Clinical Psychology and Psychiatry: A Closer Look

Alive But Inactive

2011-02-23T11:23:00.000-08:00

I just checked my blog email account for the first time in months. It's possible - not likely - that I will sort through the spam and actually read and reply to your emails. It's also possible and not likely that I will actually post something sometime in the next month or two.

Cymbalta and Effexor: Hype Over Science

2010-10-01T11:13:00.000-07:00

Remember the hype around the serotonin-norepinephrine reuptake inhibitors (SNRIs)? Effexor and Cymbalta impact both serotonin and norepinephrine, so they should be more effective than SSRI’s in treating depression? Mind you, that’s not a high bar to clear - it’s not like SSRI’s are much better than placebo. So get the hell outta the way, Prozac and Paxil, because Cymbalta and Effexor will unleash their incredible efficacy onto the world of psychiatry. Doubt me? Read this 2009 article regarding the wonders of Pristiq (son of Effexor) and learn about how “The emergence of the selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRI) antidepressants has improved the treatment of MDD.” Or this press release from Wyeth. Or Dr. Danny Carlat’s experience selling Effexor to his peers. I don’t think anyone who has followed drug marketing would deny that both Wyeth and Lilly tried to pimp Effexor and Cymbalta as working better because of their SNRI properties.

But is that actually true? A team of German researchers examined the data and concluded that neither Effexor nor Cymbalta really work better than SSRIs. They actually found a small advantage for Effexor over SSRIs for treatment response (but not depression remission), but they also found that the manufacturer was hiding studies from them (and the rest of the world). I haven’t said this for a while, but enter Charles Nemeroff. To understand the research by the Germans, we first need to recall that a 2008 study (lead author: Nemeroff) found

...the pooled effect size across all comparisons of venlafaxine versus SSRIs reflected an average difference in remission rates of 5.9%, which reflected a NNT of 17 (1/.059), that is, one would expect to treat approximately 17 patients with venlafaxine to see one more success than if all had been treated with another SSRI. Although this difference was reliable and would be important if applied to populations of depressed patients, it is also true that it is modest and might not be noticed by busy clinicians in everyday practice. Nonetheless, an NNT of 17 may be of public health relevance given the large number of patients treated for depression and the significant burden of illness associated with this disorder. [my emphasis]

As I wrote then, the benefit to public health claim is ridiculous. To understand the reasons why this is so laughable, please check out my prior post on the topic. This meta-analysis included a bunch of data from Wyeth that was previously unpublished...

Which leads to the freshly published meta-analysis on how Effexor compares to SSRIs. The German researchers requested unpublished data from Wyeth and only got some of it - you’d think that just maybe Wyeth sent them the “good news” data and maybe held back on some of the “bad news” data. So when an ever-so-small benefit emerged for Effexor (5% high treatment response rate), well, call me crazy, but I ignored it. We’re not playing with a full dataset because the manufacturer wants to keep some of it hidden, so shame on Wyeth and let’s look at Effexor with a little bit of suspicion. So Effexor vs. SSRIs - no difference. Except that more people drop out of clinical trials on Effexor due to side effects compared to SSRIs (about 3% more). So even if you believe that Wyeth’s hidden data really doesn’t impact these findings, we’re left with a very small advantage for Effexor that is probably negated by its slightly higher dropout rates.

Cymbalta. It had a 3% higher dropout rate due to adverse events and the same efficacy as SSRIs. So nothing to write home about, except that it costs a boatload more than generic SSRIs and is harder to tolerate. But Cymbalta has been marketed to the gills and is clearing $3 billion a year in sales. Hey, this is the company marketed Zyprexa for dementia (oops), and for, well, lots of other stuff (1, 2). So it’s not surprising at all that they can take a mediocre antidepressant like Cymbalta and turn it into a big moneymaker - the wonders of a good marketing department. But Depression Hurts and Cymbalta is a painkiller. Well, that’s fine and dandy until you actually look at the data which show Cymbalta doesn’t do much for pain in depression.

It’s time to get over the hype surrounding SNRIs. The next “advance” in antidepressants, well, who knows what it will be - but let’s hope it’s something a little more substantial than SNRIs. But I’m not hopeful. And no, I don’t want to hear anything more about agomelatine.

I know it’s been a long time between posts. So pardon me if my writing is more awful than usual. And it doesn’t mean I will be posting regularly. Thanks to the multiple readers who sent me a copy of this article.

Citation to new meta-analysis of Effexor and Cymbalta:
Schueler, Y., Koesters, M., Wieseler, B., Grouven, U., Kromp, M., Kerekes, M., Kreis, J., Kaiser, T., Becker, T., & Weinmann, S. (2010). A systematic review of duloxetine and venlafaxine in major depression, including unpublished data Acta Psychiatrica Scandinavica DOI: 10.1111/j.1600-0447.2010.01599.x

Eli Lilly: Our Drug Failed, So it Has Serious Potential

2010-05-14T08:18:00.000-07:00

These folks at Lilly must think we are exceptionally stupid. As in can't tie our own shoes. A study in the Journal of Psychiatric Research recently found that their experimental antidepressant LY2216684 was no better than placebo. Here are a couple of quotes from the abstract:

LY2216684 did not show statistically significant improvement from baseline compared to placebo in the primary analysis of the Hamilton depression rating scale (HAM-D17) total score. Escitalopram demonstrated significant improvement compared to placebo on the HAM-D17 total score, suggesting adequate assay sensitivity.

On the primary outcome measure, the experimental drug failed whereas Lexapro worked to some extent. I know what you're thinking - "the sample size was probably too small to find a significant effect." Um, you're wrong. How about 269 people on the Lilly drug, 138 on placebo, and 62 on Lexapro.

But wait, here comes the good news...

Both LY2216684 and escitalopram showed statistically significant improvement from baseline on the patient-rated QIDS-SR total score compared to placebo... The results of this initial investigation of LY2216684’s efficacy suggest that it may have antidepressant potential.

The good news for Lilly is that most people who claim to "read journal articles" really just browse the abstract without actually looking at the full text of the paper. For the select few who have nothing better to do than read Lilly propaganda, take a look at Table 2. A total of 12 secondary outcome measures are listed. The Lilly drug beat placebo on... ONE of them. Lilly doesn't say much about how much better their drug was than placebo on the QIDS-SR measure beside throwing around that often meaningless term of "statistically significant." People on the drug improved by 10.2 points whereas placebo patients improved 8.3 points. So about a 20% difference. If you bother to calculate an effect size, it is d = .24, which is quite small and clinically insignificant. So on the ONE measure where the drug was better than placebo, it was by a small margin, and it missed the mark on 11 other secondary measures as well as on the primary outcome measure. But "it may have antidepressant potential." Hell yes, I've never been so exited about a new drug.

By the way, Lilly is apparently trying this wonder drug out in at least five trials. The journal in which this article appeared has published other dubious Eli Lilly research in the past. The editorial review process is clearly working wonders over at the Journal of Psychiatric Research. Sad, really. The journal publishes some really good work, but then runs this kind of junk as well.

Depression Self-Report Sidebar: The self-reported measure on which the drug had an advantage, the Quick Inventory of Depressive Symptoms (QIDS) - it's really awesome, according to Lilly. Remember, it's the only measure on which their experimental ~~failure~~ drug had an advantage over placebo. So the authors wrote "Self-reported depression symptoms, such as those obtained by the QIDS-SR, may be more sensitive than clinician-administered scales for signal detection in clinical studies of depression."

What does Bristol-Myers Squibb think? In three trials of Abilify for depression, self-reports of depression were unfavorable. So the publications for these studies made sure to downplay these depression self-reports by saying that these measures were not sensitive, that they weren't picking up improvements in depression.

So if a self-report provided positive results, then BAM, it's an awesome measure of depression. But if it provided negative results, then it's a horrendously inaccurate measure and should never have been used in the first place.

Citation below. Yes, one of the authors' last names is Kielbasa.

Dubé, S., Dellva, M., Jones, M., Kielbasa, W., Padich, R., Saha, A., & Rao, P. (2010). A study of the effects of LY2216684, a selective norepinephrine reuptake inhibitor, in the treatment of major depression Journal of Psychiatric Research, 44 (6), 356-363 DOI: 10.1016/j.jpsychires.2009.09.013

Charles Nemeroff, Consultant Extraordinaire

2010-04-02T12:16:00.000-07:00

The key opinion leader of key opinion leaders. Or Boss of Bosses, if you prefer. In any case, take a peek at the following from Charles Nemeroff's page on the University of Miami's website. Seems like something must have happened in 2006 to slow down Chuck's momentum...

What? This is old news? Yeah, I know. But I just hadn't written much about our friends in the world of drug sales/"academics" lately, so I just had to do this.

Pharmaceutical and Clinical Research Company Scientific Advisory Boards

Abbott Laboratories
- Consultant, Abbott Laboratories, Diagnostics Division, 1986-1992.
- Research and Education Advisory Board for Psychiatry
- Member, 1990 - 2006
- Executive Board, 1991 - 1993, 2003 - 2006
-Antidepressant Advisory Board, 1991 - 1992

ACADIA Pharmaceuticals Clinical Advisory Board
- Member, 2000 - 2006.

AstraZeneca Pharmaceuticals
- Psychiatry Advisory Board, 1997 - 2001.
- Chairman, 1999 - 2002.
- Neuroscience Scientific Advisory Board, 1999 - present.

Bristol-Myers-Squibb
- Antipsychotic Advisory Board, 2003 - 2006.
- Antidepressant Advisory Board, 2003 - 2006.
- EMSAM Advisory Board - Chairman, 2005-2006.

Cephalon Pharmaceuticals
- Scientific Advisory Board, 2002

Comprehensive Neuroscience, Inc.
- Scientific Advisory Board, 1999 - 2004.

Corcept
- Scientific Advisory Board, 2001 - 2006

Cyberonics
- Scientific Advisory Board, 2002 - 2006.
- Chair, Mechanism of Action Board, 2003 - 2006.

Cypress Biosciences, Inc.
- Board of Directors, 2001 - 2004
- Consultant, 2004 - 2006

Eli Lilly and Company
- Psychiatry Advisory Board, 1990 - 2000.
- Bipolar Advisory Board, 1998 - 1999.
- Consultant, 2002 - 2003.
- Global Neuroscience Advisory Board, 2005 - 2006.

Forest Laboratories
- Citalopram Clinical Advisory Board, 1997 - 2002.
- Psychiatry Scientific Advisory Board, Chairman, 1999 – 2008.

GlaxoSmithKline Advisory Board of Psychiatrists
- Chairman, 1991 - 2004.

Janssen Pharmaceuticals
- Mood Disorders Advisory Board, Member and Chairman, 1998 - 2004.
- Topiramate Advisory Board, Member and Chairman, 1999 - 2001.
- Antipsychotic Advisory Board, Member, 1999 - present.

Johnson & Johnson Scientific Advisory Board, 2007- present.

Lundbeck
- Consultant, 2006

Merck Sharp & Dohme Research Laboratories
- Consultant, Neuroscience Research Center, 1994.
- Mood Disorders Advisory Board, 1999 - 2003.

Merck-MedCo Mental Health Advisory Board
- Member, 1996 – 1998

Mt. Cook Pharma
- Board of Directors, 2007 - Present

Neurocrine Biosciences
- Scientific Advisory Board, 1994 - 2004.

Neuronetics
- Scientific Advisory Board, 2006

Novadel Pharma
- Board of Directors, 2003 - present
- Chair, Scientific Advisory Committee
- Member, Compensation Committee
- Member, Nominating Committee

Novartis Pharmaceutical Company
- Bipolar Advisory Board Chairman, 2001 - 2003.
- Pediatric Bipolar Advisory Board, 2002 - 2003.
- Antidepressant Advisory Board, 2006.

Organon Pharmaceuticals Psychiatry Advisory Board
- Member, 1997 - 2004.

Otsuka Psychiatry Advisory Board
- Chairman, 2003 - 2006.

PharmaNeuroboost
- Scientific Advisory Board, 2006 – present.

Pfizer Pharmaceuticals
- Clinical Neuroscience Advisory Board, 2004 - 2006.
- Chair, Antipsychotic Advisory Board, 2004 - 2006.

Quintiles Scientific Advisory Board, 2004 - present

Revaax
- Stockholder

Roche Laboratories, a Division of Hoffman-LaRoche, Inc.
- Mania Advisory Board, 1993.
- Pharmocogenomics Advisory Board, 2006

Sanofi/Synthelabo
- Psychiatry Advisory Board, 2002 - 2005.

SciRex
- Scientific Advisory Board, 1999 - 2003.

Solvay Pharmaceuticals Psychiatry Advisory Board
- Member, 1991 - 1999.
- Chairman, 1991 - 1999.
- Antipsychotic Advisory Board, 2005 - 2006.

Somerset Pharmaceuticals Psychiatry Advisory Board
- Chair, 2000 - 2004.

Vela Pharmaceuticals
- Scientific Advisory Board, 2001 - 2002.

Wyeth-Ayerst Psychiatric Advisory Board
- Chairman and Member, 1995 - 2002.

Research Blogging Awards 2010

2010-03-16T06:52:00.000-07:00

Holy cow, I've been nominated for an award?!? Under the category of best health blog, with eight other nominees. Voting is already closed, and I can pretty much guarantee I didn't win, but it's an honor to have been nominated.

Editorial Support, CME, and the Primary Care Companion

2010-03-16T06:42:00.000-07:00

By now, everyone who has been paying attention should know that a journal article which lists "editorial support" is an article that was ghostwritten. Yet the average reader of these articles is apparently uninformed enough to not care. Why else would so many articles get published which feature "editorial support provided by [insert name of ghostwriter here]." One my my favorite journals, under the "so bad, it's good" category, is the Primary Care Companion to the Journal of Clinical Psychiatry. Good articles certainly make their way into the journal, perhaps by accident, but the journal can always be counted on to provide a steady supply of utter garbage.

Here's the acknowledgements section from one recent piece in the journal: "Editorial support was provided by George Rogan, MSc, Phase Five Communications Inc, New York, New York. Mr. Rogan reports no other financial affiliations relevant to the subject of this article." And in case you're wondering, "Funding for editorial support was provided by Bristol-Myers Squibb." If you've somehow guessed that this is an advertorial for Abilify, you win. Other ghostwritten pieces of fluff paid for by BMS include an article discussing the safety profile of Abilify in depression. It states that "In conclusion, this post hoc analysis extends previous findings demonstrating that aripiprazole is safe and generally well tolerated as an augmentation strategy to standard ADT in patients with MDD with a history of an inadequate response to antidepressant medication." But Abilify caused akathisia in a quarter of patients - I think that's a problem.

But wait... there's more. An article based on data from two trials, which showed (allegedly) that Seroquel improves anxiety in patients with bipolar disorder. This piece also acknowledges that it was ghostwritten. And we know that AstraZeneca, manufacturer of Seroquel, has cooked the books on Seroquel in the past. Feel free to look through the journal every month and have a giggle at some of the ridiculous pieces that make their way into print.

CME

You can get your continuing medical education (CME) from the Primary Care Companion as well. One particularly awesome piece of medical wisdom ~~pimped Abilify~~ educated physicians about the best ways to manage resistant depression. This one is a beauty. It was supported by cash from BMS, which features prominently in the "treat aggressively" message of the piece. The article features none other than Michael Thase as the leading discussant. The same guy who was the leading author on a paper which allegedly showed the wonders of Abilify for depression - despite the pesky fact that patients said it didn't work.

Back to the CME.. Thase starts off by stating that only a third of patients achieve remission of depressive symptoms during treatment. Given that Abilify is being marketed for treatment-resistant depression, this is a perfect way to start off this ~~infomercial~~ educational piece. He adds that failure to achieve remission increases the risk of suicide and puts people at risk for more depression, worse psychiatric outcomes, and all sorts of other bad things. So we better get rid of all symptoms of depression. Thase suggests that clinicians should closely monitor patients to see if their symptoms are remitting.

In particular, "Relying on the global statement “I’m definitely better” from the patient overlooks persistent, minor, or residual symptoms. Dr Thase recommended using a standardized symptom assessment measure and keeping track of the patient’s levels of symptom burden." So even if the patient says he or she is much better, don't believe it. Have the patient fill out rating scales and if any symptoms at any level are present, keep treating. In Thase's words, "If the current treatment is well tolerated and the individual has made significant symptom improvement but is still experiencing residual symptoms, then it may be necessary to adjust the treatment dose, add another medication, or combine pharmacotherapy and psychotherapy." Note that adding psychotherapy comes after adding another medication.

Then a series of other objective, expert psychiatrists chime in. Dr. Gaynes offers his wisdom, which includes "Dr Gaynes concluded that incomplete remission requires aggressive identification and management." Don't be afraid - be aggressive. The unspoken message: Hey, using an antipsychotic like Abilify for depression may seem freakin' crazy. But don't worry, you need to be aggressive. Dr. Trivedi then comments about using rating scales to measure side effects. I don't have much to say about his section, but things get worse momentarily...

Dr. Papakostas then checks in. "A meta-analysis of randomized, double-blind, placebo controlled studies found that augmentation of various antidepressants with the atypical antipsychotic agents olanzapine, risperidone, and quetiapine was more efficacious than adjunctive placebo therapy. In addition, Dr Papakostas noted that the atypical antipsychotic aripiprazole was recently approved by the US Food and Drug Administration (FDA) for use as an adjunctive therapy to antidepressants in MDD. Augmenting with atypical antipsychotics has so far been the best studied strategy for managing treatment-resistant depression, said Dr Papakostas." Dr. P was the coauthor of a meta-analysis that provided "considerable evidence" regarding the wonders of antipsychotic therapy for depression. The only problem was that the analysis actually did not find convincing evidence that the drugs were particularly effective, which I discussed in December 2009.

Next comes Dr. Shelton. Time to be aggressive, again: "Thus, said Dr Shelton, the long-term management of depression should be viewed in the context of acute treatment and the need for early aggressive management to get the patient as well as possible." Be aggressive by adding Abilify to the antidepressant regimen. If not, your patient won't achieve full remission and will suffer needlessly... "Dr Shelton advised clinicians to be aggressive in treatment and stay active over time, asking themselves if everything has
honestly been done to help the patient." Psychotherapy is given a brief mention in this section, but let's face it -- most physicians think of "be aggressive" as upping the dosage and/or adding medications - not as "let's be aggressive by adding psychotherapy."

Then there's the exam at the end. Write up your answers, mail them in, and get your medical education credit. Here's one of the questions...
3. Scores on both patient- and clinician-rated scales found that Ms B is still experiencing residual depressive symptoms. You optimize her current SSRI dose, which produces some improvement. She has not reported any problems with side effects. What course of action to improve her outcome has the most comprehensive efficacy data?
a. Increase the dose of her current SSRI again
b. Augment her current SSRI with another SSRI
c. Switch her to a serotonin-norepinephrine reuptake inhibitor
d. Augment her current SSRI with an atypical antipsychotic

If you guessed that D is the correct answer, you're one step closer to CME credit. And one step closer to writing a prescription for Abilify despite the fact that it is as likely to induce akathisia as to induce remission of depressive symptoms. Or that its advantage over placebo is small on several measures and nonexistent on a patient-rated measure of depression. But D is still the "correct" answer.

The offending educational piece is cited below:
Thase, M., Gaynes, B., Papakostas, G., Shelton, R., & Trivedi, M. (2009). Tackling Partial Response to Depression Treatment The Primary Care Companion to The Journal of Clinical Psychiatry, 11 (4), 155-162 DOI: 10.4088/PCC.8133ah3c

If You Don't Learn Your Lesson the First Time

2010-03-03T09:52:00.001-08:00

I'm short on time, so I apologize for the lack of details. The short of it: A researcher at the University of Sheffield (Guirong Jang) submitted research findings regarding Procter & Gamble's osteoporosis medication Actonel. However, Sheffield had a contract with P & G to only release Actonel data with the permission of P & G. So Dr. Jang is in BIG trouble - as Sheffield wouldn't want to offend its corporate sponsor by releasing any potentially unflattering data. More can be found here.

P & G, Actonel, and trying to effectively manage data to best suit the needs of Actonel's marketing. Hey, wait, this sounds familiar. You may recall the case of Aubrey Blumsohn - a researcher at the same university investigating the same drug, followed by all sorts of strange happenings. Read more on the Blumsohn story here.

