end of story..

Posted on Sunday 27 July 2014

The only "author’s response" I’ve ever seen where the author of a medical paper admitted culpability in response to criticism was when Dr. Gibbons, Dr. Kupfer, et al apologized for lying about COI after being exposed. And in that apology, they didn’t get around to apologizing to Dr. Carroll for their initial nastygram in response to his criticism of their paper [careful watching…]. So I’m not surprised that Dr. Lu et al [Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study] defended their recent attempt to malign the Black Box Warning on antidepressants in youth. They’ve mounted two responses to the outcry about that flawed paper – both of which are filled with marshmallows and have the substance of the Pillsbury Dough·Boy.

But to be honest, it doesn’t matter. Once an editor lets a paper like that slip through the cracks, the damage is done. No amount of criticism undoes the fact that the average expectable doctor reads the abstract and looks at the graphs – then moves on unless it’s an area of particular interest. There’s an enormous amount of stuff to keep up with and frankly, physicians have lives too. It’s only us die-hard hobby-vetters who pore over these articles and read the responses. That’s why the Editor/Peer Reviewer functions are so vital. Lu et al either slipped through or was ushered through the cracks. There’s just one paragraph I want to mention from their responses:
by Christine Y. Lu, Gregory Simon, and Stephen Soumerai
British Medical Journal. 2014 348:g3596.
by Gregory E Simon, Christine Lu, and Stephen Soumerai
British Medical Journal. 2014 348:g3596.

… Nevertheless, we must acknowledge that psychotropic poisoning is an imperfect proxy for suicide attempt and that use of this proxy measure might reduce the sensitivity of our methods. But this proxy measure is preferable to use of cause-of-injury codes in settings where use of those codes varies over time [precluding any valid time series analysis].
First, and most obvious, in a definitive Rapid Response [Re: Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study], the originators of that proxy roundly criticize Lu et al for using a bastard copy of their well studied complex proxy. But the paragraph above by Simon et al deserves an honorable mention for omitting its obvious conclusion. They say, "But this proxy measure is preferable to use of cause-of-injury codes in settings where use of those codes varies over time." The truth is that what would actually have been preferable would be for them to realize that since their database did not have accurate cause-of-injury codes, it was unsuitable to use in trying to address this question. Their commercial database doesn’t have the answer to the question asked in it – end of story.

They want us to argue with their pretty graphs:

I don’t care to enter that argument because I don’t accept that the graph is related to the question at hand – because it isn’t. Again, end of story. I was tempted to argue with their analysis after removing their imputed lines from the graph. I’m not convinced that a straight line isn’t a better fit than their fancy quadratic quaisi-experimental fitting, particularly if you remove the last data point [that creates something of an optical illusion]. But I realized that line of criticism is just my bias engaging their flawed study. As I said previously in our own eyes…:
If someone actually did a non-jury rigged study that said that the black box warning is wrong, I wouldn’t change a single thing in the way I personally do things. David Healy says why best when he talks about getting doctors to "doubt our own eyes." See Akathisia once, a dramatic change in personality and the aggression that comes with the drug, that then disappears when the drug is withdrawn, and you’re on alert. See it the second time and that’s enough for this old man. It might as well be an epidemic. And given the fact that I’m an infrequent prescriber, that I’ve seen it often enough makes it real for me. I would bet it’s even under-reported because the patients stop that drug and don’t go back to see that doctor. I’ve prescribed SSRIs to adolescents and young adults infrequently, and only when I’ve said my spiel and am comfortable that I and competent others can keep close tabs. I can’t imagine anything ever changing that. There have been some successes, some failures, and much indifference. So I’m glad the black box warning slowed down the accelerating rate of prescribing – even in an HMO. And what I’ve seen with my eyes trumps epidemiology on large datasets.
So I resisted the temptation to play dueling line fitting games. It’s a much sounder scientific point to say that their database had no place in trying to address the question.

