My Response To Dr. Pies

In the October 2015 issue of the Behavior Therapist (pages 206-213), Jeffrey Lacasse, PhD, and Jonathan Leo, PhD, published an article titled Antidepressants and the Chemical Imbalance Theory of Depression: A Reflection and Update on the Discourse,

I thought the article had particular merit, and I drew attention to it in a post dated November 2.  The post, More on the Chemical Imbalance Theory, was also published on Mad in America.

In that post, I quoted a number of passages from the Behavior Therapist article, including:

“When our physicians are educating us, we prefer they not tell us any lies, white or otherwise.  Unfortunately, characterizing the chemical imbalance metaphor as a ‘little white lie’ communicates a paternalistic, hierarchical approach that sounds suspiciously like the days of medicine that we thought we had left behind.  It’s a ‘little white lie’ if you’re a psychiatrist; if you’re a confused, vulnerable depressed person who agrees to take an SSRI after hearing it, you might not consider it so little.  After all, if your trusted physician tells you that you have a chemical imbalance in your brain that can be corrected with medication, not doing so sounds foolish, if not scary (Lacasse, 2005).  How many patients with reservations about SSRIs have agreed to take medication after being told this ‘little white lie’?”

and

“Pies blames the drug companies for running misleading advertisements about chemical imbalance, belatedly admits he should have said something sooner, but fails to mention that he was paid to help them promote their products at the time the advertisements were running.”

On November 5, I received the following email, forwarded from Mad In America:

Message sent by: Ronald Pies MD

Message:Dear Mr. Cole:

Philip Hickey\’s blog, \”More on the Chemical Imbalance Theory\”—posted on your website—references a recent paper by Lacasse & Leo (\”Antidepressants and the Chemical Imbalance Theory of Depression\”) which contains incorrect and misleading information re: my views, as well as an unsupported claim re: supposed “conflicts of interest”  Lacasse & Leo impute to me. These misstatements by Lacasse & Leo are, unfortunately, repeated in Hickey\’s blog.  This is unacceptable and must be publicly corrected. In brief, Lacasse and Leo’s misrepresentations are as follows:

1.  They misattribute the phrase “little white lie” to me, with regard to the so-called “chemical imbalance theory.” In reality, this unfortunate phrase was originally used by Mr. Robert Whitaker in an interview with Bruce Levine. The link is: http://brucelevine.net/psychiatry-admits-its-been-wrong-in-big-ways-but-can-it-change-a-chat-with-robert-whi/

In the article I subsequently wrote, cited by Lacasse & Leo (http://www.medscape.com/viewarticle/823368), my use of that phrase was in direct reference to Whitaker’s interview and to his own choice of words. I made this clear as far back as April, 2014, in a comment I posted beneath my Medscape article (available online). Careful scholars would surely have observed this and not falsely attributed Whitaker\’s phrase to me. The Medscape article has since been corrected.

2.  Citing information properly disclosed by me over a decade ago, Lacasse & Leo allege that I was “paid to help [pharmaceutical companies] promote their products…” This is categorically false. The allegation by Lacasse & Leo was not based on any direct knowledge of my professional or contractual arrangements dating back to 2003. Never, at any time, have I accepted any monies from pharmaceutical companies (or anyone else) with the intent or purpose of promoting their products. Nor have I ever had any ongoing financial relationships with any pharmaceutical companies.

A detailed rejoinder to Lacasse & Leo will appear in the winter issue of \”The Behavior Therapist,\” where the Lacasse & Leo article originally appeared. However, I respectfully request that you run a correction on your website as soon as possible; e.g., by posting this communication. I consider this a matter that impinges on my professional reputation, and I reserve all rights in pursuit of a just resolution.

Sincerely,
Ronald Pies MD
Professor of Psychiatry

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MY RESPONSE

In his email, Dr. Pies raises two objections.  Firstly, he contends that the phrase “little white lie” as applied to the chemical imbalance theory was misattributed to him, on the grounds that the phrase had been used earlier by Robert Whitaker.  Secondly, he states that he has never accepted payment from pharmaceutical companies with the intent or purpose of promoting their products.

THE LITTLE WHITE LIE

On April 15, 2014, Dr. Pies published an article – Nuances, Narratives, and the ‘Chemical Imbalance’ Debate in Psychiatry – on Medscape.

The third paragraph of this article reads:

“Now, if you were to give credence to a recent online polemic posing as investigative journalism¹, you would probably choose the first or second statement. In the narrative of the antipsychiatry movement, a monolithic entity called ‘Psychiatry’ has deliberately misled the public as to the causes of mental illness, by failing to debunk the chemical imbalance hypothesis. Indeed, this narrative insists that, by promoting this little white lie, psychiatry betrayed the public trust and made it seem as if psychiatrists had magic bullets for psychiatric disorders. (Lurking in the back-story, of course, is Big Pharma, said to be in cahoots with Psychiatry so as to sell more drugs).”

The “polemic posing as investigative journalism” (Ref #1) is an ungracious, and, in my view, unwarrantedly cynical, reference to Bruce Levine’s March 5 2014, interview with Robert Whitaker.  In that interview, Robert is quoted as saying:

“By doing so [promoting the chemical imbalance theory], psychiatry allowed a ‘little white lie’ to take hold in the public mind, which helped sell drugs and of course made it seem that psychiatry had magic bullets for psychiatric disorders. That is an astonishing betrayal of the trust that the public puts in a medical discipline; we don’t expect to be misled in such a basic way.”

It is obvious in this quote, and from the surrounding text, that Robert is using the term “little white lie” as an understatement.  This is clear from the next sentence:  “…an astonishing betrayal of the trust that the public puts in a medical discipline…”.  It is also noteworthy that the phrase is inside quotation marks, which are often used to negate the substance of the enclosed material.

But in Dr. Pies’ statement in the Medscape article, there is nothing to suggest that understatement was intended, and nothing to suggest that the sentiment entailed was anything other than Dr. Pies’ own position.

Specifically, he did not place the phrase inside quotation marks.  And more generally, characterizing the chemical imbalance theory as a “little white lie” is consistent with the psychiatry-exculpating tone of Dr. Pies’ piece.  It is also consistent with the tone of other articles that Dr. Pies has written.  For instance, in Doctor, Is My Mood Disorder Due to a Chemical Imbalance? (2011), Dr. Pies wrote:

“Many patients who suffer from severe depression or anxiety or psychosis tend to blame themselves for the problem. They have often been told by family members that they are “weak-willed” or “just making excuses” when they get sick, and that they would be fine if they just picked themselves up by those proverbial bootstraps. They are often made to feel guilty for using a medication to help with their mood swings or depressive bouts.…So, some doctors believe that they will help the patient feel less blameworthy by telling them, ‘you have a chemical imbalance causing your problem.'”

A little white lie is an inconsequential falsehood, told to avoid causing embarrassment or hurt.  And this is precisely how Dr. Pies is presenting the chemical imbalance hoax in the passage quoted above:  a benign falsehood that will “help the patient feel less blameworthy”.

So, those of us reading Dr. Pies’ “Nuances…” article had every reason to read his description of the chemical imbalance theory as a little white lie, as his own position, and absolutely no reason to infer anything to the contrary.

In addition to this, Dr. Pies himself seems knowledgeable of these matters, and skilled in navigating these kinds of linguistic intricacies.  For instance, in the “Nuances…” article, Dr. Pies states:

“In the narrative of the anti-psychiatry movement, a monolithic entity called ‘Psychiatry’ has deliberately misled the public as to the causes of mental illness, by failing to debunk the chemical imbalance hypothesis.”

Here, Dr. Pies has made it perfectly clear that the characterization of psychiatry as a “monolithic entity” is not his position, but rather that of the antipsychiatry movement.

But no such construction is attached to his use of the phrase “little white lie”.

For Dr. Pies to contend that Drs. Lacasse and Leo misattributed the phrase to him is inaccurate and unreasonable.  The notion that “careful scholars” would have searched through the comments string and found Dr. Pies’ clarification is not convincing.  If Dr. Pies was aware that there was a misleading phrase in the article, he should have corrected it, not relied on his readers to search through a comments string looking for a correction, of whose existence they had no inkling.  The responsibility for the miscommunication sits squarely on his own shoulders.

And there are indications that Dr. Pies clearly understands this.  The “Nuances…” article which appeared in Medscape on April 15 2014, had been published earlier, on March 11, 2014, in Psychiatric Times.  But a month later, on April 11, it was updated on that site.  In the later version, the phrase “little white lie” has been changed to “simplistic notion”.  My interpretation of this at the time was that Dr. Pies had recognized that his earlier statement had been woefully inaccurate, and frankly insulting to people who had been harmed by the falsehood in question, so he made the change.  For some reason, a similar change was not made in the Medscape article until about two weeks ago, when its wording was amended to “simplistic formulation”.  If Dr. Pies didn’t believe that he had misexpressed himself, why did he feel the need to make these amendments?

