the jewel in the crown…

Posted on Thursday 5 May 2016

by Jureidini, Jon, Amsterdam, Jay, McHenry, Leemon
International Journal of Risk & Safety in Medicine. 2016 28[1]:33-43.

OBJECTIVE:Deconstruction of a ghostwritten report of a randomized, double-blind, placebo-controlled efficacy and safety trial of citalopram in depressed children and adolescents conducted in the United States.
METHODS:Approximately 750 documents from the Celexa and Lexapro Marketing and Sales Practices Litigation: Master Docket 09-MD-2067-[NMG] were deconstructed.
CONCLUSION:Deconstruction of court documents revealed that protocol-specified outcome measures showed no statistically significant difference between citalopram and placebo. However, the published article concluded that citalopram was safe and significantly more efficacious than placebo for children and adolescents, with possible adverse effects on patient safety.
This paper is just out, and from my perspective, it’s the jewel in the crown. The abstract doesn’t do it justice. They’ve pored over the subpoenaed documents and pieced together a story worthy of a Masterpiece Mystery Theater series – ghost writing, data manipulation, omissions, guest authorship, etc. I hesitate to summarize all of their findings as I don’t yet know if it will be available full text on-line, so I’ll hold off for the moment in hopes it will be widely available. Various bloggers have written about this study before, including me, but this study’s authors have gone much further, detailing things that are outright fraud. If it’s not available full text, I’ll paraphrase its narrative soon. In our Paxil Study 329 RIAT article, we were able to show that the claims of efficacy and safety in the original publication were wrong, but the format was not one where we could show that they were wrong on purpose. This paper shows not only that the study was wrong on purpose, but it goes on to detail exactly how that was accomplished. My hat’s off the these authors for a job well done and to the journal for publishing it…

Background for Reference:

Paradoxically, Karen Wagner and some of her co-authors in these studies were later on the ACNP [American College of Neuropsychopharmacology] Task Force convened to report on these questions after the Black Box Warning was added by the FDA in 2004:
And this kind of hyperbole was standard fare whenever ghost-writing was exposed:
    A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. The manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

by Karen Dineen Wagner, Adelaide S. Robb, Robert L. Findling, Jianqing Jin, Marcelo M. Gutierrez, and William E. Heydorn
American Journal of Psychiatry. 2004 161:1079-1083.

Objective: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric pa- tients with major depression.
Method: An 8-week, randomized, double- blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children [ages 7–11] and adolescents [ages 12–17] with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School- Age Children—Present and Lifetime Version. Patients [N=174] were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children’s Depression Rating Scale— Revised; the response criterion was defined as a score of ≤ 28.
Results: The overall mean citalopram dose was approximately 24 mg/day. Mean Children’s Depression Rating Scale—Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study [effect size=2.9]. The difference in response rate at week 8 between placebo [24%] and citalopram [36%] also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinua- tion due to adverse events were comparable in the placebo and citalopram groups [5.9% versus 5.6%, respectively]. Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.
Conclusions: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.

Editors’ Note
by Robert Freedman and Michael D. Roy
American Journal of Psychiatry. 2009 166[8]:942-943.

The article "A Randomized, Placebo-Controlled Trial of Cilalopram for the Treatment of Major Depression in Children and Adolescents," published in the June 2004 issue of The American Journal of Psychiatry [vol. 161, pp 1079-1083] is alleged by the United States Department of Justice in an ongoing suit to have been written and submitted to the Journal by a commercial medical writer on behalf of Forest Laboratories, Inc.

We requested responses from Drs. Karen Dineen Wagner, Adelaide S. Robb, and Robert L Findling [authors in their role as investigators in the clinical trial at their respective universities], Dr. William E. Heydom [the senior Forest laboratories study director], and Forest laboratories. Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydom to which they contributed through several drafts, This paper was submitted as a Brief Report, which the Journal’s editors requested be resubmitted as a full-length Article. Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.

A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. Hie manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

We are satisfied that the named contributors of this article satisfy the criteria for authorship as set forth in the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" from the International Committee of Medical Journal Editors. However, the Journal’s Instructions to the Authors in 2004 and our policy today do not allow contributions by unnamed writers to the preparation of a paper. Thus, the editorial contributions of Prescott Medical Communications Group should have been acknowledged in the published article as required at the time the article was published.

Furthermore, Forest Laboratories failed to disclose to the Journal that it was aware of data from a study by Lundbeck that showed increased suicidality in children and adolescents who were treated with citalopram. Authors and sponsors are expected to disclose the existence of all data that affects the interpretation of their study. This note will appear in Medline and other databases as a Comment on the paper.

The official complaint [United States and Christopher R. Gobble v. Forest Laboratories Inc. and Forest Pharmaceuticals Inc. Civil Action No. 03-10395-NMG] is posted at …
Mickey @ 8:26 PM

the Decade of “Jumping the Gun“….

Posted on Wednesday 4 May 2016

It may seem peculiar, but it makes sense to me. As a young guy in medicine, I was pulled in two directions – research into things we don’t yet know, and the application of things we do know. The former was where my mind naturally headed, but the latter was what gave me a sense of purpose. While it’s only in retrospect, it makes perfect sense to me that I would’ve ended up being a psychoanalytically oriented psychotherapist [n=1 research with a practical application] where every case is something new. Similarly, my retirement fun has been re·search·ing the post-DSM-III psychiatric research where I’ve stayed on the practical side – psychopharmacology, clinical trials, diagnosis. I’ve shied away from the neuro·anatomy, neuro·physiology, neuro·science side of things, I think because I’m not convinced we know enough yet for there to be a practical side to the equation.

In med school, I had a great professor for neuroanatomy, a feiry red-headed lady with a passion for her subject matter. I loved the course like I might enjoy a course in mapmaking, but how all those structures we learned about related to higher mental life was a great mystery. I left with a Neurologist’s picture of the brain – how to locate lesions by a neurologic examination. Of late, there have been claims that we know more. But as a beyond knowledgeable blogger [Neuroskeptic] recently commented here [in the chemistry of paint…]:
The whole of the past decade in psychiatry might be called the Decade of Jumping the Gun.

The fact is that we simply don’t have good enough neuroscience tools yet to allow us to answer the clinically important questions. We just don’t. We might get there eventually but at the moment we are not there.

Given which, any attempt to ‘translate’ our primitive neuroscience into clinical practice will be an effort to jump the gun.
by Neuroskeptic…  
In the recent past, there have been several remarkable technological advances. One was the fMRI:
Blood-oxygen-level dependent contrast imaging, or BOLD-contrast imaging, is a method used in functional magnetic resonance imaging [fMRI] to observe different areas of the brain or other organs, which are found to be active at any given time. Its proof of concept was provided by Seiji Ogawa and colleagues in 1990, following an experiment which demonstrated that an in vivo change of blood oxygenation could be detected with MRI. Other notable pioneers of BOLD fMRI include Kenneth Kwong and colleagues, who first used the technique in human participants in 1992.

