1 Boring Old Man

^{Did Janssen in any way support financially the Texas Medication Algorithm Project? "I can only go by what I know and what I did. So there were unrestricted educational grants given to support the Texas Medication Algorithm Project."}

^{Public Health Systems & Reimbursement Focused on Growing Risperdal Business by Focusing on Risperdal Payers.
Mission Statement: Support CNS Sales by proactively working with Public Mental Health Systems to identify, maximize and protect Risperdal sales opportunities.
Risperdal Total Sales = 85% Public Sector Payers!
Atypicals are in the top 5 most expensive drugs in most state Medicaid programs.}

^{Managed TMAP and PennMAP communications via phone conferences to ensure proper planning and execution
Persuaded KOLs in Pennsylvania to adopt guidelines favorable to Risperdal
Goal Statement: Educational Forums: Pennsylvania state OMH program to further establish atypicals as first-line with Risperdal as the standard of care.
Influence KOLs to leverage PHS&R public sector program in order to meet long-term mutual goals – TMAP adoption.
Successful TMAP meeting. Dialogue with key influencers around algorithms.
Took advantage of Steve Shon’s schedule and influenced NJAHMA to support TMAP initiative}

^{Wow!!! The Pennsylvania Public Sector Meeting was a success
Over 95 attendees from all sectors of the state with key representation from inpatient [OMH] and outpatient [Medicaid] settings were present
Every goal was focused on Integrating Best Practices for Schizophrenia patients via TMAP and measurement of outcomes based on TMAP implementation
For the first time, the state is taking the initiative to ensure patients have a successful trial on atypicals. This can have a large impact on your business since there is still a large amount of conventional usage in the state system.
Steve Shon, MD drove home the idea that algorithms make both clinical and administrative sense. He did a great job of explaining the basics of TMAP.
Key influencers in the state are now seeking further information and many are trying to ‘own’ TMAP within their own system
Overall, we have a major opportunity in Pennsylvania state hospitals and within Medicaid managed care. Both of those payers are looking to Janssen to assist them in creating algorithms}

^{Did you actually assist them in creating algorithms? Again, I only brought the people that knew about algorithms together. I was not the algorithm expert
So are you saying you didn’t help them create them?  No. Just – just saying the assistance is really by bringing the people together, not creating them
The "people" meaning like Dr. Shon – Correct, yes
and the state representative? Right}

^{What a week?" "What a week! Last week we had well over 250+ key people attend the three Janssen sponsored TMAP programs in Pennsylvania [estimated total cost" of 5 to 6K]. "We had mostly staff psychiatrists from the state hospitals; medical directors, administrators, advocacy and others attended from not only the state hospital system, but also the community. More importantly, our competition has missed this moving train!"
… they did not have a Public Health Systems & Reimbursement team and they’re – they really were not aware of Texas Medication Algorithm Project as much, or if they were, they weren’t doing anything about it.}

I doubt that it ever occurred to her that the TMAP Algorithm she was helping Dr. Steven Shon sell to Pennsylvania, New Jersey, and others had been brought into being by her own company, first in the form of the TriUniversity Guidelines – or that another part of her company was working overtime to keep the downside of Risperdal out of the public eye. Likewise, I expect that it hasn’t dawned on her yet that the selling points that Risperdal was more efficacious and safer that the alternatives, and that by spending more than forty times as much for it the State would save money, were completely indefensible fabrications – obvious even before they were definitively refuted by the large clinical trials that came later. Her  job was to "to identify, maximize and protect Risperdal sales opportunities." The Texas Medical Algorithm Project and the Director of the Texas Department of Mental Health and Mental Retardation, Steven Shon, were key pieces, maybe the key pieces, on the road to success.

Even though I know otherwise, sitting here in my cabin writing about the machinations the drug companies went through to pull off their immensely profitable over-medication of America abetted by the Laurie Snyders and my colleagues in psychiatry, I see Demons, Monsters, Sociopaths – people who knew exactly what they were doing and didn’t care about the consequences. And then I watch a Laurie Snyder and see someone you might see wearing a pink tee-shirt at a fun-run for Breast Cancer Awareness Week. I don’t think it ever occurred to her what she was a part of. I wonder if she knows even now?

Thought I had stopped thinking about that trial in Texas? Not hardly. These are the transcripts [including the video depositions]. Obviously, they don’t contain the exhibits, but most of the important parts of the email chains, the call-notes, the memos, etc. were read into the record. It’s an enormous amount of material and it reads like transcripts read – slowly. But you might want to look over Mr. Melsheimer’s Opening Statement, Allen Jones’ testimony, and the deposition of Dr. Steven Shon. At some later point, I’ll try to synopsize the essential pieces, but for the moment, this simple index was quite enough for my afternoon.

The point of this trial was to get an accurate picture of how extensively J&J [Janssen] disregarded the FDA, the State governments, and any minimal version of medical ethics in the service of an extensive marketing program with Risperdal. It’s a dark picture that needs the light of day. And financial penalties alone are not the solution. Hopefully studying what happened here will point us along the way to a saner, safer, and more ethical future.