So, to summarize the “little white lie” issue:

1. In the original Psychiatric Times and Medscape articles, Dr. Pies characterized the spurious chemical imbalance theory as “this little while lie”. There was nothing in the wording of this statement to suggest that this was anything other than his own position.

2. At some point in the next few weeks, Dr. Pies realized that his statement was inaccurate, or that he had misexpressed himself, and made an appropriate correction in the Psychiatric Times article, but not in the Medscape piece.

3. In October 2015, Drs. Lacasse and Leo, accurately and appropriately, attributed the “little white lie” phrase in the Medscape article to Dr. Pies.

4. Sometime in the last two weeks, the Medscape article was amended to read “simplistic formulation”.

5. On November 4, 2015, Dr. Pies unjustly accused Drs. Lacasse and Leo of misattributing the phrase to him.

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CONFLICTS OF INTEREST

Here’s the entire passage from the Behavior Therapist article:

“Thus, while we don’t know why Ronald Pies himself didn’t speak out on the chemical imbalance issue decades ago, readers should be aware of his past financial relationship with pharmaceutical companies. He sounds vaguely critical of the drug industry in his recent articles and never discloses any history of financial conflicts-of-interest. However, Pies has received funding from GlaxoSmithKline, Abbot Laboratories, and Jannsen Pharmaceuticals—the makers of Paxil, Wellbutrin, Lamictal, Depakote, and Risperdal (Chaudron & Pies, 2003; Pies & Rogers, 2005).  For years, Paxil and Wellbutrin were advertised as correcting a chemical imbalance in the brain. These three companies have recently been fined a combined $6.7 billion for illegal marketing of their products.¹  Pies has also consulted for ApotheCom, a ‘Medical Communications Agency’ that ‘provides services to support the commercialization of new products…[including]….publications planning, [and] promotional communications…’ (Pharma Voice Marketplace, 2015). While useful context, this isn’t uncommon among academic psychiatrists, and some would say it was par for the course in the 2000s.  However, in a public forum, more transparency is preferable.  Pies blames the drug companies for running misleading advertisements about chemical imbalance, belatedly admits he should have said something sooner, but fails to mention that he was paid to help them promote their products at the time the advertisements were running.

It’s important to realize that organized psychiatry doesn’t always remain silent, such as when the interests of psychiatric prescribers and pharmaceutical companies converge. In the mid-2000s, press releases endorsed by some of the most prominent psychiatrists in the United States were issued objecting to the FDA black box warning on SSRIs (e.g., American College of Neuropsychopharmacology, 2006; Healy, 2012). The APA also issued a press release defending antidepressants (APA, 2004; Healy, 2006). This was at a time when the chemical imbalance metaphor was omnipresent in direct-to-consumer advertising.  While that was seen as a pressing issue to present to the public, misleading messages on chemical imbalance were not.”  (p 209)

Footnote 1 reads:

“We want to be clear that we are not accusing Ronald Pies of anything.  Conflicts-of-interest are routine in academic psychiatry and many of the major pharmaceutical companies have been fined in the recent past.  We do believe that readers deserve to know of his past financial relationships with the drug companies that promoted their products as correcting a chemical imbalance.  The details of these financial relationships are not publicly available.”

I think the above text is clear, and speaks for itself.  It is noteworthy that Drs. Lacasse and Leo take specific pains to protect Dr. Pies from any kind of unjust criticism (“…we are not accusing Ronald Pies of anything.”)  It is also noteworthy that in his email Dr. Pies does not deny that he has consulted for ApotheCom.  Nor does he deny that he received payment for such consultations.  Nor does he deny that ApotheCom’s business is providing “services to support the commercialization of new products”.  Nor does he deny that he received payments from the other drug companies named.  Nor does he deny that these other companies promoted the spurious chemical imbalance theory in their ads.

Dr. Pies simply asserts that he has never accepted payments from pharmaceutical companies with the intent or purpose of promoting their products, and that he has never had ongoing financial relationships with any pharmaceutical company.  This is an unusual rebuttal, in that Drs. Lacasse and Leo never accused him of either of these activities.  I’ll discuss this in more detail later.

In the interests of clarity, I should point out at this stage in the discussion that the terms “promote” and “promotion” are value-neutral, and subject to degrees.  A person may promote a good thing (e.g. world peace), or a bad thing (e.g. racial hatred), and may promote something minimally or avidly.  In addition, a person might promote something  for payment, or gratuitously.

So, if a psychiatrist were to mention to a colleague, in the course of a private conversation, that he finds such and such a drug helpful in alleviating such and such a problem, he has, in effect, promoted the drug in question.  And, he, presumably, would consider this promotion to be a good thing.  Similarly, if a pharmaceutical company launches a massive advertizing campaign on a particular drug, this would also be considered a promotion of the product in question, and, if it resulted in an increase in sales, would be considered a good thing by the company in question.

Similarly, if a psychiatrist writes and publishes an opinion piece in which a certain drug is mentioned favorably, this is a promotion.  In fact, even a relatively neutral mention of a drug by an eminent psychiatrist could be construed as a promotion, along the lines of incidental placement of commercial products in movies.

Dr. Pies also asserts that the “allegation by Lacasse and Leo was not based on any direct knowledge” of his professional or contractual arrangements dating back to 2003.  And he indicated no intentions to make any such information public.

Here, however, are some facts that are in the public domain, interspersed with my comments and reflections.

1.  In July 2002, Dr. Pies published The ‘softer’ end of the bipolar spectrum in the Journal of Psychiatric Practice. He acknowledges that the article is “supported by an unrestricted grant from GlaxoSmithKline.”  The article is a literature review/opinion piece.  Here’s the abstract:

“The prevalence and diversity of bipolar disorder may be under-appreciated. Recent data suggest that when clinicians look beyond strict DSM-IV criteria for bipolar disorder, we find that as many as 5%-7% of the general public may suffer from some form of ‘bipolar spectrum disorder.’ At the same time, the comorbidity between bipolar disorder and other psychiatric conditions may create understandable confusion in diagnosis and treatment. Recognition of bipolar depression and the ‘soft end’ of the bipolar spectrum demands not only the identification of the hallmarks of bipolarity, but a heightened awareness of the problems of missed diagnosis and inappropriate treatment. By attending to some key historical and clinical clues, the psychiatrist is more likely to detect bipolar spectrum disorder and provide appropriate treatment for it.” [Emphasis added]

And here’s a quote from the “Treatment Recommendations and Conclusions” section:

“In the mean time, recent evidence suggests that lithium is at least moderately effective in many depressed bipolar patients,⁴¹ and that the anticonvulsant lamotrigine may be a feasible alternative to antidepressants in some depressed bipolar patients.⁴²” [Emphasis added]

Lamotrigine (Lamictal) is an anticonvulsant made by GlaxoSmithKline.

Reference 42, on which Dr. Pies’ recommendation is reliant, is Calabrese JR, Bowden, CL, et al. A double-blind, placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression, J Clin Psychiatry 1999.  This study was funded by Glaxo Wellcome, which in January 2000 merged with SmithKline Beecham to become GlaxoSmithKline.  Three of the authors, John Ascher, MD, Eileen Monaghan, and David Rudd, PharmD, were GW employees.  In addition, the authors thank Gary Evoniuk, PhD, and Elizabeth Field, PhD for “editorial assistance with the manuscript.”  Dr. Evoniuk was, and incidentally still is, an employee of GSK.  According to her bio, Dr. Field worked for GSK from 1989 to 2001, and with astonishing candor, describes her work there as follows:

“I managed an international department of 24 medical publication professionals who wrote/edited manuscripts for peer-reviewed journals describing the results of GSK-sponsored clinical trials in conjunction with the author/investigators. This group supported almost all products in development and marketed by GSK” [Emphasis added]

So it is clear that GSK had a very considerable input into the wording and presentation of the Dr. Calabrese et al article.  The conclusion of the study was:  “Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.”

So essentially what we’ve got here is:  Glaxo Wellcome funds, and is heavily involved in the production of, a 1999 study which finds in favor of its drug lamotrigine (Lamictal).  And in 2002, GSK contracts with Dr. Pies to write an article on the “bipolar spectrum”, in which Dr. Pies, largely on the basis of Drs. Calabrese’s and Bowden’s findings, recommends the drug, albeit with a measure of caution, for “some depressed bipolar patients”.

But the plot thickens, for this is the same Dr. Calabrese who was described in United States vs. GSK (2012) as “…GSK’s greatest proponent for the use of Lamictal in the treatment of bipolar disorder…”  Dr. Bowden is also mentioned frequently in the same lawsuit.

