1 Boring Old Man

The Preeminent Role of Childhood Abuse and Neglect in Vulnerability to Major Psychiatric Disorders: Toward Elucidating the Underlying Neurobiological Mechanisms

by Charles B. Nemeroff and Elisabeth Binder

Journal of the American Academy of Child & Adolescent Psychiatry, 2014 53:395-397.

Disclosure:

• Dr. Nemeroff has received research/grant support from the National Institutes of Health (NIH).
• He has served as a consultant to Xhale, Takeda, SK Pharma, Shire, Roche, Eli Lilly and Co., Allergan, Mitsubishi Tanabe Pharma, Development America, Taisho Pharmaceutical Inc., and Lundbeck.
• He has held stock in CeNeRx BioPharma, PharmaNeuroBoost, Revaax Pharma, Xhale, Celgene, and Seattle Genetics. He has served on the advisory boards of American Foundation for Suicide Prevention (AFSP), CeNeRx BioPharma, National Alliance for Research on Schizophrenia and Depression (NARSAD), Xhale, PharmaNeuroBoost, Anxiety Disorders Association of America (ADAA), and Skyland Trail.
• He has served on the Board of Directors of AFSP, NovaDel, Skyland Trail, Gratitude America, and ADAA.
• He has received income sources or equity from PharmaNeuroBoost, CeNeRx BioPharma, NovaDel Pharma, Reevax Pharma, American Psychiatric Publishing, and Xhale.
• He holds patents in Method and devices for transdermal delivery of lithium (US 6,375,990B1) and Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2).
• He has received honoraria from the Florida Council for Community Mental Health, the Las Vegas Psychiatric Society, the World Psychiatric Association, the Saudi Psychiatric Association, the Kenes MP Asia, the American Physician Institute for Advanced Professional Studies, Asociacion de Psiquiatras de la Region de Bayamon, Florida Partners in Crisis, Global Technology Community, LLC, the International Society of Psychoneuroendocrinology, CPO Hanser Service, 1er Congreso de la Sociedad Internacional de Trastornos Bipolares, Venezuela, APA/Egyptian Psychiatric Association, YPO Partners Forum, Lieber Institute, Inc., Nevada Psychiatric Association, the University of New Mexico, World Congress of Biological Psychiatry, the University of Texas Medical Branch Galveston Grand Rounds, the Volkswagen Foundation/Herrenhausen Conference, Rush University Grand Rounds, 5th International Cardio Event 2013, CCM International Saudi Arabia/APA Meetings, CME Outfitters, CINP World Congress, the Medical University of South Carolina, Harvard Medical School/Psychopharmacology: A Master Class, the Florida Psychiatric Association, the International Society for Bipolar Disorders, 16th Annual Laura Evans Memorial Breast Cancer Symposium, Delaware State University, the University of North Carolina, New York University, NARSAD/the Brain and Behavior Research Foundation, the American Foundation for Suicide Prevention, the University of Chicago, King’s College, Beth Israel Deaconess, Wright State University, the University of Texas Medical Branch, Physicians Practice Group, Augusta, GA, Londocor Event Management – South African Biological Psychiatry Congress Education SPA, Psychiatric Foundation of North Carolina, Colombian Psychiatric Association Meeting, the Anxiety and Depression Association of America, Scuola Superiore di Neuroscienze – Neuroscience School of Advanced Studies, American Psychiatric Publishing, 20th National Congress on Child Maltreatment, Bogota, Colombia, Lundbeck, Max Planck Institute, Medical Education Speaker Network, and Guarant International.
• He has received royalties from the American Psychiatric Association, John Wiley and Sons, Inc., The Authors Registry, Elsevier, Oxford University Press, and Cambridge University Press.
• He has served as an expert witness and/or legal advice consultant to Edward Health Services Corporation, Penn and Seaborn, LLC, Schochor, Federico, and Staton, PA, Great Northern Insurance Agency, Douberly and Cicero, Sotolongo, PA, and Kirby Johnson, PC.

Cultivating the Next Generation Of Psychiatrists

PsychiatricNews

by Carolyn Rodriguez, M.D., PH.D.; Jonathan Amiel, M.D.; and Jeffrey Lieberman, M.D.

March 20, 2014

The beginning of a psychiatrist’s career after residency or fellowship is an exciting, but daunting, time. Whatever career path he or she is pursuing—clinical practice, academics, public sector, or industry—the transition from trainee to professional is critically important and often stressful. There is the challenge of having primary responsibility for one’s own patients. The desire to become comfortable in a new work environment and with new colleagues. The understanding that no matter how thorough our training has been, there remain difficult situations that arise in practice, testing our knowledge and mettle. APA well understands the need to support psychiatrists at this stage of their development and even has a special name for them: early career psychiatrists [ECPs]. Every psychiatrist and member of APA has faced this juncture in their careers. Consequently, we recently reviewed APA membership survey data to learn what special needs and services applied to this important constituency of our profession.

We were surprised to see that while resident-fellow members saw value and were pleased with APA membership, many weren’t continuing their membership as they entered the field and the professional workforce. We wondered whether this may be due to the fact that, in a changing and challenging environment, we may too often focus on the challenge of the moment over our longer term professional needs and enrichment. This problem was particularly concerning since APA membership is especially helpful early in one’s career for educational and mentoring resources. And more importantly, young members strengthen APA and shape the Association now and for the future.