Say Hello to Temper Dysregulation Disorder with Dysphoria

2010-02-10T06:00:00.000-08:00

The buzz around the new version of the DSM is already starting. The draft version is now online and it features a new condition with the ungainly moniker of "Temper Dysregulation Disorder with Dysphoria." That's a friggin' mouthful, so let's try T-Triple D for short. WTF is this disorder? Well, according to my first look, it closely resembles the bad-behavin' kids who have been labeled as bipolar for the last few years. The symptoms are below, and can also be found on the official DSM-V website:

A. The disorder is characterized by severe recurrent temper outbursts in response to common stressors.

1. The temper outbursts are manifest verbally and/or behaviorally, such as in the form of verbal rages, or physical aggression towards people or property.

2. The reaction is grossly out of proportion in intensity or duration to the situation or provocation.

3. The responses are inconsistent with developmental level.

B. Frequency: The temper outbursts occur, on average, three or more times per week.

C. Mood between temper outbursts:

1. Nearly every day, the mood between temper outbursts is persistently negative (irritable, angry, and/or sad).

2. The negative mood is observable by others (e.g., parents, teachers, peers).

D. Duration: Criteria A-C have been present for at least 12 months. Throughout that time, the person has never been without the symptoms of Criteria A-C for more than 3 months at a time.

E. The temper outbursts and/or negative mood are present in at least two settings (at home, at school, or with peers) and must be severe in at least in one setting.

F. Chronological age is at least 6 years (or equivalent developmental level).

G. The onset is before age 10 years.

H. In the past year, there has never been a distinct period lasting more than one day during which abnormally elevated or expansive mood was present most of the day for most days, and the abnormally elevated or expansive mood was accompanied by the onset, or worsening, of three of the “B” criteria of mania (i.e., grandiosity or inflated self esteem, decreased need for sleep, pressured speech, flight of ideas, distractibility, increase in goal directed activity, or excessive involvement in activities with a high potential for painful consequences; see pp. XX). Abnormally elevated mood should be differentiated from developmentally appropriate mood elevation, such as occurs in the context of a highly positive event or its anticipation.

I. The behaviors do not occur exclusively during the course of a Psychotic or Mood Disorder (e.g., Major Depressive Disorder, Dysthymic Disorder, Bipolar Disorder) and are not better accounted for by another mental disorder (e.g., Pervasive Developmental Disorder, post-traumatic stress disorder, separation anxiety disorder). (Note: This diagnosis can co-exist with Oppositional Defiant Disorder, ADHD, Conduct Disorder, and Substance Use Disorders.) The symptoms are not due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition.

I've not given this a lot of thought yet. The committee that examined the topic has some discussion of T-Triple D/bipolar here and here. The committee takes a couple of digs at the the child bipolar diagnosis. So if this new disorder is adopted, we're going to have yet another name for children who behave badly. Fortunately, the criteria appear to require much worse behavior than what has been passing for "bipolar" according to some child psychiatrists. The diagnostic threshold is higher and should theoretically lead to fewer kids being unnecessarily diagnosed. But even if the current criteria are adopted without any changes - look for a movement to diagnose "subthreshold" cases of T-DDD, as untreated subthreshold T-DDD will be found to cause untold psychological and physical damages across the world. Damages that can only be mitigated through aggressive treatment using [insert name of latest patented tranquilizer here]. So whatever antipsychotics or "mood stabilizers" are hot in 2013 when the DSM-V is released... they will be the "cure" for T-DDD or bipolar or whatever the hell we decide to label kids with behavior problems.

That's my first impression. This is definitely going to be a hot-button topic. There is apparently some mechanism to send comments to the DSM-V folks, since this is only a draft version - feel free to comment here or send your ideas to the DSM-V posse.

Do You Have Mild, Moderate, or Severe Depression? Here, Take This Placebo, er, Antidepressant

2010-01-05T15:08:00.001-08:00

Yet another meta-analysis with the same damn result -- antidepressants for most cases of depression are placebos. This is in a paper with authors including Jay Amsterdam, Richard Shelton, and Jan Fawcett, who are not exactly cut from the Peter Breggin mold. This was based on six studies which compared antidepressant to placebo in patients who had a wide range of depression severity. Key results:

Mild to moderate depression: Effect size of d = .11, which is tiny (and was not statistically significant)
Severe depression: Effect size of d = .17, which is pretty darn small (and not statistically significant)
Very severe depression: Effect size of d = .47, which is moderate.

Hmmmm. Not looking so hot. Of course, anyone who has paid attention to the clinical trial literature on antidepressants over the past 10 years or so already knew this. But now it's in JAMA, so a wider audience may now pay attention. Or ignore it. Good marketing usually beats science, so maybe this won't make any difference.

Antidepressants for all but very severe depression: All the benefits of placebo plus the added bonus of side effects. Sign me up! To quote the authors: "What makes our findings surprising is the high level of depression symptom severity that appears to be required for clinically meaningful drug/placebo differences to emerge, particularly given the evidence that the majority of patients receiving ADM in clinical practice present with scores below these levels." In other words, most people who receive antidepressants would likely have done just as well on placebo (without the side effects).

A few other posts on the topic:

The long-lasting placebo effect
Sexual side effects of SSRIs
Paxil: How to lie
The much-vaunted public health benefits of antidepressants
Antidepressants offer weak efficacy for all but most severe depression
Hiding negative data on antidepressants
Suicidal tendencies? Nah, not here

I've linked the abstract of the latest JAMA study here. Enjoy.

Atypical Antipsychotics For Depression: Now With "Considerable Evidence"

2009-12-16T12:46:00.000-08:00

I've been wanting to write about this for months. Here goes. We know that antipsychotics are the new panacea for all things mental health-related, including depression (1, 2, 3). But critics kept pointing to a pesky lack of evidence that such treatments actually worked. Bristol-Myers Squibb, manufacturer of Abilify, has been running a disinformation campaign in medical journals to tout its drug as an antidepressant. Their attempts to paint a positive picture of Abilify's antidepressant properties and its allegedly fantastic safety/tolerability profile have been simultaneously tragic and amusing (1, 2, 3).

We're now moving on to something bigger... It ain't just Abilify, folks. It's all the atypicals. They are all antidepressants. According to the authors of a recent meta-analysis, for atypical antipsychotics: "At present, this body of evidence is considerably larger than that for any other augmentation strategy in the treatment of major depressive disorder." In other words, if you are not prescribing atypicals for your patients who don't show adequate response to antidepressants, you are not practicing evidence-based medicine. You are a [bleeping] cowboy who is willfully disregarding science. You are denying your patients the best possible treatment. The authors don't actually say any of those things, but those are the implications. If the evidence for using antipsychotics is "considerably larger" than the evidence for anything else, then the implications are clear-cut. And this is exactly how this study will be cited. Salespeople, from drug reps to academic psychiatrists, to practitioners looking to earn a few thousand extra bucks on the side through pharma speaking gigs, will discuss this study as if it were a landmark finding.

Response and Remission: But the "evidence" is not all that convincing. Here's why... The authors pooled together the results of 16 randomized controlled trials. In these studies, patients had failed to respond adequately (using various definitions) to an antidepressant. Patients were then assigned to receive either an atypical antipsychotic or a placebo in addition to their antidepressant. Outcomes were then tabulated somewhere between 4 and 12 weeks later. The results seem clear cut -- if your brain is turned to "off" -- the response rates for atypicals was 44% compared to 30% for placebo. The remission rates were 31% for atypicals and 17% for placebo. The advantage for atypicals is statistically significant. Well, there you have it. Done deal. Ask your doctor about Abilify/Zyprexa/Seroquel today...

But the most important thing in a treatment outcome study is... the outcomes. The authors of the meta-analysis did not bother to actually measure change in scores on rating scales. Instead, they only used response and remission rates. There is absolutely no good reason for doing this. It's potentially quite misleading. Doctors like remission and response rates because they provide the illusion that we are measuring depression exactly. A "responder" got a lot better and is functioning reasonably well whereas a "non-responder" is in bed 12 hours a day while spending the rest of her time watching the E! Network, eating Bon-Bons, and sobbing constantly. But it's not nearly that scientific. A "responder" is usually defined as someone who got 50% better on his or her depression rating score during the study period. So Bob's depression rating score improved by 52% (he's a responder), but Amy's score only improved by 48%, so she's a nonresponder. Is this 4% difference really meaningful?

Let's look at the following dataset for 20 participants in a fictional study...

Improvements in depression over course of 10 week study

Drug	Placebo
40%	30%
55%	60%
50%	45%
55%	48%
52%	48%
60%	55%
60%	55%
10%	25%
20%	10%
25%	30%

Using a 50% improvement to determine if a patient is a "responder", we get a 60% response rate on drug and a 30% response rate on placebo. Lazy logic says: Oooh -- the drug is twice as effective as placebo. But is we take the average for each group, we get an average improvement of 42.7% on the drug compared to 40.6% on placebo. See the problem with response and remission rates? Similar arguments have been made by smarter people than myself.

Putting outcomes into convenient little categories makes good sense when the categories themselves make sense - events like having a heart attack, getting pregnant, or dying. If the death rate on a drug is 4% compared to 2% on a placebo, then the drug really reduced death by 50%. But if the "remission rate" or "response rate" for depression is 40% on drug compared to 20% on placebo, that does not mean the drug is twice as effective as placebo in treating depression. If you need to score a 7 or below on a depression rating scale to be "in remission", but you score an 8, are you really much worse off than the person who scored a 7?

Am I saying that the drugs really just squeaked by placebo in these studies? Well, I've read the Abilify studies and posted on them previously - in those studies, Abilify barely beat the placebo. And in the opinion of the patients themselves, Abilify didn't beat placebo at all. And the studies were designed to benefit Abilify, not to actually see if the drug worked. As I noted previously...

Patients were initially assigned to receive an antidepressant plus a placebo for eight weeks. Those who failed to respond to treatment were assigned to Abilify + antidepressant or placebo + antidepressant. Those who responded during the initial 8 weeks were then eliminated from the study. So we've already established that antidepressant + placebo didn't work for these people -- yet they were then assigned to treatment for 6 weeks with the same treatment (!) and compared to those who were assigned antidepressant + Abilify. So the antidepressant + placebo group started at a huge disadvantage because it was already established that they did not respond well to such a treatment regimen. No wonder Abilify came out on top (albeit by a modest margin).

Here's an analogy. A group of 100 students is assigned to be tutored by Tutor A regarding math. The students are all tutored for 8 weeks. The 50 students whose math skills improve are sent on their merry way. That leaves 50 students who did not improve under Tutor A's tutelage. So Tutor B comes along to tutor 25 of these students, while Tutor A sticks with 25 of them. Tutor B's students do somewhat better than Tutor A's students on a math test 6 weeks later. Is Tutor B better than tutor A? Not really a fair comparison between Tutor A and Tutor B, is it?

I've not read the other antipsychotics for depression studies. I'll even give them the benefit of the doubt and assume they were not designed in the same biased manner as the Abilify trials. It is, however, worth noting that the "benefit" of Abilify, in terms of response and remission rates compared to placebo, was about the same as for the other atypicals. Which leads me to think that the other atypicals probably show similar marginal benefits for depression.

But now, based solely on potentially quite misleading response and remission rates, an article appears in the American Journal of Psychiatry - a piece that has the potential to ramp up the prescribing of antipsychotics for depression to an even more ridiculous level. Let the good times roll.

Source of ironclad evidence that atypical antipsychotics are antidepressants (until you actually read the paper):

Nelson, J., & Papakostas, G. (2009). Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials American Journal of Psychiatry, 166 (9), 980-991 DOI: 10.1176/appi.ajp.2009.09030312

Transcranial Magnetic Stimulation for Depression: Not so Effective, but FDA Approved

2009-10-30T06:39:00.000-07:00

Apparently, the FDA will approve just about anything as an antidepressant. Despite patients indicating that they don't perceive Abilify to work as an antidepressant, the FDA approved it, likely leading to tens of thousands of Americans being able to enjoy a taste of akathisia while getting all the psychological benefits of a placebo. Good work, FDA. The shift of antipsychotics into antidepressants has been documented in many places and is, ironically, very depressing (1, 2, 3, 4).

The FDA's "anything goes" attitude regarding antidepressants apparently extends to mediocre medical devices. In 2007, a paper in Biological Psychiatry presented results from a large trial comparing TMS to sham TMS. The article concluded that the treatment was a fantastic option for depression. Well, close to that anyway. That actually wrote that "Transcranial magnetic stimulation was effective in treating major depression with minimal side effects reported. It offers clinicians a novel alternative for the treatment of this disorder."

Before all of us poor depressed souls get in line for some sweet magnetic stimulation, maybe we should, like, look at the evidence. On the primary measure of outcome, the Montgomery-Asberg Depression Rating Scale, the results weren't quite statistically significant. So the sponsor tried to convince the FDA Neurological Devices Panel that the secondary measures showed super-impressive results. The problem: They didn't. The FDA review panel thought a few things (as can be seen in its entirety here):

The Panel’s consensus was that the efficacy was not established; some stated that the device’s effectiveness was “small,” “borderline,” “marginal” and “of questionable clinical significance.” The Study 01 endpoint with a p value of 0.057 per se was not considered a fatal flaw in the study analysis. The Panel did not believe that clinical significance was demonstrated with these results.
In general, the panel believed that the analyses of the secondary effectiveness endpoints did not contribute significant information to help establish the effectiveness of the device.
The Panel agreed that unblinding was greater in the active group, and considering the magnitude of the effect size, it may have influenced the study results. (35.8% of people receiving TMS reported pain at the application site compared to only 3.8% in the sham TMS group. This is a quick way to make a study unblind, as people experiencing pain could logically surmise that they were receiving TMS).
The Panel stated that there were too many non-random dropouts to reliably interpret these results. The Panel’s consensus was that the Week 6 data was of limited value and did not provide supportive data for establishing effectiveness. (After week 4, patients who did not show adequate improvement were given the option to quit the double-blind study; over half of patients departed the study after week 4).

One more doozy. A quote follows from a letter to the editor in Biological Psychiatry in which TMS is taken to task.

The authors note that some patient outcome measures were collected in the trial but omitted from the article. Of the 15 secondary end points the authors included in the paper, 11 were statistically significant. Of 11 secondary end points not included, 2 were statistically significant. Thus, the published end points were three times more likely to be statistically significant than the unpublished ones.

TMS was denied FDA-approval in January, 2007. But in October 2008, the FDA had a change of heart, approving the device. I'm not quite sure what changed the mind of the FDA.

The following disclaimer on the device's website is a bit funny:

NeuroStar TMS Therapy has not been studied in patients who have not received prior antidepressant treatment. Its effectiveness has also not been established in patients who have failed to receive benefit from two or more prior antidepressant medications at minimal effective dose and duration in the current episode.

So it's only demonstrated (weak) efficacy in people who have failed one (not zero, not more than one) antidepressant trial. Impressive, eh? To summarize, the sponsor and its affiliated academics wrote a paper in a major psychiatry journal in which positive outcomes were three times as likely to be reported as negative outcomes. The efficacy data were unimpressive according to an FDA panel -- and these panels are not known for being particularly choosy about efficacy data. It seemed that TMS was dead in the water, only to be resurrected in the form of a surprising FDA approval. And if being resurrected from the grave doesn't make for a great Halloween post, then what does?

Offending Study:
O’Reardon, J., Solvason, H., Janicak, P., Sampson, S., Isenberg, K., Nahas, Z., McDonald, W., Avery, D., Fitzgerald, P., & Loo, C. (2007). Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multisite Randomized Controlled Trial Biological Psychiatry, 62 (11), 1208-1216 DOI: 10.1016/j.biopsych.2007.01.018

Letter to Editor:
Yu, E., & Lurie, P. (2009). Transcranial Magnetic Stimulation Not Proven Effective Biological Psychiatry DOI: 10.1016/j.biopsych.2009.03.026

Lend Me Your Name

2009-09-19T08:28:00.000-07:00

Journalism regarding the horrors of ghostwritten papers in medical journals is all the rage these days (1, 2, 3). Here's my very small contribution. The document shown below from a medical writing company has been described elsewhere. But it is worth seeing in its glory firsthand. The document is from Wyeth's ghostwriting firm, DesignWrite. It was part of the Premarin/hormone replacement therapy disaster (see below). Perhaps you remember the era when hormone replacement therapy was being prescribed for all sorts of people because it was supposedly a wonder treatment. So what if it increased risk for breast cancer and perhaps other conditions as well? Not to worry, DesignWrite could get around that...

In layman's terms, it goes like this... Wyeth -- you give us some hints about the marketing spin you'd like us to put on your studies. We'll then write up the studies accordingly and have big-name academics sign off as if they had something to do with our oh-so-objective "research". And don't worry, Wyeth, you get to review all papers we write up to make sure we market your drug appropriately.

We now know that several academics participated in this program. To quote one ethicist, regarding the academics who lent their names as authors: "They sold their credentials for false credit and money." DesignWrite's current slogan is: "Where we put clinical data to work." Hmmm. DesignWrite gets paid, Wyeth gets paid, and the academics who lend their names get paid and/or get another publication to boost their stock in the academic world.

Oh, and patients, what did they get out this... breast cancer. But who cares about them anyway -- patients are just little buckets of money; it's not like they're real human beings.

A summary of the results that led to the downfall of hormone replacement therapy

Three years after stopping hormone therapy, women who had taken study pills with active estrogen plus progestin no longer had an increased risk of cardiovascular disease (heart disease, stroke, and blood clots) compared with women on placebo. The lower risk of colorectal cancer seen in women who had taken active E+P disappeared after stopping the intervention. The benefit for fractures (broken bones) in women who had taken active E+P also disappeared after stopping hormone therapy. On the other hand, the risk of all cancers combined in women who had used E+P increased after stopping the intervention compared to those on placebo. This was due to increases in a variety of cancers, including lung cancer. After stopping the intervention, mortality from all causes was somewhat higher in women who had taken active E+P pills compared with the placebo.

Based on the findings mentioned above, the study’s global index that summarized risk and benefits was unchanged, showing that the health risks exceeded the health benefits from the beginning of the study through the end of this three year follow-up. The follow-up after stopping estrogen plus progestin confirms the study’s main conclusion that combination hormone therapy (E+P) should not be used to prevent disease in healthy, postmenopausal women. The most important message to women who have stopped this hormone therapy is to continue seeing their physicians for rigorous prevention and screening activities for all important preventable health conditions.

I'm glad to see that ghostwriting is now the topic du jour in health journalism. But in a few weeks, the attention will vanish as the drug industry and its associated writing firms will agree to allegedly stringent guidelines that ensure this never happens again. And nothing will actually change. I mean, seriously, do you think academic researchers are going to write their own papers? Do you think drug companies are going to stop hiring writers to expertly spin the data? The current system works too well for it to simply go away.

Thanks to an alert reader for sending this document along. You can search for more documents at the Drug Industry Document Archive, including those from Wyeth and DesignWrite. Happy digging!

Wanted: Drug Pimp/Key Opinion Leader

2009-09-09T10:00:00.000-07:00

Daniel Carlat from the Carlat Psychiatry Blog received an invitation to the key opinion leader club from the good people at Schering-Plough. The company wanted him to read their slides to other physicians in order to promote their brand spanikn' new antipsychotic/mood stabilizer Saphris (asenapine). Because, of course, if he reads the slides, they are more credible than if read by one of those sleazy drug reps; it's so much more classy and believable if an "independent" psychiatrist reads the company's marketing copy.

Carlat posted the documents used in the attempt to recruit him (cover letter, speaker bureau arrangement, pimp, er, speaker fees) Everyone should read them. Speakers are only allowed to rake in $170,000 of dirty money through this program. I suppose anything more would make them look like shameless drug pimps. But if you were to take, say, $50k for your "educational" services, that would be totally acceptable, right? I hereby nominate anyone who accepts Schering-Plough's generous offer for the much coveted Golden Goblet Award.

What's the deal with this Saphris drug, anyway? One neuropsychologist reviewed the data and found that it promises to be yet another also-ran atypical antipsychotic, at best. Some have also raised questions of whether the drug deserved FDA approval at all. Get ready for some ghostwritten articles that present the evidence surrounding Saphris in a ridiculously biased manner, for key opinion leaders to travel to conferences extolling its virtues, and for the rest of the usual marketing tricks.

Key Opinion Leader Syndrome

2009-08-31T05:47:00.001-07:00

I ran across a rather hilarious article from Medical Hypotheses, in which David Healy described "Krapelin-Fraud Syndrome", which I have also dubbed "Key Opinion Leader Syndrome." See below for the diagnostic criteria.

