Award Winning Journalism (?)

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.

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."

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.

Nemeroff Confirms Kirsch: SSRIs Offer Little Benefit

This post will discuss how the latest meta-analysis claiming to show public health benefits for Effexor actually also showed that antidepressants aren't up to snuff. Part 1 detailed how the study authors found a very small advantage for Effexor over SSRIs, which they then suggested meant that Effexor offered significant benefits for public health over SSRIs. Ghostwriters, company statisticians, questions about transparency, etc. Even the journal editor jumped on board. All the usual goodies.

Bad News for SSRIs: But now, on to part deux. Remember that the authors used a Hamilton Depression Rating Scale of 7 or less as indicative of remission, which was the one and only outcome measure of import in their analysis. In their database of studies analyzed in the meta-analysis, there were nine studies that had an Effexor group, an SSRI group, and a placebo group. In these studies, there was a 5.5% difference in remission rates for SSRIs versus placebo. Read it again: there was a 5.5% difference in remission rates for SSRIs versus placebo. You should be shaking your head, perhaps cursing under your breath or even aloud. Using the number needed to treat statistic that the authors used in their analysis of Effexor versus SSRIs, that means you would have to treat 18 people with SSRI instead of a placebo to get one additional remission that you would not get if all 18 had received a placebo. Damn -- that is pathetic! In these same nine trials, the difference between Effexor and SSRIs was 13%, for a number needed to treat of 8. One might conclude that Effexor was more than twice as effective as SSRIs based on these figures, but one would be wrong. Please see my prior post for why depression remission should absolutely not be used as the only judgment of a drug's efficacy. Granted, the numbers for SSRIs were based on nine trials, which limits the generalizability of the findings, but the findings sure fit well with the Kirsch series of meta-analyses that found only a small difference for SSRIs over placebo in all but the most severe cases.

If you told most people that you would have to treat 18 depressed patients with a SSRI rather than a placebo to get one additional remission in depressive symptoms, you'd get laughed out of the room, but that is exactly what Nemeroff et al found. Do the authors conclude with: "The findings confirm earlier work by Kirsch and colleagues showing that the benefits of SSRIs over placebo are quite modest"? Not exactly. Here is their interpretation:

To achieve one remission more than with placebo, 8 patients would need to be treated with venlafaxine (NNT = 8) compared with 18 patients who would need to be treated with an SSRI (NNT = 18). From this perspective, the magnitude of the advantage of SSRIs versus placebo in the placebo-controlled dataset (NNT=18) is similar to the advantage of venlafaxine relative to SSRIs in the combined data set (NNT = 17).

This is right after the authors wrote about how a NNT of 17 was possibly important to public health (see part 1), which was about the time I fell out of my chair laughing. A more plausible interpretation is that SSRIs yielded very little benefit over placebo and that Effexor, in turn, yielded very little benefit (in fact, a statistically significant benefit over only Prozac) over SSRIs. But that sort of interpretation does not lead to good marketing copy or press releases that tout the benefits of medication well beyond what is reasonable. What if the press releases for this study read: "Nemeroff confirms findings of Kirsch: Antidepressants offer very little benefit over placebo." That would have been refreshing.

Sidebar: Here is my standard statement about antidepressants -- they work. Huh? Yeah, the average person (surely not everyone) on an antidepressant improves by a notable amount. The problem is that the vast majority (about 80%) of such improvement is due to the placebo effect and/or the depression simply getting better over time. Give someone a pill and that person will likely show some improvement, but nearly all of the improvement is due to something other than the drug. If most improvement is due to the placebo effect, couldn't we usually get such improvement using psychotherapy, exercise, or something else, which might avoid some drug-induced side effects? Moving on...

Key Opinion Leaders: But notice how this Wyeth/Advogent authored piece featuring Charles Nemeroff as lead author (as well as Michael Thase as last author) throws down a major spin job regarding the efficacy of antidepressants. As reported previously, their measure of efficacy was quite arbitrary. It could have been supplemented with other measures, as Wyeth is in possession of such relevant data, but such analyses were not conducted. But even using their questionable measure of efficacy, antidepressants put on a poor performance. Similarly, Effexor's advantage over SSRIs was meager. Yet the authors (remember, three medical writers worked on this paper) conclude that venlafaxine offers a public health benefit over SSRIs. Maybe the authors were afraid of being sued for writing anything negative in their paper? Or perhaps they just know who is buttering their bread. It is also possible that the authors truly cannot envision the idea that SSRIs offer such a meager advantage over placebo and that Effexor yields very little (if any) benefit over SSRIs. And that is the problem. The "key opinion leaders" are all stacked on one side of the aisle -- drugs are highly effective and each new generation of medications is better than the last. So plug in the name of the next drug here, and you'll see a key opinion leader along with a team of medical writers rushing out to show physicians that the latest truly is the greatest. Since we don't really train physicians to understand clinical trials or statistics particularly well, you can also expect many physicians targeted by such marketing efforts to simply lap up unsupported claims of "public health benefit."