Neurons do not have internal reserves of energy in the form of sugar and oxygen, so their firing causes a need for more energy to be brought in quickly. Through a process called the hemodynamic response, blood releases oxygen to them at a greater rate than to inactive neurons. This causes a change of the relative levels of oxyhemoglobin and deoxyhemoglobin [oxygenated or deoxygenated blood] that can be detected on the basis of their differential magnetic susceptibility.

In 1990, three papers published by Seiji Ogawa and colleagues showed that hemoglobin has different magnetic properties in its oxygenated and deoxygenated forms, both of which could be detected using MRI. This leads to magnetic signal variation which can be detected using an MRI scanner. Given many repetitions of a thought, action or experience, statistical methods can be used to determine the areas of the brain which reliably have more of this difference as a result, and therefore which areas of the brain are active during that thought, action or experience…
from Wikipedia… 

The fMRI [1992] and the mapping of the human genome [2000] had the bio-medical psychiatrists  peeing in their pants  filled with excitement at the turn of the century. And it was pretty exciting. Tom Insel became the Director of the NIMH and announced psychiatry was to become clinical neuroscience. The DSM-5 Task Force tooled up to add biomedical findings to their coming diagnostic manual. A new century and a new psychiatry based on solid brain science was just around the corner. They had already jumped the gun some in the Decade of the Brain [the 1990s], but this time, they forgot the adages, "look before you leap" "don’t count your chickens before they hatch", and dove into the deep end, and ended up with a long chain of disappointments fueling disillusionment and skepticism. So now we’re presented with a big NIMH Study, this time about neural circuits [see weary…].

As far back as 2005, the NIMH’s Tom Insel has talked about neural circuits:
Already we are seeing multiple approaches to identifying abnormal functional activity in the brain, from functional MRI to in vivo neurochemistry and studies of brain receptors. One approach uses functional imaging to identify differences in regional activity. For instance, evidence from several different approaches implicates circuitry involving ventral, medial prefrontal cortex [Area 25] with major depressive disorder… Individuals with the short allele of the serotonin transporter gene have reduced expression of the transporter and appear to be at a higher risk for developing depression following stressful life events. Recently, this short allele has been shown to be associated with reduced gray matter volume of Area 25 and uncoupling of an anterior cingulate-amygdala circuit necessary for extinction of negative affect, providing a model for linking genetic risk and environmental stress to a specific neural circuit implicated in depression. One might imagine that studies of this circuit could be used to predict response to treatment, just as imaging in cardiology or oncology can be used to predict treatment response.
As best I can tell, this research proposal from Dr. Leanne Williams et al is a fishing trip. Throughout the two papers, they talk about what they might find and what it might mean. But the study itself is pretty simple. Take all the patients who show up in their clinic who will agree and measure just about any and everything you can think of, including a resting and a testing fMRI. Then let them be treated by their clinicians, then retest them in 12 weeks [see weary…]. I guess the next step is to run multiple correlation tests to see what goes with what. They offer all sorts of possible translations – all speculative. So, when it’s all said and done, it’s simply a repetition of the Brain Resources BRAINnet database, iSpot, EMBARC – in other words, it populates the RDoC database with complete subject datasets. I suppose that’s a reasonable thing to do.

But what I would’ve preferred from these articles would have been something solid and well referenced about the neural circuits themselves. Perhaps such things are widely talked about and known in neuroscience circles, but they’re not in the general population of practitioners, psychiatrists, or others who aren’t specifically immersed in the world of neuroimaging. The articles are so busy addressing possible translations that they give short shrift to  the basics – basics that most readers [like me] don’t know much about. Since this study is essentially a data gathering exercise with the behavior of the neural circuits on the front burner, I ought to know more about that than I do after reading these papers repeatedly.

There has been so much jumping the gun in the past that the ball’s in their court to prove that they’re not doing that here. And I’m not convinced. Anybody have any good references that explain neural circuits more clearly?
Mickey @ 12:44 PM


Posted on Monday 2 May 2016

Five years ago, I ran across an Australian company called Brain Resources. It appeared to be primarily a Brain Training enterprise, but they were into a lot of other things too. They were financing iSPOT, a clinical trial of personalized medicine trying to predict antidepressant drug choice based on Genetic and/or other testing. And they were amassing a Database of subjects testing all things neuro [testing, genetics, imaging, etc]. There were two principals: Evian Gordon, a Brain Training guru type, and Leanne Williams, second in command, in charge of the database which was to be made publicly available. They had put together an amazing conference in the US about personalized medicine, attended by KOLs from far and wide [roster][video] called the Mayflower Initiative. And there were a number of KOLs involved in their iSPOT trial. To be honest, I didn’t know what to make of it. The personalized medicine meme swept through psychiatry. Besides Brain Resources’ iSPOT, there was EMBARC, a similar trial funded by the NIMH with Madhukar Trivedi as P.I. Nemeroff gave talks about it. Insel blogged about it. Papers were published along the way.

Meanwhile, right around the same time, Tom Insel’s NIMH introduced its Research Domain Criteria [RDoC] [Genes and Circuitry, Not Just Clinical Observation, to Guide Classification for Research January 2010]. Born from the frustration of the poor specificity of psychoactive drugs for clinical diagnosis, the RDoC proposed to search for other parameters that might define syndromes that more accurately map to drug response. But while personalized medicine and the RDoC may sound like different things, operationally, they’re the same – broad surveys of objective parameters [genomic, imaging, clinimetrics, etc] analyzed looking for clusters or correlations not apparent in the traditional clinical categories [using big data statistical techniques].

But that’s not all folks! When I first wrote about this five years ago, Leanne Williams was the curator of the data being collected by the Brain Resources Company in Australia. Now Leanne Williams [one and the same] is the Director of the Panlab at Stanford and the VA Palo Alto MIRECC and the curator of the data being collected by the NIMH as PI of a big NIMH grant – part of their RDoC Initiative.
by Leanne M Williams
Lancet Psychiatry. 2016, Published Online April 14, 2016

Although there have been tremendous advances in the understanding of human dysfunctions in the brain circuitry for self-reflection, emotion, and cognitive control, a brain-based taxonomy for mental disease is still lacking. As a result, these advances have not been translated into actionable clinical tools, and the language of brain circuits has not been incorporated into training programmes. To address this gap, I present this synthesis of published work, with a focus on functional imaging of circuit dysfunctions across the spectrum of mood and anxiety disorders. This synthesis provides the foundation for a taxonomy of putative types of dysfunction, which cuts across traditional diagnostic boundaries for depression and anxiety and includes instead distinct types of neural circuit dysfunction that together refl ect the heterogeneity of depression and anxiety. This taxonomy is suited to specifying symptoms in terms of underlying neural dysfunction at the individual level and is intended as the foundation for building mechanistic research and ultimately guiding clinical practice.
Brain waves
By Tracie White
Stanford Medicine, Winter 2016

… a fluff-piece in the Stanford Medicine Magazine about Dr. Leanne Williams…
by Leanne M. Williams, Andrea N. Goldstein-Piekarski, Nowreen Chowdhry, Katherine A. Grisanzio, Nancy A. Haug, Zoe Samara, Amit Etkin, Ruth O’Hara, Alan F. Schatzberg, Trisha Suppes, and Jerome Yesavage
BMC Psychiatry. DOI: 10.1186/s12888-016-0771-3. Published: 15 March 2016