To provide context for this discussion, I have attached to this post  – as Appendix A – a copy of the Lamictal section of the GSK lawsuit.  It’s a sordid tale, which describes in close detail how GSK illegally and vigorously promoted Lamictal as a “treatment for bipolar disorder”.  The outcome of this lawsuit was that GSK was fined $3 billion, the largest fine for activity of its sort in American history.

I need to emphasize that my introduction of the GSK lawsuit material is to provide context.  Dr. Pies is not named in the complaint, and there is no suggestion from any source that he was complicit in GSK’s illegal activities.  Nor am I suggesting that Dr. Pies was complicit in the activities of Drs. Calabrese and Bowden.  But Dr. Pies did lend credence to their work, by quoting them, and by relying on their findings, even though the extensive GSK involvement in the creation of their report was, and still is, public information.

There are two paragraphs in the United States vs. GSK complaint that have particular relevance.

“471. Just as troublesome as the Lit Alerts and Faxbacks, were the numerous studies by Calabrese, distributed by GSK, which suggest the efficacy and use of Lamictal in patients with bipolar II.”  [Emphasis added]

In other words, the distribution of the Calabrese studies was an integral part of the illegal promotion of Lamictal for bipolar disorder.  And Dr. Pies, by publicizing, and lending credence to, these studies, became a significant, though unwitting, link in this distribution chain.

Paragraph 474 is also important.

“474. GSK’s extremely aggressive off-label campaign for Lamictal included spending large sums of money in the form of unrestricted grants, membership on advisory boards and speaker’s fees on physicians and researchers who served as ‘national thought leaders.’ As with campaigns for other drugs, the campaign for the use of the drug Lamictal in the treatment of bipolar disorders began with the widespread promotion of ‘disease awareness.'”  [Emphasis added]

In other words, GSK’s awarding of unrestricted grants was also an integral part of their promotional campaign, and as we shall see below, Dr. Pies was the recipient of several unrestricted grants from GSK.  Additionally, Dr. Pies’ opening statement in the “Softer End” article that “… 5%–7% of the general public may suffer from some form of ‘bipolar spectrum disorder.'” sounds very like the “widespread promotion of ‘disease awareness'” mentioned in paragraph 474 above.

Given the extent and vigor of GSK’s illegal promotional campaign, it was perhaps almost inevitable that a person of Dr. Pies’ academic stature and unimpeachable reputation for personal integrity, would become a “target” for GSK’s talent scouts.

In 2008, Nassir Ghaemi, MD, et al published an article Publication Bias and the Pharmaceutical Industry: The Case of Lamotrigine in Bipolar Disorder in Medscape.  The article takes to task the drug industry generally (and GSK in particular) for not publishing, and perhaps even concealing, research studies that show their products in a negative light.  Dr. Ghaemi et al focus specifically on “studies with lamotrigine in bipolar disorder”.  Here’s a quote from their abstract:

“In this paper, we review the case of studies with lamotrigine in bipolar disorder, describing evidence of lack of efficacy in multiple mood states outside of the primary area of efficacy (prophylaxis of mood episodes). In particular, the drug has very limited, if any, efficacy in acute bipolar depression and rapid-cycling bipolar disorder, areas in which practicing clinicians, as well as some academic leaders, have supported its use.” [Emphasis added]

Obviously I don’t know if Dr. Ghaemi et al  had Dr. Pies in mind when they were writing this, but as quoted earlier, Dr. Pies had written in 2002 that “recent evidence suggests that…lamotrigine may be a feasible alternative to antidepressants in some depressed bipolar patients.”

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In passing, I should probably comment on the term “unrestricted grant”.  Strictly speaking, this means that the money is given with no strings attached.  The grantee is assured the freedom to express and publish his views with no pressure from the grantor.  In practice, there often are pressures, subtle and otherwise.  Here’s what the distinguished Professor Emeritus of Medicine at UCLA, Jerome Hoffman, MD, wrote on this matter on June 12, 2013, in a guest post on the blog site Common Sense Family Doctor:

“Excuse me, but Pharma doesn’t throw away its money. There is no such thing as an unrestricted grant; if it didn’t buy value in return, why would they pay for it? And if the author didn’t write something they like to read, do you think he’d ever get another unrestricted grant?”

And here’s what the highly-respected psychiatrist Daniel Carlat, MD, wrote on June 17, 2007:

“While the term ‘unrestricted’ implies that the company had no strings attached to its money, the reality is that any physician or MECC (medical education communication company) who receives drug company funding knows that their lecture or article will be closely perused by those with the cash, and that future ‘gigs’ will be dependent on whether the company feels their product is shown in a favorable light.”

As we will see later, Dr. Pies has received several unrestricted grants from GSK.

. . . . . . . . . . . . . . . .

2.  In December 2002, Dr. Pies wrote an opinion piece: Combining lithium and anticonvulsants in bipolar disorder: a review, for the Annals of Clinical Psychiatry.  The article was funded  ” by an unrestricted grant from GlaxoSmithKline.”  Here’s a quote from the abstract:

“More recent reports suggest that lithium may be safely and effectively combined with lamotrigine, and perhaps with topiramate, although controlled studies are required.” [Emphasis added]

Here are some quotes from the body of the article:

” Since 1994, there have been at least 21 open-label, uncontrolled case reports or studies examining lamotrigine in bipolar disorder, with a cumulative control group of over 300 patients ^(26,27). While a review of this literature is beyond the scope of the present paper, a few points are worth noting. In their own review of 14 open clinical reports involving 207 patients with bipolar disorder (66 with rapid cycling), Calabrese et al. ⁽²⁶⁾ concluded that lamotrigine demonstrated moderate-to-marked efficacy in depression, hypomania, and mixed states; however, efficacy in hospitalized manic patients was not clearly shown, and many of these studies used lamotrigine as add-on (adjunctive) therapy. In the Bowden et al. study ⁽²⁷⁾, lamotrigine was evaluated in patients with refractory bipolar disorder, either as monotherapy (n = 15) or as add-on therapy (n = 60). A total of 23 subjects (31 %) were taking lithium at the initiation of the study; three additional patients received lithium later in the study. Overall, both rapid-cycling and nonrapid-cycling patients experienced symptom reduction and functional improvement over the course of 48 weeks.” [Emphasis added]

Reference 27 is a Glaxo Wellcome-funded study by Drs. Bowden, Calabrese, et al.  Four of the authors were GW employees.

Here are some more quotes from Dr. Pies’ article:

“The patient populations in open studies of lamotrigine have been quite heterogeneous, and lamotrigine has been used as both add-on and monotherapy.  These studies have suggested lamotrigine’s efficacy in depressed, hypomanic, and mixed bipolar patients.” [Emphasis added]

“Lamotrigine monotherapy is generally well tolerated.” [Emphasis added]

“From the standpoint of pharmacokinetic interactions, the combination of lamotrigine and lithium appears to pose no significant problems. Specifically, administering lamotrigine with lithium does not significantly alter the pharmacokinetics of lithium (35). Preliminary indications indicate that the combination of lamotrigine and lithium is well tolerated in most patients.” [Emphasis added]

“The addition of lamotrigine to lithium seems most useful for patients refractory to lithium alone who show prominent depressive symptoms and/or rapid cycling.”

But a product can also be promoted by criticizing the competition, in this case, divalproex, (Depakote):

“A larger cohort study of lithium-divalproex [Depakote]combination has yielded mixed results. Specifically, in an open study, Calabrese et al⁽¹⁹⁾ examined large cohorts of rapid-cycling bipolar patients ( N = 271), over a 6-month study period. Of the total group, 215 had comorbid alcohol or drug abuse, 56 did not. In the group as a whole, the combination of lithium and divalproex was associated with marked acute and continued antimanic efficacy in 85% of patients and marked antidepressant efficacy in 60%. However, only one half of patients experienced bimodal mood stabilization.  Premature discontinuation of treatment was disproportionately associated with refractory depression compared with refractory hypomania/mania/mixed states ( n = 41 vs 14). Comorbid alcohol/substance abuse did not directly affect response rates in compliant patients, but did worsen prognosis by increasing rates of poor compliance. The majority of patients receiving lithium/divalproex therapy who required additional treatment were depressed. Indeed, at the time of presentation, most patients with rapid-cycling bipolar disorder are in the depressed phase of illness, which appears to be the “hallmark” of rapid cycling ⁽¹⁹⁾.  Given this observation, and that antidepressant use has been discouraged in rapid cyclers, the authors note the pressing need for a pharmacotherapy that markedly reduces depressive symptoms without provoking ‘switching’ or cycle acceleration.” [Emphasis added]

Here again, note that reference 19 which Dr. Pies is citing is a study conducted by Dr. Calabrese, Bowden, et al in 2001, and was funded by Glaxo Wellcome and NIMH.

. . . . . . . . . . . . . . . .