And another thing. In the Author’s Response, they say:
There were clinically and statistically significant changes in antidepressant use [both marked slope and level changes that did not recover for 6 years] and psychotropic poisonings [sharp, immediate and sustained increases in slope] immediately after the warnings among young people. But, to be conservative, we calculated effect sizes only in the second year, even though they persisted for several years.
Only in their dreams! In my figure without their lines, it’s abundantly clear that if there’s a meaningful change in slope at all, it didn’t occur until three years after the Black Box Warning. Are they proposing that the press coverage has a three year waiting period? A further end of story
Mickey @ 1:13 PM
Filed under: politics
in their lifetimes…

Posted on Saturday 26 July 2014

Mendel's notesGregor Mendel was an Augustinian Monk in Moravia whose studies of plant inheritance brought such things into the realm of science. My sister’s blue eyes meant that both of our Gregor Mendel [1822-1884]brown-eyed parents carried recessive blue-eye genes. The postman was out of the picture. Mendel’s schemes of inheritance were like that – very precise statistical predictions based on dominant genes. Things stayed pretty clean through Watson and Crick’s images of the double helix DNA structure, even Nirenberg’s nucleotide code sequences. But then things got out of hand…

The Human GenomeThe Human Genome Project was completed in draft form in 2000, and declared finished in 2003. With that, they left most of us mere mortals in the dust with their volumes and volumes of books filled with Cs, As, Ts, and Gs running on towards the end of time. And so much for pea plants, eye color, dominance, etc. It starts with a gene being "a locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions, transcribed regions, and or other functional sequence regions" and complexifies geometrically from there.  We thought it would be easy, but that was just a dream some of us had [as a kid, I set out to count the stars too].

There are some 4000 single gene diseases known at this point – diseases that somewhat follow the Mendelian modes of inheritance [a big "somewhat"]. There are scores of conditions that have long been known to "run in families," but the precision of Mendal is nowhere in sight. The techniques for trying to bring them into focus involve comparing huge databases – vast cohort numbers each with endless nucleotide sequences. And as much as we lobby for Data Transparency in other areas, here we can use all the simplification we can muster. At least that’s true for me. I’m several steps beyond my level of competence just trying to figure out what they did, much less knowing if the results mean what the authors say they mean.
by the Schizophrenia Working Group of the Psychiatric Genomics Consortium
Nature. 2014 511:421–427.

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
The ordinate axis is probability with Genome Wide Significance [P < 5x10-8] represented by the red line. The abcsissa represents the physical chromosomes [1-22 & X]. The comparison is between 45,604 controls and 34,241 persons with Schizophrenia. The green spikes are the variations between those two groups that are statistically significant [it's a Log scale, so many are in the range of very significant].
Variations? Here’s how Dr. Insel describes what is being measured:
This genome wide association study revealed 108 different loci where variations were associated with schizophrenia; 83 of these had not been reported previously. Note, these are not “108 genes for schizophrenia.” These are areas of the genome where variations in sequence are associated with schizophrenia. Most of these are not in or even near genes. And any one of these 108 regions contributes only a tiny fraction of risk in the population…
How that is specifically determined is something we’d be glad to hear about in the comments if you know. These spikes are, as he says, not near genes but are in regions of the chromosomes that relate to brain structure, neuro-transmission, and immunity.

If my name were among the army of authors [302 total] on this study, I’d be proud too. They strengthened the case for a strong genetic loading in Schizophrenia [though most of us already accept that formulation]. Their large study contains variations found in previous studies [confirmation]. They’re intrigued by the regions being near areas already implicated in Schizophrenia research. And I expect the wheels are turning for the next steps based on these findings. Steven Hyman at the Stanley Institute is no doubt beside himself thinking about the coming $650 M from Mr. Stanley and Tom Insel is pretty excited too.