Background: Understanding how brain circuit dysfunctions relate to specific symptoms offers promise for developing a brain-based taxonomy for classifying psychopathology, identifying targets for mechanistic studies and ultimately for guiding treatment choice. The goal of the Research Domain Criteria [RDoC] initiative of the National Institute of Mental Health is to accelerate the development of such neurobiological models of mental disorder independent of traditional diagnostic criteria. In our RDoC Anxiety and Depression [“RAD”] project we focus trans-diagnostically on the spectrum of depression and anxiety psychopathology. Our aims are [a] to use brain imaging to define cohesive dimensions defined by dysfunction of circuits involved in reactivity to and regulation of negatively valenced emotional stimulation and in cognitive control, [b] to assess the relationships between these dimension and specific symptoms, behavioral performance and the real world capacity to function socially and at work and [c] to assess the stability of brain-symptom-behavior-function relationships over time.
Methods and design: Here we present the protocol for the “RAD” project, one of the first RDoC studies to use brain circuit functioning to define new dimensions of psychopathology. The RAD project follows baseline-follow up design. In line with RDoC principles we use a strategy for recruiting all clients who “walk through the door” of a large community mental health clinic as well as the surrounding community. The clinic attends to a broad spectrum of anxiety and mood-related symptoms. Participants are unmedicated and studied at baseline using a standardized battery of functional brain imaging, structural brain imaging and behavioral probes that assay constructs of threat reactivity, threat regulation and cognitive control. The battery also includes self-report measures of anxiety and mood symptoms, and social and occupational functioning. After baseline assessments, therapists in the clinic apply treatment planning as usual. Follow-up assessments are undertaken at 3 months, to establish the reliability of brain–based subgroups over time and to assess whether these subgroups predict real–world functional capacity over time. First enrollment was August 2013, and is ongoing.
Discussion: This project is designed to advance knowledge toward a neural circuit taxonomy for mental disorder. Data will be shared via the RDoC database for dissemination to the scientific community. The clinical translational neuroscience goals of the project are to develop brain-behavior profile reports for each individual participant and to refine these reports with therapist feedback. Reporting of results is expected from December 2016 onward.
Trial registration: Identifier: NCT02220309.
I don’t know much about neural circuits. Let me rephrase that – I don’t know anything about neural circuits. I first heard the term here…
British Medical Journal
by Caroline White
1 September 2011

The field of mental health is on the cusp of a revolution, which is set to transform the diagnosis and treatment of mental illness and reverse the lack of major progress made in curbing associated ill health and death over the past 100 years, the director of the US National Institute of Mental Health, has claimed. “We are at an extraordinary moment when the entire scientific foundation for mental health is shifting, with the 20th century discipline of psychiatry becoming the 21st century discipline of clinical neuroscience,” Thomas Insel said before a meeting on the challenges facing mental health research at the Royal Society in London on 31 August…

The seismic shift had been driven by what he described as three “revolutionary changes” in thinking, the first of which was that mental illness was increasingly being recognised as a disorder of brain circuitry, rather than as a chemical imbalance, thanks to neuroimaging techniques and the discovery of some key biomarkers. Secondly, mental ill health was now recognised as a developmental disorder for which early intervention was vital, said Professor Insel, highlighting US research showing that 50% of study participants had reported the onset of mental health problems by the age of 14, and 75% by the age of 24. “We are still stuck with getting to the problem very late. The future will be about understanding the trajectory of illness so that we can identify the first signs before it develops into psychosis,” he said…

… so the main person talking about neural circuits has been Dr. Insel up until now. I can’t even tell if this is coming from his standard neuroscience cheerleading or some solid thread in neuroscience research. Likewise, I don’t know how all this boundary blurring connectedness between Evian Gordon’s Brain Resources and Insel’s NIMH works, or how Leanne Williams fits into the story, or how Dr. Insel’s gloomy quip about the indadequate analytic firepower mentioned in the chemistry of paint… relates. Reading these papers, clearly intended to be an enthusiastic launching pad for this study of neural circuits, I’ll admit to feeling something sort of like weary – like "here we go again [sigh]". I guess we’ll see…
Mickey @ 9:27 PM

some voices in the clouds…

Posted on Sunday 1 May 2016

All this talk of the recent suicide statistics and what they might mean isn’t my native land. I’m more used to thinking about suicide and meaning[s] one case at a time. I recalled something from my earliest days as a resident. One of the first lectures we had was about the standard suicide statistics. You probably heard one too – women attempts [9:1], men successful suicides [9:1]; social isolation, alcohol/drugs, older, plan – all ominous signs; etc. etc.
    One late night on-call, I was interviewing a man brought to the hospital because he was contemplating suicide. I no longer recall the specifics, but I do remember what occurred to me while I was talking to him. I realized that when I saw a suicidal patient, I got anxious and didn’t think quite right. I became focused on things like "is he really going to do it?" "does he have a plan?" With suicidal patients, the stakes were suddenly raised by the threatened action, and I started worrying that I was going to do the wrong thing, "blow it." Without really knowing it was happening, I was abandoning the patient as a suffering person and becoming focused on risk management and suicide prevention. Not that there’s anything wrong with that – in fact it’s the right thing to do [evaluating risk], but not the only thing. It certainly didn’t mean that I should forget that I was talking to someone in a lot of pain and confusion – a unique person, not a category. And if ever there were a group of people who deserve our fullest individual attention, they’re among this group…
I don’t think much of population statistics or Tom Insel when I’m seeing patients. Let me introduce some of the people that do live in the clouds when I think of suicidality and suicide in clinical work:

William ShakespeareMy sister, an academic, wrote a paper long ago analyzing Shakespeare’s Hamlet using double-bind theory. I think I would’ve thought it brilliant even if we didn’t share a name and a history. She showed how Hamlet’s soliloquy on suicide applied to all of the characters, each of whom was in a double bind, and how madness and suicide were tempting solutions to the impossible situations each of them faced. I can’t count the number of suicidal patients I’ve seen where parsing the double binds they were experiencing was the key to finding their way out of a suicidal dilemma. I owe both Shakespeare and my kid sister for that insight.

William StyronAnother great writer who made a major contribution was William Styron, the author of Sophie’s Choice, another variation on the theme of double binds, impossible situations. It’s a must-read book and a must-see movie if you are someone who sees suicidal patients. One will never find two better teachers than William Styron and Meryl Streep. And Styron gave us something else. His Darkness Visible is a first hand account of the pain of Melancholia that makes the why of the suicidal risk in the afflicted patients unforgettable. Another must-read.

Virginia WoolfAnd speaking of the great writers, Virginia Woolf and her Mrs. Dallaway are in close contention with the next paragraph’s featured author as the best piece of fiction ever written. The book is, in part, about her character, Septimus, a man with a War Neurosis who kills himself to avoid being committed. Some 16 years after writing the book, Woolf herself committed suicide as an episode of her periodic psychotic illness was coming on – likely for the same reason. I have three books on my shelf, each explaining her illness convincingly, each with a different diagnosis [Schizophrenia, Bipolar Disorder, and PTSD]. I can’t summarize her themes – but they’re all there.