3.  In October 2002, Dr. Pies published Have we undersold lithium for bipolar disorder? as an editorial in the Journal of Clinical Psychopharmacology. The editorial was funded by an unrestricted grant from GSK.  Here’s a quote from the conclusion:

“Lamotrigine looks very promising for bipolar depression and prophylaxis, but more studies are needed to define and solidify its role. The same goes for topiramate. Olanzapine, while useful in mania and perhaps as an adjunctive agent in bipolar depression, has yet to prove itself as monotherapy in bipolar prophylaxis. Furthermore, concerns about the neuroendocrine effects of valproate and olanzapine—both of which have FDA labeling in bipolar disorder—must also give us pause. As for gabapentin, there are still no randomized, controlled studies of monotherapy showing this agent to be effective in any type or phase of bipolar disorder.”  [Emphasis added]

Here’s another quote from the body of the editorial:

“Recently, Calbrese et al.¹³ presented data from two large, double-blind, placebo-controlled, studies comparing lamotrigine and lithium in the maintenance treatment of bipolar I disorder. While both active agents delayed time to ‘any’ bipolar event, a separate analysis (manic/hypomanic/mixed vs. depressive events) found that lamotrigine had more robust effects than lithium in delaying onset of depressive episodes.” [Emphasis added]

Reference 13 is to: Calabrese JR, Bowden CL, et al. Lamotrigine or lithium in the maintenance treatment of bipolar I disorder [abstract NR 236]. Presented at the American Psychiatric Association Annual Meeting, Philadelphia, PA, 2002.

. . . . . . . . . . . . . . . .

4.  In February 2006, Dr. Pies and Patricia Marken, PharmD, co-authored an opinion piece Emerging Treatments for Bipolar Disorder: Safety and Adverse Effect Profiles in the Annals of Pharmacotherapy. The article was “supported by an unrestricted grant from GlaxoSmithKline.”  Here are the authors’ conclusions:

“Pending the results of ongoing controlled studies, several emerging agents may be useful additions to the therapeutic arsenal for BPD.” [bipolar disorder]

And here are some quotes from the body of the paper:

“Lamotrigine [Lamictal] is the only newer AED [anti-epileptic drug] with randomized, placebo-controlled data supporting its use as maintenance treatment in BPD.” [Emphasis added]

“Lamotrigine is the most studied of all emerging treatments for bipolar maintenance.⁷² It appears to be more useful in bipolar depression than in mania.⁷²” [Emphasis added]

“Lamotrigine was well tolerated, with an adverse event profile similar to that of placebo. Lamotrigine did not appear to induce mania and was not associated with sexual adverse effects,⁷⁹ weight gain,⁸⁰ or withdrawal symptoms.⁷⁹” [Emphasis added]

Reference 72 is to a study by Drs. Bowden, Calabrese et al, 2003.  It was funded by GSK.  Four of the authors were GSK employees, and a further five GSK employees are acknowledged for assistance “in the preparation of this article.”

Reference 79 is to Bowden et al, 2004.  Three of the six authors were GSK employees.

And at the end of the Drs. Pies and Marken article (before the references) it states:  “We gratefully acknowledge Drs. Jacqui Brooks MBBCh MRC Psych and Laurie Barclay MD for their contributions during the preparation of this manuscript.”  No information is provided as to Dr. Brooks’ or Dr. Barclay’s affiliations, or who was paying for their contribution.  But Dr. Brooks’ bio is online, and according to this, she is currently Senior Vice President Medical Strategy at RMEI [Robert Michael Educational Institute].

Dr. Brooks’ bio also states:

“Seasoned healthcare executive with strong blend of clinical (trained psychiatrist) and strategic leadership accomplishments. Documented capacity to analyze evolving environments, provide strategic direction, and successfully lead teams in developing innovative, high-quality products and brand strategies. Proven success in business growth and development in the medical communications environment.” [Emphasis added]

There is no indication in Dr. Brooks’ bio that she ever worked as a psychiatrist.  Her employment history shows that from 2002 to 2005, she was working for ApotheCom Associates as VP Scientific Affairs, Senior Medical Director.  ApotheCom describes itself as “…a Global Medical Communications Powerhouse…”  PharmaVoice provides the following description:

“ApotheCom provides services to support the commercialization of new products at a global level as well as promotional programs for the US market. Services include thought-leader optimization, publications planning, promotional communications and education programming.”

Drs. Pies’ and Marken’s “Emerging Treatments…” article was published on January 10, 2006, so was probably developed during 2005, and it seems likely that Dr. Brooks’ contribution to the manuscript was in her capacity as an ApotheCom employee.  I have no way of knowing who was paying for ApotheCom’s services with regards to this paper, but it is in the public domain that in 2002, GSK made an educational grant to ApotheCom Associates for an article by Robert Hirschfield, MD.

Nor have I any information as to what kind of contribution Dr. Brooks might have made to the manuscript in question.  But her career and bio summary suggest that it might have been more in the area of “brand strategies” and “business growth” than psychiatric technicalities.  Why would an experienced and eminent psychiatrist-writer, like Dr. Pies, need help with a manuscript on the treatment of bipolar disorder from a “seasoned healthcare executive”, employed by a company that specializes in thought-leader optimization, publications planning, promotional communications and educational programming?  It is, I think, particularly noteworthy, that in the acknowledgement of Dr. Brooks’ contribution to “the preparation of the manuscript”, no information is provided concerning her affiliations, or who was paying for her services.  This, I suggest, constitutes, at a minimum, incomplete disclosure.

I was unable to find any information on Laurie Barclay, MD.

. . . . . . . . . . . . . . . .

5.  In August 2006, Dr. Pies and D.F. MacKinnon, MD, published: Affective instability as rapid cycling: theoretical and clinical implications for borderline personality and bipolar spectrum disorders in the journal Bipolar Disorders.  The article, which is a literature review/opinion piece, was “Supported by an unrestricted grant from GlaxoSmithKline.”

Here are the article’s conclusions:

“The same mechanism may drive both the rapid mood switching in some forms of bipolar disorder and the affective instability of borderline personality disorder and may even be rooted in the same genetic etiology. While continued clinical investigation of the use of anticonvulsants in borderline personality disorder is needed, anticonvulsants may be useful in the treatment of this condition, combined with appropriate psychotherapy.” [Emphasis added]

Note that lamotrigine (Lamictal) is an anticonvulsant.

And here are some interesting quotes from the article:

“To our knowledge, there are only two randomized,  double-blind, placebo-controlled studies of anticonvulsants in well-defined rapid cycling populations, both by the same group, and only one currently in the literature ⁽⁵⁹⁾. In the published study, 182 rapid cycling patients were randomized to lamotrigine monotherapy or placebo. The study found that 41% of lamotrigine-treated versus 26% of placebo-treated patients were stable without relapse during 6 months of monotherapy. Patients with rapid cycling bipolar II disorder consistently experienced more improvement than did bipolar I patients. Most patients who were assigned to double-blind treatment were in the midst of a depressive episode, suggesting antidepressant effects of lamotrigine in bipolar disorder, consistent with the results of a separate, open-label trial of lamotrigine versus lithium in rapid cycling patients ⁽⁶⁰⁾.” [Emphasis added]

Reference 59 is to a 2000 Calabrese, JR, Bowden, CL et al study funded by Glaxo Wellcome.  Four of the authors were GW employees, and the authors acknowledge assistance from Gary Evoniuk, PhD and Tracey Fine, MSc “in the preparation” of the article.  Both Dr. Evoniuk and Ms. Fine were GW employees at the time this study was conducted.  Ms. Fine’s position was Medical Publications Specialist.

Here’s another quote from Drs. Pies’ and MacKinnon’s opinion piece:

“Preliminary data suggest that lamotrigine may also have benefits in borderline personality disorder, with or without comorbid bipolar disorder.  In an open case series of eight medication-refractory borderline personality disorder patients without concurrent major mood disorders, lamotrigine produced sustained remission in half of those who completed the trial, with notable benefit against impulsive sexual, drug-taking, and suicidal behaviors.⁽⁶⁹⁾” [Emphasis added]

Reference 69 is to: Pinto OC and Akiskal HS, 1998 which was funded by Glaxo Wellcome.

Here are more quotes from the Drs. Pies and MacKinnon opinion piece:

“Randomized, double-blind, controlled studies using lamotrigine appear warranted in this population; however, until these are completed, the utility of lamotrigine in borderline patients remains uncertain.  Nevertheless, one can conclude from the juxta-position of these studies of anticonvulsants in rapid cycling bipolar disorder and borderline personality disorder that at least some anticonvulsants are effective in alleviating not only the affective instability common to both conditions, but also specific measures of what have heretofore been considered fixed traits among borderline patients.” [Emphasis added]

Note how the initial note of skepticism pending the completion of randomized controlled trials is effectively neutralized by the material after the words:  “Nevertheless one can conclude…”.  And note the strength of the assertion:  One can conclude that some anticonvulsants (e.g. Lamictal?) can remediate what have previously been considered fixed traits!