In line with current neo-Kraepelinian thinking, we put forward operational criteria for this new disorder for provisional inclusion in ICD-XI or DSM-V. An affected subject should meet at least 2 of criteria A–D and 2 more from criteria E–J. Fulfillment of all criteria A–D in the absence of any other features of the disorder will make the diagnosis, although this may represent a syndromal variant.
(A) A pervasive pattern of travelling to scientific conferences and talking about research data that he has had no involvement in generating.
(B) Episodic logosagnosia.
(C) Unusual abilities to compartmentalise information.
(D) Will have a significant number of ‘‘ghost-written” articles.
(E) Actively seeks admiration by peers and subordinates.
(F) An exaggerated sense of own talents, which can be inferred from expectations of recognition as an expert in the absence of commensurate achievements. Happy in the role of opinion leader.
(G) Has a sense of entitlement, i.e. unreasonable expectations of favorable treatment from symposium and congress organisers.
(H) Liable to profound dysphoria if not involved with the ‘‘academic action”.
(I) May be unreasonably envious of the scientific achievements of others and is liable to denigrate these. Would also be unhappy if his colleagues had appeared on ‘‘educational” videos and he had not.
(J) Is unaware of the disorder quality of the syndrome.

Two case studies are included, one of which reads in part:

One of the striking features of his lecturing is the dissociation between his reputation as a critical and skeptical lecturer when dealing with topics on the main programme of the meeting and the extent to which he may be prepared to offer apparently enthusiastic and uncritical endorsement for a compound in a satellite symposium. Very frequently this uncritical endorsement will involve the recycling of outdated ideas, which it is difficult to believe that either B or indeed many of his audience can conceivably believe and which indeed he may contradict within the hour at another symposium.

Hmmmm. Enthusiastic and uncritical endorsement of [insert product name here]. That reminds me of a post or two I've written... I made a rough list of symptoms for KOL Syndrome in July 2008. Different symptoms, but same idea.

The Asenapine Chronicles?

2009-07-29T09:28:00.000-07:00

I'm not sure what to make of this. A lot of documents have become available on the Shearlings Got Plowed blog, which deal with the new antipsychotic drug asenapine. If I had the time, I'd be burying myself in the documents, as SGP claims that something fishy is going on. I encourage all interested readers to take a good, long look at the documents to see what (if anything) is happening.

Documents such as this one will catch your interest...

Thanks For Your Service, Now Take This Pill

2009-07-20T18:11:00.001-07:00

According to a freshly published study, one in five depressed patients receiving services through the VA healthcare system in the United States is taking an antipsychotic. Of those taking antipsychotics, 43% were taking them at high doses (schizophrenia doses rather than lower doses typically used in treating depression). The study, published in the Journal of Clinical Psychiatry, excluded patients with schizophrenia or bipolar diagnoses -- this means that the antipsychotics given to the depressed folks weren't mainly used to treat psychosis or mania. The sample size was over 190,000 patients, so one can't fault the study for not including enough patients. The researchers examined drugs taken within one week of their last antipsychotic prescription and found that 24% of patients were taking multiple antipsychotics at that point.

The most used medication was Seroquel. This is not suprising. Patients seen in mental health speciality clinics were the most likely to receive antipsychotics. So what are the consequences? Well, let's see. There's the high rate of akathisia and medicore efficacy of Abilify. And there's some tricky research involving Risperdal that seemed to suggest the manipulation of the statistics was more impressive than the actual drug in treating depression. Seroquel's unimpressive efficacy and problematic side effects are also not a ball of fun. And so forth. Isn't "progress" beautiful?

I know what some people are thinking, so before you waste your valuable time with a comment, consider this. I'm aware that many of these patients are suffering much more than a simple case of the blues. That doesn't mean we should throw heavy duty antipsychotics at them, particularly at high doses. Certainly there has to be something else. What might that be? Some psychotherapy, some medications, some case management - I ain't saying it'll be easy. But I'm willing to bet that chucking antipsychotics at them en masse is not the solution.

Will Pharma's (Tax) Free Speech Be Limited?

2009-07-15T13:29:00.000-07:00

Dan Neil has an absolutely marvelous column in the LA Times about pharma's bitching/moaning regarding increased regulation of its advertising and its potential loss of tax writeoffs associated with drug ads. It's nice to know that when I'm watching a misleading advertisement for, say, Cymbalta or Abilify, pharma is writing off the advertising cost on its tax bill. Big Pharma's legal consultants have weighed in for years on this topic, using such terms as "starkly unconstitutional," "censorship," "plainly violates the First Amendment", and adding that taking away the tax deduction is "Draconian punishment" - see this document from the pharma-friendly Washington Legal Foundation and just try to keep a straight face.

Neil writes that:

Currently in draft form, these [FDA] rules would dramatically raise the legal bar for risk disclosure. Not only would advertisements have to fully explicate serious side effects, the nature of adverse reactions, the risk of dependence, dangerous drug interactions and so on, but all of that would also have to be communicated in the most direct, unambiguous and, if you will, artless form possible.

And, picking some of the low-hanging fruit, Neil goes on to describe two of my most hated ads:

Consider, the current 75-second spot for Abilify, a powerful antipsychotic drug marketed as a potential add-on to antidepressants. At the 33-second mark, the warnings start: "thoughts of suicide," "elderly dementia patients . . . have an increased risk of death or stroke," "uncontrollable muscle movements [that] may become permanent" and so on. The astonishing thing is that Bristol-Myers Squibb spent more than $35 million in the first quarter alone to market this witch's brew.

Seizures, death, trouble swallowing. Jeez, I get depressed just watching the ad. Maybe that's the idea.

Another wonder drug -- as in, I wonder if this will kill me? -- is Wyeth's Pristiq. Again, the potential adverse reactions are alarming: "Antidepressants can increase suicidal thoughts and behaviors in children, teens and young adults," the ad says. "May cause or worsen high blood pressure, high cholesterol and glaucoma."

Scary stuff. And yet, the FDA might say, not scary enough. Because the voice-over rambles on with a litany of potential side effects, some of which is quite hard to follow, the commercial seems to violate the FDA's constraint that advertisements not overwhelm viewers' "cognitive load." On a more prosaic level, the imagery of this suffering woman suddenly redeemed by this medication, so that now she's playing with her family at the park, seems to vastly over-promise relief.

Vastly over-promising relief, indeed. Watching Congress, the FDA, the pharma-funded academic hired guns, and lawyers on these issues will make for an entertaining spectator sport. Not nearly as engrossing as watching the DSM-V drama unfold (1, 2, 3), but still a lot cheaper than going to a Yankees game.

Award Winning Journalism (?)

2009-07-14T18:44:00.000-07:00

Erroneous reporting wins prestigious award, starring Charles Nemeroff. Oy. Brought to you courtesy of Health Care Renewal. Read the full story and shake your head. Teaser:

Something about the simultaneously complex and sympathetic nature of mental health reporting is making reputable journalistic organizations and well-meaning reporters sloppy.

New American Psychiatric Association Prez: We Want Money

2009-06-19T10:59:00.000-07:00

In a recent speech, incoming American Psychiatric Association president Alan Schatzberg was quoted as saying:

"As the recent attacks on APA and leaders of the profession have occurred, it has struck me that some of the detractors in the press have voiced concern that some folks have earned too good a living, often by doing presentations," he said. "I have heard from colleagues and directly from one reporter asking me about one of my colleagues having too high an annual income. I can assure you these detractors would not ask the same question of a surgeon or radiologist earning 10 times the amount paid our colleagues. None of us do what we do for money. Yet, it is also time for us to realize that our members and residents have never taken vows of poverty, and the complexity of the work deserves to be recognized. We need to ask ourselves how we have contributed to our own devaluation with which others seem to resonate, and we need to reverse the course. The rewards for our dedication should not be limited to a sense of pride, but we are also entitled to be paid commensurate to the challenge.

So Schatzberg must be diving into dumpsters, begging at interstate off-ramps, and the like. Oh, wait a minute. This is the same Alan Schatzberg who in 2007 owned close to 5 million shares of Corcept (which translates into roughly 5 million dollars). I have no idea how many shares he owns currently. Corcept, in case you missed it, has shown its drug mifepristone (aka RU-486: "The Abortion Pill") is ineffective in relieving depression among patients with psychotic depression. Schatzberg, at one time, was the chief scientific officer of Corcept and was also the cofounder of the company. According to Corcept's website, he is still a scientific advisor. Despite the stuides of mifepristone showing negative results, the results were spun in a manner to make them sound as if they were positive (1, 2, 3, 4). In a press release, Schatzberg was quoted as saying that mifepristone "may be the equivalent of shock treatments in a pill." Right, with all of the negative studies, it's definitely shock treatment, meditation, and running a marathon all wrapped together in a capsule. Should he be paid "commensutate to the challenge" of trying to weave positive findings from negative results? I don't know what role, if any, he played in the misleading publications surrounding mifepristone. But in his role as chief of the scientific advisory board, I'd venture a guess that he had some involvement. But worry not, the negative results were not spun into positive findings for the sake of money, but for an altruistic love of patients with depression. I'm touched.

Schatzberg was also busted by yours truly putting his name on a duplicate publication that pimped Cymbalta, Lilly's antidepressant. The study presented data from the same set of patients who were involved in a previously published Cymbalta study. Scientific results are not meant to be published in nearly identical form in two different journals. But that didn't stop Schatzberg and his coauthors. If you've not read the lengthy post on this topic, please feel free to check it out in order to understand my cynicism regarding his recent speech.

Another quote from his talk:

We need to sit down with industry and come up with ways of interacting that are acceptable to both sides and fit with future guidelines. I have pledged to follow up on recent initiatives and work with Dr. Scully [APA's medical director] and our Board of Trustees to effect a new partnership—a partnership we can be proud of for what it contributes to the well-being of our patients and our profession.

I can only wonder what type of mutually agreeable interactions would meet Schatzberg's standards. Duplicate publication, serving as a scientific advisor for a company that writes scientifically dubious papers? And it appears that he's encouraging psychiatrists to be greedy -- take the money and don't feel bad about it. Taking industry money is perfectly acceptable in some instances, but it needs to be transparent, and there are plentiful examples of academics getting paid by industry and slanting science in a sponsor-friendly way.

And the clincher:

"The time has come," he said, "to be proud of what we do and to advocate for what we and our patients justly deserve."

Right, psychiatrists deserve to make as much money as possible bending science for corporate sponsors -- and they should be proud of it too. Am I being too cynical? Maybe. But when a guy with Schatzberg's record starts talking about psychiatrists needing to rake in more money from industry, it makes me think I'm living in Bizarro World. Get ready, APA memebers; it's going to be an interesting ride.

Greedy and Ghostly Scientists

2009-06-12T06:09:00.000-07:00

Story one: Zachary Stowe, psychiatrist at Emory University becomes Charles Nemeroff, Jr. Read all about it the Carlat Psychiatry Blog and University Diaries. And check out the WSJ Health Blog as well. The gist is that Stowe apparently did not report all of his external income from his many pharmaceutical industry gigs. Better yet, he was a frequent speaker for GlaxoSmithKline, which had the gall to cancel two of his commercial talks. He then wanted GSK to pay him even though he wasn't going to give the speeches. Read the relevant emails toward the bottom of this document. After reading about Stowe, refresh your memory about Golden Goblet Lifetime Achievement Award Winner, former Chair of Psychiatry at Emory University: Charles Nemeroff. Is there something in the water at Emory? Or is that just how we roll in modern academic psychiatry? Stowe is hereby nominated for a coveted Golden Goblet for his string of emails in which he attempted to shake down GlaxoSmithKline. Sometimes I think that the only thing worse than drug companies are the narcissistic academics who they employ as "key opinion leaders." Not all key opinion leaders are jerks; some are probably even able to reasonably balance their industry cash with being good scientists. But Stowe didn't really portray himself as Mr. Nice Guy in his string of soon to be infamous emails.

Oh, and this little gem:

"Especially disturbing is an email between employees at GSK and a public relations (PR) firm that the GSK hired. The email was titled “For your review/Paxil Breast Milk Press Release” and states:

"[P]lease review the attached press release and forward me any comments/edits.
As you may know, Dr. Stowe is on board for publicity efforts and NAME
REDACTED and I are coordinating time to meet with him next week to arm him
with the key messages for this announcement, which is slated for early February.
We are sending the release for your review at the same time in efforts to secure
distribution on Emory letterhead (as you know, would provide further credibility
to data for the media)."

In his testimony, Dr. Stowe confirmed that the press release was written by the PR
firm and concerned his research on Paxil and its presence in breast milk. He also
explained that placing the press release on Emory letterhead, as opposed to GSK letterhead, would make the data more credible to the public."

If I have this straight, Stowe was willing to place a press release written by a PR firm hired by GSK on official university letterhead to enhance its credibility. Apparently he wasn't concerned about his own credibility. Read the full document of Senator Charles Grassley's investigation of Dr. Stowe.

Part 2: Enter the Ghostwriters

One snippet, then go to Bloomberg for the rest:

Ensuring that medical journal articles presented Zyprexa study results in a positive light was one way for Lilly to reach its sales goal, company officials said in its plan, according to the documents. To do that, Lilly officials hired ghostwriters to prepare submissions to journals such as Progress in Neurology and Psychiatry, according to the unsealed documents. “The paper for the Progress in Neurology and Psychiatry supplement has been completed and sent to the journal for peer review,” Kerrie Mitchell, an employee of the public relations agency Cohn & Wolfe, wrote in a Feb. 23, 2001, e-mail to Michael Sale, a Lilly marketing official. The message was among the unsealed files. “We ‘ghost’ wrote this article and then worked with author Dr. Haddad to work up the final copy,” Mitchell said in the e- mail. Eric Litchfield, a spokesman for Cohn & Wolfe, didn’t immediately return a call requesting comment.

The Bloomberg story is based on a recently released set of internal Lilly documents. That's right -- more Zyprexa documents are on the loose. And the first round of documents provided some good stuff (1, 2, 3), so I can't wait to see what kind of chicanery will be revealed by the latest round. In one sense, it's not exactly news that Lilly ghostwrote Zyprexa papers. We all know that ghostwriting is rampant. How else do key opinion leaders get their names on dozens of papers per year when they are also flying around the country pimping drugs, holding administrative meetings, and doing all sorts of other tasks? But it's nice to have it officially documented that Lilly was playing the ghostwriting game with Zyprexa.

Abilify for Depression: Patients Give it an Oh-For-Three

2009-06-09T04:17:00.000-07:00

Abilify for depression: you've seen the ads. You've hopefully read this blog (1, 2) and the excellent series in the LA Times from Melissa Healy. The advantage over placebo is nothing to get particularly excited about. Especially from the patients' point of view. As I have mentioned previously, the two studies that were touted by key opinion leaders are supporting the efficacy of Abilify for depression suffered from a number of problems. Most germane to this post, the patient self-report rating scales did not indicate a significant advantage for Abilify in either study.

Well, yet another Abilify for depression study is out in CNS Spectrums and guess what... Still not a significant advantage over placebo according to patients. So in each of three large studies, Abilify has failed to beat a placebo according to patients' self-report. These three trials are the basis for the massive marketing campaign and an FDA approval. Abilify started off as an also-ran antipsychotic. But times have changed. Bristol-Myers Squibb's CEO prophetically stated in 2004 after Abilify's approval as a treatment for bipolar disorder:

This approval underscores our commitment to delivering innovative solutions that address unmet needs for a broad spectrum of patients with mental illness, as well as their families and health care providers.

He could as easily have stated: "This approval underscores our commitment to rebranding our unpopular antipsychotic as a Swiss Army Knife/broad spectrum psychotropic that treats everything under the sun. If I can get the FDA and the public to believe that this akathisia-inducing bottom feeder can treat depression, then I'll be LOADED, BWAAH, HA HA HA HA!!!"

OK, maybe he didn't actually say any of those things, but his "broad spectrum" comment was literally right on the money. Just don't ask those pesky patients what they think; they might tell you it's no better than a damn sugar pill.

Yes, I'm aware that on some other rating scales, Abilify was rated as superior to a placebo, but I'm thinking that if the patient self-report of depression is consistently not favorable for Abilify, then who are we kidding by calling it an antidepressant?

Robert M. Berman, Maurizio Fava, Michael E. Thase, Madhukar H. Trivedi, René Swanink, Robert D. McQuade, William H. Carson, David Adson, Leslie Taylor, James Hazel, & Ronald N. Marcus (2009). Aripiprazole Augmentation in Major Depressive Disorder: A Double-Blind, Placebo-Controlled Study in Patients with Inadequate Response to Antidepressants CNS Spectrums, 14 (4), 197-206

Pseudoscience, Candy, and Lamar Odom: Brought to you by Daniel Amen

2009-06-03T05:56:00.000-07:00

If you follow professional basketball, you've probably noticed that LA Lakers forward Lamar Odom has a well-deserved reputation for inconsistent play. When he's good, he's close to amazing, and when he's bad, he's of little use to his team. So how is this related to mental health? Does he have social anxiety disorder? No, get out of Ricky Williams mode and pay attention...

Odom eats candy. Lots of it. And that's why his play is inconsistent. At least that's the story according to Dr. Daniel Amen, who, according to the Los Angeles Times stated:

Odom freely confesses that he just can't help himself when it comes to the sweet stuff and always keeps a stash on hand of Gummi Bears, Honey Buns, Lifesavers, Hershey's white chocolate, Snickers bars, cookies and more. He eats the sugary snacks morning, noon and night, and even says he sometimes wakes up in the middle of the night, chows down on some treats, then falls back asleep.

This is bad news for the Lakers. I've been telling my patients for years that sugar acts like a drug in the brain. It causes blood sugar levels to spike and then crash, leaving you feeling tired, irritable, foggy and stupid. Eating too much sugar impairs cognitive function, which may explain why Odom doesn't always make the smartest decisions on the court. . . .

As a fan and a physician, it concerns me that our professional sports organizations and players are not more concerned about brain health, which includes nutrition. My advice to Odom and to all sugar addicts is to get your sugar consumption under control. You'll feel so much better and your brain will function better too. And, maybe the Lakers can get their 15th championship and Odom can get his first.

Now, remember that Odom's play is inconsistent, not consistently bad. And if he is eating sugar all the time, shouldn't his play be consistently poor? Oh, and is there any science at all to support the idea that eating sugar impairs athletic performance...? I'll admit to not being a top expert on this, but my brief search of PubMed did not bring up anything to support Dr. Amen's suggestions.

So who is this Amen guy, anyway? He claims that Alzheimer's can be detected early through the use of SPECT brain imaging (single photon emission computed tomography). And he sells vitamins/nutraceuticals on his site which, of course allegedly help to prevent cognitive deterioration. There is sooooooooo much more to read about Amen, and I encourage y'all to head over to Salon to read an excellent debunking of Amen's many pseudoscientific claims.

I've rolled my eyes at this guy for years, but now that he's trying to shoot his witchcraft at the fine sport of basketball, I've hit my breaking point. But what do I know... I mean, Amen apparently wrote that

From the first month that I started to order these (SPECT) scans, I felt that they had a special place in science and that I was led by God to pursue this work

And who am I to argue with a guy who was sent by God to practice medicine. But back to Lamar Odom; he insists that he ate candy for breakfast on the game days in which he played well against the Denver Nuggets. Well, maybe, but I bet a SPECT scan or two would figure out why his performance is inconsistent.

Dr. Amen also has some hot, hot science about the men, sex, and the brain. On The View, of all places. Get ready to cringe.

OK, fine. One more. Dr. Amen can target treatment for ADHD appropriately by... yes, using pricey and unproven brain scans! See below...

Open Up Yer Wallets

2009-05-22T09:58:00.000-07:00

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

Donate here.

Phase V, Abilify, and Vanishing Akathisia

2009-05-07T10:53:00.000-07:00

If you've been reading about Abilify for depression on this site, you've probably noticed that I've been down on Abilify for causing akathisia in a frighteningly high percentage of patients. In two recent trials, akathisia occurred in 25% of Abilify patients compared to 4% of placebo patients. What, exactly, is akathisia? That's still a matter of some debate. Let's turn to a recent Journal of Clinical Psychiatry article on the topic. Entitled "Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics," the paper purports to provide "a review of the literature on the incidence of drug-induced akathisia associated with the use of second-generation antipsychotics (SGAs) and first-generation antipsychotics (FGAs)."

It provides a few different characteristics associated with acute akathisia, including:

"Intense dysphoria
Awareness of restlessness
Complex and semipurposeful motor fidgetiness"

It mentions "...suicidal behavior has been described in patients with akathisia in case reports, both in patients receiving antipsychotic medication and in patients receiving selective serotonin reuptake inhibitors (SSRIs)."A couple of descriptions from another journal:

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

So we can all agree that akathisia does not sound like fun.