William FaulknerWilliam Faulkner is the other contender for the greatest piece of fiction ever written [personal opinion]. It’s two books: Absolom, Absolom and The Sound and the Fury. The books explore the interplay of culture, history, myth, and personal biography as they lead his character Quentin to suicide. I expect that my own history as a Southerner has something to do with my reverence for these two books. But even with that COI declaration, their complex messages have frequently come to mind with suicidal patients and opened up fruitful avenues for exploration.

Émile DurkheimWhile countless academics and graduate students have had their way with Émile Durkheim’s 1897  Treatise, Suicide, his insights have weathered the century. His study compared suicides among Catholics and Protestants using a scientific method. "Overall, Durkheim treated suicide as a social fact, explaining variations in its rate on a macro level, considering society-scale phenomena such as lack of connections between people [group attachment] and lack of regulations of behavior, rather than individuals’ feelings and motivations." Wikipedia. It’s a piece of Sociology important to consider at the individual level with suicidal patients..

Karl MeningerWe all likely know about Karl Abraham’s and Sigmund Freud’s thoughts about the relationship of anger to depression and suicide. But Karl Meninger‘s 1938 contributions in Man Against Himself are what actually come to mind with every suicidal person I’ve ever seen. Paraphrased, suicidal people want to die [escape], to be dead [relief], and to kill [rage] – and I try to find the personal version of each one of them in every interview. This is a timeless book that isn’t often mentioned these days, but it should be. I had to occasion to reread it a few years ago along with a student, and it was as fresh and useful as it was the first time I read it.

Albert CamusAlbert Camus’ Myth of Sisyphus is a classic on many fronts. While the philosophical point is that Hamlet’s existential dilemma has to be resolved to truly live authentically, to choose to live, I found it helpful with any number of patients. Concretely, I had cases who had a lethal cache of medications as a beloved possession, a talisman, a way of holding out, a way of not fully stepping into life until life proved itself. And there were a significant number who kept their cache secret until they decided to throw them away and step into life after all. That’s a whole psychotherapy topic of its own, but for the moment, suffice it to say that Camus is definitely a required read.

So where did this post come from? I’ve spent a couple of days thinking about those suicide statistics, and their meaning  vis–à–vis the NIMH and Insel’s leaving [what’s missing…, off of my plate…, all aboard!…, and the chemistry of paint…]. But what those numbers really brought up in my mind were cases I’ve seen over the years. What I was writing seemed so disconnected from those real people, sterile, and I wanted to populate the posts. But I can’t write about the cases in my mind so I started writing about some of the people in the clouds with them that I could talk about. Voilà
Mickey @ 8:00 AM

the chemistry of paint…

Posted on Saturday 30 April 2016

Dr. Insel’s selection as Director of the NIMH in 2002 was a surprise choice. After losing his position in the NIMH Intramural program, he came to Atlanta to head the Yerkes Primate Center. After one term, he was not reappointed [the scuttle-but – too controlling] and then became Director of a Translational Center, a research consortium of the area Universities put together by Emory Chairman, Charlie Nemeroff. It was a time when Dr. Nemeroff was known as boss-of-bosses with influence felt far and wide, and locally we assumed that Nemeroff had a lot to do with Dr. Insel’s surprise appointment at the NIMH. Years later, after Dr. Nemeroff’s fall from grace, Dr. Insel presumably returned the favor by helping Nemeroff secure another Chairmanship in Miami.

I heard him speak several times in his Atlanta days. He was interesting, knowledgable, enthusiastic, personally humble [unlike his boss]. He struck me as more like an academic biologist than a physician. During his long tenure at the NIMH, it seemed to me that he has come in three distinct flavors over the years:
  1. Clinical Neuroscience: That was a surprise – his becoming a champion for making a dramatic change in a clinical specialty. He wasn’t a clinician himself, and for the NIMH to set the direction for a medical specialty [and even try to change how that specialty approaches diagnosis] is unprecedented. But that’s what happened [fulfilling the scuttle-but – too controlling]. Admittedly, it was a time when biological psychiatry and psychopharmacology were in their ascendency, but Dr. Insel catapulted brain science to an almost exclusive centrality. His enthusiasm for neuroscience breakthroughs was in every talk, every blog post, almost every call for proposals. By natural selection, the NIMH iterated towards becoming the National Institute of Brain Science – at least that’s how it looked to me. And while he often talked about public health statistics, the growing menace of depression, and the need for more treatments, the research was heavily weighted towards basic neuroscience – brain circuitry
  2. Blaming: In the summer of 2011, it became apparent that the pharmaceutical industry was fleeing CNS drug development like rats from a sinking ship. After twenty-five years of variations on a couple of simple themes, they ran out of molecules, and were under siege for overplaying their hands in almost every dimension. Dr. Insel changed. He seemed disgruntled, angry, blaming. He talked of our current treatments as inadequate and seemed to be trying to gear up the NIMH to do something about that through a series of policy changes: RDoC, short trials, accessing industry’s discarded molecules. He was becoming even more controlling than before. It was as if he’d suddenly noticed that the NIMH was out of the loop with treatment research and he was frantically trying to catch up.
    I expect that I’m not the only person who saw those Suicide Statistics as an indictment of our mental health systems and the NIMH directions. And while we’ll probably never know the story, I would expect that those numbers along with other disheartening indicators probably had something to do with Dr. Insel’s surprise exit as Director of the NIMH. I suspect it was a suggested exit. It’s apparent in the things he’s said since announcing his retirement that he’s in the blaming mode:
      •Why did you leave the National Institute of Mental Health to work for Google?
      I have to confess that after giving heart and soul to mental-health problems over the last 13 years working in government, I have not seen any improvement for either morbidity or mortality for serious mental illness – so I’m ready to try a different approach. If it means using the tools available in the private sector, let’s go for it.
      • Are you saying Google is a better place to do mental-health research than the NIMH?
      I wouldn’t quite put it that way, but I don’t think complicated problems like early detection of psychosis or finding ways to get more people with depression into optimal care are ever going to be solved solely by government or the private sector, or through philanthropy. Five years ago, the NIMH launched a big project to transform diagnosis. But did we have the analytical firepower to do that? No. If anybody has it, companies like IBM, Apple or Google do – those kinds of high-powered tech engines…
    Who is he mad at? He was in charge, the leader, yet it sounds like he’s mad at somebody for letting him down. He sounds bitter. And I find that hard to hear, because from my perspective, he grabbed the wheel, set the course. He’s the one that let us down. And while we haven’t heard about it directly, it specifically sounds to me like they had the idea that they could use some kind of big data technology [analytic firepower] and extract a basis for their RDoC – but somehow it just didn’t work out [speculation alert – see below].
  3. Reflection: However, in a few of his more recent comments, he’s also beginning to do some self-reflecting:
      • What could you have done differently to change that trajectory?
      We need better science. Just as we need that in cancer and heart disease and diabetes, we need to do that for mental illness. So we have to keep raising the bar, investing in science, getting the very best science done. When I first came into the job in 2002, one of the very first talks I gave I talked about the excitement of the science, and at that point, I was talking mostly about epigenetics [the study of how environments affect genes], which was just becoming a reality. And it seemed to me to be transformative and so exciting. It was such an innovation. And [then] someone in the audience said, “Excuse me, but our house is on fire, and you’re talking to me about the chemistry of the paint.” I never forgot that. And I think we have to be very honest with ourselves. That indeed the chemistry of the paint is important and very interesting and it will probably make sure it’s a better and safer house in 10 to 20 years. But we have to do something with the house that’s on fire as well. I worry that we didn’t do well enough on that score.
      • What would you have liked to have done at NIMH that you were not able to do?
      When I look at what I would say is my biggest failure, it’s that I don’t think that the investment we made with the money that we were given had an impact on the suicide rate, on the morbidity of any major mental illness. There are lots of explanations for why the rapid progress in science didn’t translate to much better outcomes for people with serious mental illness. I hear all that, but what keeps me up at night is knowing that the suicide rate is now higher than the mortality rate from breast cancer — I just find that extraordinary. That there are almost three times the number of suicides as homicides in this country — the homicide rate has come down by 50 percent and the suicide rate is trending up. That is, to me, unacceptable…
    The chemistry of paint story is poignant, but I have trouble believing Dr. Insel never forgot it. It seems to me that he ignored its essence throughout his tenure, even fought back against its lesson. So I’m cataloging that vignette under recent reflections accompanied by "the return of the repressed" or lamentations over the "road not taken."
I have no credentials to speculate about things that happened up there on Mount Olympus, but I’m going to anyway. There was nothing in these last 13 years that I know of happening in the research that justifies him saying "There are lots of explanations for why the rapid progress in science didn’t translate to much better outcomes for people with serious mental illness." They all say it [all being the NIMH, APA, and KOL brass] – over and over. I think they’re implying rapid progress was in their science, but what they really mean is science in general. The truth is that we have Translational Centers all over the place. Insel was even involved in setting them up. They’re all dressed up to translate, but in psychiatry, there hasn’t been anything much to translate.