Hey, is there a counter-detailer in the room somewhere?

Effexor Beats SSRIs (Kind of, Sort of, In a maybe meaningless way...)

A recent study in the journal Biological Psychiatry claimed to show that Effexor's (venlafaxine's) alleged advantages over SSRIs "may be of public health relevance." Unstated in the article, but a more accurate reading of their findings, is that antidepressants yield little benefit over a placebo. I'm breaking this into two parts. The current post deals with the authors' claims regarding venlafaxine's superiority over SSRIs. A second post will examine their understated finding that antidepressants are not particularly impressive compared to placebo.

The study was a meta-analysis, where data from all clinical trials comparing Effexor to an SSRI were pooled together. The authors used remission on the Hamilton Rating Scale for Depression (HAM-D) as their measure of treatment effectiveness. On the HAM-D, a score of less than or equal to 7 was used to define remission. They found that remission rates on Effexor were 5.9% greater than remission rates on SSRIs. Thus, one would need to treat 17 depressed patients with Effexor rather than an SSRI to yield one remission that would not have occurred had all 17 patients received an SSRI. Not a big difference, you say? Here's what the authors said:

...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]

Public Health Relevance/Remission: The public health claim is pretty far over the top. If one had to treat 17 patients with Effexor to prevent a suicide or homicide that would have occurred had SSRIs been used, then yes, we'd be talking about a significant impact on public health. But that's not what we're dealing with in this study. The outcome variable was remission on the HAM-D, which is a soft, squishy measure of convenience. The authors state that remission rates are "the most rigorous measure of antidepressant efficacy," but to my knowledge there is no evidence supporting their adoption of the magic cutoff score of 7 on the HAM-D as the definition for depressed/not depressed. Are people who scored 8 or 9 on the HAM-D really significantly more depressed than people who scored 6 or 7? Take a look at the HAM-D yourself and make your own decision. I know of not a single piece of empirical data stating that such small differences are meaningful. So I'm not buying the public health benefit -- in fact, I think it is patently ridiculous.

Outcome measures can be either categorical (e.g., remission or no remission) or continuous (e.g., change on HAM-D scores from pretest to posttest). Joanna Moncrieff and Irving Kirsch discuss how using cut-off scores (categorical measures) rather than looking at mean change (continuous measures) can result in the categorical measure making the treatment appear much more effective than examination of continuous measures. Applied to this case, one wonders why the data on mean improvement was not provided. One can make a very weak case that Effexor works better than SSRIs based on an arbitrary categorical measure but not one shred of data was presented to show superiority on a continuous measure. If the data supported Effexor on both categorical and continuous measures, then I'd bet they would have been discussed in this article, as it was funded by Wyeth (patent holder for Effexor). Thus, the absence of data on continuous measures (e.g., difference in mean improvement on the HAM-D between Effexor-treated patients and SSRI-treated patients), is suspicious.

Even if the authors decided to use only categorical measures, it would have been nice had they opted to use multiple measures. They could have used the equally arbitrary 50% improvement criterion (HAM-D scores drop by 50% during treatment), for example. However, such data were not provided. So the authors decided to use one highly arbitrary measure, on which they found a very small benefit for venflafaxine over placebo. Whoopee.

I received an email from a respected psychiatrist (who shall remain anonymous) about this study. He/she opined:

...it would have been interesting if the authors had used other cutoffs for the Hamilton scale besides 7 to define remission; i.e., if they had done a sensitivity analysis. Apparently, Wyeth has all the raw data from the studies, so a lot of interesting science could be done with this very large aggregate database. For example, there are robust factor analyses of the Hamilton scale that indicate reasonably independent dimensions of depressed mood, agitation/anxiety, diurnal variation, etc., and it would be of great interest to determine the relative effects of the various drugs on these different illness dimensions

In other words, the authors could have attempted to see if there were meaningful differences between Effexor and SSRIs on important variables, yet they opted to not undertake such analysis. A skeptical view is that they analyzed the data in such a fashion, found nothing, and thus just reported the "good news" about Effexor. I don't know if they conducted additional analyses that were not reported. However, it would seem to me that someone at Wyeth would have run such analyses at some point, perhaps as part of this meta-analysis, because any advantage over SSRIs would make for excellent marketing copy. In fact, Effexor has been running the "better than SSRIs" line for years, based on rather scant data. If there were more impressive data, they would have been reported by now.