Now back to the Journal of Clinical Psychiatry review article. What did the authors conclude? "The comparative incidence of akathisia among the newer antipsychotic agents remains poorly characterized." And "...SGAs are generally associated with a lower propensity for movement disorders compared with their FGA counterparts, an emerging body of comparative literature shows that second-generation medications are not completely free from inducing akathisia."

The authors go through a long list of second-generation antipsychotic medications. The drug that receives the least attention is aripiprazole (Abilify). The authors conclude that "in studies comparing aripiprazole with placebo, akathisia rates in the aripiprazole arm were similar in some studies, and higher in others. As with other SGAs, akathisia rates with aripiprazole were lower than those of FGAs." So Abilify causes less akathisia than older medications and it's unclear if it causes more akathisia than placebo. But, wait, wasn't akathisia related to much higher rates of akathisia than placebo in treating depression? Fortunately, the authors had a little trick to erase that inconvenient piece of evidence; they only examined trials trials involving people diagnosed with schizophrenia or bipolar disorder. So the depression studies -- POOF -- vanished, along with their damning data.

Why would the authors want to censor negative data about Abilify? Well, one author is an employee of Otsuka America Pharmaceutical, Inc., and another is an employee of Bristol-Myers Squibb, companies that market Abilify. And the other authors: All but one of them have a financial relationship with Bristol-Myers Squibb. The best part:

Editorial support provided by Maria Soushko, Ph.D., Phase Five Communications, Inc., New York, N.Y., with funding provided by Bristol-Myers Squibb.

So a paper that excludes the most inconvenient evidence regarding akathisia on Abilify had major parts of the writing done by... a medical writer hired by Bristol-Myers Squibb. If one goes to Phase Five's website , the first animation that pops up says "Spinning Your Science Into Gold." I'd say that this article was indeed 24 karat gold. I hereby nominate all authors of the study for a much coveted Golden Goblet Award.

Citation Below:

Kane, J., Fleischhacker, W., Hansen, L., Perlis, R., Pikalov, A., & Assunção-Talbott, S. (2009). Akathisia: An Updated Review Focusing on Second-Generation Antipsychotics The Journal of Clinical Psychiatry DOI: 10.4088/JCP.08r04210

Update: See a related post at the Carlat Psychiatry Blog. A partial quote:

Publishing an article that was carefully crafted to draw attention away from Abilify's main liability was shameful, and is exactly the kind of deceptive editorial practice that we as a society can no longer tolerate.

Abilify Runs Amok, Runs Stealth Safety Campaign in Medical Journal

2009-04-29T05:45:00.000-07:00

Furious Seasons has a rather distressing piece of news from a recent Bristol-Myers Squibb conference call. To sum it up quickly, BMS claims that 10.6% of depressed patients are now receiving atypical antipsychotics. Of those 10.6%, 21.7% are taking Abilify. So that would mean roughly 10-11 in 100 depressed patients are taking antipsychotics and 2 of them are on Abilify. I shudder to think how many are on Seroquel. Or Zyprexa. It made me think of a post I wrote a few weeks ago in which I described the marketing of Abilify for depression. A huge market of depressed people just ripe for the picking.

Going along with this, BMS is pushing back on the issue of akathisa, the side effect that has garnered the drug much bad publicity (at least in the blog world; 1, 2, 3) via a medical journal article that distracts attention from Abilify as an akathisia-inducer. More on that to come soon. Ghostwriters, ignoring contradictory evidence; basically, an attempt to completely obscure the evidence on the topic. It's not the first time BMS has successfully placed a study with major flaws into a medical journal (1, 2). Details will be forthcoming.

David Healy: Marketing, Bipolar, and Biobabble

2009-04-17T05:35:00.000-07:00

In an interview with Chrisopher Lane on Psychology Today's blog, David Healy covers the gamut, including the marketing techniques used to pimp Zyprexa, academic spokespersons/key opinion leaders, and bipolar diagnoses run amok. I've been a fan of Healy's work for a long time, but this interview in particular is captivating. Some will claim that Healy is a "bipolar denialist" -- he states that bipolar is overdiagnosed and that the disorder is entirely misunderstood. The fur will continue to fly on bipolarity for years to come, or at least until drug companies run out of products to push for as "mood stabilizers." In the interest of being fair and balanced, Nassir Ghaemi has a rebuttal to Healy's opinion that is also worth reading.

Though I'm tempted to provide a snippet here, I'll instead direct readers to the interview. After a very interesting interview with Philip Dawdy, and now one with David Healy (and other interesting posts), I am really glad the Psychology Today has Christopher Lane on board. I'm sure some people are not pleased with Lane interviewing two of the more prominent critics of modern psychiatry. Giving both of them an outlet to express their views at length runs the risk of Lane being labeled as a Scientologist, as "antipsychiatry," a pharmascold, and as a general rabble-rouser. Good for him. Nice to see that a fairly mainstream publication is willing to step outside the box.

Abilify Marketing Blitz: Atypical Antipsychotics Gone Wild

2009-04-14T05:49:00.000-07:00

"The results are extremely unimpressive; they just squeak by," says Massachusetts psychiatrist Daniel Carlat, editor of the respected Carlat Psychiatry Report. For a clinician or a patient's family, the difference between those on Abilify and those who took a placebo "would be hard to actually see," he adds.

Dr. Carlat is referring to the comparison between Abilify and placebo in the treatment of depression, a topic I have discussed in depth previously (1 , 2 , 3, 4). The above quote comes from a Melissa Healy piece in the Los Angeles Times that throws a damper on Abilify's parade through depression.

Another Melissa Healy piece from the LA Times starts off as follows:

About a year ago, patients began trooping into the office of UCLA psychiatrist Andrew Leuchter, asking whether an antipsychotic drug called Abilify "might be right for them." Few appeared to be delusional, plagued by hallucinations or suffering fearsome mood swings. Mostly, they were depressed or anxious, and frustrated by the pace of their recovery.

Leuchter wondered what was up: Depressed patients didn't usually seek out drugs used to quell psychiatry's most disturbing symptoms.

What was up, he soon discovered, was spending on a new advertising campaign touting Abilify as an "add-on" treatment for depression. For the first time since the arrival of a new generation of antipsychotic medications -- six drugs called the "atypicals" because they work differently from the earlier generation of antipsychotic drugs -- the makers of one, Abilify, had been granted the legal right to market to a vast new population of patients beyond those with schizophrenia or bipolar disorder.

Here's Bristol-Myers Squibb's advertisement for the drug:

This is classic. BMS notes that two-thirds of depressed patients who take antidepressants will still have symptoms after a course of antidepressants. And they have a point: Antidepressants ain't exactly miracle pills. So the commercial implies that Abilify must be really helpful... But if patients add Abilify to their treatment regimen, then only about 25% of them experience remission of depressive symptoms. Isn't it a bit strange that Abilify is appealing to the two-thirds of patients who still have depressive symptoms after taking an antidepressant and offering them a treatment that will lead to remission for only one-quarter of them? Of course, no studies have compared adding Abilify to adding another antidepressant, adding psychotherapy, adding an exercise routine, or adding anything except a placebo. Oh, and given that Abilify led to remission of symptoms in about 25% of patients, while placebo led to remission in about 15% of patients, um, that's a pretty small difference. And keep in mind that the studies were designed in a manner that was almost sure to find a benefit for Abilify, as I have noted previously.

If Abilify was generally benign, then a relatively small benefit over placebo is acceptable. But, as I mentioned previously, the side effects are troubling. I took issue with a BMS-funded journal article/puff piece that tried to spin side effect data on Abilify:

The authors note that "adjunctive aripiprazole is relatively well-tolerated in patients with MDD." Relatively? Relative to what -- being hit with a baseball bat repeatedly? They note that akathisia occurred in 25% of patients on Abilify compared to 4% of patients on placebo. Restlessness: 12% vs. 2%; insomnia: 8% vs. 3%; fatigue: 8% vs. 4%; blurred vision: 6% vs 1%. The authors report that akathisia resolved in 52% of patients by the end of the study, which would also mean that for 48% of patients with akathisia, they were stuck with it at the end of the study. But don't worry, it's "relatively well-tolerated."

You gotta like any drug that induces akathisia at the same rate that it induces symptom remission. Psychiatrist Doug Bremner had a similar take on Abilify as showing a poor cost-benefit ratio. For a few descriptions of akathisia, see comments at this post on Furious Seasons.

Given the unimpressive scientific data regarding Abilify for depression on one hand and the drug's exploding sales on the other, I was sure glad to see a big paper such as the LA Times note that there really is a controversy here. And if Seroquel receives official FDA approval as an add-on treatment for depression, get ready for the marketing machine to reach a fever pitch. Viva Zyprexa, anyone? Melissa Healy covers the expansion of atypical antipsychotics from schizophrenia and bipolar disorder into depression in an article that y'all simply must read. I'll close with a sad-but-true quote from Yale psychiatry professor Robert Rosenheck:

The story's pretty clear, and pretty embarrassing for the profession of psychiatry, which has allowed itself to be led by marketing," says Robert Rosenheck, a psychiatrist at Yale University who has studied the effectiveness and expanded use of the atypical antipsychotics. "We know now what these companies' strategies are: The number of people with schizophrenia is limited, so the road to profitability goes through soccer moms. They need to market these drugs to ordinary people who have dissatisfactions in life.

Leading Psychiatrist Slammed in Leading Journal

2009-04-03T08:29:00.000-07:00

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

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

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

Back to the review...

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

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

The Vioxx Hit Squad

2009-04-01T05:59:00.000-07:00

"We may need to seek them out and destroy them where they live." The words of a Merck employee regarding people who dared to criticize its bestkilling, er, bestselling painkiller/heart attack inducer Vioxx.

According to The Australian , Merck

...made a hit list of doctors who had to be "neutralised" or discredited because they criticised the anti-arthritis drug the pharmaceutical giant produced. Staff at US company Merck & Co emailed each other about the list of doctors - mainly researchers and academics - who had been negative about the drug Vioxx or Merck and a recommended course of action.

The email, which came out in the Federal Court in Melbourne yesterday as part of a class action against the drug company, included the words "neutralise", "neutralised" or "discredit" against some of the doctors' names.

More about this and similar tales of evil at Before You Take That Pill. You might recall that the superhero team in videos used to train Vioxx sales reps was known as the V-Squad. Perhaps the V-Squad was sent out to "destroy them where they live?" Check out the V-Squad videos here and decide for yourself.

APA Monitor: We Don't Need No Stinking Evidence

2009-03-25T06:02:00.000-07:00

The American Psychological Association publishes two monthly publications for members, the well-regarded journal American Psychologist, and the APA's newspaper, Monitor on Psychology. I've been having issues with The Monitor for as long as I can remember. At times, I think the magazine makes claims that are not at all substantiated by evidence, which really bothers me. Why? Because psychology is supposed to be a science; it is what separates psychologists from life coaches or snake oil salesmen. I usually skim the Monitor for about 30 seconds per month, but when I saw the cover for this month's issue, my intuition told me to look out for voodoo. The title: Brain imaging: New technologies for research and practice.

So I browsed through the glossy pages, looking for something to catch my eye. Then, on page 36, there it was...

A pacemaker for your brain? Electric brain stimulation may give hope to people with unremitting depression

Oooh. Sounded promising, so I gave it my full attention. Keep in mind that this was in the "Science Watch" section. The article begins:

It's about the size of the letter "o" in this sentence and may have the power to lift deep, unrelenting depression.

OK, there's the attention-grabber. It then goes on to describe deep brain stimulation (DBS). Before long, I ran across:

Since 2005, more than 60 people worldwide have received DBS for treatment-resistant mood disorders. For about 60 percent of them, there's a "striking improvement in their symptoms of depression," says Andres Lozano, MD, PhD, a neuroscientist at the University of Toronto who performs DBS surgery.

Well, that practically screams "valid scientific findings," asking a surgeon if his technique works. What was he gonna say, "Nah, I think DBS is a bunch of hooey. I only do it because it pays really well." I'm willing to bet that physicians who practiced bloodletting were also quite confident that the majority of their patients showed "striking improvement," which is why we conduct controlled trials rather than rely on subjective opinion. Later in the article, the author notes that the results from DBS are "dramatic and promising." The author also notes that

A number of other behavioral and mood disorders might also benefit from DBS. Benjamin Greenberg, MD, PhD, a psychiatrist at Brown University in Providence, R.I., is using DBS to treat obsessive-compulsive disorder, with success rates similar to [Helen] Mayberg's and Lozano's. Also similar is Greenberg's claim that OCD people who've had DBS are then able to tolerate and respond to behavioral therapy.

This broad success leads Mayberg to believe that DBS is establishing itself as an important tool for treating disorders that otherwise won't budge.

OK, so Lozano claims that 60% of people make "striking improvement"; what about others? As mentioned above, Helen Mayberg has done some research on this topic. The article describes one of her studies. Here comes the most convincing evidence I've ever witnessed:

The initial trial included six people who met diagnostic criteria for major depressive disorder. The two researchers and their colleagues implanted electrodes in the white matter adjacent to their patients' subgenual cingulate cortexes and fired up their pacemakers. All the patients, who were awake during the procedure, reported a "sudden calmness or lightness," Mayberg and Lozano reported in the paper.
The researchers followed up with the patients by administering monthly depression scales. After six months, four of the six showed significantly fewer depressive symptoms. To make sure they weren't getting a placebo effect, Mayberg and Lozano secretly switched off the electrodes in their best-responding patient. After about two weeks, the patient's scores began to drop. After about a month, his depressive symptoms had returned. The researchers switched it back on and six weeks later he was back up to non-depressive levels.

So the author of the article, based on the subjective opinion of a psychiatrist and a neurosurgeon, along with and an uncontrolled study of six people concludes that DBS:

Has shown "broad success"
"A number of other behavioral and mood disorders might also benefit from DBS"
"May have the power to lift deep, unrelenting depression"
Has shown "dramatic and promising" results

The author threw in a few caveats about side effects (though he essentially gave it a clean bill of health), and also noted that DBS should be reserved for patients with longstanding depression and who have not shown positive results with other treatments. So it stopped short of being a blanket endorsement of DBS, yet it did really make it sound like a fantastic treatment for longstanding depression despite the very meager evidence cited in its support. I often complain about poorly designed studies, suppression of negative data, or misinterpreted results leading to drugs being touted as unrealistically safe and effective. But this article shows that it doesn't necessarily take drug company involvement to pimp a treatment well beyond the scientific evidence.

For all I know, DBS may turn out to be The Holy Grail in treating depression of all shapes and sizes. I cast no aspersions on the researchers mentioned in the article, as searching for ways to treat seemingly intractable cases of depression is doing God's work. But the writer did a horrendous job of overblowing the evidence in favor of DBS. This kind of article feeds the popular notion that psychologists are a bunch of flakes who know nothing about science. The APA Monitor can do much better than this.

Seroquel, Haldol, and The Full Court Media Press

2009-03-20T09:41:00.000-07:00

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

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

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

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

In an interview with the Pioneer Press last week, Schulz defended his research and presentation of Seroquel as accurate and ethical. However, he acknowledged the corporate press release from his APA presentation might have exaggerated in calling Seroquel "significantly superior."
"You know," he said, "I can't disagree with that."

Schulz said the following in the Star Tribune:

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

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

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

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

Abilify, Depression, and the Memory Hole

2009-03-10T04:46:00.000-07:00

The Primary Care Companion to the Journal of Clinical Psychiatry has a piece on Abilify for depression that illustrates many of psychiatry's woes. Full text of the article is here. The journal published an article titled "Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of two studies." The paper combines data from two previously published studies which examined the addition of Abilify to existing antidepressant treatment (1, 2). One of psychiatry's big-name academics, Michael Thase, signed on as lead author. I'm hoping that he didn't actually write the paper. Actually, there are eleven authors of the paper, which seems a little ridiculous given that the paper is an analysis of data which had already been collected for two previously published clinical trials. Seven of the authors are employees of Bristol-Myers Squibb (BMS) or Otsuka, which both market Abilify. Wait... If you look closely, you can see my favorite disclosure... In the fine print on the first page...

In case you can't read the fine print: In defense of Thase and the other academic authors, they may have not actually written any of the paper. Much or all of the writing appears to be creditable to Ogilvy Healthworld Medical Education. On their site, they note that they perform:

Clinical Development and Publications Management
Experienced medical writers work closely with authors, editors and publishers to provide our clients with a full range of publishing options.

Whatever BMS/Otsuka paid you for this one simply was not enough. Why? Because whomever wrote this thing did an admirable job of focusing on the positive and completely ignoring the negative.

Erasing the Patient's Opinions: Remember, the article's title states that it examines the efficacy of adjunctive Abilify (adding Abilify to existing antidepressant treatment). So you'd think the article would mention all of the relevant depression data from the two relevant studies. Well, no. In the two stuides which are discussed in the article, patients were assessed on depression using the following measures:

Montgomery Asberg Depression Rating Scale (MADRS)
Inventory of Depressive Symptoms-Self Report Scale (IDS)
Quick Inventory of Depressive Symptoms Self-Report Scale (QIDS)

Using the MADRS, the authors conclude that adding Abilify to antidepressant treatment is more effective than adding placebo to antidepressant treatment. OK, fine, though it's not by a particularly huge margin. Mysteriously, the authors do not even mention that the self-report scales (IDS and its subscale, the QIDS) were used in the two trials. And why would they? In both trials, Abilify was not significantly better than placebo on these measures. A letter to the editor pointed out this glaring weakness in Abilify's claims of efficacy, the response to which was weak:

Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.

In the publications of each of the two clinical trials, the authors tried to downplay the fact that Abilify was no better than placebo according to patient self-reports. Then, when publishing an analysis that combined the results of the two trials, the authors go a step further by not even mentioning that patients completed a self-report. Right down the memory hole. In my opinion, any reasonable academic author writing about such research would want to note the strengths and limitations of Abilify in treating depression. The lack of benefit on patient-rated measures is a major weakness. Yet several big-time academics signed off on this paper despite its complete scrubbing of negative data. For that, I hereby nominate each author for a coveted Golden Goblet Award. And I credit the ghostwriter at Ogilvy with a fantastic job of serving his/her corporate clients. You, sir or ma'am, deserve kudos for a marketing job well-done.

The instructions for authors who submit to the Primary Care Companion to the Journal of Clinical Psychiatry state: "Conclusions should flow logically from the data presented, and methodological flaws and limitations should be acknowledged." Um, does completely scrubbing negative data count as failing to acknowledge limitations? I can see that the peer reviewers and/or editor really paid close attention to this paper.

Safety: The authors note that "adjunctive aripiprazole is relatively well-tolerated in patients with MDD." Relatively? Relative to what -- being hit with a baseball bat repeatedly? They note that akathisia occurred in 25% of patients on Abilify compared to 4% of patients on placebo. Restlessness: 12% vs. 2%; insomnia: 8% vs. 3%; fatigue: 8% vs. 4%; blurred vision: 6% vs 1%. The authors report that akathisia resolved in 52% of patients by the end of the study, which would also mean that for 48% of patients with akathisia, they were stuck with it at the end of the study. But don't worry, it's "relatively well-tolerated."

Overall, another example of a "research" publication being little more than a puff piece in favor of a drug. With big-name academics signed on as authors to add credibilty and just a fine print mention of a ghostwriter.

I thank an anonymous reader for alerting me to this study.

Citation:

Thase ME, Trivedi MH, Nelson JC, Fava M, Swanink R, Tran Q, Pikalov A, Yang H, Carlson BX, Marcus RN, Berman RM (2008). Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of 2 studies Primary Care Companion to the Journal of Clinical Psychiatry, 10, 440-447

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

2009-03-06T10:33:00.000-08:00

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

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

Internal Documents Suggest that Seroquel Data Were Not Presented Accurately

2009-03-02T08:23:00.000-08:00

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

2009-02-27T08:36:00.000-08:00

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

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

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

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

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

What's Next for Schatzberg?

2009-02-13T11:04:00.000-08:00

An advertisement in the Psychiatric Times (page 34 of .pdf) calls for applicants for the Chair of the Department of Psychiatry and Behavioral Sciences at Stanford University, a position now filled by Dr. Alan Schatzberg. The Stanford Psychiatry Department webpage currently states, in part:

Under the direction of the Chairman and Chief Alan F. Schatzberg, M.D., the Stanford University Department of Psychiatry and Behavioral Sciences, a center for the advancement of psychiatric practice, research and education, has three goals:

To advance the understanding of the etiologies of psychiatric or sleep disorders and to lay the foundation for new treatment development.
To develop innovative treatments and to deliver comprehensive services on a continuum of care to patients in a high quality efficient and compassionate manner.
To train medical students, residents and clinical and research fellows in the science and practice of psychiatry and sleep medicine.