Grief Could Join List of Disorders
New York Times
By BENEDICT CAREY
January 24, 2012

In a bitter skirmish over the definition of depression, a new report contends that a proposed change to the diagnosis would characterize grieving as a disorder and greatly increase the number of people treated for it. The criteria for depression are being reviewed by the American Psychiatric Association, which is finishing work on the fifth edition of its Diagnostic and Statistical Manual of Mental Disorders, or D.S.M., the first since 1994. The manual is the standard reference for the field, shaping treatment and insurance decisions, and its revisions will affect the lives of millions of people for years to come…

The new report, by psychiatric researchers from Columbia and New York Universities, argues that the current definition of depression — which excludes bereavement, the usual grieving after the loss of a loved one — is far more accurate. If the “bereavement exclusion” is eliminated, they say, “there is the potential for considerable false-positive diagnosis and unnecessary treatment of grief-stricken persons.” Drugs for depression can have side effects, including low sex drive and sleeping problems. But experts who support the new definition say sometimes grieving people need help. “Depression can and does occur in the wake of bereavement, it can be severe and debilitating, and calling it by any other name is doing a disservice to people who may require more careful attention,” said Dr. Sidney Zisook, a psychiatrist at the University of California, San Diego…

Under the current criteria, a depression diagnosis requires that a person have five of nine symptoms — which include sleeping problems, a feeling of worthlessness and a loss of concentration — for two weeks or more. The criteria make an explicit exception for normal grieving, which can look like depression. But the proposed diagnosis of depression has no such exclusion, and in the new study, Jerome C. Wakefield of New York University and Dr. Michael First of Columbia concluded that the evidence was not strong enough to support the change. “An estimated 8 to 10 million people lose a loved one every year, and something like a third to a half of them suffer depressive symptoms for up to month afterward,” said Dr. Wakefield, author of “The Loss of Sadness.” “This would pathologize them for behavior previously thought to be normal.”

But Dr. David J. Kupfer, a professor of psychiatry at the University of Pittsburgh School of Medicine and the chairman of the task force making revisions, disagreed, saying, “If someone is suffering from severe depression symptoms one or two months after a loss or a death, and I can’t make a diagnosis of depression — well, that is not being clinically proactive. That person may then not get the treatment they need”…

Getting the diagnosis increases the likelihood of being treated for what is normal behavior, or close enough. Task force members argue differently: if a person is in distress and seeking help, then treatment ought to be offered — and covered by insurance…

By Kenneth S. Kendler, M.D.: Member, DSM-5 Mood Disorder Work Group

Misconceptions about the proposal to eliminate the grief exclusion criterion from DSM-IV have been presented online and in the media. Writers have expressed fear that the change will lead to automatic diagnosis of individuals who are grieving with Major Depressive Disorder. I would like to provide some background on the grief exclusion and some insight into thinking behind the proposal to remove it for DSM-5 in order to put this change into perspective.

First, the grief exclusion criterion – which states that someone who has experienced a recent bereavement is not eligible for a diagnosis of major depression – was not present in the two major psychiatric diagnostic systems that formed the basis for the DSM-III – the diagnostic manual that is the immediate precursor of our current DSM-IV. Rather, it was added to DSM-III largely on the basis of the work of one of the DSM-III task force members who was then studying grief and was carried forward with little modification into DSM-IV.

Second, the other major psychiatric diagnostic system used in the world – the International Classification of Diseases – has never had a grief exclusion criterion for major depression.

Third, a broad range of evidence agreed to by both sides of this debate shows that there are little to no systematic differences between individuals who develop a major depression in response to bereavement and in response to other severe stressors – such as being physical assaulted and raped, being betrayed by a trusted spouse whom you learn has been unfaithful or a beloved child whom you are told is dealing drugs, having your doctor tell you that your breast or prostate biopsy for cancer is positive or the loss of your treasured job. So the DSM-IV position is not logically defensible. Either the grief exclusion criterion needs to be eliminated or extended so that no depression that arises in the setting of adversity would be diagnosable. This latter approach would represent as major shift, unsupported by a range of scientific evidence, in the nature of our concept of depression as epidemiologic studies show that the majority of individuals develop major depression in the setting of psychosocial adversity.

Fourth, the vast majority of individuals exposed to grief and to these other terrible misfortunes do not develop major depression. That does not mean, and here is the source of much confusion, that they do not grieve. They do. It does not mean that they do not feel terrible pain and loneliness. They do. Depression is a slippery word and we are so used to using it to mean “sad”, “blue”, “upset” or, in this specific case, “grieving.” Major depression – the diagnostic term – is something quite different. Finally, diagnosis in psychiatry as in the rest of medicine provides the possibility but by no means the requirement that treatment be initiated. Watchful waiting is important tool for all skilled clinicians. As a good internist might adopt a watch and wait attitude toward a diagnosable upper respiratory infection assuming that it is unlikely to progress to a pneumonia, so a good psychiatrist, on seeing an individual with major depression after bereavement, would start with a diagnostic evaluation.