Prozac and the Rest: The findings showed that Effexor was only superior to a statistically significant degree (i.e., we'd not expect such differences by chance alone) when compared to Prozac (fluoxetine). The authors, to their credit, pointed this out on multiple occasions. However, their reporting seems a little contradictory when, on one hand, they report that venlafaxine was superior to SSRIs as a class (see quote toward the top of the post), but then note that the differences were only statistically significant when compared to Prozac. The percentage difference in remission favoring Effexor over Zoloft (sertraline) was 3.4%, over Paxil (paroxetine) was 4.6%, Celexa (citalopram) was 3.9%, and Luvox (fluvoxamine) was 14.1%. I think just about anyone would concur that the difference versus fluvoxamine seems too high to be credible, and it was based on only one study, making the fluke factor more tenable. Again, the advantage of Effexor over all SSRIs except Prozac was not statistically significant. Even if these differences were statistically significant, would the authors claim that needing to treat 26 patients with Effexor rather than Celexa to achieve one additional depression remission would improve public health? Small differences on a soft, squishy, arbitrary endpoint combined with not performing (or not reporting) more meaningful data = Not news.

The Editor Piles On: In a press release, the editor of the journal in which this article appears jumped on board in a big way:

Acknowledging the seemingly small advantage, John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, comments that this article “highlights an advance that may have more importance for public health than for individual doctors and patients.” He explains this reasoning:

"If the average doctor was actively treating 200 symptomatic depressed patients and switched all of them to venlafaxine from SSRI, only 12 patients would be predicted to benefit from the switch. This signal of benefit might be very hard for that doctor to detect. But imagine that the entire population of depressed patients in the United States, estimated to be 7.1% of the population or over 21 million people, received a treatment that was 5.9% more effective, then it is conceivable that more than 1 million people would respond to venlafaxine who would not have responded to an SSRI. This may be an example of where optimal use of existing medications may improve public health even when it might not make much difference for individual doctors and patients."

Seeing a journal editor swallow the Kool-Aid is not encouraging. Again, the 5.9% difference is based on an endpoint that may well mean nothing.

Ghostwriter Watch: Who wrote the study and who conducted the analyses? The authors are listed as Charles Nemeroff, Richard Entsuah, Isma Benattia, Mark Demitrack, Diane Sloan, and Michael Thase. Their respective contributions are not listed in the text of the article. The contribution of Wilfrido Ortega-Leon for assistance with statistical analysis is acknowledged in the article, as are the contributions of Sherri Jones and Lorraine Sweeney of Advogent for "editorial assistance."

Ortega-Leon appears to be an employee of Wyeth. So did an employee of Wyeth run all of the stats, then pass them along to the authors for writeup? Last time I checked, there were sometimes problems associated with having a company-funded statistician run the stats then pass them along without any independent oversight. I don't know what happened, but my questions could have been easily resolved: Describe each author's contributions in a note at the end of the article.

Sherri Jones and Lorraine Sweeney have served in an "editorial assistant" role for other studies promoting Effexor, such as this one. I suspect that they are familiar with the key marketing messages for the drug. An important question: What does "editorial assistance" mean? Did Jones and Sweeney simply spell-check the paper and make sure the figures looked pretty? Did they consult the authors to get the main points, then fill in a few gaps? Or did they write the whole paper then watch the purported authors rubber-stamp their names on the author byline? Simply listing "editorial assistance" is not transparency. I have no problem with medical writers helping with a manuscript, depending on what "helping" means. Many researchers are not skilled writers and cleaning up their writing is a good idea for all parties. But having a medical writer who is paid by a drug company to make sure that key marketing messages are included in the paper can lead to problems.

Part 2, regarding the unemphasized, but important, finding from this study that antidepressants yield mediocre benefits over placebo.

Update (03-03-08): See comments. A wise reader has pointed out that there are actually three authors from Advogent. Well, um, one author and two editorial assistants. A skeptical person would add that the presence of three medical writers and a Wyeth statistican who appears in a footnote at the end of the study obviates the need for those pesky academic authors except for the need to lend the study a stamp of approval from "independent scientists." Is that too cynical?

Key Opinion Leaders, Continuing Medical Education, and Utter B.S.

Psychiatrist Bernard Carroll has another brilliant post on corrupt, er, continuing medical education (CME) and how the process has been co-opted by various commercial interests. His post a few days ago was certainly great, and in combination with his current post, I officially declare that Bernard Carroll is ON FIRE!

Here's a bit of what he had to say. Commit this paragraph to memory:

Medical journals are not the only compromised medium. Continuing Medical Education (CME) is a second front in the campaign to expand the AAP [atypical antipsychotic] drug market. The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.

Guess what... Charles Nemeroff is also featured -- regular readers will note that his name has appeared on a few occasions on my site. Carroll takes apart a recent CME exercise in which Nemeroff featured information that appears to be false. In fact, I detailed some of the problems with this CME exercise here. Carroll's post has a number of updates. Chances were given for this CME exercise to be redeemed in some form, but misinformation apparently prevailed yet again.