To examine this issue, we co-chaired a work group of ECP members and two senior APA advisors to find out what APA was — and wasn’t — doing to support the needs of psychiatrists just starting in the field and what could be done better. Based on the work group’s recommendations, APA, with the full support of the Board of Trustees, is focused on making sure that the needs of psychiatrists just starting their careers are optimally addressed…

In some ways, I was lucky. I was torn between two compelling interests – the hard science of medicine and the human experience of illness. I had already had my identity crisis before arriving in psychiatry training and made my choice, so I was running on my own motor towards the latter. I had no idea that psychiatry itself was about to go the other way, and during my Early Career Psychiatrist days, it did. But I didn’t. And again, I was lucky. I was able to have a rewarding career doing what I chose to do, even though it was isolated from mainstream of psychiatry. I have a thought about what Dr. Lieberman et al are saying in this article, but it’s idiosyncratic, biased by my own path.

Cultivating the Next Generation Of Psychiatrists: People talk about the neoKraepelinians [Robins and Guze etc.] or the DSM-IIIs Robert Spitzer as the movers and shakers of the changes in psychiatry in 1980, but that credit really belongs to Mel Sabshin, the Medical Director of the American Psychiatric Association from 1974 to 1997. His book, Changing American Psychiatry: A Personal Perspective, tells the story from his front line perspective. He was a strong and beloved leader who did what he set out to do – change American Psychiatry.  I didn’t even know he existed at the time. The APA under Sabshin took the reins of the direction of psychiatry and lead the radical changes we all already know about, some of which were positive and long needed, some of which were either ill-considered or had inadvertent negative consequences.

The above article is really about the APA’s continued waning membership roles, and why young psychiatrists see APA membership as superfluous. I wasn’t so young when I let my APA membership expire. At that time, the APA was leading psychiatry in a particular biomedical direction that had little to do with my life and practice. In contrast, I didn’t see the APA taking leadership at all in areas that were of interest to me, but rather following Managed Care and PHARMA who were shaping and redefining psychiatry in their own image. So the APA was more than superfluous. It was a negative force that I couldn’t do anything about, but I sure wasn’t interested in supporting.

The way the story’s told, psychiatry needed a Melvin Sabshin to consolidate power to motivate change, and that may well have been absolutely true. I wasn’t around for that so I don’t really know the answer. But there were some unaddressed consequences that linger. The first was that the APA hadn’t read Bion’s books about groups and became lethal – extruding the psychoanalysts and the psychologically minded almost en mass [exception: Aaron Beck’s CBT], actually assigning us to the status of scapegoats. That attitude unfortunately bled over into the APA’s relationship with the other mental health professions. So people like me didn’t actually withdraw from the APA, we were marginalized. But more importantly, the APA under Sabshin consolidated and centralized the power, and never gave it back. History is filled with similar stories – a strong leadership that brings off a coup d’etat as a reform movement, creating the environment for a future oligarchy in the process. Sometimes, that’s the only way to get the job done [by revolution], but the wise know that a subsequent restoration of balance is essential.

Introducing AMP: The Accelerating Medicines Partnership

NIH Director’s Blog

by Dr. Francis Collins

February 4, 2014

It would seem like there’s never been a better time for drug development. Recent advances in genomics, proteomics, imaging, and other technologies have led to the discovery of more than a thousand risk factors for common diseases—biological changes that ought to hold promise as targets for drugs…

There are some other stock phrases that come to mind: unmet·clinical·need and global·burden·of·disease. Both of these are used routinely in reports of clinical trials or in pleas for more research funding for some particular project. The latter was almost guaranteed to be in the introduction to the ghost written clinical trial reports that were so popular during the last several decades, the age of psychopharmacology. And unmet·clinical·need is all purpose – can either go in an article to introduce a new drug that’s being hawked as an advance or later when discussing how that last drug wasn’t really very good and we need to find a new one [it’s actually hard to think of a medical situation or grant proposal where you couldn’t throw in an unmet·clinical·need].

Time for New Schizophrenia Rx

Science

by Steven Hyman

March 14, 2014

Last month, the battle against four major diseases received some good news. The U.S. National Institutes of Health [NIH] and 10 of the world’s largest pharmaceutical companies decided that instead of working ineffectively in silos, they would work together to discover therapies for Alzheimer’s disease, type 2 diabetes, rheumatoid arthritis, and lupus. This initiative — the Accelerating Medicines Partnership [AMP] — recognizes that progress toward new therapies for common chronic diseases increasingly requires large-scale collaborative efforts that range from the need to grapple with heterogeneous polygenic disease phenotypes to the validation of biomarkers in large populations. What is disappointing is that, at least for the time being, the consortium dropped schizophrenia from its list, despite vast unmet medical need and substantial, albeit still recent, scientific advances. Was schizophrenia deemed too risky to pursue? If innovative partnerships such as the AMP are not willing to take on common and serious but otherwise neglected disorders such as schizophrenia, then the scientific community will have to find new ways of pooling intellectual and financial resources to address them…

Schizophrenia is a severe and disabling brain disorder that also creates enormous costs and challenges for caregivers and for society. Antipsychotic drugs that partially treat hallucinations and delusions were discovered in the early 1950s but have serious side effects and leave entirely untreated schizophrenia’s characteristic cognitive impairments and “negative” symptoms such as blunting of emotion, loss of motivation, and impoverishment of thought and speech. The past six decades have witnessed many commercially successful antipsychotic drugs, but no new mechanisms of action and no gains in efficacy since the early 1960s. Cognitive behavioral therapies show promise, but even when combined with current medications, individuals with schizophrenia live with profound limitations resulting from diminished control over thought, emotion, and behavior. Many pharmaceutical companies have exited psychiatry in recent years because of high failure rates in clinical trials, only rudimentary understanding of disease mechanisms, and the lack of treatment biomarkers. Under these circumstances, patients and families would have scant hope for the arrival of better drug treatments….