Not long after Insel arrived, he announced his plan to rebrand Psychiatry as a Clinical Neuroscience Discipline. Illustrated with this slide:

Look at the Ordinate Axis [Y]. It’s Technology, specific new technologies. The APA was making the same bet in planning for their DSM-V [A Research Agenda for the DSM-5]. They [NIMH, APA, APF] jointly spent a ton of money on a long series of Symposia aiming to make the neuroscience/biological jump they’d been hoping for since the beginning [1980 – DSM-III]. As it became apparent they were going nowhere, the NIMH [AKA Insel] came up with the idea of revamping psychiatric diagnosis Research Domain Criteria [RDoC] – to revamp diagnosis along other than clinical lines. Nobody seems to know quite what it is, but it’s often mentioned as the coming thing. It’s actually not that hard to figure out. The plan is to assemble a great huge database of subjects and then use big data techniques to find correlations and clusters – then construct the RDoC based on the results. It has 100,000 subjects right now. It’s there to nose around in already, but you’ve got to be vetted to gain access.

But that’s all we know. Based on Insel’s comment above, "Five years ago, the NIMH launched a big project to transform diagnosis. But did we have the analytical firepower to do that? No. If anybody has it, companies like IBM, Apple or Google do – those kinds of high-powered tech engines…", I’m thinking the RDoC is not working out. They haven’t said that yet, but I’m willing to wager good money that’s where all this bitterness is coming from. They bet the ship on Genomics, Neuroimaging, Proteinomics, etc the first time around and it didn’t come through. Then they turned to the power of data search engines to find their bio-diagnoses for them. And one by one, the technologies they worshiped didn’t come through for them.

So Dr. Insel et al blame the technologies [or the version of those technologies they can access] for their inability to find what they’re sure must be there. But I wonder if they’ve considered the simpler possibility? that it’s not there to find in the first place, at least not there in anything close to the magnitude they  expected   predicted  wished for…

Occam’s razor, also known as Ockham’s razor, and sometimes expressed in Latin as lex parsimoniae [the law of parsimony, economy or succinctness], is a principle that generally recommends selecting from among competing hypotheses the one that makes the fewest new assumptions…
Mickey @ 2:52 PM

all aboard!…

Posted on Thursday 28 April 2016

All Aboard! As the ripples from the recently released suicide figures spread across the water, the usual suspects are being lined up to take the blame: not enough antidepressants, too many antidepressants, biomedical psychiatry, the American Psychiatric Association, the FDA’s Black Box Warning, Tom Insel’s NIMH, Managed Care, the Pharmaceutical Industry, Hospital Corporations, things like 911 or the Iraq War, the great recession, Republicans, Democrats, the NRA. And the non-psychiatric community who have been reimbursed to take over ongoing mental health care [along with their guilds] earned their right to be added to the list: Psychologists, Social Workers, LPCs, etc. Nobody gets off the hook here. There’s room on this train for every one of us. All Aboard!
by Kantor ED, Rehm CD, Haas JS, Chan AT, and Giovannucci EL
JAMA. 2015 314[17]:1818-1831.

hat tip to Justin Karter
and for review, the recent suicide statistics with equivalent abscissa scaling…
National Center for Health Statistics
Centers for Disease Control and Prevention
by Sally C. Curtin, Margaret Warner, and Holly Hedegaard
NCHS Data Brief No. 241, April 2016

It’s obvious that there’s no reason to hypothesize that there’s an antidepressant deficiency upon the land. And as for the APA President’s predictable [and irresponsible] quip:
"Now, the other thing that we were anticipating with some dread was the aftermath of the black box on antidepressants," says Oquendo, referring to a warning label that in 2004 the Food and Drug Administration required for commonly prescribed antidepressants. The label says that in people under age 26, the medications can actually increase the risk of suicidal thoughts and actions. Research has suggested that the warning scared doctors away from prescribing antidepressants to people of all ages. "And some of the increment in suicide deaths in the younger populations is potentially linked to an understandable reluctance by physicians who see these youngsters to prescribe antidepressants, even when they’re aware that the individual is suffering from depression," says Oquendo. Research has shown that the benefits of prescribing antidepressants to mentally ill children tend to outweigh the risk of suicidal tendencies…
All the Black Box Warning did was slow the acceleration of antidepressant use in kids, unlikely to have had the kind of impact shown, for example, in teenaged girls. The graph on the left is from Lu et al with the recent suicide figures on the right:
My takeaway from these suicide figures is that it’s a solid indictment of our entire mental health system, not of any particular element. The tragedy is that we actually know how to deliver the care at a much more effective level. We’ve known for a long time. But we’re too busy haggling with each other to do it…
Mickey @ 5:30 PM

off of my plate…

Posted on Wednesday 27 April 2016

When I read population statistics like the suicide figures in the last post [what’s missing…], I don’t exactly know what to do with them, what to take away that might help in my own work. Ned Shorter points us to one thing – the dramatic increases in suicides in teenaged girls [Teen Suicide: Parents Guard Your Daughters], likening it to the well known historical waves of peer suggestability in this demographic. I would only add that it elevates the newer teen identity "emo" to something bigger and more ominous than a fad. It’s an area often discounted as attention seeking, but it apparently needs more of our attention.