Regarding another of the atypical antipsychotics discussed in this wonderful CME piece, Carroll wrote (in part) the following:

When discussing aripiprazole for nonresponding depression, Dr. Nemeroff once again was economical with the truth. Note that Bristol-Myers Squibb, the marketer of aripiprazole, sponsored this PeerView/UCLA program. To document his claims about aripiprazole, Dr. Nemeroff cited one Abstract from the American Psychiatric Association meeting in May 2007. That does not meet ACCME standards of documentation for learners, most of whom would be unable to access the cited Abstract (not that it would tell them much even if they could). For some reason, Dr. Nemeroff did not inform learners that the complete report of the aripiprazole study had appeared in June 2007 (Berman RM et al. J Clin Psychiatry 2007;68: 843-853), fully 5 months before the CME event went on-line. From that readily available report it is clear that the Number Needed to Treat (NNT) for response with aripiprazole is 10, which compares unfavorably with a NNT of 4 for lithium, the best established augmenting option in placebo-controlled trials. A NNT of 10 means a clinician would need to treat 10 patients with aripiprazole before obtaining one remission that would not have occurred anyway with placebo. That does not constitute compelling clinical benefit. Dr. Nemeroff did not candidly discuss these troubling data. Dr Nemeroff provided his CME audience none of the remission or response data from the published aripiprazole study, though these data were readily available. These omissions of published, highly relevant information signify disrespect for his audience by Dr. Nemeroff, incompetence by the MECC, and failure of due diligence by the accrediting institution, UCLA, to ensure that accurate, balanced information and adequate documentation are provided.

I shall not steal any more of Carroll's thunder. Head over the Health Care Renewal and check it out in full.

Key Opinion Leader Provides False Information in Psychiatry CME

Just when I thought it was safe to stop writing about the ARISE-RD study, which was an attempt to demonstrate the efficacy of risperidone (Risperdal) for depression, even more evidence of misleading salesmanship regarding the study surfaces. Feel free to read six prior posts regarding the study, described in a bit more detail here.

Here's the rub. Dr. Charles Nemeroff is the presenter for this continuing medical education activity entitled Add On Atypical Antipsychotics Efficacious in Short Term for Unipolar Depression. This post concerns slides 5, 6, and 9, which reference the aforementioned ARISE-RD study, which examined the use of risperidone as an add-on to citalopram (Celexa) in treating depression. The full presentation is available for your examination.

Slide 6 reads in part:

• Global Impressions of Sexual Functioning scores improved significantly in men and women (p < .02) with RIS augmentation.
• RIS may ameliorate sexual dysfunction associated with SSRIs.

There is a reference to a published study in Neuropsychopharmacology at the bottom of the slide. The kicker: The published study contains no mention of improved sexual functioning on risperidone. This is called lying. Remember, Nemeroff was an author on the study published in Neuropsychopharmacology; he'd know if sexual functioning was referenced in his article, so there is no pleading ignorance on his part.

Slide 9 reads in part:

• Augmentation options for treatment-refractory depression include adjunctive atypical antipsychotics.
  -Controlled studies: short term efficacy with OLZ, ARI, RIS [risperidone]

This is a baldfaced falsehood. The study took people who had not responded to citalopram treatment, then added risperidone to the mix. There was no placebo control during this phase. So it was not a controlled study and should not be referred to as a controlled study in Nemeroff's presentation.

In fact, here is what the lead author (Mark Rapaport) of the ARISE-RD study had to say about its results in a letter to the editor (currently in press):

The paper repeatedly states in Abstract, Methods and in Discussion that continuation of risperidone augmentation therapy was not more beneficial than placebo, and hence the working hypothesis was disproven...

I would like to thank the reviewers and the editors of Neuropsychopharmacology for having the courage to allow us to publish this negative finding.

Compare and contrast: Nemeroff's presentation indicates that the study was a controlled trial showing that risperidone was more effective than placebo. The lead author admits that the study was a "negative finding" and that risperidone was "not more beneficial than placebo."

To summarize, Nemeroff did the following:

• Claimed that a peer-reviewed study showed risperidone improved sexual functioning, when the effects of treatment on sexual functioning were not even mentioned in the paper.
• Claimed that the study showed risperidone to demonstrate efficacy over placebo, which it in fact did not.
  

This is what passes for education for physicians. Being lied to about study results is how physicians receive continuing medical education to keep them abreast of the latest research findings so that they can better serve their patients. If you are not disgusted, you are not paying attention. It is far from reassuring that this incident involves one of the biggest names in academic psychiatry.

Another Key Opinion Leader Contradicts Himself

It appears that Lindsay DeVane, who called his own continuing medical education article (appearing in CNS Spectrums) a "commercial piece of crap" has retracted his story (via the excellent Carlat Psychiatry Blog). Apparently, his take on the former "crap" piece has now changed to "there should be no question about the integrity of the CNS Spectrums publication as a CME activity" The article went from, in his own words, a "ridiculous text" to an article that reflects "the inherent limitations in providing practicing clinicians with fundamental descriptions of complicated issues." Is he implying that practicing clinicians lack the intellectual fortitude to understand "complicated issues," so he had to dumb it down to meet their limited capacity? Perhaps there is another interpretation.