Much about this grim scientific picture has changed in the past 5 years. New genomic technologies, combined with global collaborations to identify study participants and collect samples, have permitted the identification of a large and rapidly growing number of alleles associated with schizophrenia, bipolar disorder, and autism. Molecular pathways involved in neuronal function are emerging from the data and are beginning to suggest drug targets. Animal and in vitro models in which to investigate hundreds of gene variants of small effect remain works in progress. However, promising tools have emerged here too. For molecular and cellular analyses, stem cell technologies make possible the generation of human neurons in vitro. When combined with remarkable new genome engineering tools, these approaches permit the study of individual risk alleles, multiple alleles in molecular pathways, and the correction of risk alleles in neurons derived from patient samples. Studies at neural circuit levels are yet more challenging, but one can even envision transgenic nonhuman primate disease models with the genome engineering tools at hand. Proposals to the AMP have focused on advancing the genetic analysis of schizophrenia; improving in vitro human neuronal models to study disease-associated alleles; and a project to identify biomarkers, modeled on the early stages of the successful Alzheimer’s Disease Neuroimaging Initiative.

Perhaps recent exits by companies from psychiatry made schizophrenia too great a reach for the AMP, despite continued strong support from NIH leadership. It is precisely when new knowledge opens challenging but real possibilities to make major advances in health that partnerships such as the AMP seem most warranted. The scientific community, including industry, academia, patient groups, and government, must find ways of sharing financial risk while developing effective and well-governed partnerships. Otherwise, important basic science investments will go untranslated while patients and society continue to bear painful and costly burdens.

Revolution stalled.

by Hyman SE.

Science Translational Medicine. 2012 4[155]:155.

[full text online]

Drug discovery is at a near standstill for treating psychiatric disorders such as schizophrenia, bipolar disorder, depression, and common forms of autism. Despite high prevalence and unmet medical need, major pharmaceutical companies are de-emphasizing or exiting psychiatry, thus removing significant capacity from efforts to discover new medicines. In this Commentary, I develop a view of what has gone wrong scientifically and ask what can be done to address this parlous situation…

Psychiatric Drug Development: Diagnosing a Crisis

The Dana Foundation: Cerebrum

By Steven E. Hyman

April 02, 2013

[full text on-line]

[see whither the crisis…]

Change, Challenge, and Opportunity: Psychiatry Through the Looking Glass of Research

PsychiatricNews

From the President

by Steven Hyman, M.D. and Jeffrey Lieberman, M.D.

October 17, 2013

[full text on-line]

[see the monotony…]

Revitalizing Psychiatric Therapeutics

by Steven E. Hyman

Neuropsychopharmacology Reviews. 2014 39:220–229.

[see hope and hype…]

the·revolution: A lot of meanings here. One is the burst of discovery in the 1950s of medications that were effective in psychiatric conditions [lithium, antipsychotics, antidepressants, anxiolytics]. Another revolution was the coming of the neoKraepelinians and Robert Spitzer’s DSM-III in 1980. I think by the time Hyman arrived at the NINH, he might think of his tenure there as a revolution of sorts. By then, multiple classes of psychoactive drugs were flowing from the pharmaceutical pipeline at a steady rate. It was the decade of the brain, and the NIMH was front and center. Acadedemia and industry were collaborating [above and below the table]. And Hyman’s NIMH set out on a bold path to test the emerging drugs in mega clinical trials. During those years, the human genome project was completed and psychiatric genomics was becoming quite the rage. There was a feeling that the biological basis of psychiatry was just around the corner, and Hyman’s NIMH joined with the American Psychiatric Association to fund a series of symposia to plan for the next revolution, a biomedical DSM-V/5.

the·crisis: Another phrase with multiple meanings. After Hyman left the NIMH, his replacement, Tom Insel, came from a large academic/industry translational program and carried the banner of biomedical psychiatry, adding his psychiatry·as·clinical·neuroscience phrase to the base well laid by Hyman. But then came the crises. First there were a series of disillusionments as the misadventures of prominent academic psychiatrists became increasingly apparent, along with the exposure of widespread research misdemeanors in industry funded clinical trials. That culminated in Senator Grassley’s investugation of a number of high ranking psychiatrists for financial hanky-panky. Then came the legal suits exposing unmentioned adverse effects, accompanied by the release of documents that showed epidemic ghost-writing, the antics of the KOLs, the jury-rigged analyses of drug trials, and the deceitful marketing practices of PHARMA. And then there was another big crisis, the collapse of the grandiose wishes for the DSM-5 and its other foibles. But none of these are the crisis Hyman is talking about.