If the criteria for major depression are met, then he or she would then have the opportunity to assess whether a conservative watch and wait approach is indicated or whether, because of suicidal ideation, major role impairment or a substantial clinical worsening the benefits of treatment outweigh the limitations. As with the psychiatric response to the other major stressors to which we humans are all too frequently exposed, good clinical care involves first doing no harm, and second intervening only when both our clinical experience and good scientific evidence suggests that treatment is needed.

Validity of the bereavement exclusion to major depression:
does the empirical evidence support the proposal to eliminate the exclusion in DSM-5?
^{by Jerome C. Wakefield and Michael B. First}
World Psychiatry. 2012 11:3-10.

^{The DSM-IV major depression “bereavement exclusion” [BE], which recognizes that depressive symptoms are sometimes normal in recently bereaved individuals, is proposed for elimination in DSM-5. Evidence cited for the BE’s invalidity comes from two 2007 reviews purporting to show that bereavement-related depression is similar to other depression across various validators, and a 2010 review of subsequent research. We examined whether the 2007 and 2010 reviews and subsequent relevant literature support the BE’s invalidity. Findings were: [a] studies included in the 2007 reviews sampled bereavement-related depression groups most of whom were not BE-excluded, making them irrelevant for evaluating BE validity; [b] three subsequent studies cited by the 2010 review as supporting BE elimination did examine BEexcluded cases but were in fact inconclusive; and [c] two more recent articles comparing recurrence of BE-excluded and other major depressive disorder cases both support the BE’s validity. We conclude that the claimed evidence for the BE’s invalidity does not exist. The evidence in fact supports the BE’s validity and its retention in DSM-5 to prevent false positive diagnoses. We suggest some improvements to increase validity and mitigate risk of false negatives.}

The whole point of the DSM-III moving to a diagnostic scheme based on description rather than proposed causality was because we don’t really know what causes many mental illnesses. But there’s no question that if we did, classifying diseases by cause would return with lightning speed. Causality is the bedrock of medical thought. Grief has a known cause. Furthermore, we accept that Grief is normal – an integral component of the human experience reflecting the importance of our attachments to each other. Whether it looks the same as another condition deemed to be pathological or not is immaterial. In medicine, signs and symptoms are generally thought of as pointers to disease causality. The Pneumonias look the same, but we diagnose Pneumococcal Pneumonia or Mycoplasma Pneumonia. Congestive Heart Failure is a symptom complex, but Rheumatic Heart Disease and Coronary Artery Disease are what we list in classifications. The symptom lists of psychiatric diagnosis are a fall-back position – only useful until a cause becomes known. Grief has a cause so it doesn’t belong with depressions where we don’t know the cause. Dr. Kendler’s comment "…there are little to no systematic differences between individuals who develop a major depression in response to bereavement and in response to other severe stressors" is correct but his implication is backwards. The sensible conclusion would be to have a category for depression-in-response-to-severe-stressors. We used to have such a thing that needed refining and clarifying, not eliminating. Grief and other precipitated depressions are different from the depressions where there is no precipitant. What’s the difference? The history. History is a time honored diagnostic tool. The notion that we can only use symptom lists for our diagnoses bears no resemblance to the methodology or traditions of medicine.

Dr. Kupfer opens another window into why this DSM-5 Revision Task Force has so many people in a wad. He says, “If someone is suffering from severe depression symptoms one or two months after a loss or a death, and I can’t make a diagnosis of depression — well, that is not being clinically proactive. That person may then not get the treatment they need.” What is he talking about? First, he says "the treatment they need" we can bet he’s talking about antidepressant medication. The diagnosis would be complicated grief, or pathological, grief, or some-other-kind-of grief. He too seems unable to recognize that the symptom lists are a fall-back position, meaningless when the cause is actually known. And, by the way, antidepressants are hardly known for their effectiveness in patients who are clinically depressed in response to real life events. Does he see patients? And if he thinks a given person needs medication for their protracted complicated pathological grief, he could write a prescription. That’s what the rest of us do.

But then there’s this: "Getting the diagnosis increases the likelihood of being treated for what is normal behavior, or close enough. Task force members argue differently: if a person is in distress and seeking help, then treatment ought to be offered — and covered by insurance…" On the face of things, that last part might sound like a benevolent comment, that the DSM-5 Task Force is using these diagnostic categories to make sure that 3rd party payers will reimburse patients for their medical visits and medications when they see the doctor for their protracted grief symptoms. But if you step back a few feet, this is an outrageous motive for a group charged with revising our diagnostic criteria, as outrageous as Dr. Kupfer’s notion that people with pathological grief won’t be treated if we call it what it is. No right-thinking physician runs to the DSM-anything to look up a diagnosis to decide on treatment. Diagnosis doesn’t define treatment, it’s just a piece of the story – sometimes a very small piece.

