily the most classic ones. It’s when you start pathologizing mild things that occur infrequently that it gets to be harmful.

  No, I don’t know where the line should be drawn. But I’d say somewhere way before “subthreshold bipolar disorder” as defined in that journal article, anyway. [I agree that many mental conditions exist on a spectrum and agree that the line in this case is too inclusive.]
  

• Dr. X said:

  My prediction: treatment will be good for pharmaceutical stocks and will cause patients to gain a lot of weight. [Cynical, but I have no evidence that Dr. X is wrong]
  

• Bipolar Chicks Blogging said:
  

  We're not doctors here; but we do have years of combined experience and you may read stuff here that you won't hear from your physician or on television and more and more, what you hear coming from your doc's mouth mimics what is spewed from drug advertising; and the bitch is, none of it is hard science. [Good point -- especially in the latest SBD study, the argument for treating SBD is currently science-free]
  

• Ruth at Off-Label hilariously wrote:
  

  "The problem is all inside your head", he said to me
  The answer is easy - you just take it orally
  I'd like to help you in your quest for normality
  For there are 21 ways to be subthreshold bipolar
  
  Have you increased your goal-directed activity?
  Are you subject to distractibility?
  Engaged in an unrestrained buying spree?
  There are 21 ways to be subthreshold bipolar
  
  You been flat on your back, Jack
  Making grand plans, Stan
  Cheatin' on your boy, Roy
  Well, listen to me
  Hop on the shortbus
  We don't need to discuss much
  Just drop this off at the pharmacy
  And get yourself free... [And it goes on further -- you must read it!]
  

Skeptics are wrong...

• Empirical Insanity said:

  Check this post out, in which the author, whose bio states that he is an academic with clinical experience, starts with that article and works up to arguing that anyone who isn't bipolar type I should not be receiving long-term medication because "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" (subthreshold bipolar disorder).
  
  I do not think he is an academic with training on the research side of psychology. He also seems to have difficulty understanding that different diagnoses of bipolar disorder almost certainly involve similarities in etiology which are relevant to treatment. [If anyone can locate a single study showing positive treatment results for SBD, I'd love it see it.]

• Maddy said:

  ...I'm BPI but this kind of thing still pisses me off. How can they completely discount another persons condition? Calling it "Life's little ups and downs" is such bullshit. Don't they realize how they are contributing to the mental health stigma? Not to mention the fact that by not controlling mania/hypomania can cause even more serious issues down the road?
  
  AARRRGGGHHH! I just want to rip these idiots a new asshole or two![I question whether people should receive meds for a questionable diagnosis in the face of no evidence and thus I'm an idiot who needs to be ripped a new orifice.]

• reddog said:

  Maddy: they already ARE assholes. *sigh* (i keep having issues with a coworker who believes 'stress' causes MI..that you 'snap' and develop schiz or bp or MD or whatever. *sigh*) [Thanks. Of course stress has nothing to do with one's mental well-being(?,?)]

• herrfous said:

A relatively newly-adopted but pervasive maxim of modern allopathic medicine is "treat the patient, not the symptoms".

It seems that these pop-psych pundits (and perhaps a few doctors) haven't yet gotten past "treat the symptoms, not the DSM-coded diagnosis". [And if someone has one minor symptom of hypomania [i.e. has SBD], these symptoms require treatment?]

Well that was fun. Please feel free to read my original post on the topic as well as a couple of followups (1, 2). Also check out posts at Furious Seasons on the topic (1, 2). Be warned, however, that Philip Dawdy, author of Furious Seasons, like myself, is a "pop-psych pundit," an "idiot," and is in need of a new anal orifice or two.

Time for a New Name DUMBASS-$

Philip Dawdy at Furious Seasons has started a contest where readers can throw in their bid for naming the newly christened version of bipolar disorder currently known as "subthreshold bipolar disorder." SBD sounds pretty lame, so I am quite excited about this new event. Please feel free to add it your two cents here. Background on this story here, here, and here.

For my vote, can we go with DUMBASS-$ (Diagnosing Usually Mundane Behavior As Seroquel Scripts $oar) That's my off-the-cuff take, but others have already offered much better. Sigh...

More on the New Bipolar Disorder

Philip Dawdy has chimed in smartly on the subthreshold bipolar diagnosis and its implications. Background here and here. Here's one snippet:

My reading of this is that much of that increase is linked to an expanded definition of bipolar disorder as a spectrum disorder (spectrum disorders are all the rage these days) with SBD being the catch basin for all the soft bipolar researchers claim they are detecting in America these days. And so begins the war on the weird, the productive and the agitated of America.

Much more at his site.

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.