Abilify For Depression: I'm Not the Only Skeptic

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

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

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

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

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 the Census administered the NESARC using laptop computer–assisted software that included built-in skip, logic, and consistency checks. On average, the interviewers had 5 years’ experience working on census and other health-related national surveys. The interviewers completed 10 days of training. This was standardized through centralized training sessions under the direction of NIAAA 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

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

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

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tended to get published in medical journals while articles reaching less favorable conclusions tended to remained unpublished.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

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

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

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

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

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

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

Lamictal: Break Out the Shovel

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Key Opinion Leader With A Very Short Fuse

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

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

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?

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

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

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

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

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

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

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

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.