^{Your correspondents focus rather narrowly on four issues surrounding our review of novel melatonin-based treatments: the efficacy of agomelatine, the clinical significance of agomelatine for managing depression, the comparative side-effect profile of this compound, and our professional relationships with its manufacturer [Servier Laboratories].}
^…
^{Fourth, the paper was commissioned by The Lancet and developed solely by us. It was not initiated or supported financially by Servier Laboratories. The additional research assistants who assisted with the paper’s preparation are long-standing employees of our institution who have worked previously on many similar datasets via our own financial resources. After initial submission [July 31, 2009], the paper progressed through a lengthy process of external peer review, revision, and consultation with the editorial staff of The Lancet. As outlined previously, issues of fact with regard to clinical trials of agomelatine were checked against international trial registers and with representatives of the manufacturer, Servier Laboratories. The opinions expressed and the conclusions drawn are those of the authors.}

And when the drug was approved in Australia for private prescriptions, there he is again in Servier’s press release:

Psychiatric Group Push to Redefine Mental Illness Sparks Revolt
Bloomberg
By Elizabeth Lopatto
January 24, 2012

An effort that promises to broaden the definitions of mental illnesses is spurring a revolt among health-care professionals in the U.S. and the U.K. A panel appointed by the American Psychiatric Association is proposing changes to the industry’s guide for mental illnesses, which determines how patients are diagnosed and treated, and whether insurers pay for care. The new edition of the Diagnostic and Statistical Manual of Mental Disorders is scheduled to be published next year. The draft is sparking a backlash among practitioners concerned the expanding mandate will increase the number of patients treated with drugs. The guide would loosen diagnostic criteria on some existing ailments and brand as mental disorders some common behaviors, including having temper tantrums three times a week or a lack of sexual arousal. The changes may spur unneeded and dangerous treatment of the healthy, said Allen Frances, a psychiatrist who helped write the current guidelines.

Everyday disappointments, sufferings and eccentricities are being redefined as psychiatric disorders, and that could lead to medication treatment,” said Frances, a professor emeritus at Duke University who lives in San Diego, California. “This is expanding the boundaries of psychiatry.” In many cases, family doctors will use the new definitions to treat patients, Frances said by telephone. Pressure from drugmakers to use medications can combine with media representations to create “an epidemic,” he said. “Once primary care doctors and patients have the idea that they saw a certain condition on TV, it becomes real.”

Darrel Regier, the psychiatric group’s research director, characterized critics as being unconvinced medical treatment is better than counseling. The idea of “medicalizing normality comes from a perspective that there are no psychiatric disorders, and you need to avoid stigmatizing people by giving them one,” he said in a telephone interview…

But there’s another logical fallacy – The Straw Man Fallacy that pervades Dr. Regier’s comments [both here and elsewhere]. It’s a common rhetorical trick. First create a caricature of the person you are debating [someone who is "unconvinced medical treatment is better than counseling"]. And then point out the absurdity of of the argument made by this caricature. There’s an even better example in the next sentence "The idea of “medicalizing normality comes from a perspective that there are no psychiatric disorders, and you need to avoid stigmatizing people by giving them one,” he said in a telephone interview." The critic who talks about "medicalizing normality" is Dr. Allen Frances. Dr. Frances is the Emeritus Chairman of Psychiatry at Duke. He was in charge of the DSM-IV Revisions that were filled with "psychiatric disorders" – more than in the DSM-III that preceded it. He has been an active member of the mainstream of the organized psychiatric community throughout his career. Still is. It is beyond ludicrous to portray him as being a person with the "perspective that there are no psychiatric disorders." What is Dr. Regier talking about? And none of the Psychologist organizations who have supported the petition in the upper left portion of this blog are arguing that there are "no psychiatric disorders." Dr. Regier’s comment is about a pseudocommunity that may exist in his own mind [or in his argument], but has no representation in the real world of critics he’s responding to. There are people in the world who think those thoughts, I suppose. I remember some from the 1960s and 1970s, but I haven’t seen any such people for a very long time.

The trap at this point would be to either make a Straw Man out of Dr. Regier, or to argue with his argument as he states it. The only reasonable course would be to speculate about why he would respond to a Bloomberg reporter with two obvious logical fallacies – known to be fallacies since the Greek philosophers first walked around in robes pondering such things. Why would he answer a question by creating a False Dichotomy or a Straw Man, instead of addressing the actual questions on the table? Criticism is painful – that’s one possibility. Maybe he’s an overly sensitive person who can’t hear criticism as constructive. Or maybe he’s an arrogant person who doesn’t recognize that the opinions of others are as valuable as his own. We could make up things like that for hours, but we know it would be a waste of time, an exercise in psychological speculation of the kind that has itself been criticized in recent years. The reason that we know it would be a waste of time is that Dr. Kupfer and Dr. Regier always respond this way – evasion, placation, logical fallacies. They never engage the criticisms directly. I don’t even feel called to document being so categorical – like I’m creating a Straw Man. If you’ve kept up with this topic, you already know what I’m saying is true – always, never.