He’s referring to the recent·exits·by·companies·from·psychiatry that came in the summer of 2011, around the time Hyman left the Provost job for the Stanley Center – returning to the game, so to speak. The phrase I picked is Hyman’s, and it’s telling. Not recent·exits·by·companies·from·CNS·drug·development. He says recent·exits·by·companies·from·psychiatry. And I think that’s how it felt to the NIMH, to the APA, and to Steven Hyman – like they’d been abandoned by an essential ally.

"The scientific community, including industry, academia, patient groups, and government, must find ways of sharing financial risk while developing effective and well-governed partnerships."

There’s certainly another way to look at these phrases. It’s in all the papers. In the last thirty years, psychiatry has largely equated itself with drug treatment and colluded with the PHARMA advertisement that radically inflates efficacy and downplays risk. Psychiatry has largely taken the position that all mental illness is brain disease. Over the last thirty years of this monocular biomedical psychiatry, there has developed of a huge academic·pharmaceutical complex that has functioned like a symbiosis – operating on the the capital provided by PHARMA in return for lots of things. So the recent·exits·by·companies·from·psychiatry threatens this complex with financial collapse. This second view takes into account the scientific and financial misbehavior of PHARMA and the KOLs in psychiatry. It offers a more accurate view of the medications available. And it knows that PHARMA sees the recent·advances·in·genomics·proteomics·and·imaging as offering little that’s to their advantage – likewise seeing unmet·clinical·need as well as the global·burden·of·disease for what they really are, rhetorical gimmicks. PHARMA [and the rest of the world] also knows that just·around·the·corner is a fantasy that has run out of legs.

Arkansas court tosses $1.2B judgment against J&J

Associated Press

By CHUCK BARTELS

Mar 20, 2014

The Arkansas Supreme Court on Thursday overturned a $1.2 billion judgment against Johnson & Johnson in a lawsuit challenging the drugmaker’s marketing of the antipsychotic drug Risperdal. The court ruled that the state improperly sued under a law that applies to health care facilities, not pharmaceutical companies. The ruling comes in an appeal of lawsuit filed by Arkansas against the drugmaker and subsidiary Janssen Pharmaceuticals. The state says the companies didn’t properly communicate the drug’s risks and marketed it for off-label use, calling the practices fraudulent. Johnson & Johnson said there was no fraud and Arkansas’ Medicaid program wasn’t harmed…

In a separate action brought by the U.S. Department of Justice, Johnson & Johnson agreed in November to pay more than $2.2 billion to federal and state governments and in penalties to resolve criminal and civil allegations that the company promoted powerful psychiatric drugs, including Risperdal, for unapproved uses in children, seniors and disabled patients. The agreement was the third-largest settlement with a drug maker in U.S. history.

Johnson & Johnson and Janssen are also awaiting a ruling by the South Carolina Supreme Court, where the companies have an appeal pending of a $327 million judgment in a similar case. A $330 million verdict against both companies in Louisiana was overturned in January.

hat tip to pharmagossip…

It will be champagne around in New Jersey at headquarters. Another bullet dodged by the hard [well paid] work by their lawyers. I reckon there have been many other champagne celebrations about Risperdal® in the past – pulling off TMAP, buying Omnicare’s business, Excerpta Medica’s flooding the medical literature, turning Biederman by funding a Harvard Center and cashing in on his Bipolar Child epidemic. The $ 2.2 B settlement with the feds was a set-back, but well within their cost of doing business budget. The Risperdal® roll-out was a big success for its leader Alex Gorsky, who is now CEO of the whole company. He turned a schizophrenia drug into an all-purpose blockbuster many times over. And he couldn’t have done it without the help of skillful lawyers and marketers. Well, that’s not the whole story.

• Mistakes were made, Part 2
• the unforgotten unremembered…
• the twilight zone…
• Like Salem’s ‘witches,’ it’s time for NC to exonerate the Edenton Seven
• The Little Rascals Day Care Case
• Sex and Satanic Abuse: A Fad Revisited
• learning from mistakes…
• Psychiatric Times retracts essay on “satanic ritual abuse”
• perhaps bigger…
• of all people…
• Satanic Ritualistic Abuse – Revisited?

Instead of paying doctors to promote their drugs, GlaxoSmithKline has decided to pay doctors to promote their drugs.

Glaxo to Bring Doctors In-House as Educational Speakers

Bloomberg

By Makiko Kitamura

Mar 17, 2014

GlaxoSmithKline plans to hire doctors to educate their peers about its drugs instead of paying external speakers, a further change to its marketing practices following a record fraud settlement in the U.S. The drugmaker is also investing in improving its multichannel marketing strategy through media such as online streaming of educational content, Deirdre Connelly, head of Glaxo’s U.S. pharmaceuticals business, said in an interview in Philadelphia. The changes come at a time when London-based Glaxo is introducing products recently approved to treat skin cancer, HIV and respiratory diseases.

Glaxo has been reforming marketing practices to improve its reputation. In 2012, the company agreed to pay $3 billion to settle allegations that it illegally promoted its Paxil and Wellbutrin anti-depressants and failed to report safety data on the Avandia diabetes drug. Hiring doctors and medical experts to speak as in-house representatives of Glaxo will provide more transparency, Connelly said.