“Once the biological roots of mood instability are better understood, there may be much more to contribute to the understanding of the development of our conventional notions of character and personality.”

And, presumably, more perceived justification for the use of psychiatric drugs to “fix” problems of personality and character.

“We conclude that in at least a sub-group of cases, borderline personality disorder may be an atypical presentation of a primary mood disturbance, probably related to the broad spectrum of bipolar-like disorders. It is premature to recommend anticonvulsants in the routine treatment of patients with borderline personality disorder; however, it seems that anticonvulsants may belong in the psychiatrist’s armamentarium for treatment of this condition.”

Here again, note how the appropriate cautionary lead-in is neutralized by the statement after the word “however”.  The suggestion that anticonvulsants belong in a psychiatrist’s “armamentarium” clearly entails the notion that these products should be used in the “treatment” of “borderline personality disorder”.

And as mentioned before, a drug can be promoted by knocking the opposition, in this case divalproex (Depakote).

“The second randomized, double-blind, controlled study ⁽⁶¹⁾ involved a 20-month, parallel group comparison of 60 patients with a history of recent rapid cycling bipolar I or II disorder.  Patients were randomized to lithium or divalproex monotherapy in a balanced design after stratification for bipolar type I and II. For subjects on either lithium or divalproex, about half suffered a relapse: a third into depression, and one-fifth into mania or hypomania. Although clearly better than placebo, it appears there was no benefit of divalproex versus lithium.”

Reference 61 is to a study by Dr. Calabrese, et al.  The study was funded by the NIMH and the Stanley Medical Research Institute.

. . . . . . . . . . . . . . . . .

DISCUSSION

I don’t think there can be any doubt, that in the five papers discussed above, Dr. Pies and his various co-authors did make numerous favorable mentions of the drug lamotrigine, and that the articles were funded by grants from GSK.

Dr. Pies could, of course, respond to all this by stating that he helped promote Lamictal on its merits alone, and that this promotion had nothing to do with the funding and/or manuscript assistance that he coincidentally received from the manufacturer of this product (GlaxoSmithKline).  And he could contend that he cited the studies by Drs. Calabrese and Bowden purely on their merits.  And all of this could well be true.

But as Dr. Pies himself wrote in a Psychiatric Times article – The Age of Conflicts—of Interest – on August 1, 2008:

“…the physician or researcher may not even be aware of his real motivation. We are all quite capable of rationalizing our own self-interest in the name of the patient’s well-being,’  ‘the need for the latest technology,’ and so on.”

Dr. Pies could also argue that in the above examples, I have cherry-picked the quotes, and that his treatment of these topics is more balanced than I have portrayed.  And indeed, there would be an inevitable measure of truth to this contention.  Obviously I can’t quote the articles in their entirety, and  Dr. Pies does sometimes mention drawbacks in the sponsor’s drug, and positive aspects of a competitor’s product.  But I have tried to be fair, by selecting quotes that convey the general tone of each piece with regards to lamotrigine, and, I encourage readers to consult the articles in question, and decide this matter for themselves.

Dr. Pies could certainly quibble over any particular quote – or even over any particular paper – as to whether it constitutes promotion of a pharma product.  But of greater importance is the cumulative effect of the multiple passages quoted above in the context provided by the GSK lawsuit complaint and the multiple GSK-sponsored studies.  In this post I have discussed and quoted from five opinion pieces, authored or co-authored by Dr. Pies.  All of the articles were funded by GSK, and all refer to studies conducted by Dr. Calabrese et al.  And remember, Dr. Calabrese is described in the GSK lawsuit as “…GSK’s greatest proponent for the use of Lamictal in the treatment of bipolar disorder…”

In my view, Dr. Pies’ statements in the various articles would appear, to an impartial reader, as recommendations or promotions of lamotrigine.  And it is worth pointing out that I am neither particularly skilled, nor particularly systematic, in conducting literature searches.  It is entirely possible that a more competent searcher would uncover a great deal more material of a comparable nature.  And it also needs to be borne in mind that I have focused on only one drug – Lamictal.  A search of Dr. Pies’ writings concerning other pharma products could conceivably reveal similar complications.  I did, for instance, come across a 2005 article written by Dr. Pies and Winkelman which stressed the efficacy of the sleeping pill eszopiclone (Lunesta), manufactured by Sepracor, now Sunovion.

This reported efficacy was based on Ref # 146, a 2003 study by Andrew Krystal, MD et al.  The Krystal et al study concluded:

“Throughout 6 months, eszopiclone improved all of the components of insomnia as defined by DSM-IV, including patient ratings of daytime function. This placebo-controlled study of eszopiclone provides compelling evidence that long-term pharmacologic treatment of insomnia is efficacious.”

There were seven authors of this study.  Three of the authors are listed as “consultants, investigators and advisory board members to Sepracor.”  A fourth author is listed as a Sepracor consultant.  And the remaining three authors were Sepracor employees.

In their opinion piece, Drs. Pies and Winkelman did not point out that the Krystal et al study was largely a Sepracor in-house project.  Nor did they disclose the funding source (if any) for their opinion piece, but in their acknowledgement section, they wrote:

“The authors would like to acknowledge Sepracor Inc. for its assistance in the preparation of this manuscript.”

I have no way of knowing what this assistance entailed, but it does imply that Sepracor did – at the very least – have some collaborative input in the wording of the article.  It seems unlikely that any such input would work to the detriment of their product.  Why would an eminent psychiatrist of Dr. Pies’ stature need help from a pharmaceutical company to write an opinion piece on the treatment of insomnia?  What kind of help did Sepracor provide?

. . . . . . . . . . . . . . . .

It also needs to be stressed that, as far as I know, Dr. Pies has done nothing wrong, in any formal sense of the term.  He has accepted grant money from pharmaceutical companies to write opinion pieces on various psychiatric topics, and if he came down in favor of the grantor’s product, there are no definite indications that his motivations were anything but pure.  It also needs to be stated that Dr. Pies is a prolific writer, and that the articles cited above represent only a tiny fraction of his published work.  It is possible that a more comprehensive review of his writing over the period in question would show that these kind of industry-sponsored opinion pieces constituted a small fraction of his overall output.

A further question in all of this is why Dr. Pies should be so upset at the suggestion that he had received payment to write articles that helped promote psychiatric drugs.  If Dr. Pies believes that the drugs are efficacious and generally benign, why shouldn’t he help promote them, and why shouldn’t he be afforded reasonable compensation for this activity, particularly when he discloses these arrangements in the papers.  Why should the acceptance of payments in these matters have any bearing on his professional reputation?

But over-riding all of this, is the obvious fact that Dr. Pies has mis-read the phrase  “…he was paid to help promote their products…”  Specifically, he has apparently formed the belief that the phrase purports to describe his motivation in these transactions.  In fact, the use of the passive voice (he was paid) makes it clear that it is the payer’s motivation that is the matter of focus, not the payee’s.

To clarify the distinction, compare the two statements:

He was paid to help promote the drugs.

And

He accepted payment to help promote the drugs.

The first statement clearly entails the notion that the payers were paying the individual with the intention – and presumably expectation – that he would help promote the drugs.  The statement tells us nothing about the payee’s intentions, or even his awareness, of the payer’s intentions.  The second statement, by contrast, clearly purports to describe the payee’s motivation, but Drs. Lacasse and Leo made no statement of that kind.

There is a perfect parallel to this in the drug industry’s widespread use of “thought leaders” to promote their products.  This particular hoax was thoroughly explained by Daniel Carlat, MD, in his 2010 book “Unhinged”.  Here’s how it worked:

A drug rep would approach a psychiatrist and tell him that he – the psychiatrist – was considered a “thought leader” or “key opinion leader” in the area, and that they would like to recruit him to give lectures and presentations to other psychiatrists on the value of a particular drug.  The drug company would train the psychiatrist, and would provide slides and other teaching aids, and would pay the psychiatrist for delivering the presentation.

And this is where it gets subtle.  The psychiatrist thought that the targets of these endeavors were the psychiatrists in the audience – that he was being paid to promote the drug in question to them.  In reality, and this was what Dr. Carlat exposed, the lecturer-psychiatrist himself was the actual target.  By getting him to extol the merits of a drug to his peers, the drug company was actually generating pressure within the lecturer to prescribe the drug more frequently himself.  And the tactic was extremely successful!

So, from the psychiatrist’s point of view, the following statement would be true:

I was paid to give lectures on this drug.

But from the drug company’s point of view, the following statement was true.

We paid him so that he would prescribe this drug more often.

Obviously the psychiatrist in question would object to the latter statement, because he had no knowledge of the drug company’s motivation or tactics.