Looks like Schatz is out. I have noted previously that Schatzberg was deeply involved with a duplicate publication that pimped Cymbalta. Schatzberg's close involvement with Corcept, maker of mifepristone (Corlux), has also raised eyebrows. Mifepristone has been an utter failure in clinical trials, but the manufacturer has attempted to spin the data in ways that should be obvious to anyone with a smidgen of critical thinking skills. Charles Grassley has hit Schatzberg as part of the investigation into the tangled web of conflicted interests involving psychiatrists and drugmakers. There is also some evidence that Schatz was involved in the launch of Zyprexa for bipolar disorder.

Schatz is apparently out as department chair. I wonder who will take his place...

Thanks to an alert reader for the tip.

Abilify For Depression: I'm Not the Only Skeptic

2009-01-27T05:52:00.000-08:00

In April 2008, findings were published in the Journal of Clinical Psychopharmacology which claimed that the atypical antipsychotic aripiprazole (Abilify) was an effective add-on treatment for depression. I heartily disagreed with the study's conclusions, noting that the patient-rated depression measure did not demonstrate an advantage over placebo, an inconvenient result that the authors tried to explain away as if was unimportant. I also pointed out that the study design was biased in favor of Abilify:

Study Design. Patients were initially assigned to receive an antidepressant plus a placebo for eight weeks. Those who failed to respond to treatment were assigned to Abilify + antidepressant or placebo + antidepressant. Those who responded during the initial 8 weeks were then eliminated from the study. So we've already established that antidepressant + placebo didn't work for these people -- yet they were then assigned to treatment for 6 weeks with the same treatment (!) and compared to those who were assigned antidepressant + Abilify. So the antidepressant + placebo group started at a huge disadvantage because it was already established that they did not respond well to such a treatment regimen. No wonder Abilify came out on top (albeit by a modest margin).

Here's an analogy. A group of 100 students is assigned to be tutored by Tutor A regarding math. The students are all tutored for 8 weeks. The 50 students whose math skills improve are sent on their merry way. That leaves 50 students who did not improve under Tutor A's tutelage. So Tutor B comes along to tutor 25 of these students, while Tutor A sticks with 25 of them. Tutor B's students do somewhat better than Tutor A's students on a math test 6 weeks later. Is Tutor B better than tutor A? Not really a fair comparison between Tutor A and Tutor B, is it?

Some commenters agreed with my take on the matter while others did not. Two letters to the editor published in the latest Journal of Clinical Psychopharmacology raised concerns about the study. Alexander Tsai, from UCLA, wrote that he was concerned that the advantage for Abilify was small (2.8 points on the Montgomery-Asberg Depression Rating Scale ) and that the study design was biased in favor of Abilify (agreeing with my earlier point).

Dr. Bernard Carroll, wrote in his letter that:

The advantage of Abilify over placebo was small
There was no advantage on the patient-rated measure
Due to the notable side effect profile of Abilify, clinical raters could likely distinguish patients who were taking Abilify from those who were taking placebo, which could have biased their ratings. Thus, he questions if the study was truly double-blind.
The authors did not report whether the occurrence of several side effects were more common on Abilify than placebo. Dr. Carroll calculated that akathisia, fatigue, restlessness, and insomnia were all significantly more common on Abilify and wondered why the authors did not include such data in their report.
The authors did not note the relationship between akathisia (severe restlessness/tension) and suicide, which is concerning given that Abilify produces akathisia in droves.

The Defense: Robert Berman from Bristol-Myers Squibb wrote back to defend the study. His points were not impressive. Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.

Adverse Events: As for not reporting adverse events, well, there's a perfectly good explanation hidden somewhere in here...

...we have clearly reported rates of spontaneously reported treatment-emergent events that occurred at a rate of 5% or greater in any treatment group. As this study is not designed to collect adverse events in a systematic manner, statistical comparison between treatment groups is not appropriate.

So let me get this straight. They discussed "spontaneously reported" events, which would refer to the events reported by the patients without much questioning. Everyone knows that spontaneous reports are a joke because most side effects are not spontaneously reported. Based on spontaneous report, the rate of sexual side effects in SSRI's is quite low. But when you bother to ask people taking SSRIs questions about their sexual functioning, the rates of sexual problems increase drastically. So when Dr. Berman goes on to write that no suicide-related adverse events were reported in the study, keep in mind that the study investigators were not asking about such events. So it may be more accurate to say that nobody committed suicide during the study, but nobody was tracking suicidal ideation unless patients reported such problems themselves. Yes, suicidal ideation was covered a little bit by measures used in the study, but a more systematic assessment would have been helpful. To give the authors credit, at least they did include a couple measures of extrpyramidal symptoms, from which we gathered that akathisia happened in 25% of patients. Yikes.

Saying that the study was not designed to collect adverse event data in a systematic manner is frightening. If adverse event collection was not systematic, then the authors writing in the study report that "adverse events were generally mild to moderate" is meaningless. You can't say that adverse event data were not collected in any sort of systematic manner then also say that the study is "safe," as the authors claim in their paper. This is the definition of duplicitous. In any case, the authors should have reported that several adverse events were significantly more likely to occur on Abilify than placebo rather than making the ridiculous claim that comparing adverse event rates between treatment and placebo is not appropriate.

Dr. Berman does not address the less than 3-point benefit for Abilify over placebo. There is also no real explanation to address the concerns of Dr. Tsai and myself, who noted that the study design was biased in favor of Abilify.

Kudos to Dr. Caroll and Dr. Tsai for taking the time to write excellent letters which addressed quite problematic issues in this study. Every time I see a commercial pimping Abilify for depression, I cringe. It's good to know that some people in the medical community are seeing through the weak research that "supports" the use of Abilify as an antidepressant.

Citation for the offending study below:

Ronald N Marcus et al. (2008). The Efficacy and Safety of Aripiprazole as Adjunctive Therapy in Major Depressive Disorder Journal of Clinical Psychoopharmacology, 28 (2), 156-165

Zyprexa: Lilly Admits Guilt, But Also Blame Physicians

2009-01-16T07:33:00.000-08:00

In February 2007, I wrote a post in which I described evidence that Lilly's antipsychotic olanzapine (Zyprexa) was marketed off-label for dementia. The evidence I discussed was based on documents generously and bravely hosted at Furious Seasons. At the time, I was careful to avoid labeling the practices as illegal -- they were definitely unethical but I couldn't really say for sure what if a law was broken. However, a law firm known to represent Lilly was regularly visiting my website at the time, which made me think that Lilly was seriously concerned about legal troubles. I suppose they had good reason to be worried.

I can now officially say that the off-label marketing of Zyprexa for dementia was criminal. Lilly just admitted to committing a crime in the off-label marketing of the drug for dementia and settled legal charges for a cool $1.4 billion. And there are more cases still on the books.

For a really interesting take on this situation, listen to New York Times reporter Gardiner Harris. You can find his talk embedded in the New York Times story from January 14, 2009, which is linked here. The plea agreement in the latest case is available here.

It is important to remember that pimping Zyprexa for dementia is far from a victimless crime. Antipsychotics, including Zyprexa, have been linked to an increased rate of death in elderly patients and have also been shown to be of little to no more benefit than a placebo in reducing dementia-related symptoms (1, 2). For a disturbing account of the widespread inappropriate use of such medications, read this post and weep.

This is truly a case where lust for profits likely led to the early demise of who-knows-how-many patients. And we're just talking about dementia, not the other cases where Lilly went berzerk with marketing Zyprexa (1, 2).

Blame the Physicians Too: While much of the blame for the overuse of antipsychotics in the elderly can be placed on corporations such as Lilly, it is also true that Lilly does not directly administer the drugs. Physicians need to understand that prescribing drugs which have been found to offer little benefit but are linked to killing patients -- how is that legitimately practicing medicine? First, do no harm?? Yes, I know that dementia is a hell of a difficult condition to handle. But does that mean we should be doling out ineffective and potentially deadly treatments to "manage" persons with dementia. Yes, reps from Lilly (and likely others) wined and dined physicians, "educating" them about the benefits of Zyprexa and other antipsychotics. That's their job -- to positively spin their products. No different than a used car salesperson except that drug reps are typically much better looking.

Doctors need to use critical thinking skills -- you don't just listen to a drug rep or skim a drug-company provided journal article reprint then jump on the Zyprexa bandwagon. How about learning how to evaluate evidence so that junky marketing disguised as science does not persuade you to write inappropriate scripts? Yes, we can be outraged that Lilly and others pimp ineffective and dangerous treatments, but the physicians are the most important link. If they cannot be better educated to understand clinical trial results, and cannot take time to critically review the scientific literature, then this pattern will repeat itself over and over again. It takes tricky pharmaceutical marketing in combination with an audience that is unwilling to think critically for this type of tragedy to occur. And occur again, it will.

Unfortunately, the published scientific literature is quite biased, as negative studies tend to vanish rather than grace the pages of our journals. But it's still a much better idea for prescribers to actually read journals and critically examine their findings, as opposed to relying on marketing alone. Better yet would be for research data on medications (negative and positive) to be available for all to see.

The Budget Crisis, Universities, and Key Opinion Leaders

2009-01-12T05:47:00.000-08:00

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

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

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

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

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

Sowing the Seeds of Lexapro

2009-01-07T10:11:00.000-08:00

I'm reading an article with my jaw completely agape and I thought I'd share the pain. The good people at Forest Pharmaceuticals have put together a tragic waste of journal space. The editorial board at the journal Depression and Anxiety should call an emergency meeting to see how this thing got published. Any peer reviewer who put a stamp of approval on this should be forced to listen to Michael Bolton's Greatest Hits at maximum volume for 12 hours straight.

OK, so what am I having a fit about? Here's what happened in this so-called study. 109 primary care doctors were recruited to participate, for which they were doubtlessly paid a decent chunk per patient (not discussed in the manuscript). The lucky depressed patients of these physicians then received escitalopram (Lexapro) for six months. The manuscript mentions that the "investigators" (the primary care docs) "were not required to have previous clinical research experience to be selected for this study." Yeah, no kidding.

There was no control group, and there had already been dozens of studies on the effects of Lexapro in depression, so how are we getting any new info out of this study? Maybe because this is investigating Lexapro in primary care settings; maybe there was no research on that beforehand. Well, no. The manuscript writes that "The efficacy and tolerability of escitalopram in MDD have been extensively evaluated in primary-care settings," citing four relevant studies. So the study is actually not an attempt to answer a scientific question. So what, exactly, is this study?

Looks and smells like a seeding trial, about which Harold Sox and Dummond Rennie wrote:

This practice—a seeding trial—is marketing in the guise of science. The apparent purpose is to test a hypothesis. The true purpose is to get physicians in the habit of prescribing a new drug. Why would a drug company go to the expense and bother of conducting a trial involving hundreds of practitioners— each recruiting a few patients—when a study based at a few large medical centers could accomplish the same scientific purposes much more efficiently? The main point of the seeding trial is not to get high-quality scientific information: It is to change the prescribing habits of large numbers of physicians. A secondary purpose is to transform physicians into advocates for the sponsor’s drug. The company flatters a physician by selecting him because he is “an opinion leader” and incorporates him in the research team with the title of “investigator.” Then, it pays him good money: a consulting fee to advise the company on the drug’s use and another fee for each patient he enrolls. The physician becomes invested in the drug’s future and praises its good features to patients and colleagues. Unwittingly, the physician joins the sponsor’s marketing team. Why do companies pursue this expensive tactic? Because it works.

So these primary care doctors now feel like "researchers," even though their investigation had essentially zero scientific merit. That probably makes these "investigators" feel important -- and the association between feeling important/scientific and Lexapro is a feeling Forest was banking on to increase Lexapro prescriptions in Canada.

Findings: So what did this extremely important piece of seeding, er, research find? Get ready... Lexapro is safe and effective. To quote the authors: "Escitalopram was well tolerated, safe, and efficacious. Escitalopram can be used with confidence to treat patients with MDD in Canadian primary-care settings." And "As adherence to antidepressant treatment is paramount to achieving long-term recovery, the present results suggest that escitalopram should be considered among the first-line choices of antidepressant used in primary care." So with no control group, we can determine that a Lexapro prescription should be among the first things that come to mind when treating depression. This is mind-boggling. This journal often published good work, but this is among the most uninformative pieces of research I have read. Unless one is thinking about marketing, in which case it is very enlightening.

Citation: Pratap Chokka, Mark Legault (2008). Escitalopram in the treatment of major depressive disorder in primary-care settings: an open-label trial Depression and Anxiety, 25 (12) DOI: 10.1002/da.20458

We're All Mentally Disordered: College-Age Edition

2009-01-05T12:46:00.000-08:00

A study in the December 2008 issue of the Archives of General Psychiatry concluded that almost half of college aged Americans suffered from a DSM-IV disorder over a one-year timeframe. Yes, I am behind the curve on this one -- Furious Seasons was all over this last month (1, 2). Rather than rant about the very odd idea that half of young adults are suffering from a mental disorder, I want to start by mentioning one aspect of the study -- perhaps the most important one. Let's look at how the diagnoses were assigned. To quote from the study:

All of the diagnoses were made according to DSM-IV criteria using the National Institute on Alcohol Abuse and Alcoholism Alcohol Use Disorder and Associated Disabilities Interview Schedule–DSM-IV version, a valid and reliable fully structured diagnostic interview designed for use by professional interviewers who are not clinicians.

If the interviewers are not clinicians, on what basis are they trained to understand what makes for truly significant distress that might justify a mental health diagnosis versus someone who is suffering from more mild symptoms that do not comprise a mental disorder? Here's some information from a different study that used a different slice of the same overall dataset on which the December 2008 study was based:

Approximately 1800 lay interviewers from the US Bureau of theCensus administered the NESARC using laptop computer–assistedsoftware that included built-in skip, logic, and consistencychecks. On average, the interviewers had 5 years’ experienceworking on census and other health-related national surveys.The interviewers completed 10 days of training. This was standardizedthrough centralized training sessions under the direction ofNIAAA and census headquarters staff.

So the figures that will be trotted out in the media ad infinitum about the shoddy mental health of American youth are based on laptop-assisted interviews conducted by people who apparently have no formal training in mental health. Maybe mental health and related disability are really so easy to assess that we don't need experienced, formally trained interviewers. If that's the case, maybe we should just have Census Bureau interviewers provide initial mental health assessments in clinical care settings -- after all, if they are such good mental disorder detectors, couldn't we just train a bunch of interviewers rather than spend millions of dollars training and paying mental health professionals? Think of the savings!

I mean no disrespect toward the Census Bureau interviewers. They are performing important work that in many instances helps us to better understand the health of the nation. All I'm saying is that we might want to avoid uncritically accepting judgments of our nation's mental health based on interviewers who lack mental health training and experience.

KOL Continues to Vanish

2009-01-02T16:09:00.001-08:00

Charles Nemeroff, about whom I have written much, continues to disappear. His latest vanishing act: From a psychiatric research gathering in Berlin in late November 2008. Their website now reads: "Dr. Charles B. Nemeroff (Atlanta, the USA) called his participation off in the congress and its scientific contributions." We can only hope that they had another key opinion leader of his stature to replace him.

Back story.

The Incredible Vanishing Key Opinion Leader

2008-12-17T06:17:00.000-08:00

Charles Nemeroff, former chair of psychiatry at Emory University and key opinion leader extraordinaire has vanished. Not quite vanished from the face of the Earth, but from Medscape CME and now from a Georgia mental health commission. Nemeroff was found to have not disclosed a whole boatload of money he received from Big (and little) Pharma according to an investigation by Senator Charles Grassley. For example, it appears that Nemeroff received about $20,000 in cash from GlaxoSmithKline in one month in exchange for promoting GSK products to his peers.

I have previously written about a number of, um, "interesting" behaviors on the part of Nemeroff, which I recommend you read in order to understand that Nemeroff has, on several occasions, engaged in behavior that certainly appears to have placed the causes of his corporate sponsors over science. Not good for an "independent" researcher.

And now, it seems that Chuck Nemeroff is vanishing. Dr. Bernard Carroll noted that Nemeroff's continuing medical education offerings had vanished from Medscape and offered the following:

Well, good for Medscape. They came in for their share of criticism, here and here, a while back. Now they deserve credit for displaying ethical standards. Meanwhile, we are waiting for another company called CME Outfitters to get the message. Dr. Nemeroff is slated to moderate a raft of new programs for this company in the coming weeks, sponsored by corporations like Pfizer, AstraZeneca, and Ortho-McNeil Janssen. CME Outfitters' logo, after all, is Education with Integrity. Sooner or later the pharmaceutical corporations, like the CME companies, will understand that they are not helping themselves by trotting out a shopworn and sleazy KOL figurehead like Nemeroff for their marketing efforts. And other KOLs who up to now were willing to "wet their beaks" in these CME forums controlled by the Boss of Bosses Nemeroff will now be leery of associating with him.

Well, CME Outfitters is still rolling with Nemeroff. For example, he has an upcoming program called "Atypical Antipsychotics in Major Depressive Disorder: When Current Treatments Are Not Enough," which is a scary thought given that he appears to have been pulling data from thin air for a prior CME exercise in which he pimped risperidone as a treatment for refractory depression. Specifically, Nemeroff's presentation claimed that risperidone improved sexual function in a clinical trial, when the published article based on the trial's results said no such thing. In addition, Nemeroff's claim that risperidone had shown efficacy in a short-term study versus placebo for depression was also unsupported. So I'm thinking the upcoming program on antipsychotics for depression might be a fantastic example of marketing beating the crap out of science.

Georgia appointed a commission to address several issues within the public mental health system. They have completed a report. Interestingly...

The final version also does not contain the name of commission member Charles Nemeroff, an Emory psychiatry professor who has been a subject of a U.S. Senate Finance Committee investigation into whether drug company money paid to doctors and academics compromises medical research and scholarship. Nemeroff, an internationally known expert on depression, did not attend recent commission meetings.

But Nemeroff was appointed to the commission with some fanfare. The press release listing Nemeroff's accomplishments is pretty lengthy. The Georgia state legislator who appointed Dr. Nemeroff said, "I am confident that Charles will be an asset to this commission and will serve as a strong advocate for the people of Georgia being served [by] our mental health systems"

Yet Nemeroff was not on the final report. If it weren't for his work on CME Outfitters, I would be worried that we might need to file a missing persons report for Dr. Nemeroff.

Update (12-18-08): The Wall Street Journal Health Blog has two interesting posts on Dr. Nemeroff (1, 2). Read them and feel free to file them under "bizarre."

Treatment Guidelines and GSK's Open Disclosure

2008-12-10T10:22:00.000-08:00

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

2008-12-04T06:29:00.000-08:00

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

Key Opinion Leader With A Very Short Fuse

2008-11-25T06:25:00.000-08:00

Psychiatrist Joe "Short Fuse" Biederman of Harvard University is really in hot water now. The sordid details can be seen in a fantastic article by Gardiner Harris of the New York Times. Here's just one snippet:

In a November 1999 e-mail message, John Bruins, a Johnson & Johnson marketing executive, begs his supervisors to approve a $3,000 check to Dr. Biederman as payment for a lecture he gave at the University of Connecticut. “Dr. Biederman is not someone to jerk around,” Mr. Bruins wrote. “He is a very proud national figure in child psych and has a very short fuse.” Mr. Bruins wrote that Dr. Biederman was furious after Johnson & Johnson rejected a request that Dr. Biederman had made for a $280,000 research grant. “I have never seen someone so angry,” Mr. Bruins wrote. “Since that time, our business became non-existant (sic) within his area of control.”
Mr. Bruins concluded that unless Dr. Biederman received a check soon, “I am truly afraid of the consequences.”
A series of documents described the goals behind establishing the Johnson & Johnson Center for the study of pediatric psychopathology, where Dr. Biederman serves as chief. A 2002 annual report for the center said its research must satisfy three criteria: improve psychiatric care for children, have high standards and “move forward the commercial goals of J.& J.,” court documents said.

And from Bloomberg,

Biederman “approached Janssen multiple times to propose the creation of a Janssen-MGH center,” according to an e-mail from a J&J executive. The center would “generate and disseminate data supporting the use” of Risperdal in children, the e-mail said. Pediatric use was approved by U.S. regulators in August 2007.