“We’ll continue to disseminate this very important information on drug benefits and risks, but we’re just not going to do that by hiring external speakers,” she said. “We want to ensure that no one even perceives us to be doing anything wrong.” Glaxo plans to hire a range of people with medical backgrounds, including doctors and scientists with expertise in specific disease areas, though how many is still unclear, according to the company. It will be fewer than the number of external speakers the company has employed, Connelly said. In December, Glaxo said that it will stop paying doctors for giving speeches and attending medical meetings by early 2016…

hat tip to pharmagossip… 

Glaxo Says It Will Stop Paying Doctors to Promote Drugs

New York Times

By KATIE THOMAS

December 16, 2013

The British drug maker GlaxoSmithKline will no longer pay doctors to promote its products and will stop tying compensation of sales representatives to the number of prescriptions doctors write, its chief executive said Monday, effectively ending two common industry practices that critics have long assailed as troublesome conflicts of interest. Andrew Witty, Glaxo’s chief executive, said the changes are part of an effort to “to try and make sure we stay in step with how the world is changing.”

The announcement appears to be a first for a major drug company — although others may be considering similar moves — and it comes at a particularly sensitive time for Glaxo. It is the subject of a bribery investigation in China, where authorities contend the company funneled illegal payments to doctors and government officials in an effort to lift drug sales…

I grew up in a family football built. My father, a small man, grew up in an immigrant family of coal miners. He escaped that fate by being the best football player ever seen in those parts, a skill he parlayed into an atheletic scholarship. After college, he became a coach for a time, which is when I came into the story – a very winning coach at that. Afterwards, he continued for years as a Scout. That meant that on weekends, we often were off in the car to scout the teams that the colleges that hired him were to play the next week. He had a notebook that he wrote in all through the game. It said things like, "They always run to the wide side of the field." or "The left guard usually lines up glancing to the side where they’re going to run." "If the left guard looks straight ahead, it’s a pass." Pages and pages. Needless to say, my dad was in high demand. After football, he managed a huge woolen mill, where he "coached" production. Another notebook. "If you backlogged too much wool to be spun, the spinners work slowly because there’s no chance they’ll ever catch up. But if you backlog just a little more than they can do, they speed way up." I often think of him when I read these PHARMA marketing ploys. While he was more or less an honest guy, he saw the IRS as an opposing team – fair game. He was an ace as a barterer. So without knowing exactly why, I avoided competitive sports and anything that had to do with business or strategizing. I pay the sticker price for cars and have always farmed my taxes out to some hyper-moral accountant. How hard is that to analyze?

The marketing departments of PHARMA are paid full time to do this kind of strategizing. It’s what they think about every day. I’ll bet they’d make fine football scouts. And I’ll bet they don’t think this kind of strategic thinking is dishonest. It’s just part of playing the game well – an end unto itself. "How do we squeeze the most profit out of Lurasidone? I know. Let’s get it approved for Bipolar Depression. When we advertise it, they’ll just see the word "Depression" and "Ask their doctor if Latuda® is right for them." "Look Sir Andrew, if we separate these announcements by three months, it won’t look like we’re just doing the same thing in a different way."

• The Fiona Godlee solution:
  "Unless we can find a solution to the commercial incompetence problem, we have to recognize that the pharmaceutical industry has an irreducible conflict of interest in relation to the way it represents its drugs, in science and in marketing. And unless we can resolve this in a way that is more in the public interest and in patients’ interest, I would argue that drug companies should not be allowed to evaluate their own products."
• The most stringent interpretation of the AllTrials solution:
  "It’s time all clinical trial results are reported. Patients, researchers, pharmacists, doctors and regulators everywhere will benefit from publication of clinical trial results. Thousands of clinical trials have not reported their results; some have not even been registered. Information on what was done and what was found in these trials could be lost forever to doctors and researchers, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated. All trials past and present should be registered, and the full methods and the results reported. We call on governments, regulators and research bodies to implement measures to achieve this."

Clinical Trial Prestidigitation – Making Old Data Look Worse So New Data Looks Better

Healthcare Renewal

by Roy Poses

03/18/2014

Presto Chango

According to Bloomberg, here is how Boehringer-Ingelheim responded to the question from the FDA about the rate of fatal bleeding.

That effort produced two separate analyses by the company, according to the unsealed court documents. One, looking only at people whose primary cause of death was bleeding, found 5.8 of 10,000 patients died per year. The other, which included anyone who had a major bleeding event and died for any reason, found a rate of 19.5 fatal events per 10,000 patients per year, the documents show.
The report sent to the FDA, though, contained only the analysis indicating the death rate from the earlier research was much higher than the numbers seen after approval, according to the court filings. Potentially, such a finding could head off any after-market action by the FDA because the data showed the drug was safer after it was approved and widely used.

So, to recapitulate, Boehringer-Ingelheim used results from the RE-LY trial to persuade the FDA that its new drug was safe and effective. However, the company did not include, at least in the results reported publicly, any measure of fatal bleeding in patients given the drug. It now appears that the rate of major bleeding in patients who subsequently died was high, perhaps high enough to have raised questions about the safety of the drug prior to approval, had it been revealed.

However, after the drug had been approved, when the question was about rates of severe bleeding after the drug had been marketed, the company furnished an analysis of data from the clinical trial that now showed a very high bleeding rate. That was the major misdirection, the sleight of hand.. It would make the rate of fatal bleeding in the post-marketing surveillance data appear low.