"Agomelatine is unique in that it is a selective agonist at MT1 and MT2 receptors and an antagonist at 5-HT2B and 5-HT." In these days of the empty pipeline for new CNS drugs, it’s not surprising that people are looking around for novel chemicals hoping for a new blockbuster drug for depression. The paper in the Lancet mentioned in my last post [of sound and fury…] gives a long rationale for trying melatonin and some of its derivatives because of their effect on the sleep cycle. There have been twelve US Clinical Trials of Agomelatine, one recently terminated in November 2011 [right]. The regulatory agency approval history for Agomelatine has been chequered at best:

^{Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union. In March 2005 Servier submitted agomelatine to the European Medicines Agency [EMEA] under the trade names Valdoxan and Thymanax. On 27 July 2006 the Committee for Medical Products for Human Use [CHMP] of the EMEA recommended a refusal of the marketing authorisation of Valdoxan/Thymanax [agomelatine]. The major concern was that efficacy had not been sufficiently shown. The CHMP had no special concerns about side effects. In September 2007, Servier submitted a new marketing application for Valdoxan [agomelatine] to the EMEA. On 20 November 2008, Valdoxan was given a positive opinion, with restrictions, by the EMEA, and was subsequently given marketing authorisation in the European Union on 20 February 2009. Release dates in the individual countries of the EU were dependent on marketing arrangements. In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis. It was undergoing several phase III clinical trials in the US, and until October 2011 Novartis listed the drug as scheduled for submission to the FDA no earlier than 2012. However, the development for the US market was discontinued in October 2011, when the results from the last of those trials became available. It is currently sold in Australia under the Valdoxan trade name.}

One of Australia’s most high-profile psychiatrists has come under fire for "overstating" the benefits of a new antidepressant that critics say is ineffective and potentially unsafe. A series of letters to the Lancet Friday accused Professor Ian Hickie of promoting the strength of evidence on agomelatine [Valdoxan], while downplaying safety concerns. They also took aim at the drug company ties of Professor Hickie and colleague Associate Professor Naomi Rogers, suggesting these had contributed to their "subjective" and "inappropriate" appraisal of the drug.

Professors Hickie and Rogers, who rejected the claims, had recently authored a Lancet review on the new class of melatonin-based antidepressants, focusing on agomelatine. They said the drug had "clinically significant" effects, with similar short-term efficacy to venlafaxine, fluoxetine, and sertraline. They concluded its favourable safety profile and positive effects on circadian function meant it "might occupy a unique place" in the management of some patients.

However, their article was dissected by six scathing letters to the journal. Several suggested the data had been cherry-picked and not systematically appraised. In one letter, French doctors said that half the placebo-controlled trials of agomelatine had been negative, and others "too weak" to draw conclusions on efficacy. In another, a US psychiatrist said the rare risk of liver toxicity with agomelatine – "a unique safety issue among antidepressant drugs"- was not highighted in published studies.

Professor Jon Jureidini and Melissa Raven, Adelaide-based members of Healthy Skepticism, said in a third letter the article’s summary contained "unjustified and misleading conclusions", and raised concerns over possible conflicts of interest. "The Lancet‘s publication of this flawed paper will undoubtedly validate marketing of Valdoxan, and we are curious to see how many paid Valdoxan advertisements will be published in Elsevier journals," they wrote. However, Professors Hickie and Rogers stood by their review, saying it had been "balanced and independent". Many of the issues, such as the challenge of demonstrating clear efficacy over placebo, were common to all antidepressants, they said, and changes in liver function tests were well recognised with agomelatine, and reflected in monitoring recommendations. They said their paper had been commissioned by the Lancet, was neither initiated nor supported financially by Valdoxan manufacturer Servier, and expressed only the authors’ opinions. Agomelatine is available on private script in Australia, having twice been rejected for PBS listing.

^{[1] Tomorrow, we are very heavily criticised for publishing a review on melatonin-based drugs for depression. Biased and overstated, say many.
[2] The bias in this paper is very disturbing – it might be fine to argue your case in a Viewpoint or letter. But…
[3] …this paper purported to be an unbiased review of a new drug class. Peer review improved it, yet not enough.
[4] As troubling is the fact that one author took part in speaking engagements for the company making one of these drugs.
[5] It is this kind of complicity that damages any hopes of a positive partnership between medicine and industry.}

• "Why did Ian Hickie, a prominent Professor of Psychiatry in Sydney Australia sign on to this industry-generated, inaccurate, infomercial review article?"
• "Why did the Lancet, one the oldest and most respected medical journals on the planet, publish this industry-generated, inaccurate, infomercial review article?"

• "Why would a Pharmaceutical Company want a favorable review article about their product published by a prominent doctor in a prestigious journal?"

The good news is that the right people were onto this article like flies onto honey as soon as it was published – responding in droves [see below]. Dr. Hickie should’ve known that the era of this kind of sheenanigans has finally passed and that his reputation will surely be forever tarnished by participating in this kind of ruse no matter how lofty his defense – because there is no defense. The other good news is that I understand that the Lancet editor has ‘abandoned this drug-focused type of review paper’ in the future altogether because of the bruhaha about this article.