He also changed his tune to "all three co-authors were heavily involved in multiple edits before agreement was reached on a final manuscript" from stating originally that he had not actually read the manuscript. That is quite a change indeed. One can only wonder which individuals pressed DeVane to change his story. Here's what I don't understand. DeVane has been in the game for a long time. Does he really have that much to lose by pointing out the joke that it today's continuing medical education system? I want to know who spoke with him and how he was persuaded to change his mind. This is such a ridiculous turnaround in stories that it makes Larry Craig look like a straight shooter. I am 99.9% doubtful that DeVane would have changed his story without significant influence from others. Drs. Charles Nemeroff and Sheldon Preskorn were the coauthors. I can't help but wonder if one or both of them took exception to DeVane's labeling of the piece as "crap" and read him the riot act. Does DeVane not realize that this turnaround in story is farcical?

Read the full story here. Two further glittering examples of continuing medical education in psychiatry gone awry can be read here and here. To see another key opinion leader contradict himself, go here.

Key Opinion Leader Contradicts Himself

In depression, is there a serotonin deficiency or not? Let’s ask a key opinion leader. Dr. Charles Nemeroff stated in a continuing medical education piece released in March 2007 that

There is a large body of evidence that the serotonin system is awry in depression in many, if not most, patients. There is truly a real deficiency of serotonin in depressed patients.

In the same piece, he stated that

Taking this together, one would suggest that the overwhelming evidence is of a relative deficiency of serotonin in the brains of patients with depression.

Yet in an article published in the Journal of Psychiatric Research in April 2007 (accepted for publication in May 2006), Nemeroff states

It is likely that no single fundamental neurobiological defect underlies severe depression.

Oh, so there is a serotonin deficiency and there is likely not a serotonin deficiency. Now I get it. That clears it up. Sounds like doublethink.

How could one contradict oneself on such an issue? This is a core problem in medicine. If these are the leaders of medicine, the scientific gurus whose opinions are thought to influence the practice of physicians throughout the world, then shouldn’t their thoughts be consistent from one day to the next? My humble guess is that this instance was due to one or both pieces being ghostwritten and the author not checking the final version of the paper. If it has your name on it, then shouldn’t you be responsible for the content of the piece? This is a lesson recently learned through the “commercial piece of crap” incident reported first on the excellent Carlat Psychiatry blog, with a similar incident being discussed on this site. The CME piece mentioned in this post is the same article on which Dr. Nemeroff did not disclose a highly relevant conflict of interest, as reported here.

For more on Dr. Nemeroff, please see this post.

CME, Key Opinion Leaders, and Responsibility

Continuing medical education continues to get slammed (1, 2), and somehow the name of Charles Nemeroff keeps finding its way into these incidents. I wrote last week that Nemeroff co-authored a CME piece, on which he failed to disclose a conflict of interest regarding CeNeRx, for whom he co-chairs the scientific advisory board. The conflict of interest that was not disclosed was quite relevant, as the CME article was a cheer piece for MAOI's, and it just so happens that CeNeRx is in the MAOI business.

Daniel Carlat noted that another CME article upon which Nemeroff was an author has been criticized harshly; this one was dissed by one of its own authors. C. Lindsay DeVane, a coauthor, called it "a commercial piece of crap." Let me state this ever-so-clearly: An author called his own article a commercial piece of crap. This should send shivers up and down your spine -- if authors can't even trust the work upon which their name appears, how the hell are physicians supposed to trust it? Taking it a logical step further, how are patients supposed to trust their physicians if M.D.'s are receiving "education" that is "commercial crap."

I should mention that to Nemeroff's credit, on the "crap" article, he discloses an interest in CeNeRx.

What is authorship, anyway? Everyone knows that CME articles are quite often ghostwritten to reflect key marketing points. It's actually fairly comical that a lot (perhaps virtually all?) of the CME litter-ature is written by ghostwriters, and then key opinion leaders such as Nemeroff, DeVane, Keller, et al sign off on them. To be fair, it's not necessarily all that different from clinical trial literature, which is also frequently ghostwritten by industry-friendly writers (1, 2 ).

So we're left with a new definition of "author" on a scientific paper or CME piece:

Author: Someone who stamps his/her name on a paper to lend extra scientific credibility to the marketing of whatever product is discussed most positively in the manuscript. Having read the paper, written the paper, or having anything to do with the paper/study whatsoever is entirely optional.

Time: Some have said that the "authors" of these CME pieces are not to blame because those mean CME outfits send the proofs of the articles to be approved by the authors so quickly that the authors don't have time to review them. That is perhaps the WORST argument I've heard in a while. If that happens to an author once, I can understand...