In my understanding of things, this is light years this side of finding a/the cause for Schizophrenia, much less a treatment. But it’s undoubtedly going in the right direction. To my way of thinking, it strengthens the case that there [are][is a] biological [causes][cause] to look for. But in terms of right now, it in no way dissuades me from the point of the last post. Those currently afflicted need our help and aren’t getting what they need. Not one of the chronic psychotic people alive right now is going to be helped by these findings, and they desperately need a lot more help than we’re giving them – in our lifetime – and in their lifetimes…

Mickey @ 2:13 PM
Filed under: politics
so are they…

Posted on Friday 25 July 2014

By Thomas Insel
July 22, 2014

It’s difficult to overstate the impact that genomic medicine is having on biomedical research and practice. For cancer diagnostics, rare disease therapeutics, and fields like microbiomics and infectious diseases, the advent of cheap, fast, precise genomic sequencing has been a game changer. What about mental disorders? There has been a lot of hype about genomics revolutionizing diagnosis or treatment of mental disorders, but is there any real hope that the kind of advances that have helped patients in the rest of medicine will help people with autism or schizophrenia or mood disorders?

The history of psychiatric genomics has been, until recently, disappointing. The search for candidate genes—such as those, like the serotonin transporter gene, suspected to be contributors to risk because of their role in medication response—led to many papers but few replications and no actionable findings. Unbiased scans of the whole genome were challenging because there is so much variation in the genome, most of which is unrelated to risk or resilience. To detect a signal from all of this background noise, one would need many thousands of samples. Over the past five years, as the field realized the need for larger numbers of samples, investigators from around the world have worked together to share results in the hope of attaining the statistical power needed to find variants associated with schizophrenia or autism. New findings demonstrate that sharing data does indeed lead to exciting results.

A report in Nature this week from the Psychiatric Genomics Consortium, a team of investigators in more than 80 institutions across 25 countries, looks at common variation (variation present in 10 percent of the general population) in nearly 37,000 cases of schizophrenia and over 113,000 controls. This genome wide association study revealed 108 different loci where variations were associated with schizophrenia; 83 of these had not been reported previously. Note, these are not “108 genes for schizophrenia.” These are areas of the genome where variations in sequence are associated with schizophrenia. Most of these are not in or even near genes. And any one of these 108 regions contributes only a tiny fraction of risk in the population. Nevertheless, this is a major step forward in describing the genetic risk for schizophrenia…
I would join Dr. Insel in acknowledging that whatever the Psychiatric Genomics Consortium is reporting in this recent Nature article is likely a step forward in genetic research, something important. I’ll probably even look into what that article actually reports. Maybe it will someday help us predict coming psychosis, and in some even more distant iteration become a part of doing something about it. But whatever its importance, there’s plenty of schizophrenia around that we don’t need any fancy new genetic tests to locate. It’s right there on the streets of just about any city in America. And some of the people we used to call patients are now occupying a growing space in our correctional facilities – labeled inmates. Neuroscience and genomics are important, but so are they.

It would be unfair to blame Dr. Insel’s NIMH for the deplorable state of the our care of the severely mentally ill in this country. But it’s not at all off base to expect him to mention their presence, to focus the NIMH on studying solutions, to lobby for them with the same energy and enthusiasm he puts into the B.R.A.I.N. initiative, or his Translational whatevers, or the unborn psychotic people. For the moment, his Clinical Neuroscience is more or less a hypothetical discipline except for a group of medications that have been around for six decades. And as Dr. Frances said in his blog mentioned in my last post [join the cry…]:
While we chase the receding holy grail of future basic science breakthrough, we are shamefully neglecting the needs of patients who are suffering right now. It is probably on average worse being a patient with severe mental illness in the US now than it was 150 years ago. It is certainly much worse being a patient with severe mental illness in the US as compared to most European countries. Access to community care and decent housing is deteriorating; hundreds of thousands of psychiatric patients are homeless or in prison…
I’ll have to admit that I lost all hope for Dr. Insel several years ago when I read this particular Director’s Blog post:
By Thomas Insel

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?”…
His conclusion was clear:
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 going to bother to summarize what he said in that post. I’ve already done that [the first Lemming…], but the point is that he blew them off. That’s what he always does. He presents both sides in such a way to give the impression that he’s being like Solomon, but he doesn’t cut the baby in half. He keeps it all for himself and his dreams and doesn’t change gears [the most recent example of that technique was in his Are Children Overmedicated?]. So long as Dr. Insel remains in his position, the NIMH will continue with its monocular focus on the narrow window of his neuroscience interests and many of our severely ill mental patients will continue to live in whatever dark spaces they can find…
Mickey @ 7:28 PM
Filed under: politics
join the cry…