Similarly, with regards to GSK’s “unrestricted grants, there can be no doubt, given the context outlined above, that GSK was awarding these grants to help promote Lamictal.  And this is the case, even though from Dr. Pies’ point of view, he was merely accepting payment from GSK to write scholarly articles.

In short, like the psychiatrists in Dr. Carlat’s account, he was systematically misled as to the real purpose of the articles.

. . . . . . . . . . . . . . . .

It is worth remembering that this matter began with Dr. Pies’ efforts to distance psychiatry from the chemical imbalance theory of depression, and to lay the blame, or at least some of the blame, for this hoax, onto pharma commercials.

The central point of this entire issue is that at the time these deceptive commercials were running, and running very successfully, Dr. Pies was contracting with these same companies to write articles about their products, and his payments came, at least in part, from revenues generated by these very ads.  Dr. Pies’ current condemnations of pharma’s past excesses would be more convincing today if he had lodged clear statements of protest at the time, or better still, if he had refused to accept their grant contracts, on the basis that the money was tainted.

FINALLY

One of my main purposes in writing this website is to draw attention to psychiatry’s spurious foundations, and to its inherently destructive and disempowering “treatments”.  I also critique the work of writers who seek to promote or exculpate psychiatry, including Dr. Pies.

But my critiques are always directed towards the issues, and are always directed at errors of fact or logic.  In particular, I take special pains to avoid anything that could, even remotely, be construed as a personal attack, or an attack on an individual’s character.  In the case of Dr. Pies, I have always afforded him the respect due to a person of his stature, and have frequently expressed the belief that his primary error is one of loyalty:  that he loves his chosen profession, in the word’s of Shakespeare’s Othello, “not wisely but too well”.

I have read and re-read Dr. Pies email, and in the light of that communication, I have re-read my earlier post.  But I can find nothing in that post that could reasonably be considered false, malicious, or defamatory.

But I’m also a realist, and I recognize the obvious fact that we are all capable of being biased in respect of our own writings.  I am open to suggestions concerning this matter, and if Dr. Pies were to specify which statement or statements on my part have generated a sense of grievance on his, I would be happy to take another look at the document.  And if, in the light of such re-examination, Dr. Pies’ expressions of concern are credibly vindicated, then I will apologize publicly, and retract the statement(s) in question.

. . . . . . . . . . . . . . . .

Appendix A:  Section IX of United States of America vs. GlaxoSmithKline, PLC

1. GSK’S OFF-LABEL MARKETING OF LAMICTAL

453. In December 1994, Lamictal (active ingredient lamotrigine) was FDA approved for use as adjunctive therapy in adults with partial seizures, and as adjunctive therapy in the generalized seizures of Lennox-Gastaut syndrome in adults and pediatric patients ages two and older.

454. However, despite the narrow indications for which it was approved, GSK heavily marketed Lamictal for the treatment of bipolar disorders both before and during the period it was pending a supplemental new drug application for treatment of bipolar I disorder, which was finally granted by the FDA on June 20, 2003.

1. Off-Label Promotion to Bipolar Patients

455. GSK’s aggressive marketing of Lamictal prior to its approval for use in the treatment of bipolar I disorder proved extremely lucrative. Lamictal grew by 33% in the year 2000 (with total U.S. sales of $210 million) and continued to grow in the following years. In a press announcement for year 2003 GSK boasted that Lamictal was approaching ‘blockbuster status’ with sales that grew by 31% to approximately $1 billion.

456. Curiously, there is no data that would support a commensurate rise in partial seizures in adults or Lennox-Gastaut Syndrome, the only approved indications for Lamictal prior to June of 2003.

457. Ultimately, the aggressive and illegal pre-approval marketing served the dual purpose of reaping significant gains prior to approval for treatment of bipolar I disorder as well as assuring GSK of a nationwide network of health care providers ready to prescribe the drug for bipolar disorders the minute it received FDA approval.

458. Over the course of nearly ten years of off-label marketing of Lamictal, billions of dollars in sales were generated prior to the 2003 indication for bipolar I, as alleged infra.

459. Accordingly, GSK, in promoting Lamictal by willfully misrepresenting the FDA approved uses, engaged in egregious and knowing off-label marketing.

1. Off Label Promotion for all Bipolar Disorders

460. Despite the fact that Lamictal was only FDA approved for treatment of partial onset seizures in 1994, since its launch, sales representatives were trained to promote the drug as an effective treatment for all bipolar disorders.

461. Although there are several types of bi-polar disorders, as alleged infra, bipolar I is the most severe and the most rare. Notably, the drug was never approved by the FDA for bipolar II disorder or any of the four (4) other variations on bipolar disorder listed below.

• Bipolar I disorder involves episodes of severe mood swings, from mania to depression.
• Bipolar II disorder is a milder form, involving milder episodes of hypomania that alternate with depression. Bipolar II is a more broadly defined mental illness and encompasses more patients.
• Cyclothymic disorder describes even milder mood changes.
• With mixed bipolar disorder, there is both mania and depression at the same time, resulting in a person having feelings of grandiosity and racing thoughts, often resulting in an irritable, angry and moody feeling.
• Rapid-cycling bipolar disorder is characterized by four or more mood episodes that occur within a 12-month period. Some people experience multiple episodes within a single week, or even within a single day. Rapid cycling tends to develop later in the course of illness. Women are more likely than men to have rapid cycling. A rapid-cycling pattern increases risk for severe depression and suicide attempts.

462. Despite the lack of any bipolar related indication until 2003, sales representatives were provided with materials designed to promote the drug for global bipolar disorders. Even after it received approval for bipolar I disorder in 2003, sales representatives were trained not to call attention to the distinctions among the various types of bipolar disorder unless a physician inquired.

463. As evidence of the pre-indication marketing and training, one need look no further than the 2001 GSK Selling Resource Guide for Lamictal. The Resource Guide provides scripts for sales reps to address requests for information on Lamictal and bipolar depression suggesting that there were numerous inquiries into this usage. 7AC 0000413-0000430.

464. In furtherance of their bipolar marketing efforts, GSK engaged in an aggressive campaign aimed at pushing sales representatives to use the FaxBack program discussed in the Resource Guide as a marketing tool.

465. Specifically, in the aforementioned 2001 Resource Guide, sales representatives were instructed to direct the physicians to “Faxback Number 5” for information regarding the use of Lamictal and bipolar disorder. This faxback incorporated the findings of Dr. Joseph R. Calabrese, and others, which positively detailed the use of Lamictal in patients suffering from bipolar I and II, mania, unipolar depression, and as a monotherapy. 7AC 0000419

466. Most troublesome is the fact that GSK was aware of its illegal strategic use of the FaxBack program, yet made a conscious and deliberate effort to cover up its actions.

467. For example, at a management training program in July 2002, Relator Hamrick was instructed by a manager-in-training that, with respect to the detailing of Lamictal for bipolar to psychiatrists, the record of every contact report should automatically include the phrase ‘Dr. inquired about bipolar disorder” thereby effectively circumventing the requirements of the FDCA with regards to disseminating literature concerning non-approved uses.

468. In addition to the FaxBacks, GSK frequently distributed “Lit Alerts” to its sales force allegedly for the purpose of educating the drug reps. The Alerts, essentially a cliff-note version of a drug specific study, were routinely carried by sales representatives to aid in answering any questions posed by physicians. The fact that the Lit Alerts were, by their very nature, off label marketing tools, makes their distribution by GSK even more egregious.

469. Specifically, in August 2002, a Lit Alert was distributed to Lamictal sales representatives discussing the use of Lamotrigine as an augmentation agent in treatment resistant depression (‘TRD’), a use for which it has never received approval. 7AC 0000431-0000433.

470. Subsequent to the TRD Lit Alert, in April 2003 GSK distributed another study titled ‘Lamictal as Maintenance Treatment in Recently Manic or Hypomanic Bipolar I Patients.’ This Lit Alert served only to fan the flames of an already rampant bipolar campaign and was referenced widely in sales calls. 7AC 0000434-0000438.

471. Just as troublesome as the Lit Alerts and Faxbacks, were the numerous studies by Calabrese, distributed by GSK, which suggest the efficacy and use of Lamictal in patients with bipolar II.

472. Although Lamictal never received an indication for bipolar II disorder, GSK maintained its effective off label campaign and continued to forge strong relationships with its prescribing physicians ultimately pushing the boundaries by suggesting Lamictal’s effectiveness as a treatment option for bipolar II disorder.

473. In fact, since the dosage of Lamictal must be increased slowly from a subtherapeutic level to a therapeutic level, acute mania and Bipolar II never received an indication.

“2. GSK’s Improper Use of National Thought Leaders to Promote the Off-Label Marketing of Lamictal

474. GSK’s extremely aggressive off-label campaign for Lamictal included spending large sums of money in the form of unrestricted grants, membership on advisory boards and speaker’s fees on physicians and researchers who served as ‘national thought leaders.’ As with campaigns for other drugs, the campaign for the use of the drug Lamictal in the treatment of bipolar disorders began with the widespread promotion of “disease awareness.”