Ian Hickie and Naomi Rogers: The original Lancet article
Letter from Corrado Barbui and Andrea Cipriani
Letter from Robert Howland
Letter from Celia Lloret-Linares, Jean-François Bergmann, and Stéphane Mouly
Letter from Bernard Carroll
Letter from Jon Jureidini and Melissa Raven
Letter from Marc Serfaty and Peter Raven
Response to Letters from Ian Hickie and Naomi L Rogers
Neuroskeptic: The Trojan Horse of Medicine
Pharmalot: A Servier Drug And A ‘Flawed’ Paper In The Lancet

^{Hat Tip to all those "right people"…}

The chart on the right is a simplification of a large table in a recently published paper. The ordinate is the mean difference of the HAM-D scores between drug and placebo [except the ghost point which is a MADRS difference - included to show non-significance]. The abscissa is the daily drug dose. Each point is a different clinical trial/dose pair from nine Double Bind, Placebo Controlled clinical trials. The significant studies [p<0.05] are in red. Those in green failed to separate from placebo. 5/14 significant. 9/14 not significant. All but one study <3.0 points Difference on the HAM-D. No dose response curve.

Five of the nine Double Bind, Placebo Controlled clinical trials reviewed had an Active Comparator included [Paroxetine (3) and Fluoxetine (2)]. Again, the significant studies [p<0.05] are in red and those in green failed to separate from placebo. The active comparators have a tan shaded background.

Certainly no improvement there. Only one trial showed clinical significance for the drug whereas 3/5 Active Comparators separated from Placebo.They also had six clinical trials where they’d studied Agomelantine "head to head" with Active Comparators:

Before getting too excited that they finally broke even on statistical significance, look at the units on the abscissa. The differences were under two points on the HAM-D scale [you could probably do that with few good nights' sleep]. They also reviewed three Prevention of Recurrence Clinical Trials. One was significant. The other two weren’t [duration unspecified]:

Novel melatonin-based therapies:
potential advances in the treatment of major depression
^{by Ian B Hickie and Naomi L Rogers}
Lancet 2011 378: 621–31.
[full text online]

^{Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT2C) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.}

^{Conclusions
Melatonin analogues provide a new and efficacious mechanism for producing notable phase shifts in human beings. Although these drugs have been mainly studied for sleep disorders, they also have the potential to be used as primary or adjunctive drugs across a wider range of neuropsychiatric disorders characterised by persistent circadian disturbance. Importantly, only agomelatine (which also binds 5-HT2C receptors) has been reported to have clinically significant antidepressant effects. Because of its favourable adverse effect and safety profile, and the potential to help to restore circadian function between depressive episodes, this drug might occupy a unique place in the management of some patients with severe depression and other major mood disorders.
Contributors
Both authors participated in the conception and writing of this article and have seen and approved the final version.
Conflicts of interest
IBH was previously chief executive officer and clinical adviser of beyondblue, an Australian National Depression Initiative. He has led projects for health professionals and the community supported by governmental, community agency, and drug industry partners (Wyeth, Eli Lily, Servier, Pfizer, AstraZeneca) for the identification and management of depression and anxiety. He has served on advisory boards convened by the drug industry in relation to specific antidepressants, including nefazodone, duloxetine, and desvenlafaxine, and has participated in a multicentre clinical trial of agomelatine effects on sleep architecture in depression. IBH is also supported by a National Health and Medical Research Council Australian Medical Research Fellowship. He is a participant in a family-practice-based audit of sleep disturbance and major depression, supported by Servier, the manufacturers of agomelatine. NLR has received grant support from Vanda Pharmaceuticals, Servier, Pfizer, and Cephalon, and has received honoraria for lectures from Pfizer, CSL Biotherapies, and Servier. She has previously received research funding from Vanda Pharmaceuticals, manufacturers of tasimelteon. She has also received an unrestricted educational grant from Servier. Research studies done by IBH and NLR are mainly funded by NHMRC project and program grants.}

^{MACINTYRE: Chair of the Department of Psychiatry at Atlanta’s prestigious Emory University, Dr. Charles Nemeroff is a highly respected and influential scientist. And a paid consultant to a dozen drug companies. A leading psychiatric magazine recently profiled him under the headline Boss of Bosses. Is the brash and controversial Charles Nemeroff, the most powerful man in psychiatry. Inside the authors wrote, Nemeroff is among the most coveted advisors to the pharmaceutical industry. And he fully expects to lead the corporate strategies of those he advises. Those who do not heed his advice are often the recipients of his wrath. Last summer at Cambridge University in England, Healy had a brush with the boss of bosses.
HEALY: Dr. Nemeroff came up to me in the course of the meeting in what was a very scary meeting between him and me and told me that my career would be destroyed if I kept on showing results like the ones that I’d just shown, that I had no right to bring out hazards of the pills like these.
MACINTYRE: In a written statement, a doctor who witnessed the confrontation told us, when it became clear that David Healy would not back down from his points of view, Nemeroff said that what Healy was publishing might harm the drug industry, specifically Eli Lilly. He, Charles Nemeroff, said that these people were ruthless and would go to great lengths to make life hard for academics who published articles associating suicide with Prozac.
HEALY: It was a fairly short encounter. It lasted about two or three minutes but a very scary one…}