My own take was that the overall increased suicide rates says something about our mental health system, or perhaps I should say the dysfunctional state of our mental health system. I would think that independent of any of the other factors that may or may not be operative. We haven’t risen to the challenge. How many articles have you read lately about emergency psychiatric services? or systems? or programs? or suicidality? – not just in Psychiatric journals? but in Psychology? or Social Work? And whatever the term Managed Care means, those forces have jumped on the concept of Evidence Based Medicine and used it to restrict or deny services that are actually vital to any functional mental health system, public or private. In many [most?] cases, suicidality is subjective, deeply rooted in the unique circumstances and narrative of the individual. As such, the only valid control would be the individual him·or·her·self. Likewise, the only thing the mental health system can do about suicide rates has to do with the patients it actually sees and engages. So we can make services easily accessed and effective. And to be effective they must include what we know, not just what we can prove with objective Evidence Based Medicine. And we’re just not doing any of it.

When I read those stats, I immediately thought of something I read last Fall that I can’t shake. It was an "exit" interview Tom Insel gave when he left the NIMH:
Washington Post
By Lena H. Sun and Amy Ellis Nutt
October 8, 2015

What could you have done differently to change that trajectory?
    Insel: We need better science. Just as we need that in cancer and heart disease and diabetes, we need to do that for mental illness. So we have to keep raising the bar, investing in science, getting the very best science done. When I first came into the job in 2002, one of the very first talks I gave I talked about the excitement of the science, and at that point, I was talking mostly about epigenetics [the study of how environments affect genes], which was just becoming a reality. And it seemed to me to be transformative and so exciting. It was such an innovation. And [then] someone in the audience said, “Excuse me, but our house is on fire, and you’re talking to me about the chemistry of the paint.” I never forgot that. And I think we have to be very honest with ourselves. That indeed the chemistry of the paint is important and very interesting and it will probably make sure it’s a better and safer house in 10 to 20 years. But we have to do something with the house that’s on fire as well. I worry that we didn’t do well enough on that score.
What would you have liked to have done at NIMH that you were not able to do?
    Insel: When I look at what I would say is my biggest failure, it’s that I don’t think that the investment we made with the money that we were given had an impact on the suicide rate, on the morbidity of any major mental illness. There are lots of explanations for why the rapid progress in science didn’t translate to much better outcomes for people with serious mental illness. I hear all that, but what keeps me up at night is knowing that the suicide rate is now higher than the mortality rate from breast cancer — I just find that extraordinary. That there are almost three times the number of suicides as homicides in this country — the homicide rate has come down by 50 percent and the suicide rate is trending up. That is, to me, unacceptable…
Insel’s reign at the NIMH was the longest in its history. He never wavered in his monocular futuristic focus on the frontiers of neuroscience to the exclusion of all else during his thirteen years. Some 10 years into his tenure, he was apparently confronted about ignoring pressing needs for his dreams for the future, and here’s what he had to say along with my comments [the monocle…, 14 November 2012]:
Tom Insel wears a monocle that always sees the same thing – a future age of understanding of the neurobiological core of mental illness revealed through a series of new technologies responsive to biological interventions, and has relentlessly driven the NIMH towards that goal. He’s even spearheading the development of a new classification of mental phenomena based on the findings from these technologies – Research Domain Criteria [RDoC]. In a January blog post, he wrote of challenges to his monocular view:
    Balancing Immediate Needs with Future Innovation
    NIMH Director’s Blog
    By Thomas 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…
His answer was clear – monotonously clear:
    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. 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.
Tom Insel has created a National Institute of Clinical Neuroscience with a particular leaning towards psychopharmacological interventions. The focus is on the future discoveries that he feels are bound to come from his efforts. If there’s a model, it’s something like the Manhattan Project or DARPA, the great examples of research teams that created the Atomic Bomb, the Space Program, and the Internet – programs whose success needed a monocle to reach their goal, programs where they really did know where they were going and a lot about how to get there. What the National Institute of Mental Health is supposed to be is a funding agency that makes it possible for creative scientists with good ideas to explore them. That’s not what it is. It’s an agency with a one track mind, and that track is not perpetuated by huge successes. It’s sustained by the monocular view of Dr. Tom Insel and like-minded colleagues who have collectively been pointing us in the same direction for close to a generation without too much to show for it. I don’t personally feel so breathless, more in the range of tired and stuck. I find myself thinking we could use a pair of new glasses with two lenses looking at mental health research with less conviction that it has only one preordained direction and limited dimensions [AKA a rut]…
While it may seem a leap to jump from these disturbing suicide statistics to Dr. Insel’s NIMH, from my point of view, it’s seamless and obvious. His goal was to rebrand Psychiatry as a Clinical Neuroscience Discipline from the very start and he never wavered during his thirteen years. As our public programs all but disappeared, and clinical psychiatry degenerated into a drug delivery system with strong ties to commercial interests, he continued to press his exclusive agenda in collusion with the academic-industrial complex.  He only began to talk of the problems when the pharmaceutical industry took flight in 2012. It was more than just a missed opportunity to fund research into mental health care delivery, his single-mindedness sucked the life out of anything else.

So his lamentations in that interview are too little too late – infuriatingly late. He leaves us with his bizarre attempt to replace clinical diagnosis with whatever the RDoC is, a mental health system that has forgotten what it’s even for, and evidence all around of what has been ignored [as in those suicide statistics].


I really do want to say something about suicide and how that relates to psychiatry, but I guess I had to vent first to get it off of my plate…
Mickey @ 11:33 PM

what’s missing…

Posted on Monday 25 April 2016

New York Times
APRIL 22, 2016

Suicide in the United States has surged to the highest levels in nearly 30 years, a federal data analysis has found, with increases in every age group except older adults. The rise was particularly steep for women. It was also substantial among middle-aged Americans, sending a signal of deep anguish from a group whose suicide rates had been stable or falling since the 1950s.

The suicide rate for middle-aged women, ages 45 to 64, jumped by 63 percent over the period of the study, while it rose by 43 percent for men in that age range, the sharpest increase for males of any age. The overall suicide rate rose by 24 percent from 1999 to 2014, according to the National Center for Health Statistics, which released the study on Friday.

The increases were so widespread that they lifted the nation’s suicide rate to 13 per 100,000 people, the highest since 1986. The rate rose by 2 percent a year starting in 2006, double the annual rise in the earlier period of the study. In all, 42,773 people died from suicide in 2014, compared with 29,199 in 1999…
This slow steady rise across the board looks like a real change to me. Of course when you see something like this, the race is on to explain it, and there are plenty of possible suspects: the rise in prescription drug abuse; wealth inequity; modern society; an epidemic of Major Depressive Disorder [requiring more antidepressant use]; the suicidality associated with antidepressant use; too many guns; the high divorce rate; PTSD ridden soldiers; etc. You probably thought of a few yourself while you were reading that last sentence. There’s plenty to decry these days.