But apparently this data also kept the eyes of the FDA focused on the question of bleeding in the post-marketing period.  Did no one in the FDA notice that while this high rate of bad bleeding in the trial made the post-marketing surveillance look good, it also raised questions about whether the drug should have been thought to have been safe enough to be approved in the first place?

Insel’s Techno-Utopia

by Psycritic

March 16, 2014

…But just like those utopian movements, much of academic psychiatry [especially the KOL segment] is driven by an ideology: the tenets of biopsychiatry, which the 1 Boring Old Man blog has described in detail. This ideology is assumed to be correct, and because its believers think that this system will result in a huge amount of good [i.e. "NIMH envisions a world in which mental illnesses are prevented and cured"], then people who seem to oppose this ideology are at best deeply misguided, at worst causing irrevocable harm. Furthermore, anything short of this grand vision is deemed not worth pursuing. In my mind, this is the best explanation for why things like Paxil study 329, or the Markingson case, or problematic conflicts of interest, or millions of mentally ill being locked up in jails and prisons, get ignored by the leaders of academic psychiatry. They’re seen as relatively insignificant bumps in the road in the grand utopian scheme. Last year, I wrote a somewhat tongue-in-cheek post about what if the NIMH succeeds in its utopian vision. With the recent news that the NIMH will only fund treatment studies that also examine biological etiology, things are much more serious than I thought.

At first, my trouble with the Utopia analogy was my observation that they’ve been perfectly happy with a cascade of new drugs, even though they were primarily minor variations on a central theme. I guess I was thinking about Utopia as a destination, and from my perspective, most of the new drugs and the activities of the KOLs were taking us nowhere. But I think Psycritic had something more profound in mind – a true designation [NIMH envisions a world in which mental illnesses are prevented and cured], a true path [driven by an ideology: the tenets of biopsychiatry], and a banner of truth. I must already agree with the banner of truth part, because some time back, I went out of my way to fabricate this graphic from a heroic poster from the days of the Russian revolution. The whole point is that quests for utiopia never get there.

Balancing Immediate Needs with Future Innovation

NIMH: Director’s Blog

by Tom Insel

January 26, 2012

NIMH, like all Institutes at NIH, has an advisory council that meets three times each year. The National Advisory Mental Health Council (NAMHC) is a distinguished group of scientists, advocates, clinicians, and policy experts. Each of our meetings includes a closed session to review individual grants considered for funding and a session open to the public that engages this diverse group in discussions about the larger issues that guide NIMH funding.

At last week’s session, we heard a recurrent tension around one such larger issue. Some members of Council bear witness to the poor quality of care, the unmet medical need, and the diminishing investments by states on behalf of people with mental disorders. They reasonably ask, “How are we ensuring that the science that NIMH has produced is implemented where the need is greatest?” They also question on the pay-off of genetics research. After all, two decades after the gene for Huntington’s disease was identified, we still have no effective treatments, and Huntington’s disease is genetically far simpler than schizophrenia or bipolar disorder. In contrast to so many neurological diseases, we have effective treatments for schizophrenia and bipolar disorder. NIMH should be investing to ensure these are available.

The opposing argument runs something like this. There has been no major innovation in therapeutics for most mental disorders since 1960. Current treatments are not good enough for too many. Rather than investing scarce dollars for incremental improvements or increased dissemination of mediocre interventions, we need invest in the fundamental science of brain and behavior so that we can understand how to develop better treatments.

While I may have oversimplified the two sides of this debate, the divide is substantial. Some advisors want more funds in services research; other advisors want more funds in basic neuroscience. Some are thinking of the immediate needs; others are focused on the paradigm shifts that may be revealed by another decade of research. And with the NIMH budget stretched, tough choices must be made.

Finally, we have an unprecedented opportunity for progress, real progress, in understanding mental disorders. The answers are likely to be more difficult and more complex than cancer or many single gene disorders, but the tools are now becoming available. High throughput sequencing for DNA and RNA, whole genome epigenomics, high resolution imaging of the human brain, connectomics — all of these tools are giving us a first opportunity to understand mental disorders at many levels beyond the reported symptoms or the observed signs. What the EKG did for cardiology, the bacterial culture did for infectious disease, and molecular biology did for oncology, neuroscience should provide for the study of mental disorders.

Sixty years ago, the nation faced a similar short-term vs. long-term debate about polio. The needs were growing and the causes were unknown. Some wanted funds invested only in better services, including improved iron lungs. Others argued for investing in a vaccine with a long-term goal of eradication. As David Oshinsky explains in his outstanding retelling of this debate, the government went with the services approach, leaving advocates and families to raise funds for vaccine development.1 Let us hope we don’t short-change our grandchildren, sixty years from today, by failing to invest in the long-term promise of more effective diagnostics and therapeutics for mental disorders.

I’m not opposing anything particular in his listing. But in spite of his attempts to say otherwise, he’s turned the NIMH into a National Institute of Neuroscience. And he has increasingly focused and controlled the directions that research takes [a little “o”…]. So he’ll get proposals that fit the letter of his requirements [like Dr. Trivedi’s project on personalized medicine – EMBARC] that have no chance of adding anything to our understanding or our patient care [like Dr. Trivedi’s project on personalized medicine – EMBARC]. The tools he mentions above are fancier versions of the tools he mentioned in the his clinical neuroscience outing a decade ago [tools: redux…] or my new chairman talked about in the early 1980s. They’re still waiting for some creative, independent researchers to find a productive place to use them. He’s correct that something like the development of a polio vaccine is the kind of thing that might need focused research. But there’s no polio vaccine analog in his plans. We knew what caused polio by then, and what was needed to treat it. Here, we’re still dancing in the dark. 