^{MACINTYRE: Just a few months after the Nemeroff incident, David Healy flew into Toronto on what should have been his last trip to the city as a visitor. He planned to give a lecture at his future place of employment, hire some staff, pick out some furniture for his office and meet with his new boss, David Goldblum.
HEALY: He was keen for me to move from the U.K. much than I was keen to move. He hoped that I would move within weeks whereas I had hoped I’d move for April first.
MACINTYRE: So it was a very positive day?
HEALY: Absolutely. Absolutely. Couldn’t have been more positive.
MACINTYRE: And no hint for you that there was any trouble at all?
HEALY: Not the remotest of hints.
MACINTYRE: But that was about to change completely. Two days later, Dr. Healy delivered his lecture at the symposium. It was a sweeping review of the history of psychiatric drugs. He covered all the old ground about S.S.R.I.’s and suicide and raised concerns about some new anti-psychotic drugs. But one of the main themes concerned conflict of interest with drug companies and the increase challenge doctors face in avoiding it. Members of the audience who filled out evaluations forms rated Healy’s lecture the best of the lot. But it seems his new boss didn’t agree.
HEALY: When I met Dr. Goldblum that evening after the lecture, my guts told me that there was a much more serious problem than my head said that there could be. I saw a man who was more worked up than I’ve seen almost anyone else before ever. He seemed to me to be at risk of a stroke he was so worked up. It’s an extraordinary switch to have happened just during the course of a few hours.
MACINTYRE: The centre wouldn’t allow us to interview Dr. Goldblum. Instead we were referred to the President and C.E.O. Paul Garfinkle. He says Healy’s lecture was to blame.
GARFINKLE: Essentially, it was the extreme nature of his views with extraordinary extrapolations based on inadequate science, that really are scientifically irresponsible. For example, the view that anti-psychotics cause more harm than good.
MACINTYRE: Did Dr. Healy actually say that anti-psychotics do more harm than good? I believe that he claims he didn’t actually say that.
GARFINKLE: I have to tell you, I wasn’t at the lecture. But I’ve been told by a number of people that he essentially said that.
MACINTYRE: Dr. Garfinkle may not have heard the lecture but someone else did. Charles Nemeroff. He was also scheduled to speak that day and it seems he didn’t restrict his comments to the podium. Although he refuses to interviewed, Dr. Nemeroff said through his lawyer, the centre asked for his opinion of Dr. Healy that day and he gave it. What he said then, we don’t know, but later that day he flew to New York where we do know he told a meeting of the American Foundation for Suicide Prevention exactly what he thought about Healy. One scientist who was there said Nemeroff’s attack was furious, angry, exercised, that the thrust was Healy was a nut.}

^{MACINTYRE: A few days later, the centre dumped Dr. Healy…}

He sees the book and the two web sites as related pieces of an effort to make the protest against the current mess into a scientific project aimed at making real changes in the system rather than just making noise about its foibles – to produce an accurate and quickly available compendium of the adverse effects of drugs. I don’t yet see the entire picture, but I think there is going to be one to see as he proceeds. If you’re looking for a star to hitch your wagon to, Dr. David Healy is as likely a candidate as we’ve seen in a very long time.

From the Pentagon Papers to Allen Jones:

Why it’s so hard to be a whistleblower
by Alison Bass
January 18, 2012

Allen Jones, the whistleblower in an ongoing landmark trial against the pharmaceutical giant Johnson & Johnson, was very much on my mind this past weekend. I was participating in a workshop to develop curriculum to teach college students about the importance of standing up for their ethical values and if necessary, blowing the whistle on wrongdoing in their place of employment. The workshop in Washington, D.C. was sponsored by the Government Accountability Project [GAP], a nonprofit organization that represents whistle-blowers of all stripes from Daniel Ellsberg, who leaked the Pentagon Papers, to Allen Jones, who blew the whistle on the illegal payments Johnson & Johnson was making to state employees to promote the off-label use of its anti-psychotic drug, Risperdal, in children.

Jones first noticed these illegal payments when he was investigator for the state of Pennsylvania’s Office of Inspector General. He discovered that the state’s top pharmacist, the guy in charge of deciding what drugs should be included in its Medicaid formulary, was receiving hidden payments from J&J, the maker of Risperdal. Jones was fired when he brought those illegal payments to light, but he persevered, and with the help of GAP, won a lawsuit against the state of Pennsylvania and eventually saw the state pharmacist who was on the take fired from his job. As 1boringoldman and others have detailed, Jones went on to sue J&J in the state of Texas, where public officials were also being paid to fly all over the country and promote the off-label use of Risperdal in children…

As I sat around the conference table this weekend and heard one horror story after another about folks who spoke truth to power and ended up losing their jobs and being permanently blacklisted from employment in their chosen field, it made me wonder why it’s so difficult to be a whistle-blower in our society. [In the case of former Department of Justice lawyer Jesselyn Radack, whose book A Canary in the Coal Mine I just finished reading, the Bush administration was so bent on retaliating against her for blowing the whistle on the administration’s failure to give an American citizen arrested in Afghanistan his due rights to legal counsel that they not only prevented her from getting another legal job in the private sector but they also put her name on the No Fly list, making her subject to humiliating body searches every time she tried to board a plane]. Yet like Radack, most whistle-blowers are people who are simply trying to do the right thing and stand up to injustice, corruption or abuses in the corporate or public sector.