475. Key figures in GSK’s national promotion of Lamictal for treatment of bipolar disorders prior to its indication were Dr. Joseph R. Calabrese of Cleveland, Ohio and Dr. Charles L. Bowden of San Antonio, Texas.

476. As previously discussed, Dr. Calabrese, in particular, was GSK’s greatest proponent for the use of Lamictal in the treatment of bipolar disorders and published articles advocating the use of Lamictal in bipolar disorder as early as 1998. Dr. Calabrese has widely published his opinion that there is need for a greater awareness of the prevalence of bipolar disorders in the United States, stating that the disease impacts as many as 4% of the total population (11,000,000 people) yet is ‘largely undiagnosed.’

477. In his promotion of the use of Lamictal for bipolar disorder, Dr. Calabrese wrote about a new nomenclature (‘above the line/below the line’) advocating that Lamictal was clearly superior to other commonly prescribed medications such as Lithium. Dr. Calabrese also defended the drug from the accusation that the risk of serious side-effects, such as Stevens- Johnson Syndrome⁴, outweighed the benefits of prescribing the medication.

⁴ Stevens-Johnson syndrome is a rare, serious disorder in which the skin and mucous membranes react severely to a medication, in this case, Lamictal, or infection. Often, Stevens-Johnson syndrome begins with flu-like symptoms, followed by a painful red or purplish rash that spreads and blisters, eventually causing the top layer of your skin to die and shed.  4612704 117

478. In addition to journal articles, in 2002 Dr. Calabrese even published a greatly abbreviated, highly commercialized version, of his 1998 study (being careful to identify Lamotrigine by its GSK product title Lamictal) in an internet bulletin called “Fast Breaking Comments.” In this interview, Dr. Calabrese blatantly publicizes his determination that “lamotrigine (Lamictal) is effective in the treatment of patients with rapid cycling bipolar II disorder.” 7AC 0000439-0000441.

479. To date, Lamictal has not received an indication for rapid cycling bipolar II disorder. However, GSK placed great emphasis on this study and sales representatives were expected to read and be familiar with Dr. Calabrese’s theories and statistics for use in off label marketing.

480. Dr. Bowden began publishing his opinions concerning the efficacy of Lamictal in the treatment of bipolar disorder as early as 1998. Dr. Bowden became a widely sought after speaker for GSK, and GSK sales representatives nationwide were encouraged to try to persuade Dr. Bowden to make presentations on his findings in their geographical area.

3. GSK’s Off-Label Marketing to Psychiatrists

481. Seizure disorders – the only approved indication for Lamictal during the 1998 through 2003 period – were treated by neurologists, not psychiatrists. Notwithstanding that fact, GSK began requiring its sales representatives to detail Lamictal with psychiatrists and family practitioners many years before the approval for bipolar I disorder.

482. It is clear that these ‘details,’ which were prevalent throughout the nation during this period, were directed at persuading physicians to prescribe Lamictal off-label for the treatment of bipolar disorder and through the use of free samples, ‘thought leader’ lunches, dinners and CME’s, and distribution of studies favorable to GSK, particularly the Calabrese 4612704 118 studies, GSK was extremely successful in persuading physicians to begin prescribing the drug off-label.

483. As confirmation of the detailing of psychiatrists, a quick review of the contact sheets written up by the sales representatives shortly after the physician visits confirm the fact that the purpose of these visits was solely to market Lamictal for the treatment of bipolar disorders. The following is representative of the quantity of the off label physician visits by sales representatives including Ron Crews, Joan Schindler and Betty Hosler⁵

• 9/13/00 Dr. Douglas Gregory (psychiatrist) ‘Had long discussion about Lamictal, is afraid of rash….Rash is severe side effect which has caused death in several patients….’Stevens Johnson Syndrome’….Gave him Calabrese article and encouraged him to talk to Marciniak [local GKS ‘thought leader’;

• 10/18/00 Dr. McClure [Dr. Scott H. McClure, psychiatrist] Is getting more comf w/ lamic, thought it [conference put on by GSK]was informative More comfortable with Lamictal for bi-polar;

• 10/26/00 Dr. Crandall (psychiatrist) “[D]iscussed Bowdens’ lecture, she is afraid of the rash;

• 10/30/00 Dr. Gamblin (psychiatrist) ‘very pos. about lam. (Lamictal) has over 50 patients on it’…’Trained with Bowden sorry he missed it ‘ (referring to lecture in Colorado Springs that GSK arranged with Dr. Bowden as the speakers);

• 10/30/00 Dr. McClure [Dr. Scott H. McClure, psychiatrist] ‘Said he is more comf.with Lamictal as monotherapy [in the treatment of bipolar disorder] after hearing Bowden likes the bottles of 25 only, not the kits (Lamictal) samples’;

• 1/8/01 Dr. Harazin [Dr. Jeffrey Harazin, psychiatrist] ‘Lamictal is on it’s way’;

• 03/21/01 Dr. Marciniak [psychiatrist] detailed by GSK District Manager for Lamictal in bipolar;

• 05/23/01 Dr. Gregory [psychiatrist] attended noon lecture at Pikes Peak Mental Health with Dr. Paul Wender speaking, detailed on Lamictal;

⁵ These notes have been reproduced exactly as they were written in the contact reports by the individual sales representatives and entered into the Passport system following each sales call.

• 06/12/01 Dr. Gamblin [psychiatrist] again detailed on Lamictal;

• 06/19/01 Dr. Richard Marciniak [psychiatrist] detailed on Lamictal and offered a free fly fishing trip;

• 06/21/01 Dr. Richard Marciniak again detailed on Lamictal and offered speaker/dinner engagement at local restaurant (Warehouse);

• 07/05/01 Dr. Gamblin again detailed for Lamictal;

• 07/19/01 Dr. Richard Marciniak again detailed on Lamictal and stated it is his choice for treatment of bipolar, as well as discussing dosage amounts and titration;

• 07/30/01 Dr. Fred Michel detailed on the use of Lamictal for the treatment of children (‘Uses very little Lamictal in kids but would like to use it more.’);

• 03/14/02 Dr. Julie Sanford [psychiatrist] detailed for using Lamictal in the treatment of bipolar;

• 03/15/02 Dr. Gamblin had not yet seen the Calabrese study but did not want to drive to Denver for CME’s;

• 03/15/02 Dr. James Spadoni [psychiatrist] detailed for the use of Lamictal in bipolar;

• 03/19/02 Dr. Marciniak agreed to be paid by GSK to speak about Lamictal for bipolar as well as Wellbutrin at a lunch for local physicians in Colorado Springs;

• 03/19/02 Dr. Stephen Mueller [psychiatrist] confirmed attendance at the bipolar/Lamictal physician’s meeting in Colorado Springs, Colorado;

• 03/20/02 Dr. Gamblin again detailed for prescribing Lamictal for bipolar disorder;

• 04/03/02 Dr. Marciniak detailed for Lamictal and confirmed that he would accept paid assignment to do GSK’s CME program on June 7, 2002;

• 04/03/02 Dr. Spadoni [psychiatrist] detailed for use of Lamictal in bipolar disorder;

• 04/10/02 Dr. Gamblin detailed for use of Lamictal in bipolar disorder with reference to the Calabreze study;

• 04/24/02 Dr. David Caster [psychiatrist] detailed for Lamictal in bipolar disorder;

• 04/25/02 Dr. Rosalyn Kneppel [psychiatrist] detailed for Lamictal in bipolar disorder;

• 04/29/02 Dr. Nancy Sharpe, a Colorado Springs psychiatrist, was detailed for Lamictal in bipolar disorder; this doctor, who has a large Medicaid practice, asked the GSK sales representative about proper dosage amounts;

• 05/01/02 Dr. Brian Grabert, a pediatric neurologist, was invited to be on GSK’s advisory board for an upcoming San Diego, California conference; 05/06/02 Dr. Gamblin detailed once again for Lamictal and now said he feels quite comfortable using it;

• 05/08/02 Dr. Rosalyn Kneppel [psychiatrist] again detailed for Lamictal in bipolar disorder;

• 05/08/02 Dr. Jeffrey Harazin again detailed for Lamictal in bipolar and now said he uses it ‘first line’ for bipolar disorder;

• 05/13/02 Dr. Stephen Mueller, psychiatrist, again detailed for Lamictal in bipolar and requested pricing information;

• 05/17/02 Dr. Marciniak agreed to do a talk and stated that he is using Lamictal more for bipolar now that he has more samples;

• 05/20/02 Dr. Elliott Cohen, psychiatrist, detailed for Lamictal and he requested more samples;