Psychiatry as a Clinical Neuroscience Discipline

by Thomas R. Insel, MD and Remi Quirion, Ph.D, FRSC, CQ

JAMA. 2005 294: 2221–2224.

[full text on-line]

In this commentary, we argue that psychiatry’s impact on public health will require that mental disorders be understood and treated as brain disorders.

One of the fundamental insights emerging from contemporary neuroscience is that mental illnesses are brain disorders. In contrast to classic neurological illnesses that involve discrete brain lesions, mental disorders need to be addressed as disorders of distributed brain systems with symptoms forged by developmental and social experiences. While genomics will be important for revealing risk, and cellular neuroscience should provide targets for novel treatments for these disorders, it is most likely that the tools of systems neuroscience will yield the biomarkers needed to revolutionize psychiatric diagnosis and treatment. This essay considers the discoveries that will be necessary over the next two decades to translate the promise of modern neuroscience into strategies for prevention and cures of mental disorders. To deliver on this spectacular new potential, clinical neuroscience must be integrated into the discipline of psychiatry, thereby transforming current psychiatric training, tools, and practices.

Two years ago [on this date oddly enough], I wrote a post about tools [tools…]. At the time, the topic was the misuse of statistical analysis. It was a couple of months after Robert Gibbons had published two articles claiming that antidepressants were both safe and effective in adolescents. I don’t believe that’s true based on experience. In fact, it was at a time when a teen had suicided in our community. I’d never met the boy, but I ended up seeing several of his friends, all of whom talked about his personality change after he started on that medicine [an SSRI]. This is not a place in the world where these kids would’ve read about that in our weekly paper. So I was particularly incensed at what I considered a misuse of the statistical tools of science to make a point that I thought is both wrong and dangerous.

But back then I was thinking, as I am now, about the ordinate labels on the figure above from Dr. Insel’s 2005 paper inaugurating his idea that psychiatry is, or should become, Clinical Neuroscience – genomics, neuroimaging, proteonomics, molecular diagnosis, the tools of a modern neuroscientist. I am personally a total sucker for tools. Of course I like them for what the can be used for, but it goes beyond that. I like them just for what they are. They distinguish us from other species. We don’t wait around for millennia to evolve structures to help us do new things. We make the new structures ourselves, and I’m still awed by that.

I first heard about those tools on the y-axis up there talked about in this way Insel is talking back in the early 1980s with the coming of a new chairman to our department. Back then, we said genetics instead of genomics, and the neuroimagers were more primitive, but the sentiment was the same. These tools were going to lead us to a new world in psychiatry. Back then I thought, as I do now, that there are some mental illnesses that were likely have a biological substrate, but certainly not all, and certainly not the ones I had come to study and learn to treat – so I exited.

At the time, I thought psychiatry was having a love affair with a new technology, and I can understand that. It was something close to our first time to really take advantage of these ultra-modern tools of science. One could actually see a living brain – even watch it do things. Very exciting. But within a few short years, the fantasies and hypotheses generated by this technology blossomed and were joined by those associated with the new drugs, fueled by the neoKraepelinian Tenets arising from Robins and Guze – a story we all know too well. They seemed to never look back, and people began to talk as if all mental illness was biologically based. For a long time, they didn’t exactly say it, but various aspects of that idea were the only things they discussed [they = Key Opinion Leaders]. Around the time I retired [2003], the embryonal DSM-5 Task Forced published a book [2002] that did as much as said it [it = Mental Illness is Brain Disease]. And Tom Insel went to the NIMH from jobs in Atlanta where he had directed a primate lab [Yerkes] and a multi-university translational science program, publishing the article above in 2005. He sure said it. So what had been widely implied for twenty years became the official paradigm.

I first ran across Tom Insel’s 2005 article three years ago [personalized medicine: the concept…] trying to chase down all the hype about personalized medicine [April 2011]. I had never seen a graph with tools on one of the axes. But it wasn’t until a few months later [the extent of it…] when I read the 2005 A Research Agenda for the DSM-V that I caught up to the full meaning. They had placed their cards on the table. Based on the tools and what they thought they were going to find using them, they were openly declaring Mental Illness is Brain Disease. And I didn’t even realize that they had made this declaration until after they had already failed to deliver and had been forced to admit that failure publicly [Neuroscience, Clinical Evidence, and the Future of Psychiatric Classification in DSM-5, see class action in the air…]. Then, as we have heard for decades, they pushed the confirmation into the future. They hadn’t gotten there "yet".

I still love tools. I spend a lot of time playing with one of the biggest ones of all – the Internet. I carry a modern tool with me whenever I venture forth from our cabin. Like everyone else, when I want to contact anyone I know in the world or find out about any topic, I expect to be able to do those things one way or another quickly – something I would never have imagined even as a younger adult. But tools are things we make to use, to explore, to communicate. They aren’t things that go on an axis of a graph. Findings go on graphs, things that tools help us discover or uncover. If you right-click on the images in this blog [leftovers from the tools… post two years ago] and then select View Image, you’ll see what I named these pictures even back then. I saved the images with a term used for objects that have outgrown their literal meaning, even their symbolic meanings, and have become magical objects in their own right – supernatural objects. These tools are misused that way by many who don’t even operate the actual tools of neuroscience themselves. They’re touted as pointers to conclusions not yet remotely reachable, conclusions that have only been dreamed.