Wow. And the plot sickens, er, thickens from there. Normally, being caught with one's hands this deep into the cookie jar would lead me to write a much more blistering piece, but the day job shows no signs of abating in its workload. Fortunately, Philip Dawdy is rolling with the story at Furious Seasons (1, 2).

Let's see if Biederman's defenders can defend him in another op-ed as they did a few months ago. Or maybe we can leave Joe to defend himself. Here's what he said a few months ago when facing criticism:

Biederman dismisses most critics, saying that they cannot match his scientific credentials as co author of 30 scientific papers a year and director of a major research program at the psychiatry department that is top-ranked in the "US News & World Report" ratings.

"The critics 'are not on the same level. We are not debating as to whether [a critic] likes brownies and I like hot dogs. In medicine and science, not all opinions are created equal,' said Biederman, a native of Czechoslovakia who came to Mass. General in 1979 after medical training in Argentina and Israel.

Nope, most of his critics cannot match his credentials of apparently shaking down hundreds of thousands of dollars from Johnson & Johnson. But maybe I just like brownies and he likes hot dogs. Another key opinion leader whose reputation is deservedly shot to shreds. Nemeroff, Biederman, and the list goes on.

Staying Alive

2008-11-20T06:42:00.000-08:00

The day job has been merciless lately and promises little relief in the near future. Thanks for the emails. I am surviving and hope to write something here relatively soon (emphasis on relatively).

You Really Can Report Safety Data

2008-10-31T05:40:00.000-07:00

A new study concluded that the combination of sertraline (Zoloft) and cognitive-behavioral therapy (CBT) worked better than either treatment alone for children with anxiety disorders. There was even a nonsignificant trend for Zoloft to outperform CBT, which was quite surprising to me. But that's not really the point of this post. The study can be read at the New England Journal of Medicine website.

I'd like to commend the researchers on doing something that is exceedingly rare in psychopharmacology and psychotherapy trials -- they gave a detailed report of adverse events. And we find that a greater percentage of kids showed suicidal ideation on... CBT. It was not a statistically significant difference, but it was nonetheless surprising. Zoloft, however, was related to significantly more disinhibition, irritability, restlessness, and poor concentration than CBT. This may have been a fluke, but two participants on Zoloft had "homicidal ideation" compared to none on CBT. I have bitched several times about missing/mysterious data on adverse events in psychiatric drug trials, and some have also complained that psychotherapy trials do a poor job of tabulating adverse event data. Again, kudos to the study authors for reporting adverse events; imagine if reporting safety data in such a manner was commonly practiced.

Source: J. T. Walkup, A. M. Albano, J. Piacentini, B. Birmaher, S. N. Compton, J. T. Sherrill, G. S. Ginsburg, M. A. Rynn, J. McCracken, B. Waslick, S. Iyengar, J. S. March, P. C. Kendall (2008). Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood Anxiety New England Journal of Medicine DOI: 10.1056/NEJMoa0804633

Psychiatric Diagnoses: Fact or Fiction?

2008-10-27T05:35:00.000-07:00

Below is a guest post from Tim Desmond. I do not necessarily agree with all of the the contents of the post below, but I thought the topic was thought-provoking and controversial, so I have agreed to publish it. Feel free to add comments as you see fit; I will likely add my two cents in the next couple days...

I would like to contribute to the discussion on this blog by summarizing the work of Richard Bentall, psychologist and award-winning author, on psychiatric diagnosis and the DSM-IV. While we may be able to agree that long-term use of neuroleptics should not be the treatment of choice for schizophrenia, or that bipolar disorder is being over-diagnosed in children, I would invite us to question whether 'schizophrenia' or 'bipolar disorder' are valid diagnoses at all. Over the course of his career Richard Bentall has critiqued the medical model of modern psychiatric diagnosis and proposed instead a more personalized symptom-based approach.

The basic question is this: Do people suffer from a finite number of discrete psychiatric disorders/diseases or do people experience varying degrees of human suffering in their own idiosyncratic ways (which include spectrums of sadness, fear, dissociation, etc)? The modern mental health establishment clearly subscribes to the former as evidenced by the structure of the DSM and the theory of 'chemical imbalance.' This belief is so pervasive that even people who claim to disagree with the medical model of diagnosis often think within its terms. For example, the idea that one can be 'misdiagnosed' presupposes that a correct diagnosis could exist. Similarly, saying that schizophrenia is partially caused by psychological factors assumes that 'schizophrenia' is a valid way to group people.

The theory that psychological distress is caused by a finite number of psychiatric diseases can be attributed to Emil Kraepelin, who first published his Compendium of Psychiatry in 1883. Kraepelin believed that the psychiatric patients he treated suffered from diseases analogous to any treated by a practitioner of internal medicine. (Note the common comparison today between psychiatric diagnoses and diabetes forwarded by the pharmaceutical industry.) He said a specific disease process should generate identical symptoms, have identical pathological anatomy and identical etiology (or cause). According to Kraepelin, all that was needed was for these diseases to be discovered in order for diagnosis and treatment in psychiatry to catch up with the rest of medicine. Since it was far beyond the knowledge of his time (or ours for that matter) to find common pathological anatomies or etiologies, he chose to group symptoms. He believed that if he grouped symptoms 'correctly' the people grouped together would be sharing the same underlying disease. They would therefore have the same anatomical problems, the same etiology and respond more or less identically to treatment. He hoped that this kind of systematizing would lead to great advances in the efficacy of treatment.

While Kraepelin's categories have changed over time and grown from 3 to over 200, the basic idea persists to this day – that there are a finite number of discrete psychiatric disorders/diseases people can have and if we were to somehow group symptoms 'correctly' we would have isolated real disorders/diseases.

The problem with this idea is that it is not at all based in evidence. It began as Kraepelin's assumption and he was unable to provide any research in his lifetime to support it. However, it has been an idea so compelling to psychiatrists that they have tried in vain to support it for over one hundred years. In fact, there is a large body of research that directly contradicts this theory.

For example, you would expect that if one doctor diagnosed you with Strep Throat, you would be able to go to any other doctor and get the same diagnosis – and you'd be right. The reason for this is that Strep Throat is a real disease associated with an infection of streptococcal bacteria. You either have it or you don't and there are reliable ways to test if you do.

However, if you are experiencing severe psychological distress and one psychiatrist diagnoses you with "bipolar disorder" there is only a 50-60% chance that the next one you see would give you the same diagnosis. Why is this? Both psychiatrists would have been highly trained in diagnosis, and they would be using the same criteria to make their judgment. So if one says you have PTSD, another says bipolar and a third says brief psychotic disorder, which is the "correct diagnosis?" What do you really have?

Bentall argues the problem is that Kraepelin's main assumption – that there are a finite number of discrete psychiatric disorders – is just not true. You don't have any of those disorders because they are not real. Instead he argues that any psychiatric patient is experiencing a high level of emotional distress that is expressing itself through a range of symptoms and these symptoms can be better understood as extreme expressions of normal human responses to distress.

Bentall advocates for abandoning psychiatric diagnoses altogether. He claims that psychiatry's stubborn attempt to treat mental distress as a medical problem is what has led to its inability to improve treatment outcomes over time. Citing a large body of research, Bentall shows that symptoms from depressed mood to hallucinations can be accounted for psychologically and that doing so is not only more in line with science but more humanizing to patients. Therefore he favors what he calls a 'complaint-oriented' approach in which each patient would be assessed according to his or her unique symptomology. The focus becomes the symptoms themselves and we avoid trying to groups them into arbitrary non-existent disorders. Symptoms can be understood and treated, while disorders cannot because they are not real.

To learn more about Bentall's work, read his 'Madness Explained' which won the British Psychological Society's Book Award.

Author Note: Tim Desmond offers phone counseling and training for therapists through his website at www.coherencecounseling.com

The Latest on Kiddie Bipolar

2008-10-18T07:46:00.000-07:00

A recent study in the Archives of General Psychiatry claimed that kiddie bipolar tends to become adult bipolar. I have read the study and have a few comments. First, the authors' main findings:

Children diagnosed with bipolar went on to have a manic episode 44% of the time.

Let's look at the study sample. Seven to 16 year olds who were experiencing a manic or mixed episode. At 8-year follow up, 54 kids had reached at least age 18. So we're talking about 24 of 54 kids who went on to experience a manic episode as adults. Not exactly a huge sample. As time moves along, there will likely be more kids from this study who experience manic episodes as adults, so it is very much possible that when all 115 kids originally enrolled in this study hit, say, age 30, more than half of them will have experienced a manic episode as adults.

The argument then goes that we must treat child bipolar early and intensely in order to prevent these kids from going on to develop bipolar disorder as adults. So, were these kids receiving treatment? Definitely. These kids received whatever treatment was offered in the community, which doubtlessly included stimulants, mood stabilizers, antidepressants, and antipsychotics. On many occasions, they were probably undergoing some serious polypharmacy driven out of desperation rather than any sort of reasonable evidence base.

So did the treatments work? 88% of people who had an original manic or mixed episode recovered, but 73% of these kids then had a relapse afterward. And if nearly half went on to experience mania as adults, doesn't that mean that treatment was not exactly working very well? At this point, the authors have not reported what treatments were used, but I am willing to bet that the polypharmacy I mentioned above was often in place and that very few of these kiddos weren't receiving regular psychopharmaceutical treatment.

Bipolar was not the only problem facing these kids. 94% had an ADHD diagnosis at some point during the 8-year followup and a similar number had some sort of disruptive behavior disorder diagnosis. So it's not just bipolar. As I've been saying for a while now, bipolar is just the name du jour for kids whose behavior is really, really bad. We used to call it ADHD or conduct disorder and now it's ADHD, conduct disorder, and bipolar disorder just abbreviated as "bipolar," driven by the market reality that there are quite profitable drugs used to oh-so-successfully treat kiddie bipolar. But it seems they can't be working that well if 73% of these kids who recover from an episode end up relapsing.

I would love to write more about how bipolar was diagnosed in these kids, but I've not been able to land a copy of the measure used to make bipolar diagnoses in the study. The authors state that they only counted episodes that met DSM-IV criteria; if I ever find time, I might look at this more closely.

And note that we don't know what happened to the youngest kids in the study (those who started at ages 7 or 8) because none of them were adults at the end of this study. This study did not include anyone younger than 7, so the rash of 4 year olds being diagnosed as bipolar is left unexamined.

Bottom Line: Assuming that the diagnoses were valid, this study makes me think that:

Kids who show really bad behavioral and emotional problems often become adults with major psychological problems. Not exactly earth-shatteringly surprising.
Treatments for child/adolescent bipolar are not working very well.

Furious Seasons also has a number of concerns about the study.

APA Membership Rejects Torture

2008-10-10T10:57:00.000-07:00

APA Membership Rejects Torture

The American Psychological Association membership recently overrode their leadership (the Council of Representatives) via member vote. After significant grassroots organization by several psychologist organizations, the APA was forced to send out a ballot asking members whether APA members should be allowed to work in settings where detainees were held in inhumane conditions and/or in sites that operate outside of the Geneva Convention. And over 60% of respondents said no to psychologists working in settings where inhumane treatment occurs unless it is in the service of detainees, treatment to military members, or a human rights organization.

Then APA President Alan Kazdin issued a letter to President Bush. The full text is available here. Here's one particularly relevant excerpt:

So now APA has finally caught up with the American Psychiatric Association and the American Medical Association, who have banned their members from participating in such activities for years. Not all psychologists are members of APA, so APA does not have any jurisdiction over their behavior. Additionally, passing a change in policy does not physically stop some individuals, in the name of sadism, peer pressure, or defense of country, from abetting or engaging in torture. Nonetheless, on at least a symbolic level, it's nice to see that the membership of APA stood behind this issue.

Let me clearly mention that I have nothing against psychologists in the military, as the mental health needs of the military and their families is a highly important issue. Another important principle: Do No Harm, including to so-called enemy combatants or whomever else was receiving "enhanced interrogation" from psychologists and others.

APA, of course, has always been against torture in principle, but the position they took against it was a little watered-down for my taste, so I'm glad to see that their stance has, by force of the membership, become more clearly anti-torture. An interesting piece from one of the most prominent advocates of altering APA policy on this matter can be read here. The disgusting work products of some psychologists who actively engaged in torturous practices are described in a rather shocking Vanity Fair article.

And please, oh please, let nobody take the tack that I am some left-wing pro-terrorist nutjob just because I believe that torturing the hell out of people is both unethical and ineffective.

A Month in The Life of Chuck "High Life" Nemeroff

2008-10-06T14:48:00.000-07:00

The psychiatry world is belatedly exhibiting outrage toward a man whose ability to lure pharma cash seems to know no bounds. He may be the textbook case of a key opinion leader. Of course, I speak of Charles "Bling Bling" Nemeroff. Rather than list the many questionable at best behaviors he has exhibited, each of which has called into question his standing as a scientist as opposed to a blatant drug marketer, I just want to a) direct everyone to a detailed list of his speaking engagements from GlaxoSmithKline and b) discuss a month of living the High Life, Nemeroff Style.

As is well known by now (1, 2), Nemeroff appears to have not been particularly forthcoming about the huge amounts he was making while moonlighting for every drug company on the planet (see below) despite requirements that he do so. According to psychiatrist Danny Carlat:

From 2000 to 2006, GSK paid Nemeroff a total of $960,488. Note that this was not research grant money, or money for Emory's psychiatry department. These were fees that went into his personal bank account, which he earned by either sitting on GSK's Advisory Board, or speaking to doctors about GSK products. His typical fee for a talk was $3500 plus expenses, but sometimes he made more.

Of this $960,488, the total amount he disclosed to Emory [his employer, to whom he was required to report such income] was $34,998.

According to a GSK document hosted by Senator Charles Grassley, Nemeroff took in over $20 grand in one month from speaking engagements for GSK. Not bad work if you can get it, eh? And this month doesn't seem unusual for Nemeroff. These are only his speeches for GSK -- he also gave speeches for several other companies. The document goes on and on -- 39 pages of paid speech listings, nearly all of them featuring Nemeroff. I just picked 03-30-00 to 04-30-00 because they were on the first pages of the document, which covers expenses from 2000 to 2008 for Dr. Bling Bling.

Nemeroff GSK Honoraria from March 30, 2000 to April 30, 2000

Date	Speaking Fee
03/30/2000	$4000
04/12/2000	$2500
04/19/2000	$4000
04/20/2000	$4175 (includes some 'expenses'; I suspect $4000 was the speaking fee)
04/27/2000	$4000
04/30/2000	$2500
TOTAL	$21, 175 (probably $21,000 excluding travel expenses)

Imagine making $20k in a month for basically reading slides a few times that were quite possibly entirely written by a drug company. And many of these talks were accompanied by posh meals, the kind that myself and most of my readers might eat once or twice a year.

Here's a Nemeroff disclosure from a recent journal article:

Dr Nemeroff has received grants from or performed research for the American Foundation for Suicide Prevention, AstraZeneca, Bristol-Myers Squibb, Forest Laboratories, Inc, Janssen Pharmaceutica, NARSAD: TheMental Health Research Association, the National Institute of Mental Health, Pfizer Pharmaceuticals, and Wyeth-Ayerst Laboratories; has been a consultant to Abbott Laboratories, Acadia Pharmaceuticals, Bristol-Myers Squibb, Corcept Therapeutics, Cypress Bioscience, Cyberonics, Eli Lilly and Co, Entrepreneur’s Fund, Forest Laboratories, Inc, GlaxoSmithKline, i3 DLN, Janssen Pharmaceutica, Lundbeck, Otsuka America Pharmaceutical, Inc, Pfizer Pharmaceuticals, Quintiles Transnational, UCB Pharma, and Wyeth-Ayerst Laboratories; has been on the speakers bureau for Abbott Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer Pharmaceuticals; is a stockholder in Acadia Pharmaceuticals, Corcept Therapeutics, Cypress Bioscience, and NovaDel Pharma Inc; is on the board of directors of the American Foundation for Suicide Prevention, the American Psychiatric Institute for Research and Education, the George West Mental Health Foundation, NovaDel Pharma Inc, and the National Foundation for Mental Health; holds patents on a method and devices for transdermal delivery of lithium (US 6,375,990 B1) and on a method to estimate serotonin and norepinephrine transporter occupancy after drug treatment using patient or animal serum (provisional filing April 2001); and holds equity in Reevax, BMC-JR LLC, and CeNeRx.

No, I didn't make that up. As Ed Silverman wrote at Pharmalot, "It also raises a question - when he did find time to do anything else?"

Uh-Oh Chuck, They Out To Get You, Man

2008-10-03T12:34:00.000-07:00

According to the New York Times and Wall Street Journal, it looks like Charlie "Bling Bling" Nemeroff is under investigation by Senator Charles Grassley. Gee, I can't imagine why. Maybe because documents indicated that he failed to report over a million dollars of income received from the drug industry? It also turns out that the Chuckster made nearly $3 million in consulting deals with pharma from 2000-2007. That doesn't mean that his behavior was ever influenced by such huge sums of cash, right? Oh, wait just a minute...

...It turns out that there were several incidences of unbecoming behavior involving Bling Bling, I mean, the esteemed Dr. Nemeroff. Who could forget the time that he conveyed what appears to be fictional data in a continuing medical education course? How 'bout an article that seems to overstate the advantages of Effexor (1, 2)? And his contradictory statements regarding the role of serotonin in depression? His involvement in a shady at best study on the effects of Risperdal in depression is also worth reading. In fact, for a summary of many issues regarding Nemeroff, feel free to read an earlier post that outlines many events and provides links for more in-depth information on each of them.

One of my first posts on Nemeroff was presciently titled: Uh-oh Chuck, They Out to Get Us, Man. Apparently, I was foreshadowing the present investigation. Don't feel too bad for Nemeroff; he should be able to afford excellent legal representation.

Maybe this latest mire in which Nemeroff finds himself explains the uptick in hits from Emory University and the Senate this site has been seeing lately?

Please also read Daniel Carlat's unflattering take on Nemeroff's behavior.

Prialt Pushed Through Duplicate Publication

2008-10-01T05:21:00.001-07:00

Apparently, the same data on Elan's pain medication Prialt (ziconotide) was published twice. Same data set. No reference in the second publication to the first publication. As I noted last week in a post about Cymbalta, that's not supposed to happen. It's the sort of thing that leads physicians to believe that a medication has a lot of supporting evidence -- "Of course I prescribe it; I've seen two positive clinical trials" -- when in fact it's just the same data being repackaged in another journal. The full story is contained in two posts at The MacGuffin (1, 2). An infomercial passing off as continuing medical education is also involved in the plot. Count The MacGuffin as an official must-read blog.

Gabitril Goes Down

2008-09-30T10:14:00.000-07:00

Gabitril (tiagabine) is an antiseizure medication from Cephalon, which just forked out a cool $425 million to settle charges that it marketed several drugs for unapproved conditions, including Provigil and Gabitril. Government investigators claimed that Gabitril was marketed as a treatment for anxiety, which is too bad considering that it struck out in three clinical trials against a placebo. Each study found no evidence that Gabitril was better than a sugar pill.

Gabitril was also allegedly marketed as a treatment for pain. I was unable to locate a single controlled study examining the efficacy of Gabitril for pain, though there were a small number of uncontrolled (i.e., not very useful) studies suggesting that maybe Gabitril could be used to treat pain. Regarding sleep, the placebo-controlled trials I located did not suggest that the drug was particularly effective (1, 2). So we're looking at a drug with essentially no controlled evidence of efficacy being pushed for pain, sleep, and anxiety. Well-done, Cephalon.

Some of the supporting evidence about the off-label marketing cases came from a sales rep who wore a wire to collect evidence on the company's marketing practices. Apparently a total of four company whistleblowers were involved. Shades of Peter Rost?

Read more about the case at the Philadelphia Inquirer.

PS. Cephalon published the negative anxiety Gabitril trials in June 2008. As is well-established, companies often fail to publish negative data about their products, so why is Cephalon being so open? A skeptic might note that with the legal case againt Cephalon gaining steam, it would look even worse if Cephalon was sitting on negative data. So perhaps knowing that bad publicity was coming due to the lawsuit led Cephalon to allow the negative anxiety results to be published, as they could state "Look at how open and honest we are." I'm just saying that it's a possibility.

Reference for anxiety trials:
Mark H. Pollack, Jane Tiller, Fang Xie, Madhukar H. Trivedi (2008). Tiagabine in Adult Patients With Generalized Anxiety Disorder Journal of Clinical Psychopharmacology, 28 (3), 308-316 DOI: 10.1097/JCP.0b013e318172b45f

Update: Also read a related post at Health Care Renewal. It mainly discusses Cephalon's opiate-laced "perc-o-pops" (Actiq) approved to treat cancer pain, but marketed in a much broader manner.