Perhaps you're a well-meaning scientist who is hoping to provide something of value to educate your colleagues in a CME piece. Great. Then the ghostwriters throw together something that might be described as, um, "a piece of commercial crap," email you the manuscript to approve in 24 hours or else their version stands as the final version. At that point, you have hopefully learned your lesson. If you are repeatedly performing this exercise, lending your name to commercials passing for education, in which your own scientific views are not represented by the CME pieces, then you have nobody to blame but yourself.

Of course, there may be some whose views are accurately represented in CME pieces. Good for them. Have dozens of CME articles under your name, by all means. But, by God, let's not have any more statements like "the article with my name on it does not reflect my own views." I sincerely applaud Dr. DeVane for admitting that the CME article in CNS Spectrums is a joke. Now let's hope that he never finds himself in such a position again. Fool me once, shame on you; fool me twice... The worst forms of CME, which are marketing points covered with a very thin veneer of science, can only exist so long as "key opinion leaders" continue to sign their names on such pieces.

On a final note, I'd like to know if Nemeroff and Preskhorn, the other two authors on the CNS Spectrums piece likewise view the article as "crap" and if they would be willing to disavow themselves of the study. Here's betting they will have not a word to say on the topic.

Also read Pharmalot's great piece on the topic.

Uh-Oh Chuck, What About the Disclosure? OR Go Team MAOI!

Introduction: As longtime readers can surmise from the headline, this post is about Dr. Charles Nemeroff. And the Dalai Lama. Let's start from the beginning. Nemeroff was featured in a CME activity on Medscape. To view it, you'll need to complete a free registration at Medscape. For those new to the wonderful world of CME, note that while CME stands for continuing medical education, it is more accurate to refer to it as commercial medical education -- it's paid advertising, dare I say cheerleading. It is rather disheartening that physicians who wish to keep their licenses must sit through a bunch of advertisements as opposed to less biased, more educational forms of training. For more on CME in general, read my earlier posts here and here, or check out Daniel Carlat's excellent work (1, 2, 3, 4, 5 ).

The Present Story: Nemeroff, in the aforementioned CME activity, discusses the transdermal patch for selegiline, a monoamine oxidase inhibitor (MAOI) and how it may serve as a good treatment option for people with depression. Here are a couple of quotes from Nemeroff:

The limited use of oral monoamine oxidase inhibitors (MAOIs) over the past decade or so has been driven largely by physicians' concerns that they might potentiate hypertensive reactions when they interact with tyramine in foods. A new transdermal system is currently available that enables the MAOI to avoid first-pass metabolism by bypassing the gut, thereby reducing the chance of hypertensive reactions caused by tyramine.

The Pande study, which I believe was done when Pande was at Lilly, compared 20 patients with atypical depression treated with fluoxetine and 20 treated with the nonselective irreversible MAOI, phenelzine. Efficacy was about equal. Certainly other data and my own experience would suggest that MAOIs are superior to SSRIs and TCAs [for atypical depression].

A case that is treated successfully (of course) with transdermal selegiline is discussed during the activity in some depth. All's well that ends well. Clearly, the CME activity backs the use of transdermal selegiline. While it discusses some of the risks associated with MAOI treatment, the program states that the transdermal system avoids many of these issues.

Chuck's Conflicts: Nemeroff lists the following disclosures in the CME activity:

Reunette W. Harris Professor and Chairman, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

Disclosure: Grants: AstraZeneca Pharmaceuticals, LP, Bristol-Myers Squibb Company, Forest Laboratories, Janssen Pharmaceutica, National Institute for Mental Health, Pfizer Inc, Wyeth-Ayerst Laboratories, Consultant: Abbott Laboratories, Acadia Pharmaceuticals, Bristol-Myers Squibb Company, Concept Pharmaceuticals, Ltd, Cypress Bioscience, Inc, Cyberonics, Inc, Eli Lilly and Company, Entrepreneur Fund Inc, Forest Laboratories, GlaxoSmithKline, H. Lundbeck A/S, Ingenix i3 DLN, Janssen Pharmaceutica, Otsuka America Pharmaceutical, Inc, Pfizer Inc, Quintiles Transnational Corporation, UCB Pharma, Wyeth-Ayerst Laboratories; Speaker: Abbott Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Pfizer Inc.; Stockholder—Acadia Pharmaceuticals; Corcept Therapeutics, Inc; Cypress Biosciences; NovaDel Pharma Inc.; Board of Directors: American Psychiatric Institute for Research and Education, NovaDel Pharma Inc, National Foundation for Mental Health

As you can gather, Nemeroff is a busy guy! According to the above, he is a consultant for 18 drug companies and a speaker for four companies. The plot is about to thicken (or, perhaps, sicken) notably...