But you know what? A lot of those are psychosocial explanations [throwing in MDD was facetious anyway]. I’m not a bit surprised that the suicide rate has crept up in almost every domain during that time period. I’d say that it’s because it represents an era when we’ve turned our backs on the patients we’re charged to take care of. If a patient shows up in a psychiatris’ts office suicidal – they’re going to get medications. If a patient shows up in a psychologist’s or social worker’s office suicidal – they’re going to be referred for medications. If they go to or are taken to an ER, they’re going to get medication. And my point is not anti-medication here. They may indeed need medication. It’s that medication is all they’re going to get. The same is true if they get admitted somewhere. It will be to a stabilization unit which they’ll leave in several days on medications [a lot of medications] and that will be that.

The one thing we know for sure is that interpersonal isolation is a part of suicidality. Another thing we know is that suicidality is as ominous sign. And if you’re a mental health practitioner and reading this, you know that the thing a suicidal person needs is engagement, having a desperate need to be heard, even when they don’t want to talk. We don’t much offer any of those things these days. It’s something we used to call treatment. So I’d propose that those graphs might have something to do with the things listed above, but they’re also about what’s missing…
Mickey @ 3:52 PM

a real loss…

Posted on Sunday 24 April 2016

Janis Joplin - painting by Grace SlickGaining perspective on a history you lived through might be the hardest thing of all. How you saw it then and how it looks to you and to others now create a ciphered dreamscape not so easily parsed. Was Janis Joplin a symbol of freedom and liberation or an early slave to a coming opioid epidemic? When you’re passed on the highway by a roaring motorcycle cavalcade, is it the marauding Hell’s Angels or a bunch of Orthopedic Surgeons out for a weekend spin on their gajillion dollar Harleys? It’s the stuff in between, the story of the transition, that often holds the key to understanding. That’s certainly true in a psychotherapy that aims to find how some childhood situation morphs into a rigid maladaptive character trait that wreaks havoc with an adult life. There was such a transition in the world of psychopharmacology that I basically slept through [mid 1980s through the mid 2000s] and I’m still at trying to fill it in – it’s slow going.

I’ve known David Healy as an activist and coauthor, but I hadn’t fully appreciated that he’s quite the meticulous historian until I recently read his earlier books – the Antidepressant Era [1999], the The Creation of Psychopharmacology [2002], and Let them Eat Prozac [2006]. I knew where we were in the early 1980s; I’ve become fluent in where we had gotten to when I picked up the thread several decades later; but the transition? Not so much. So his books were enlightening and filled in some gaps [some snippets from The Creation of Psychopharmacology]:
Within a year of the introduction of chlorpromazine, a National Academy of Sciences grant led to a conference, chaired by Ralph Gerard and Jonathan Cole, aimed at establishing the appropriate evaluative methods for the new pharmacotherapies… There was a recognition that rating scales and randomized controlled trials were needed…[see Recommendations for reporting studies of psychiatric drugs]

… further funds were forthcoming from Congress — more than could be utilized by the center. In addition, following the success of chlorpromazine, pharmaceutical companies flooded the market with copycat drugs and approached investigators to test them. These events led Cole to set up in 1959 a clinical committee chaired by Henry Brill to assemble interested clinicians in order to standardize evaluative methods in clinical studies and to avoid duplication of research efforts." Brill recruited … to serve on a steering group for what became The Early Clinical Drug Evaluation Unit [ECDEU]. The unit’s task was to study the safety of new drugs, to find their appropriate dose ranges, and to look for appropriate clinical niches. It was hoped that federal funding would confer independence on the investigators.

One of the major undertakings of the ECDEU group was the development of standardized clinical trial protocols, agreed methods of coding information, and rating scales such as Hollister and John Overall’s Brief Psychiatric Raring Scale [BPRS]. The global assessment scales, which have been a mainstay of clinical trials ever since, were developed by ECDEU. In collaboration with the NIMH, a centralized computerized system [BLIPS] was set up to collate information. These efforts were aimed in part at controlling the potential excesses of the pharmaceutical industry. But there was also a hope that clinical trials could be channeled along development routes that would yield objective and reliable data that could benefit both clinicians and pharmaceutical companies.
By 1967, the Early Clinical Drug Evaluation Unit [ECDEU] offered a centralized service for Clinical Trials to NIMH grantholders. This offer was later extended to anyone who wanted to use it for any clinical trial. This is from the 1976 ECDEU Manual:
In collaboration with The George Washington University Biometric Laboratory, the ECDEU Standard Reporting System has been made available to any investigator interested in conducting clinical trials, whether federally grant supported or not. To utilize these services, the investigator is requested to:
  1. Submit a Research Plan Report and agree to send the study data to the Biometric Laboratory.
  2. Collect sufficient information about the subjects in his study so that the data can be entered into the ECDEU data bank. This means, essentially, that a core of data must be collected for each patient…
In return, he receives a sufficient number of assessment scales to conduct his research. Once the trial is completed, the forms are returned to the Biometric Laboratory for processing and data analyses, the results of which are sent to the investigator in the form of a standard data package. The rating scales and data processing services are provided at no charge – our sole "remuneration" being the opportunity to add the investigator’s data to the data bank. It should be stressed that an investigator’s data and/or results are never published or disseminated to others without his permission.
Now, back to Healy’s The Creation of Psychopharmacology. By 1980, the ECDEU had come to a premature end:
The operational criteria embodied in DSM-III were born into a world different from the one in which they were conceived. Richard Nixon’s election in 1968 might have led to a demise of disinterested research in any event, but the administration also faced a health budget that was burgeoning alarmingly. The Vietnam War had led to an economic crisis in 1968, aggravated several years later by the oil crisis. The government began to cut back on funding for the National institutes of Health. Sensing the change, Jonathan Cole left the Psychopharmacology Research Center [PRC] and returned to clinical practice. The NIMH research budget declined by $5 million from 1969 to 1976. Grants from ECDEU came to an end in 1975. By 1980 state funds for research had dried up. Independent clinical research was over, although since "science" at the NIMH was untouched few realized it…
In 1977, Jimmy Carter established a presidential commission on mental health. This recommended greater attention to the psychiatric needs of children and minorities, support for research and in particular for epidemiology, the development of a specific plan for treating the chronically mentally ill, and the establishment of methods for monitoring the performance of the mental health services. These initiatives were embodied in the Mental Health Systems Act, which was signed into law shortly before Carter left office. This Canute-like bill faced a strong adverse tide. Two months later, the new Reagan government recommended an interruption of all mental health grant programs in research and training. This Republican administration had come into office committed to lowering taxes, deregulation, decreasing federal control, and increasing the states’ authority. The new act was dismantled. Federal care and social security support for the chronically mentally ill went into a sharp decline, and the continuing increase in health care budgets provided the matrix for the birth of managed care…
This fills in some of the transitional period for me. Actually, it doesn’t sound like it was a much of a transition at all, but rather something more like a collapse. Was the marker for change the publication of the DSM-III in 1980? or maybe the coming of the neoKraepelinians? or perhaps the fall of the psychoanalysts? In reading this material, I’m finally beginning to understand something of a different truth revealed if you follow the money…
By the mid-1970s the ECDEU program was failing. Funds had dried up. Out of the ashes of ECDEU arose a superficially similar body, the New Clinical Drug Evaluation Unit [NECDEU], but one with a very different character. This was a marketplace where companies hired clinical investigators. Previously researchers had told industry what needed to be done, but now companies did not have to approach investigators to design their trials for them, compile the statistics, or write the papers. The formulas for clinical trials that the ECDEU investigators had put together to contain the pharmaceutical industry became a petard on which psychiatry was hoist. Armed with off-the-shelf protocols, companies sought out those researchers who were prepared to do the work that suited a commercial agenda. A process had begun that led to the analysis of trial results within the company and thereafter to the writing up of the results by company personnel. Senior clinical investigators now might be used as figureheads on papers or for presentations at academic meetings, but the clinical presence was increasingly becoming ornamental rather than substantial. They were merely figureheads for studies conducted by relatively untrained nonmedical personnel and in some cases the patients did not exist…
Is this really a story of the fall of a Camelot? a group of people who set out to do things right and had to watch it crumble for lack of funding – becoming collateral damage to some bigger picture in another story? Or like the two versions of Janis Joplin’s story, impossible to tease apart?. Certainly PHARMA was right there to capitalize on the situation. From here, the ECDEU sounds like the most sensible of systems, and a real loss…
Mickey @ 6:48 PM