Follow-up mini-rant: Let's not excuse the physicians who jumped on board. Docs need to do a much better job of checking the evidence base, though when some of the evidence base consists of publishing the same data repeatedly and when negative trials are often not published, what kind of "evidence base" are we really talking about?

The Cymbalta Schatz-Storm: Duplicate Publication and Lying by Omission

2008-09-25T08:28:00.000-07:00

This post details the duplicate publication of data on the antidepressant duloxetine (Cymbalta). Marketing and "science" collide to produce hideous offspring: an experimercial that pimps Lilly's bogus "Depression Hurts" marketing for Cymbalta using the exact same (weak) data twice. Data were published in the Journal of Clinical Psychiatry (JCP), and then the same data were published a second time in the Journal of Psychiatric Research (JPR), a blatant violation of JPR policy. Oh, and Alan Schatzberg, president-elect for the American Psychiatric Association is involved in the story.

The study: Lilly conducted a rather uninteresting study of Cymbalta, in which patients who had not shown a treatment response to an SSRI were then assigned to either a) Direct switch: Switch to Cymbalta and immediately discontinue the SSRI medication or b) Start-Taper-Switch: taper the SSRI over a 2 week period while also starting Cymbalta. Note that there was not a control group of any sort, an issue that the authors dance around (i.e., essentially ignore) in the papers based on this study's data.

Publication #1 -- Journal of Clinical Psychiatry: Data from this study were published in the January 2008 issue of the Journal of Clinical Psychiatry. The findings were that, in essence, there were no notable differences between patients who were directly switched to Cymbalta as opposed to those who did the start-taper-switch method. But what do the authors conclude?

Despite the lack of control group, the authors get the message out that not only was depression improved, so were "painful physical symptoms." As anyone who has a television has probably noticed, Lilly has been pushing hard for quite some time to convince patients and physicians that Cymbalta will relieve depression and pain in depressed patients. So if the marketing points can be pushed in one journal, why not pimp the same idea using the same data in another journal?

Publication #2 -- Journal of Psychiatric Research: Data from the same study were published online (to appear in print soon) in the Journal of Psychiatric Research (JPR). And I mean the exact same data appear again in this paper. This is a huge scientific no-no. Findings are supposed to be published once, not over and over again. Journals are struggling to find space for new and interesting findings, so there is no need to waste space on duplicate data. In fact, to quote from JPR's website

Submission of a paper to the Journal of Psychiatric Research is understood to imply that it is an original paper which has not previously been published, and is not being considered for publication elsewhere. Prior publication in abstract form should be indicated. Furthermore, authors should upload copies of any related manuscript that has been recently published, is in press or under consideration elsewhere. The following circumstances indicate that a paper is related to the manuscript submitted to the Journal: a) any overlap in the results presented; b) any overlap in the subjects, patients or materials the results are based on.

So it's pretty clear -- don't submit data that has already been published. Here is a figure from the Journal of Clinical Psychiatry (JCP) article mentioned above:

And here is the same data, in a figure in JPR:

But wait -- that's just the beginning. How about the data tables... From JCP:

And the right-side half of this table in JCP:

And the exact same data appearing in JPR:

To be fair to these "researchers" in JPR, they reported data from subscales of two measures not reported in JCP. But the vast majority of the data is just reprinted from the article in JCP. Which is completely trouncing journal policy and, more importantly, conveying Lilly's marketing messages to the audiences of two different journals. Unfortunately, they apparently did not consider that some people might actually read both journals and notice that essentially the same article had appeared twice. Or, Lilly considered this prospect and said, "Who cares." I'll leave it to my readers to decide if they care.

Authors: The JCP paper was authored by David Perahia, Deborah Quail, Derisala Desaiah, Emmanuele Corruble, and Maurizio Fava. The JPR paper was "authored" by Perahia, Quail, Desaiah, Angel Montejo, and Alan Schaztberg. So to re-publish the same data, it was out with Corruble and Fava -- in with Montejo and Schatzberg. Why Schatzberg? We're almost there...

JPR describes the contributions of each author. For these two authors (Schatzberg and Montejo) who were not credited in the JCP paper, they were both described as "involved in data review and interpretation, including the development of this manuscript." How could they have been involved with data review and interpretation -- the vast majority of the data were already analyzed, interpreted and written up by other researchers in the JCP paper? Did they write the paper? Apparently not, since the JPR article mentioned that "Dr. Desaiah worked with Dr. Perahia to draft the manuscript..." So Montejo and Schatzberg could not conceivably have played any significant role in data analysis, interpretation, or writing the paper. It seems that if Desaiah and Perahia "drafted" the manuscript, then the most Montejo and Schatzberg could have done is to maybe review the paper.

So why is Schatzberg on the paper? Well, it just so happens, I'm sure by sheer coincidence, that Schatzberg is the co-editor in chief of JPR. So he'd be in a good position to help a paper that essentially republishes data from JCP with only minor additions make it into publication against his own journal's policies.

Nice work, Schatzberg. That's pimpin' it hard. That, my friend, is worthy of nomination for a coveted Golden Goblet Award. Congratulations. It is not the first time Schatzberg's "scientific" behavior has been noted. He has been stumping (in the face of much contradictory data) in favor of his pet drug RU-486/Corlux in the treatment of psychotic depression for some time. Between the bad science surrounding Corlux and Schaztberg's myriad conflicts of interest, much has been written (1, 2, 3, 4, 5) -- add another chapter to the chronicles of the storied American Psychiatric Association Leader. This reminds me of an earlier incident involving Charles Nemeroff.

Discussion: As I've noted previously, the discussion section of a journal article often contains key marketing points, science being relegated to secondary status at best. The JPR article provides a few good examples of Cymbalta's talking points:

The current paper focuses on pain-related outcomes, demonstrating that a switch of SSRI non- or partial-responders to duloxetine was associated with a significant improvement in all pain measures including six VAS pain scales, the SQ-SS and its pain subscale, and the SF-36 bodily pain domain.

Switch of SSRI non- and partial-responders to duloxetine resulted in mean improvements on all pain measures regardless of the switch method used.

Duloxetine, an SNRI, has previously been shown to be effective in the treatment of PPS associated with depression, and it is also effective in the treatment of chronic pain such as diabetic peripheral neuropathic pain (DPNP) for which it is approved in the US, Europe and elsewhere, so duloxetine’s effects on pain in our sample of SSRI non- or partial-responders was not unexpected.

Patients with MDD present with a broad range of symptoms including those related to alteration of mood and PPS, all of which may contribute to global functional impairment. Effective treatment of both mood symptoms and PPS associated with depression may therefore optimize the chances of functional improvement. Recent findings that residual PPS in depressed patients may be associated with impaired quality of life (Wise et al., 2005, 2007), decreased productivity and lower rates of help seeking (Demyttenaere et al., 2006) and a lower likelihood of attaining remission (Fava et al., 2004), further demonstrate the importance of effective treatment of PPS in patients with MDD, so duloxetine’s effects on PPS are reassuring.

Improvements in pain are consistent with previously reported studies demonstrating duloxetine’s efficacy for pain, either as part of depression, or as part of a chronic pain condition such as DPNP.

Where do I start? How about by mentioning that JPR states:

7. Discussion: The results of your study should be placed in the appropriate context of knowledge, with discussion of its limitations and implications for future work.

So maybe if there was research that questions Lilly's talking points about Cymbalta relieving pain in depression, such research should be discussed. Well, it just so happens that there is research, which analyzed Lilly's own clinical trials and found that Cymbalta was no better than a placebo or Paxil in treating pain in depression. This meta-analysis of Cymbalta trials was published in January 2008, yet the JPR article, which was originally received by JPR on March 26, 2008 did not mention the negative data. Hmmm, that doesn't exactly sound like placing the findings "in the appropriate context of knowledge," does it? All this talk about Cymbalta's fantastic analgesic effects despite Lilly's own data showing that Cymbalta is at best close to useless in treating pain among depressed patients. Another study that claimed to show Cymbalta was a helluva painkiller was also smacked in a letter to the editor a few months ago -- and the authors of the Lilly-sponsored trial conceded defeat by refusing to reply to the critiques of their study.

Better Than "Weak" SSRIs (Not Really): In the JPR study, it was mentioned that the evidence for SSRIs in treating pain is "weak." No disagreement on my end. But see, once SSRI patients switched to Cymbalta, their pain magically went away because Cymbalta, unlike SSRIs, relieves pain. Never mind the lack of control group, which was allotted a grand total of 15 words in the discussion as a potential limitation of the study. The authors also failed to note that prior research showed that Cymbalta was no better than Paxil in treating pain in depressed patients. And Perahia, the lead author of the JCP and JPR "studies" is certainly aware of the research showing that Cymbalta works no better than a "weak" SSRI, since he was the lead author on one such study! So he is quite aware that Cymbalta has never been shown superior to Paxil in treating pain, yet he accurately describes research indicating that SSRIs are "weak" pain treatments, but then neglects to mention that Cymbalta failed to demonstrate superiority to Paxil in treating pain in depression. This is called lying by omission.

I may pass along my concerns to the Journal of Psychiatric Research. My prior experiences in passing along such concerns to journals via my blog identity is that they either a) ignore my concerns entirely or b) instruct me to write a letter to the editor which would be considered for publication, with the stipulation that I use my real identity. Sorry, but a published letter to the editor is not worth blowing my cover.

Call for Action: Rather than my running into point b. from the last paragraph, how about one or more scientifically inclined readers submit your concerns to the journal, under the following condition: Make sure you read the original papers first to judge if my concerns are valid. Then, if you feel similarly, why not send a letter to the editor? This is bad science which does nothing to advance patient care -- it seeks only to advance sales of Cymbalta by pimping it as a painkiller in depression while ignoring all contradictory data. So let's try a little research of our own -- see if JPR is willing to address these issues or if they will be swept under the rug.

Reference to JPR article:

D PERAHIA, D QUAIL, D DESAIAH, A MONTEJO, A SCHATZBERG (2008). Switching to duloxetine in selective serotonin reuptake inhibitor non- and partial-responders: Effects on painful physical symptoms of depression Journal of Psychiatric Research DOI: 10.1016/j.jpsychires.2008.07.001

Update: Also see an excellent follow-up post on the topic at Bad Science.

Dear American

2008-09-23T09:24:00.000-07:00

As for our latest economic crisis, I couldn't resist stealing this from Angry Bear:

Dear American:

I need to ask you to support an urgent secret business relationship with a transfer of funds of great magnitude.
I am Ministry of the Treasury of the Republic of America. My country has had crisis that has caused the need for large transfer of funds of 800 billion dollars US. If you would assist me in this transfer, it would be most profitable to you.
I am working with Mr. Phil Gram, lobbyist for UBS, who will be my replacement as Ministry of the Treasury in January. As a Senator, you may know him as the leader of the American banking deregulation movement in the 1990s. This transactin is 100% safe.
This is a matter of great urgency. We need a blank check. We need the funds as quickly as possible. We cannot directly transfer these funds in the names of our close friends because we are constantly under surveillance. My family lawyer advised me that I should look for a reliable and trustworthy person who will act as a next of kin so the funds can be transferred.
Please reply with all of your bank account, IRA and college fund account numbers and those of your children and grandchildren to wallstreetbailout@treasury.gov so that we may transfer your commission for this transaction. After I receive that information, I will respond with
detailed information about safeguards that will be used to protect the funds.
Yours Faithfully Minister of Treasury Paulson

Doing Some Digging

2008-09-23T06:09:00.000-07:00

Some good material is coming. Unfortunately, it involves the same old people doing the same old tricks. But the scandal factor is reasonably high, so I assure that regular readers will not be disappointed.

In the meantime, check out another hot, hot psych blog: The MacGuffin. This fellow anonymous mental health blogger hates bad science. We're peas in a pod that way. And he's willing to diss research on both psychotherapy and meds. Dripping with sarcasm and with a sharp eye for spotting scientific shortcomings, I wholeheartedly encourage all readers to add the site to your list of faves.

Also, Danny Carlat is continuing to get into scrums with the CME industry and it's fun to read about.

Furious Seasons updates us on the FDA and child bipolar disorder.

As per usual, the Scientific Misconduct Blog has items related to scientific misconduct. Questions surrounding the behavior of a so-called regulatory agency and drug safety are brought to the fore yet again.

Findings from my latest investigations will hopefully be unveiled soon. Stay tuned!

Big Drugs, Small Brains?

2008-09-18T07:48:00.000-07:00

I've read on and off about brain shrinkage being linked to antipsychotics. I have not paid a lot of attention to research on the topic but kept it on my mental backburner. And now Furious Seasons notes that Nancy Andreasen is reporting that her research shows antipsychotics are strongly linked to brains getting smaller. The longer one takes these drugs, the smaller the brain. Does anyone want to set up a YouTube "This is your brain on drugs" video?

Interestingly, a group of researchers has claimed that olanzapine (Zyprexa) has "neuroprotective" qualities; it's good for your brain. Um, color me skeptical. Their research was based on rats, whereas Andreasen's work is on humans. Andreasen's latest work is not yet published, making it difficult to judge the quality of the findings. But research on monkeys exposed to antipsychotics found that:

In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume.

I am not a neuroscientist, but if both sets of findings were accurate, then we'd have people taking antipsychotics who have smaller but better brains. The more neuroscientifically inclined may wish to comment on this possibility, because it seems a little odd to me.

Bipolar Overawareness Week: New York Times Magazine Edition

2008-09-15T04:03:00.001-07:00

Jennifer Egan has a roughly 29,000 word piece in the New York Times magazine regarding child bipolar disorder. OK, maybe it just seemed that long. As is apparently required for such articles, there is a very lengthy story about an allegedly bipolar child that constitutes much of the article. I'll not be focusing on that. Instead, I'll be looking at how the article discusses the controversy surrounding the diagnosis. Quotes from the article followed by my comments follow:

The Diagnostic and Statistical Manual of Mental Disorders (the current edition is referred to as D.S.M.-IV) describes bipolar disorder as a condition whose average age of onset is 20, but virtually all the leaders in the field now say they believe it exists in children too.

Well, then. I found two psychiatrists whose opinion appears to differ. Jon McClellan seems to disagree that bipolar exists in young children, as does David Healy. I could probably find others without much difficulty. Maybe they are not "leaders in the field?" But ok, let's say that it does exist in young kids. I'll grant Jennifer Egan that most agree that bipolar exists in adolescents (but toddlers???), though at what rate is a matter of debate. And more importantly, who gives a rat's behind what people think? Um, maybe we should be more concerned about what the actual science has to say about it. And in that regard, there are some serious unanswered questions, as I've described before.

1. Does child bipolar really exist in substantial quantity?
2. Does treatment help kids with this "disorder"?

But to be fair to Egan, maybe I took the last quote out of context, because she adds a somewhat more balanced view by stating that:

Many clinicians say the illness looks significantly different in children than in adults, but the question of how it differs, or what diagnostic terms like “grandiosity,” “elevated mood” or “flight of ideas” (all potential symptoms of adult bipolar disorder) even mean when you’re talking about kids, leaves room for interpretation. For example, it’s normal for children to pretend that they are superheroes, or believe that they can run faster than cars, whereas in an adult, these convictions would be signs of grandiosity. Equally unclear is whether a child who is identified as having a bipolar disorder will grow up to be a bipolar adult. Work on the D.S.M.-V is under way, and discussions have begun on how to address the issue of bipolar children.

As Ellen Leibenluft, who runs the pediatric bipolar-research program at the National Institute of Mental Health, told me, “There definitely will be — and needs to be — more description of what bipolar disorder looks like in children, how one diagnoses it and some of the challenges.”

OK, that's better. But in general, the article focuses on the proponents of the child bipolar paradigm rather than those who raise concerns. And Egan discounts a big study in a pretty odd way...

A study last fall measured a fortyfold increase in the number of doctor visits between 1994 and 2003 by children and adolescents said to have bipolar disorder, and the number has likely risen further. Most doctors I spoke with found the “fortyfold increase” misleading, since the number of bipolar kids at the beginning of the study was virtually zero and by the end of the study amounted to fewer than 7 percent of all mental-health disorders identified in children.

Huh? So it's misleading to say that for every one treatment visit for bipolar in 1994, there were 40 in 2003? No, that's exactly what the study found. Let's try an analogy. The rate of suicide among kids and teens, on an absolute scale, is very low. Very few children and adolescents actually commit suicide. So if the suicide rate went up by a factor of 40 in the next 10 years, would we then say, "Well, that's misleading because suicide was very rare in 2008, when the study began?" That makes no sense whatsoever. And to say, hey bipolar is now only 7% of kids diagnosed with mental disorders, so it's no big deal -- ??? What treatments do you think these kids get? Play therapy and lollipops? Uh, try antipsychotics, often in combination with anticonvulsants, antidepressants, and who knows what else? If you think this is all based on science, go take a spin over to Pubmed and see what you can find. What, there's no evidence that carpet bombing developing brains with a wide variety of psych drugs is effective for "bipolar"? Count me as shocked, shocked, that medications would be prescribed so widely in the absence of supporting evidence. Sure, maybe if you provide highly tranquilizing medications, they mellow out bad behavior a bit in the short-term. Is that an effective long-term solution? And at what cost?

In Leibenluft’s studies at the National Institute of Mental Health, only 20 percent of children identified with bipolar disorder are found to meet the strict criteria for the disease. Breck Borcherding, a pediatric psychiatrist in private practice in the Washington area, said: “Every time one of my kids goes into the hospital, they come out with a bipolar diagnosis. It’s very frustrating.”

OK, so a study that finds that bipolar diagnoses have shot through the roof is "misleading," but at the same time, other Egan then discusses research suggests that bipolar is being misdiagnosed at a high clip. Am I the only one who is confused?

Then there is “The Bipolar Child,” a successful book published by the psychiatrist Demitri Papolos and his wife, Janice, in 1999, and referred to by more than one parent I spoke to as a “bible.” The Papoloses’ description of pediatric bipolar disorder was amassed partly by using responses to an online questionnaire filled out by hundreds of parents on an electronic mailing list, who said they believed their children were bipolar (and who often had strong family histories of the disease). The Papoloses’ diagnostic criteria include some idiosyncratic items — a severe craving for carbohydrates, for example — that are found nowhere in D.S.M.-IV. Nevertheless, many parents walk into doctors’ offices having already read “The Bipolar Child” and concluded that their children are bipolar. Because doctors rely heavily on parental reports when diagnosing disorders in children, these “prediagnoses” may have an impact on the outcome.

Well, if that isn't the most airtight method for a study that I've ever heard. Put up an online questionnaire, have people who insist that their kids are bipolar fill it out, then use whatever these parents say as criteria for the disorder. And... severe craving for carbs? Nope, I've never ever seen a kid who really, really wants candy before. But if I do see such behavior, I'll turn on my bipolar radar; I'll be keeping my eyes peeled at the candy store.

And of course, there are pressures and blandishments from the pharmaceutical industry, which stands to profit mightily from the expensive drugs — often used in combination — that are prescribed for bipolar illness, despite the fact that very few of these drugs have been approved for use in children.

You mean like the part where key opinion leaders sign on for Big Bucks to give talks for psych drugs in treating kiddie bipolar? No, you won't find discussion of that anywhere in the article. Because we are making progress in understanding the biological disease of bipolar disorder and how to treat it. Progress is slow but everything is headed in the right direction -- the time-honored narrative of the academic-pharmaceutical complex always making progress in mental health. There is a sentence dedicated to discussing the influence of Big Pharma. One. Off-label marketing of antipsychotics for kids is never mentioned, despite Otsuka/Bristol Myers Squibb settling a federal lawsuit for pimping Abilify for kids. I suppose mentioning such shenanigans might poke a bit of a hole in the idea that we are making perpetual progress.

And here comes the hammer. Sure, bipolar might be overdiagnosed, but of course the biggest problem is the undertreatment of bipolar kids:

For all the possible overdiagnosing of pediatric bipolar disorder, however, many in the field also say that a lot of truly bipolar children who could benefit from therapy are falling through the cracks. This is a critical issue; studies clearly show that the longer bipolar disorder goes untreated, the worse a person’s long-term prognosis.