• 05/20/02 Dr. Rosalyn Kneppel [psychiatrist] again detailed for Lamictal in bipolar disorder and said she is using half the dosage [recommended for seizures] because of concerns about the rash;

• 05/20/02 Dr. James Polo detailed for use of Lamictal in bipolar disorder in adolescents;

• 05/22/02 Dr. Ralph Everett, child psychiatrist detailed for Lamictal in bipolar and after having stated he did not like it, was given a comparison to Zoloft by the GSK rep;

• 05/22/02 Dr. Scott McClure, psychiatrist, again detailed for Lamictal in bipolar and Dr. McClure asked the GSK rep. how to dose if a patient was already on Depakote for bipolar and was given ‘the Calabrese study’ by the rep;

• 05/23/02 Psychiatrists Dr. Anne League, Dr. James Spadoni and Dr. Julie Sanford were treated to lunch at a local Colorado Springs restaurant by the GSK sales representative and given American Psychiatric Association guidelines relating to Lamictal;

• 05/23/02 Psychiatrist Pamela A. Brickers of Colorado Springs, CO was detailed by a GSK representative and was given a copy of ‘the calabrfese [sic] study’;

• 05/29/02 Dr. Julie Sanford was detailed on Lamictal for bipolar and the GSK rep went over a study/comparison with Zoloft that was favorable to GSK’s product;

• 05/29/02 Dr. James Spadoni and Dr. Richard Marciniak detailed for Lamictal;

• 05/30/02 Dr. Brian Grabert detailed for Lamictal for his pediatric patients;

• 06/05/02 Dr. Brian Grabert again detailed for Lamictal and discussed the rash;

• 06/17/02 Dr. Honie Crandell again detailed for Lamictal in the treatment of bipolar disorder and confirms that it is her drug of choice for this disorder.

484. In addition to targeting psychiatrists for detailing, prior to the FDA approved indication for bipolar I, GSK sales representatives were instructed to devote virtually all of their free sampling activities to psychiatrists, rather than neurologists. A routine practice that was documented in the contact reports of physician details as well as the first-hand experience of Relator Thorpe.

1. GSK’S Off-Label Promotion of Lamictal Resulted in Patient Harm

485. Although the FDA issued recommended dosing for Lamictal for its seizure indications, there were no such dosing guidelines for use in patients suffering from any form of bipolar disorder prior to the FDA approval in 2003. As such, there existed an acute risk of overdosing and resulting complications.

486. Since the FDA did not establish a recommended dosage for Lamictal for use off label, and because the potential side effects were so severe if not dosed correctly, once the sales representatives had successfully gotten a physician to inquire about its use for bipolar, they were instructed to use the phrase ‘start low and go slow.’

487. On information and belief, this “catchphrase” came directly from the GSK marketing department and was used by sales representatives throughout the country as a way to remind physicians to start with a small dose and raise the dosage very slowly in the treatment of bipolar I disorder in children and adolescents especially.

488. Given the lack of dosing information, coupled with the intense campaign for use as a treatment for bipolar disorders, the contact reports referenced in the preceding paragraphs evidence physicians routinely inquiring about dosage and titration from the sales representatives themselves.

489. On information and belief, as a direct and proximate result of the lack of proper dosing of Lamictal when used off-label, patients suffered both reported and unreported severe side effects including death.

490. The Federal Drug and Cosmetic Act (“FDCA”) and its regulations require that adverse events due to prescription medications be promptly reported. However, ample evidence exists of widespread under-reporting of adverse drug reactions, even when drugs are being prescribed for their approved uses. (Mintzes, B., Bassett, K., Wright J.M.. Drug Safety without Borders: Concerns about Bupropion. Can. Med. Assoc. J., 2002;167(5); Moride Y, Haramburu F, Requejo AA, Begaud B. Under-reporting of Adverse Drug Reactions in General Practice. Br J Clin Pharmacol 1997;43(2):177-81; Bates DW. Drugs and Adverse Drug Reactions. How Worried Should We Be? JAMA 1998;279(15):1216-7; Okie, S., Safety in Numbers – Monitoring Risk in Approved Drugs, N.E.J.M., 352:1173-1176, March 2005.)

491. On February 14, 2003, Relator Hamrick became aware of an incident involving the dangers of off-label prescription particularly when combined with the widespread laxity in adverse event reporting when he called on Dr. J. Vitanza, an allergist.

492. Mr. Hamrick was informed that one of Dr. Vitanza’s patients had been prescribed Lamictal for bipolar I disorder (prior to its approval by the FDA) and noted in the patient’s chart an incidence of rash. Assuming that the patient’s psychiatrist would report the rash incident, Dr. Vitanza failed to report the occurrence to the FDA. After observing that the physician was not going to file an adverse event report, Mr. Hamrick filed his own, based upon his second-hand knowledge of the incident. 7AC 0000442-0000443.

493. As a result of the underreporting of rash occurrences, physicians failed to be properly alerted to the potential danger of the rash which had, on a few occurrences, developed into Stevens-Johnson Syndrome.

494. In addition to the unreported incidents of rash, often resulting from off-label prescriptions, at least one death resulted from the use Lamictal for bipolar I disorder.

495. Dr. Julie Sanford, a psychiatrist who was consistently detailed by GSK sales representatives to prescribe Lamictal for bipolar disorders, prescribed the drug for a patient that subsequently died. Since Dr. Sanford was not a neurologist likely to be treating a patient for a seizure disorder, it should have been apparent to GSK officials receiving a copy of her adverse event report that the drug was, in all likelihood, prescribed for a non-indicated use.

496. Nevertheless, in a May 22, 2001 letter to Dr. Sanford from GKS’s “Global Clinical Safety and Pharmacovigilance” division, there is a reiteration of adverse event reporting: the patient, who had been given Lamictal experienced headache and died, and other patients of whom she was aware also experienced rashes subsequent to receiving therapy with Lamictal. 7AC 0000444.

497. Significantly, the “Global Clinical Safety and Pharmacovigilance” division, while allegedly interested ‘in obtaining as much information as possible concerning reports of suspected adverse reactions for the purpose of continuing to monitor and evaluate drug safety’ made no inquiry into the issue of the purpose of the supposed therapy.

498. Of even more concern, in a conversation with Relator Thorpe, Dr. Sanford, a psychiatrist married to key opinion leader Dr. Marciniak, revealed that the patient who died was in fact being treated for bipolar I disorder.

499. Clearly, when combined with the lack of recommended dosage, the off-label use of Lamictal made for a recklessly dangerous combination for patients resulting in severe rashes, including Stevens Johnson Syndrome, and even death.

1. GSK Targeted Federal Health Care Programs for Off-Label Use

500. GSK’s off-label marketing tactics also helped put their products on Tricare/Champus formularies for uses not approved by the FDA.

501. For example, GSK focused on psychiatrist Dr. James Polo because of his position at Evans Army Hospital, Fort Carson, Colorado. As a result of the persistence of GSK, Lamictal was actually placed on formulary for treatment of bipolar disorders prior to receiving such an indication.

502. GSK began seriously attempting to influence Dr. Polo in the late 1990’s by making arrangements for and paying for all of the food and liquor at the annual Colorado Spring Psychiatric Association Christmas party at Dr. Polo’s home, with 60-70 physicians in attendance.

503. A simple review of just a few GSK contact reports in 2001 and 2002 clearly indicates that GSK sales representatives “detailed” Dr. Polo to enlist his aid in placing Lamictal on the Tricare/Champus formulary at Fort Carson for use in the treatment of bipolar disorders:

• 4/23/02 Dr. James Polo detailed on Lamictal and Wellbutrin, invited to GSK speakers program, ‘he saw the green journal and asked if on lamictal on formulary, he said yes but for neurology only; he will champion it for p.t.’

• 5/20/02 Dr. James Polo detailed on Lamictal with note ‘he was not attending the Tricare meeting this week, wsr for pts. w depression and concentration difficulties, lamictal is now a favorite of his and uses it in adol with bi-polar.’

• 7/15/02 Dr. James Polo detailed on Lamictal and reported that ‘Lamictal is no longer restricted to neurology’ meaning it was now available on the Tricare formulary.

• 07/24/02 Dr. James Polo detailed on Wellbutrin and Lamictal and reported “Lamictal free for all psyches.’

504. As evidence of the success of the GSK engineered approval of Lamictal for use as a psychiatric treatment on the Fort Carson Tricare formulary, Dr. Kenneth Gamblin, a high volume Medicaid psychiatrist was told, (according to the July 17, 2002 GSK contact report) about availability of Lamictal on the Tricare formulary. Subsequently, according to the aforementioned contact report, he ‘…has started several new pts.’

505. Upon information and belief, GSK targeted other high volume federal healthcare providers for off-label use of Lamictal and by the second quarter of 2007, Lamictal held a 14.1% share of the Medicaid market.”