Watching the celebrities parade up and down the red carpet at the Oscars, I kept wondering what that was about, how it got started. And who were those dress designers that they kept mentioning? Who wears those dresses anywhere else? Certainly no one I know, or have ever known. And the awards and acceptance speeches – epics, giants, "I couldn’t have done it without …", a gathering with rules, an etiquette, a place in our culture. The Superbowl of something. But throughout the program [which I also watched like many of the rest of us], I kept having snippets of thoughts about two meetings of psychiatrists that struck me as similar. The first was the Mayflower Conference [video] in 2009. It was a gathering of US KOLs from far and wide assembled by Evian Gordon, an Australian guru, to roll out his entrance into the Personalized Medicine market. Personalized Medicine is the notion that by some technology [any technology will do], doctors will be able to pick the antidepressant that’s "right for you," just like in the commercials. The quote above from Dr. Trivedi was my take-home. He, and the assembled guests, thought that they had been called to tell us how to practice medicine [a position that I thought was right arrogant] – treatment guidelines, algorithms, lab tests. In my mind, that meeting marked the expansion of commercialism in psychiatry – from alliances with the PHARMA medications to other lucrative products used to practice psychiatry.

• Jeffrey Lieberman, M.D.: “There are huge unmet clinical needs in mental disorders and addiction. There should be tremendous interest in this area, but there is not.”
• Steven Paul, M.D. [Eli Lilly], pointed out that the industry as a whole is challenged with “less innovation, longer development cycles, shrinking margins, and less investment in R&D.”
• Armin Szegedi, M.D. [Merck]: “[a] lot of drug targets [that were] validated in the lab have not panned out in clinical trials.” The reason? Psychiatric disorders are not single-pathway diseases. For example, what is known as major depressive disorder may be a heterogeneous group of diseases with different etiologies and genetic factors, he said. Targeting one pathway may not help patients with other pathologies, and no one yet knows how to differentiate patients by their biology.
• Joseph Belanoff, M.D. [Corcept Therapeutics], said that based on his experience, the attitude toward industry-sponsored drug research seems very different between endocrinologists and psychiatrists… Pharma-sponsored research is considered not prestigious and “a bit dirty” among top-notch academic researchers in psychiatry, a sentiment that is absent in endocrinology. He urged APA to take a strong stand to support industry research. Others also commented that some academic psychiatry departments are reluctant to collaborate with industry.
• Herbert Pardes, M.D., president of the Scientific Council of the Brain and Behavior Research Foundation commented that if there is an innovative treatment with convincing effectiveness coming out of industry, “the vast majority of psychiatrists will embrace it.”
• Amir Kalali, MD. [Quintiles CRO]… urged APA to “help normalize academia’s relationship with industry” and encourage psychiatrists to take up industry-supported research.
• Mudhukar Trivedi, M.D. [Pharma anywhere]… observed that “we are creating a virtual world in which [psychiatric] trials are conducted in the [least-severely ill] patients by the least-qualified people, and then [we] are surprised by the placebo effect.” Consequently, the general public and part of the medical community believe that antidepressants are no better than placebo.
• … It was suggested that the proposed dimensional approach in DSM-5, along with NIMH’s ongoing development in Research Domain Criteria, could provide more precise clinical and biochemical targets for new and rational drug design.
• One of APF and APA’s roles, Schatzberg said, is to continue to fight the stigma against psychiatry and psychiatric drugs. In addition to facilitating more collaboration between the government and the private sector, he proposed that APF and APA work with other stakeholders to create incentives for industry to reinvest in psychiatry. Philip Skolnick, D.Sc., Ph.D., of NIDA raised the issue of whether extending market exclusivity for compounds that are first in class and/or first in indication as is done abroad could promote investment.
• Thomas Laughren, M.D., director of the Division of Psychiatric Products at the FDA, suggested that APA could help the agency by organizing public discussions and publishing consensus on clinical endpoints, biomarkers, and standardized clinical definitions such as response and partial response.

The psychopharmacology era from 1987 to the recent past has been like that. The next wonderful new antidepressant has to be more desirable than the last one. The novel way of accessorizing [sequencing, combining, augmenting] has to be value added. Without a pipeline producing something new periodically, the shine wears off of the old drugs and their foibles begin to show. So we need a new design, a new line [as they say in the garment industry], something to keep the momentum flowing. But our KOLs haven’t been like the dress designers, they’ve been more like the Red Carpet commentators who talk about other peoples’ designs – giving talks like recent advances in …, or neurobiology of ..., or writing review articles, or signing on to the industrial clinical trials – more groupies than stars. That must be why they’re so frantic. Commentators with nothing to comment about.

So they are trying to find a way to lure PHARMA back into CNS drug development. How to make sure academic psychiatry stays connected with industry. How to keep the bonanza of the 1990s and 2000s alive. This is the American Psychiatric Foundation [Pharma funded APA auxilliary], the NIMH, NIDA, the FDA, all meeting in APA headquarters, moderated by the then APA president elect and an APA past president, with suggestions for incentives to sweeten the pot for PHARMA. In the words of Dune author, Frank Herbert, "The spice must flow."