If you are so into "studies clearly showing" things, then maybe you could point to studies that clearly show benefits of treating bipolar disorder in children. I'm waiting. In fact, I've been waiting for years. As the rate of drugging kids for bipolar has increased drastically, the research showing treatment benefits is... where? And if you're telling me that kids behaving very badly, which seems to be fit roughly 100% of kids who wind up diagnosed with bipolar disorder, are not getting treatment, I think you aren't paying attention. Desperate parents want a solution, and whether the diagnosis is opposition defiant disorder, conduct disorder, ADHD, autism, pervasive developmental disorder, WTF NOS, or bipolar, I'm pretty sure that these kids are getting treated in droves. But maybe I'm wrong.

Gabrielle Carlson, the director of child and adolescent psychiatry at the Stony Brook University School of Medicine, has studied childhood mania for many years and says bipolar disorder is uncommon in children under 10, revealing itself in the same discrete episodes of mania and depression that we see in bipolar adults — not in chronic irritability. According to Carlson, a large group of aggressive and explosive children, who in fact are “diagnostically homeless,” are being relabeled as bipolar, which is a development she says is unhelpful both to the children and the field. “Diagnostically it ends up being a very important consideration of what the kid really has,” she told me. “If he really has A.D.H.D. and it’s not mania, then you give him medication for his A.D.H.D. You also give him behavior modification.” One patient she saw that day, who was thought to have bipolar disorder, actually had autism, she said. “If you say, ‘Hey, his problem is bipolar disorder,’ then you’re not going to treat his language disorder, you’re not going to give the social-skills treatment he needs,” she said. Problematic conditions in a child’s home life are also less likely to be addressed if the child’s behavioral issues are attributed to bipolar disorder, Carlson said. “Many people, when they hear bipolar disorder, their brain slams shut.”

After including quotes from Janet Wozniak of the ever-present Harvard bipolar child team, it was nice to see comments from someone who has a bit more skepticism. A harsher critic could have been included in the story, but was not. No, I'm not going to quote Wozniak because you already know what she said, which is that we discovered that bipolar disorder in kids is way, way, way, way, more common than previously thought.

The most basic question about bipolar kids remains a mystery: Will they grow up to be bipolar adults?

No, four of the most basic questions are, in no particular order:

How many of these kids labeled as bipolar have been misdiagnosed?
What are the benefits and risks of treatment, in the short-term and in the long-term?
What happens if we try nonmedical interventions aimed at changing discipline strategies, proving more structure at home, etc.
Is child bipolar at least partially a medical term for bad behavior? And where does the bad behavior stem from? Could social problems have anything to do with it? Think of things like poverty, absent parenting, violent TV programming and video games, vastly unequal income distribution, gangs, unemployment/underemployment, and the list goes on... In other words, our society ain't exactly ideal and some of these problems will impact mental health. Isn't throwing pills (or even therapy) at these problems a little shortsighted? This ain't the place to discuss how to improve society; I'm just saying that many of these problems discussed on the site probably arise from more than just intrapsychic issues or troubles with an alleged (not proven) "chemical imbalance." Do you think there is a reason, for example, that foster kids are so frequently on antipsychotics? As written by The Last Psychiatrist: "A 20% increase in therapy visits will be interpreted by psychiatry as a 20% increase in depression and anxiety. It will say depression has a prevalence of X, it will say it is underdiagnosed and undertreated, etc. And it will creep into the social consciousness that these are pre-existing diseases with triggers, not the consequences of external events. Society needs that illusion, it needs that lie, because it has created unrealistic expectations in people and no way of fulfilling them."

Think my question 4 is a little weird, that it's wild speculation? Well, if you want some wild speculation that exceeds mine, try a few slices from the NYT mag piece:

Some studies suggest that bipolar disorder may actually be on the rise among young people. One intriguing hypothesis involves a genetic phenomenon known as “anticipation,” in which genes become more concentrated over generations, bringing a stronger form and earlier onset of an illness with each successive generation. Another theory is “assortative mating,” in which a more mobile and fluid society, like ours, enables the coupling of people whose mutual attraction might be partly due to a shared genetic disposition to something like bipolar disorder, thus concentrating the genetic load in their offspring.

Yeah. That's the ticket. We've had how many thousands of generations of human existence and now, suddenly, bipolar is becoming more concentrated in kids. Intriguing hypothesis? Wouldn't such a trend be gradual, not sudden? Same story with "assortative mating" -- is it just now that bipolar folks would choose to mate with each other? Presumably, this would have happened throughout human existence, so pulling this kind of thing out of a hat now makes absolutely no sense. But there's an answer to that -- we're living in a "more mobile and fluid society." So now that we're "mobile," bipolar folks breed with bipolar folks, but before cars and planes, they couldn't breed with each other. Huh?

Kiki Chang, director of the pediatric bipolar-disorders program at Stanford, has embraced the kindling theory. “We are interested in looking at medication not just to treat and prevent future episodes, but also to get in early and — this is the controversial part — to prevent the manic episode,” he told me. “Once you’ve had a manic episode, you’ve already crossed the threshold, you’ve jumped off the bridge: it’s done. The chances that you’re going to have another episode are extremely high.”

Oh boy. Preventive psychopharmacology. If you are a hyper kid, we'll give you antipsychotics because they might keep you from becoming bipolar later. Trust us, your son is fine in our hands, ma'am.

Also see Furious Seasons' take on the matter. And give him some $$$ to help with his fundraiser. If you ever wanted to give me money, don't. Pass it his way.

Atypical Antipsychotics for All, Oregon Chapter

2008-09-08T07:39:00.000-07:00

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

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

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

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

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

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

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

Not to Get Political or Anything

2008-09-05T13:37:00.000-07:00

I write about all sorts of BS that relates to mental health treatment. Mostly about marketing infiltrating science. But hey, it's a freakin' election year. And when I see good political comedy, I have to post it. Yes, I'm sure there are also duplicitous Democrats. But matching the like of Dick "Apron Strings" Morris and Karl "Thriving Metropolis of Wasilla" Rove is probably going to be a tough task.

I would also like to go on the record as saying that I am totally against banning books from libraries, which might make me a poor candidate for higher office.

Hat Tip: Respectful Insolence

That Pesky Long-Lasting Placebo

2008-09-03T06:13:00.001-07:00

You are depressed, take a placebo, and feel better. Conventional wisdom in the psychiatric community would have your depression coming back shortly because we all know that a placebo can't make you feel better for very long. Right? Um, sorry to crash the party, but... no. A study from Arif Khan and colleagues in the August 2008 Journal of Psychiatric Research debunks this myth by putting together results from 8 antidepressant trials which examined what happened to study participants who (a) showed a response to treatment in the short-term and (b) continued to take either an antidepressant or placebo in the long-term. Of those who continued to take antidepressants, 93% maintained their improvement 4 weeks to over a year afterwards. So did 79% of participants who took a placebo. So yeah, people on drugs did a bit better, but about 4 in 5 people taking a freaking sugar pill were still doing well in the long-term. Anyone still want to seriously argue that the vast majority of the antidepressant effect is not the placebo effect?

The authors, who incidentally are not exactly in the Peter Breggin camp, opine that: "The widely held – and probably erroneous – belief that the placebo response in depression is short-lived appears to be based largely on intuition and perhaps wishful thinking." Ouch. Wishful thinking about psychiatric medications? Hmmm, that is giving me Effexor flashbacks for some reason...

The V-Squad Finale

2008-08-27T05:30:00.000-07:00

Here is the final of the 3 training clips for Vioxx salespersons. The first and second clips are also available.

Be The Power:
2 efficacy
2 GI risk (and ZERO cardiovascular risk)

How 'bout a nice dose of data? Oh, this clip is SO rich!

More From the V-Squad

2008-08-26T07:33:00.000-07:00

The Superhero team of Merck sales reps continued to work hard to push Vioxx. The ending of this clip is definitely a cliffhanger, so be sure to tune in for the finale tomorrow! See clip 1 in my most recent post.

Meet the V-Squad

2008-08-25T12:20:00.000-07:00

How did Merck go about training reps to sell Vioxx? Here's part one of three. Thanks to an anonymous reader for sending me along this trilogy. Part 2 is great and part 3 is outrageously funny. Well, I mean except for the part (not included in the videos) where people were dropping dead from taking this newer, "safer" painkiller. Parts 2 and 3 coming soon.

Go to vioxxdocuments.com for more such goodies.

Investigative Journalism Par Excellence

2008-08-19T09:38:00.000-07:00

I am a little late in reporting this story, but there is a must-read post from Jonathan Leo over at Chemical Imbalance that I must bring to your attention. Many bloggers have chimed in about the radio program The Infinite Mind broadcast about SSRIs. Most writers have focused, understandably, on the myriad unreported conflicts of interest of the guests on the show. But the conflicts of interest are not the most important part of this saga -- the terribly misleading information on the program, which aired on National Public Radio outlets, is the main problem.

Leo compares the data on SSRIs and suicide to the blatantly false statements made by the The Infinite Mind commentators. He notes, for example, that it is utter BS to state that nobody committed suicide in antidepressant trials submitted to the FDA -- in children there were no suicides, but among adults there certainly were. And kids who dropped out of the studies due to poor response or side effects, well, who knows what happened to them?

Leo also notes that the commentators were dead wrong about their alleged evidence linking decreased prescriptions of SSRIs to an increase in suicides. I also noted the same problem. He then proceeds to make point after point about the commentators overstating the efficacy of antidepressants.

As I've written before, conflicts of interest are important. But rather than just noting that people have conflicts, it is important to show the data -- are people with conflicts of interest misstating the evidence in a manner that reflects the conflict of interest? In the case of The Infinite Mind, the answer is a clear yes. Leo's post is quite lengthy, but well worth the time.

Update (08-31-08): My mistake. I had earlier called the program All in The Mind, which is vastly incorrect. The program was The Infinite Mind (as has been corrected above). This post has absolutely nothing to do with All in The Mind, which is a program which airs on Australia's Radio National. In fact, I've listened to a couple of All in the Mind broadcasts previously and found them to be well-done. Thanks to a commenter for catching my error.

SSRI Doesn't Work? Try Zyprexa

2008-08-19T05:45:00.000-07:00

...So said Lilly sales reps who pushed the drug in Alaska. I did a little reading on the topic from the new Zyprexa document set from the recent Alaska case, but was scooped by Furious Seasons, where it was written that:

Lilly was using cases of patients--apparently with bipolar disorder, likely type 2--who ran into problems on SSRIs such as agitation to create a scenario for selling doctors on using Zyprexa in these patients.

Snippets from sales call notes are then added to strongly support this assertion. Well worth a read. Especially the clincher that involves the old-fashioned trick of bribing docs with candy to get them to write Zyprexa scripts. If I get a little spare time, I hope to wrangle through the new Zyprexa docs and spread the word about whatever horrors lie therein.

Sowing the Seeds of Vioxx

2008-08-18T15:02:00.000-07:00

A new article in the Annals of Internal Medicine lays bare how research was commandeered by marketing in the promotion of Vioxx, Merck’s former all-star painkiller and personkiller. The article is based on a chunk of internal Merck documents revealed during legal proceedings (not unlike the infamous Zyprexa documents). Merck set up the study known as ADVANTAGE, in which 2785 arthritis patients were given Vioxx and 2772 arthritis patients took naproxen. Physicians across the nation were recruited to enroll patients to participate in the study, which was intiated during the FDA approval process for Vioxx.

The study, however, was conceived and conducted by Merck’s marketing department. Why? As Vioxx was about to come to market, Merck needed to develop a need for their product. By hiring physicians to participate as “investigators” on this trial, Merck was exposing its product to an important group of potential customers. To quote Merck:

The objectives were to provide product trial among a key physician group to accelerate uptake of VIOXX as the second entrant in a highly competitive new class and gather data important to this customer group. The trial was designed and executed in the spirit of the Merck marketing principles.

Other snippets from a Merck marketing memo, with pithy commentary added free of charge:

"...the trial was targeted to a select group of critical customers.” So the main qualification to be a “research investigator” in this trial was to be a customer that Merck wanted to win over.

“The sales force nominated potential investigators and completed intake forms, allowing a very large number of sites to be evaluated and enrolled and ensuring equal distribution of investigators across the business groups.” Again, the sales force chose the physicians, apparently based on how easily they could be swayed to prescribe Vioxx as a result of participating in this study.

“An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group of VIOXX 99 prescribers (see attached). Feedback from the field has been overwhelmingly positive about their ability to access key customers and the influence that being involved in the trial has had on their perceptions of VIOXX and Merck.” The program apparently had its desired results – more docs prescribing Vioxx as a result of their participation in Merck marketing-designed “research.” As for the patients dying due to taking Vioxx, well, what’s a little collateral damage when there are quarterly sales goals to be met?

The name for such an exercise in marketing is a “seeding trial,” referring to a company planting seeds in physicians to use their product under the guise of research.

II. What about getting the results out?

According to Merck: “Preparations are now underway for analysis and publication of the data, which will utilize key investigators as authors and advisors.” Turns out that worked pretty well – as the lead author on the main ADVANTAGE publication told the New York Times that “Merck designed the trial, paid for the trial, ran the trial. Merck came to me after the study was completed and said, “We want your help to work on the paper. The initial paper was written at Merck, and then it was sent to me for editing.” – it was sent to him to place a veneer of academic credibility on Merck’s marketing-run trial.

Even Merck’s head of research said that trials such as ADVANTAGE are “intellectually redundant” – as they tend to focus on results that are already well-established, such as showing Vioxx to be somewhat easier on the gastrointestinal tract that naproxen.

Harold Sox and Drummond Rennie, also writing in the Annals of Internal Medicine, in a critique of Vioxx’s marketing wrote:

This practice—a seeding trial—is marketing in the guise of science. The apparent purpose is to test a hypothesis. The true purpose is to get physicians in the habit of prescribing a new drug. Why would a drug company go to the expense and bother of conducting a trial involving hundreds of practitioners— each recruiting a few patients—when a study based at a few large medical centers could accomplish the same scientific purposes much more efficiently? The main point of the seeding trial is not to get high-quality scientific information: It is to change the prescribing habits of large numbers of physicians. A secondary purpose is to transform physicians into advocates for the sponsor’s drug. The company flatters a physician by selecting him because he is “an opinion leader” and incorporates him in the research team with the title of “investigator.” Then, it pays him good money: a consulting fee to advise the company on the drug’s use and another fee for each patient he enrolls. The physician becomes invested in the drug’s future and praises its good features to patients and colleagues. Unwittingly, the physician joins the sponsor’s marketing team. Why do companies pursue this expensive tactic? Because it works.

This is hardly the biggest problem with Vioxx, as its tendency to kill people en masse via heart problems is obviously a far more important issue. And we all know at this point that Merck made sure to underplay the risks of Vioxx, and that the medical community was also asleep at the wheel when it came examining published studies on the risks of Vioxx. Nonetheless, using the guise of science to recruit naive (or greedy) physicians to serve as Vioxx pushers is contemptible.

Merck was out pushing how wonderfully safe and well-tolerated was via a “study” designed solely to turn “investigators” into top Vioxx prescribers, while at the same time, more and more people were meeting an early end due to this purportedly safe new drug.

For more hot Vioxx action, check out this site.

Update (8-19-08): Check out an interview with Dr. Kevin Hill, lead author of the investigation of the ADVANTAGE trial, over at the Carlat Psychiatry Blog. As always, Pharmalot also has a good post on the topic.

Don't Call it a Comeback

2008-08-18T09:49:00.000-07:00

I've received a couple of nastygrams from readers asking when the *&^% I plan to return to blogging. If all goes well, I plan to return to writing more regularly soon.

Zyprexa Marketing: We Don't Need No Stinkin' Diagnosis and Hiding Risks

2008-08-01T07:01:00.000-07:00

From an excellent piece at Bloomberg:

"The doctor's thinking that he does not see a schizophrenic or bipolar patient,'' [Zyprexa brand manager] Bandick said in a December 2000 internal e- mail to the marketing department. "But he probably does see patients with symptoms of behavior, mood and thought disturbances,'' he wrote. "Even if the doctor does not have diagnosis, he should treat anyway.''

Adding more fuel to the fire I discussed in February 2007:

The document discussed in this post is called the “Zyprexa Primary Care Presentation”. It appears to be a transcript of a speech Mike Bandick, the Zyprexa Brand Manager, gave at the Eli Lilly National Sales Meeting on March 13, 2001.

It is important to note that Zyprexa is only FDA-approved for use in schizophrenia and bipolar disorder. The document appears to indicate that Bandick was encouraging salespeople to market Zyprexa for treating more than just these two conditions.

Bandick said:

We intend, quite simply, to redefine the way PCPs treat mood, thought and behavioral disturbances. We will continue to focus on symptoms and behaviors that PCPs see every day.

Later he said, referencing Zyprexa:

Broad symptom efficacy in mood, thought, and behavioral disturbances.
It seems curious that Lilly states they did not market Zyprexa for off-label purposes, yet the term “Mood, thought, and behavioral disturbances” seems a fair amount broader than schizophrenia and bipolar disorder. In addition, schizophrenia and bipolar disorder (especially bipolar I, which is the much more severe form of bipolar in comparison to bipolar II) are uncommon disorders. It is highly unlikely that primary care physicians would see patients with such conditions “every day.” However, it is certainly possible that a PCP may run across individuals who are manifesting much less severe “disturbances”, and it may well have been that it was this group, the patients who exhibited mild “mood, thought, or behavioral” symptoms, for whom Zyprexa was being marketed.

But don't worry -- Lilly will tell you that they don't promote off-label. Do keep in mind that I'm not singling out Lilly, as this kind of thing seems to be par for the course.

As for risks of Zyprexa, well, according to Bloomberg...

Lilly added a warning to its packaging in October 2007 saying that more than half of patients in 13 studies gained an average of 12 pounds after taking the drug for less than a year. It said Zyprexa was more associated with higher blood sugar levels, a risk factor for diabetes, than similar medications.

Before the October 2007 label change, Lilly didn't instruct its sales force to say Zyprexa's diabetes rates were higher, former marketing director David Noesges said in a January deposition.

"We will NOT proactively address the diabetes concern,'' the Zyprexa sales force was advised in 2002, the documents show. "The competition wins if we are distracted into talking about diabetes."

The Bloomberg article is a must-read.

FDA Gives Thumbs Up To Kiddie Bipolar: Is KOL Syndrome Next?

2008-07-31T06:35:00.000-07:00

Philip Dawdy at Furious Seasons noted that the FDA has officially approved the existence of child bipolar disorder. Prior to it being included in the DSM, and with considerable controversy in the professional community, the FDA jumps on board. Nice. Thanks to Philip for chasing down the FDA's official view.

A few questions for consideration by the FDA (and others) that I mentioned a few months ago:

1. Does child bipolar really exist in substantial quantity?
2. Does treatment help kids with this "disorder"?
3. Why would a leading "expert" in child "bipolar disorder" say that up to 75% of children who are "bipolar" become suicidal without citing any supporting evidence?

Joe Biederman must be proud -- the FDA will now help him and his posse save countless lives through the administration of treatments (like, say, Seroquel) for "child bipolar" that lack any sort of substantive evidence base. But who cares -- even without professional consensus or any sort of official word from the FDA, the treatment of child bipolar has already flown the coop in a big way. Realistically, I suppose that the FDA's view is irrelevant -- drug marketers and key opinion leaders wield more influence than anyone at FDA when it comes to how physicians view psychiatric diagnoses.

KOL Syndrome: On a related note, perhaps the FDA (or the DSM-V committee) can approve KOL Syndrome as a disorder. That would be Key Opinion Leader Syndrome. For case examples, please see here, here, here, here, here, and here. The prevalence of KOL Syndrome seems to be increasing and seems related to the widespread adoption of irrational prescribing as well as information laundering. Symptoms include:

Providing false "education" to physicians as a service to your corporate clients
Calling one or more of one's own articles "commercial pieces of crap," then recanting
Hiding blatant conflicts of interest
Writing misleading review articles that falsely tout the efficacy of one or more drugs,
Magically converting results that show a product is a dud into results showing that a product is safe and effective
Making a boatload of money through ties to various drug or medical device companies, then claiming that such corporate ties have absolutely no influence on your professional judgment
As an author, calling a study's results positive, then calling these same results negative a few years later without noticing the contradiction.
Giving tasty sound bites in press releases about the wonders of various medications in one's capacity as an "independent" scientist

Back to kiddie bipolar: Do some adolescents have bipolar disorder? Sure. Five-year-olds? That's where I start getting suspicious...

Also see an excellent post from John Grohol at Psych Central on youth bipolar and some of the logical problems regarding how its treatment is advocated. And Furious Seasons also notes that the FDA database raises questions about two of the drugs touted as safe and effective for kiddie bipolar.