The Missing Disclosure: Remember how the above CME was all about pushing a newer, safer MAOI drug for depression? Well, it just so happens that Nemeroff is the co-chair of the Scientific Advisory Board for CeNeRx, a company that is developing a (you guessed it) newer, safer MAOI drug for depression! Note that Nemeroff did not mention his position with CeNeRx in his disclosure for the Medscape CME activity. Here's what the CEO of CeNeRx had to say about the MAOI they are testing:

In contrast to other MAO inhibitors, our third generation RIMA series is designed to bind selectively and reversibly, with the goal of significantly reducing the cardiovascular risks and other side effects typically associated with the MAOI class. These safety results, along with the high plasma levels and favorable pharmacokinetics demonstrated in the study, support advancing Tyrima into a multiple dose safety study in late spring.

Note the similarity to what was being said about the MAOI patch in the Medscape CME. Let me put this plainly: Nemeroff stumps for an MAOI in a CME activity, yet does not disclose that he is being paid by a company which also manufactures an MAOI. Can you say "hiding a blatant conflict of interest?"

The Dalai Lama: Nemeroff is appearing with His Holiness the Dalai Lama for a presentation on depression at Emory University. Thankfully, Nemeroff is not scheduled to speak about MAOI's. He is actually scheduled to speak about the relationship between early life experience and depression, about which the research is quite interesting and important. However, given the history of Nemeroff's scientifically questionable behavior (read a summary here, which has links to more detailed stories), it strikes me as strange that he'll be presenting alongside the Dalai Lama.

Golden Goblet: Does this earn Nemeroff a nomination for a Golden Goblet ? I believe so.

When to Say Sorry?

In a recent post, Daniel Carlat apologized to Charles Nemeroff for nicknaming him "Bling Bling" in a prior post. So what? Who cares? Well, I think we need to take a look at what behavior requires an apology and what does not. I'm not saying I have the answers, but I think the issue is quite important.

Let's look at some documented issues regarding Nemeroff:

ARISE-RD 1: Nemeroff was an author on a study (called ARISE-RD) examining the use of risperidone as an antidepressant. The study results did not demonstrate that the drug worked, especially after the authors issued a correction indicating that one of the findings in the published version of the study was incorrect (oops -- sorry that we mentioned that the drug worked; we screwed up -- it really did not work).

ARISE-RD 2: The study results were clearly not reported in full, leaving open the possibility that unfavorable data for risperidone was simply swept under the rug.

ARISE-RD 3: The study was published in a journal of which Nemeroff was the editor. Strangely, he did not report that he had a financial conflict of interest in the study, though the journal requires such relationships to be disclosed.

ARISE-RD 4: Authorship was switched around, leading one to wonder if the authorship line was an accurate reflection of who contributed significantly to the study or if it included an effort to stamp on the names of several "key opinion leaders" in order to improve the study's marketing value (1, 2 ).

I strongly encourage readers to read the linked posts above in order to plumb the depths to which this study appeared to be flawed. But there's more...

VNS: In his role of journal editor, Nemeroff again failed to disclose relevant conflicts of interest regarding a study that appeared in his journal and upon which he was an author. Read more on that tale here and here.

Mifepristone/RU-486: Nemeroff wrote an article reviewing various treatments. One treatment he mentioned was mifepristone (Corlux/RU-486). Nemeroff serves in a paid advisory role to Corcept, maker of the drug. He concluded, based upon incredibly weak evidence, in the review, that mifepristone was "very effective" in treating psychotic depression.

Lithium patch: In the same review article as mentioned above, Nemeroff mentioned that the lithium patch improved tolerability and compliance. So the patch made patients stick with treatment better and lowered the side effect burden. Oh, and Nemeroff did not cite a single source to back up these claims. Um, the entire point of a review article is to make claims and back them with sources. Nemeroff holds the patent for the lithium patch, by the way.

David Healy: According to some sources (not entirely confirmed, though I believe it), Nemeroff was part of the effort to get David Healy ousted from his position at the Univeristy of Toronto. It's a long story, worth reading about here and here. As readers of my site know, I have cited Healy's work here many times due to his close knowledge of data regarding psychiatric medications (particularly SSRI's) -- he's a good scientist with, in my mind, a very strong conscience. If Nemeroff was involved in getting Healy's position rescinded, then I say shame on him.

CME and Dr. Nemeroff: Dr. Nemeroff, like many key opinion leaders, is willing to set his name on journal supplement papers which are then used for continuing medical education. Daniel Carlat has a great post about a recent CME activity, upon which Nemeroff was an author, that seemed to magically transform unfounded ideas into "science" by just adding a sprinkling of money from the sponsor, Bristol Myers Squibb. Kinda made me think of a Chia Pet for some reason. Suh-Suh-Suh-Science! to the tune of Chuh-Chuh-Chuh-Chia!

So looking at the above list of items involving Nemeroff, I ask readers: Is it okay to nickname someone "Bling Bling" or to nominate someone for a Golden Goblet award? Please chime in with a comment to let me know. Is it acceptable sarcasm or is it character assassination, or something else?