So why it is so difficult to raise ethical concerns today? It’s true that derogatory words like snitch, rat and tattle-tale have always been a part of our culture, and there’s no question that corporations put a premium on loyalty and conformity. But despite Congressional efforts to protect whistle-blowers [with the Whistleblower Protection Act], it seems to be more difficult than ever to speak up. Even though more workers are witnessing violations of company rules, retaliation against employees has risen to a new high, the 2011 National Business Ethics Survey found. More than a fifth of employees who reported a violation at work said they experienced some kind of retaliation, according to the Huffington Post. Most of those employees, of course, never went any further and leaked the information to the media, as Radack and Ellsberg did, subjecting both of them to enormous retaliatory pressures, such as concocted criminal charges…

I agree with Alison that the retaliation against whistle-blowers has regularly been vicious – something we all witnessed publicly in the Joseph Wilson / Valerie Plame affair and with other Iraq War whistleblowers – Katherine Gun and Dr. David Kelley. But there are other personal forces at work as well. In order to ethically expose wrong-doing, one has to divert one’s whole life into the encompassing identity of whistleblower. Mordechai Vanunu who exposed the Israeli nuclear bomb program is a paradigmatic example – spending 18 years in prison as a traitor and still living under government imposed restrictions even today. Daniel Ellsberg’s name is now synonymous with being The Whistleblower of the Pentagon Papers.

I met someone recently who made me aware of another problem that I wouldn’t have thought of. Potential whistleblowers don’t know how to do it – none of us do. They don’t know what resources are available, and may have the naive idea that simply exposing a wrong will lead to a just conclusion. But the truth is that once the whistle blows, the whistleblower loses any access to more information. So if you sound the alarm prematurely and you don’t have incontrovertible evidence already in hand, one can be retaliated against as well as watch the guilty party slide out of danger – then be haunted by the missed opportunity. On the other hand, waiting can be perilous. Daniel Ellsberg now regrets waiting too long to release the Pentagon Papers.

^{What has to be understood is that most whistle-blowers are not natural activists – this one certainly wasn’t. We usually work in anonymous jobs, far from the spotlight. We are not campaigners or journalists or wannabe celebrities craving a platform. Our conscience tells us we must reveal what we know. We do that, we blow the whistle, and overnight the whole media circus descends on us. You just don’t know what to do … that’s why we stick together.}

As I watched this parade of witnesses, I kept thinking about how many potential whistleblowers there were in this case, how many people were in a position to know something very wrong was going on and didn’t say a word – who, in fact, participated enthusiastically. Only two of them [Bill Struyk, of Reimbursements, and Tone Jones, a District Manager] were forthcoming and non-defensive in answering questions in their depositions – even though most of those testifying were former employees of Janssen. It’s easy to decry their complicity, their misplaced loyalties, their silence, their continued defensiveness even in a deposition under oath. But as this case makes abundantly clear, not being a whistleblower is the norm.

I agree with Ms. Gun about what whistleblowers are not ["We are not campaigners or journalists or wannabe celebrities craving a platform"]. In fact that seems to be a part of the story in many cases, people who are outside the main flow of things who come upon their information, not because they’re looking for it, but in the normal course of doing their jobs. My impression is that these exceptional people [as in an exception to the norm] are people who can’t not become whistleblowers, even though it is an extremely hard thing to do as Alison Bass points out in this post. It’s also my impression that the majority of them who are unsuccessful or even hurt don’t look back on the experience regretting that they spoke out, but are instead disappointed, disillusioned, or even bitter about the outcome.

It’s not fashionable to talk about the mind these days, or the forces at work in the development of the psyche. That gets dangerously close to sounding Freudian [as in superego] or not evidenced-based or measurement-based. But I doubt seriously that there’s a whistleblower gene people are born with. The development of morality is a complex compendium of experience, observation, teaching, and modelling by important figures along the way. I would propose that whistleblowers are people who have been enabled to develop a conscience that is more independent of the surround than others, that they are indeed exceptional in more ways than one. And while there may be whistlebowers that are motivated by financial gain, I don’t see any people highlighted in this post who fit that category, including Allen Jones.

From what we know about the development of ethics and morality, fear of personal punishment or disapproval is a tool used by parents since the dawn of time to shape moral development. But the example parents set by their own behavior is probably an even more powerful force. I’m all for making the path for the kind of exceptional people who become whistleblowers easier, but I think we’d be well placed to begin to punish people in high places who misbehave rather than just the corporations they work for. And it wouldn’t be a bad idea to have consequences for people further down the chain who participate in things that are clearly illegal. If Sales Reps for Pharmaceutical Companies had to be licensed, or at least registered, and the consequence of something like promoting drugs off label resulted in a loss of that license or registration, this would have been a very different story.