i think not…

Posted on Friday 22 April 2016

Wikipedia: The Journal of Psychopharmacology is a monthly peer-reviewed scientific journal published by Sage Publications on behalf of the British Association for Psychopharmacology. It was established in 1987 and is a member of the Committee on Publication Ethics. The editors-in-chief are David Nutt [Imperial College London] and Pierre Blier [University of Ottawa]. The journal covers all aspects of psychopharmacology.

While it is possible that medicine actually needs the British Association of Psychopharmacology to issue guidelines about the off-label use of psychotropic agents in children and adolescents, it is at least equally possible that there’s another agenda driving this editorial in their Journal of Psychopharmacology

by Aditya N Sharma, Celso Arango, David Coghill, Paul Gringras, David J Nutt, Peter Pratt, Allan H Young, and Chris Hollis
Journal of Psychopharmacology. 2016, 30[5]:416 –421.

The off-label use of medicines for children and adolescents remains a common and important issue for prescribing practice across child and adolescent psychiatry, paediatrics and primary care. This editorial focusses on psychotropic drug treatment, which plays an essential part in the comprehensive management of a range of child and adolescent psychiatric disorders. Despite a growing evidence base for drug treatment in child and adolescent psychiatric disorders, much psychotropic medication continues to be prescribed off-label [i.e. outside the limits of the marketing authorisation or product license]. The reasons for and implications of off-label prescribing, including the potential clinical benefits/risks and medico-legal implications, are often poorly understood by both patients and prescribers. An important unintended consequence of the uncertainties and confusion surrounding the status of off-label prescribing for children and adolescents may be that effective drug treatments are being withheld or underused. This BAP Position Statement aims to clarify these issues, challenge some of the myths surrounding off-label prescribing for children and adolescents and offer practical guidance for prescribers.

Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Shaniui, Professor Gringnis, Mr Pratt, and Professor Hollis have no conflicts of interest.
Dr Arango has been a consultant to or has received honoraria or grants from Abbot, AMGEN, AstraZeneca, Bristol-Myers Squibb, Caja Navarra, CIBERSAM, Funddacion Alicia Koplowitz, Forum, Institutu de Salud Carlos III, Janssen Cilag, Lundbeck, Merck, Ministerio de Cicncia c Itmovacion, Ministerio de Sanidad, Ministerio de Economla y Competitividad, Muiua Madrikna, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough and Takeda.
Professor Coghill has been a consultant to or has received honoraria or grants from Novartis, Sandov, Shire, Eli Lilly, Vifor Pharma and Glaxo Smith Kline. He has also received royalties from Oxford University Press.
Professor Nutt has ownership or part ownership in Equasy Enterprises and Chaperon, with interests in the area of psychopharmacology. He has acted as a consultant for Lundbeck, Nalpharm, Shire, MSI arid Actelion. He has acted as an expert witness for Separator and received research grant income from Lundbeck. He has also accepted paid speaking engagements in industry supported symposia for Lundbeck, Otsuka, Lilly, RMS, Janssen, Glaxo Smith Kline, Pfizer, AstraZeneca, Pharma and Servier.
Professor Young has been a consultant to or has received honoraria or grants from AstraZeneca, Lundbeck, Eli Lilly, Janssen, Servier. Sunovion, Cyberonics and Wyeth.
And while it’s possible that we need a new nomenclature for psychotrophic drugs, it is at least equally possible that there’s another agenda driving this editorial in their Journal of Psychopharmacology. Be sure to watch the video [it may take a few tries]…
by David J Nutt and Pierre Blier
Journal of Psychopharmacology. 2016, Vol. 30[5]:413– 415.
WEB SITE: Watch Video

As of May 2016, the Journal of Psychopharmacology will fully adopt Neuroscience-based Nomenclature [NbN] for all publications and correspondence. In this, we join many other leading journals in our field, including European Neuropsychopharmacology, Biological Psychiatry, CNS Spectrums, European Psychiatry, International Journal of Neuropsychopharmacology, Journal of Clinical Psychopharmacology, Neuropsychopharmacology, Pharmacopsychiatry, World Journal of Biological Psychiatry and others that will also recommend the use of NbN. This decision has been ratified by the British Association for Psychopharmacology [BAP] council.

For the Journal of Psychopharmacology and the BAP, this step marks the output of a process that we have been involved in developing with the European College of Neuropsychopharmacology [ECNP]. Part of the impetus to this initiative came from an editorial in Journal of Psychopharmacology back in 2009. Most of the vital background data collecting and organisation of the knowledge base has been done by a BAP member, Dr Sue Wilson.

Under the leadership of the ECNP in 2008, a taskforce for psychotropic nomenclature composed of representatives from five international organisations: the ECNP, American College of Neuropsychopharmacology, Asian College of Neuropsychopharmacology, International College of Neuropsychopharmacology and International Union of Basic and Clinical Pharmacology. The group tasked itself ‘to examine ways of improving the current nomenclature in psychopharmacology’. Specifically, the new nomenclature was to [a] be based on contemporary scientific knowledge, [b] help clinicians to make informed choices when working out the next ‘pharmacological step’, [c] provide a system that does not conflict with the use of medications and [d] be future proof to accommodate new types of compounds. An initial proposal was discussed in the scientific community and accordingly revised. It is this revised system that Journal of Psychopharmacology will use…

That other agenda? Use more antipsychotics in treating children and adolescents. Use antipsychotics in depressed people. Is it the legitimate place of scientific organizations or their journals to lobby for particular treatments in clinical medicine? Perhaps a better way to phrase that would be "If scientific organizations and their journals lobby for particular treatments in clinical medicine, are they really scientific organizations and journals?

I think not…
Mickey @ 3:57 PM