The Point: I'm not in favor of name calling, nor am I in favor of being a jerk. But where does one draw the line? Where is the line drawn between acceptable reporting on controversial and important issues and being a bully? Over at the Drug Wonks blog, there are several posts that take aim at Steve Nissen and others, often using a nastier tone than nicknaming people "Bling Bling." Plenty of mudslinging occurs in blogs and in the "old media" -- watch most of the talking heads on so-called cable "news" networks and see what I mean. How often, and to what degree, is someone allowed to use sarcasm before it becomes rude and bullying? Part of writing is entertaining one's audience, and let's face it -- sarcasm can be very entertaining. How is a blogger to be entertaining, stick to the facts, and bring important information to readers without crossing the line into being offensive? I don't know. Perhaps you do -- again, leave a comment and see if you can shed light on this issue.

Bipolar in Kids: The BS Train Keeps Running

Earlier in this week, I wondered how Charles Nemeroff, "key opinion leader" in psychiatry at Emory University could make the following statement with a straight face...

"The concerns about antidepressant use in children and adolescents has paradoxically resulted in a reduction in their use, and this has contributed to increased suicide rates."

Note that the data do not actually show a decrease in SSRI prescription for teens during the timeframe when suicides increased, and that even if it did, such a relationship could have just been a coincidence.

But now, I believe that Nemeroff's statement does not even make for the least-supported (i.e., most fictional) statement of the week in psychiatry. The award instead goes to (extended drum roll, please...)

Jean Frazier of Harvard University. The New York Times quoted her as follows:

Dr. Jean Frazier, director of child psychopharmacology at Cambridge Health Alliance and an associate professor at Harvard, said that up to three-quarters of children who exhibit bipolar symptoms become suicidal, and that it is important to treat the problem as early as possible.

"We’re talking about a serious illness with high morbidity, and mortality," Dr. Frazier said, "and for some of these children the medications can be life-giving."

NICE! To my knowledge, there is little to no data to show that bipolar disorder is a valid diagnosis in young children, nor that early treatment is helpful, nor that treatment reduces risk of suicide for "bipolar" children, nor that 75 percent of "bipolar" children become suicidal. This is absolute nonsense, the type of statement that leads to unnecessary medication and leads people to falsely believe that bipolar disorder is a terrible epidemic among youth.

It gets even more detached from reality when we consider the case of Rebecca Riley, a four year old who was prescribed a very high dose of Clonidine, as well as being prescribed Seroquel and Depakote, and who died, reportedly due to the effects of her meds (clonidine seems to be the leading suspect).

Hat tip: Furious Seasons, who has been absolutely on fire as of late.

Less SSRI's, MORE Suicide (?)

Some "key opinion leaders" were in the papers again last week stating that the increase in suicide rates for teens was related to a lower prescription rate of SSRIs. Of note, in the news stories I've seen on the topic, no data have actually been provided to show that antidepressant prescription rates went down when the suicide rate increased. The lack of data, naturally, did not prevent the media from running with the story, much in the same way that children sometimes run with scissors.

For examples of reporting on the topic in the media, try MedPage, or ABC for example. The AHRP blog dug up information from the American Psychiatric Association that stated:

In 2003, U.S. physicians wrote 15 million antidepressant prescriptions for patients under age 18, according to FDA data. In the first six months of 2004, antidepressant prescriptions for children increased by almost 8 percent, despite the new drug labeling.

The point here is that antidepressant prescription rates were actually rising when suicide rates were rising, so it is a bit hard to see how FDA warnings were leading to fewer prescriptions which were, in turn, leading to more suicides.

So how does this kind of story gain traction?

Enter Chuck. According to ABC News, Dr. Charles Nemeroff, a "key opinion leader" in psychiatry, (background here and here) said that

"I have no doubt that there is such a relationship," said Dr. Charles Nemeroff, chairman of the department of psychiatry and behavioral sciences at the Emory University School of Medicine.

"The concerns about antidepressant use in children and adolescents has paradoxically resulted in a reduction in their use, and this has contributed to increased suicide rates."

It would appear that Nemeroff has either seen some data nobody else has seen or that he is making things up. Given his cozy relationship with a plethora of drug companies, I'm guessing it's the latter. Even if there were data showing a decrease in SSRI prescriptions as suicide rates increased, surely Nemeroff would know that there could be numerous other factors involved. As is stated in every introductory research class, correlation does not imply causation. Of course, this point appears to be moot, as I've yet to see any evidence that SSRI prescription rates went down as youth suicide rates increased.

It would appear that this latest scare over SSRI deficiency causing suicide is another case of pseudoevidence based medicine.

Hat Tip: AHRP, Hooked.

Update: Nemeroff indeed had some data indicating that SSRI prescriptions have fallen. Yet it now appears that while SSRI usage fell, suicides did not increase. Nemeroff's statement above thus appears incorrect.