Posted on Friday 25 July 2014

Chasing the genetics holy grail neglects current patient need
Psychology Today
by Allen J. Frances, M.D.
July 24, 2014

I am a great supporter of mental health research, but worry that it has lost its sense of proportion and is chasing the wrong priorities. The really glamorous stuff consumes almost all of the enormous NIMH budget and now has behind it the huge addition of a $650 million dollar private donation aimed at solving the genetics of mental illness. Neuroscience is an extremely easy sell to Congress and rich philanthropists because it promises so much – that we are on the brink of achieving fundamental breakthroughs in understanding how our genes and brains work [and sometimes don't work]. But such overpromising ignores the painful lessons of history. The neuroscience and genetic revolutions have been astounding in their technical virtuosity and fascinating in their findings- but to date have not helped a single patient. We have learned a great deal in basic science, but nothing at all that translates to better clinical care.


But there is a cruel paradox when it comes to mental disorders. While we chase the receding holy grail of future basic science breakthrough, we are shamefully neglecting the needs of patients who are suffering right now. It is probably on average worse being a patient with severe mental illness in the US now than it was 150 years ago. It is certainly much worse being a patient with severe mental illness in the US as compared to most European countries. Access to community care and decent housing is deteriorating; hundreds of thousands of psychiatric patients are homeless or in prison; there is little system in the mental health system; and almost all research is strictly biological.

I think the welcome infusion of $650 million dollars would have been much better spent to achieve current tangible results [by funding research and model programs to improve the dreary lives of our patients], rather than betting everything on the future long shot that big bucks can dramatically speed up what will doubtless be decades of painstaking and frustrating genetics research. The neglect of the severely mentally ill is a blight on our society that genetics research will not solve. Its OK to shoot for the stars, but not when we are failing in our day to day responsibility. Less glamour, more compassion.

more compassion.
As a young man in love with science, medicine was a perfect choice. All the sciences were represented: mathematics, chemistry, physics, engineering, social science, etc. It was a cornucopia that felt like it was just made for a dabbler like me – always something new, endless unanswered questions. I was pretty far along in things before it dawned on me really that medicine may have been a science playground, but what it really was had to do with taking care of sick people. While that may seem patently obvious, it was a realization that profoundly revised my subsequent directions. I never got over the joys of science, but it became a tool rather than an end unto itself.

When I read about the $ 650 M commitment to the Stanley Center [$650M gift to Broad seeks to propel psychiatric research], my reaction mirrored Dr. Frances’. I think he’s even more honest than I might have been when he says, "The neuroscience and genetic revolutions have been astounding in their technical virtuosity and fascinating in their findings- but to date have not helped a single patient. We have learned a great deal in basic science, but nothing at all that translates to better clinical care." I might have been too timid to put it quite that strongly, but I sure thought it as soon as I read it. It’s Mr. Stanley’s money and he can choose to do with it whatever he wants to do. He didn’t ask me or Dr. Frances. But if he had…

I guess people think that neuroscience research is like the Manhattan Project, or NASA, or DARPA. If we just throw money and talent at it, it will yield up its secrets. Those were projects where we knew where we were going and a lot about how to get there. The infusions of brainpower and treasure insured that the details would be ironed out and we sped towards the goal. Neuroscience research, particularly genetic neuroscience research, is a horse of a different color. It’s exploratory, a trip into the unknown. We don’t really even know the questions to ask or what we’d do with the answers if we had them. And with much mental illness, we don’t even know if the problems have anything to do with neuroscience, in spite of hearing little else for decades. With Steve Hyman in charge of the Stanley Center and Tom Insel in charge of the NIMH, regrettably, that’s not likely to change.

And this is no country for old men. We badly need more younger voices to join the cry…
Mickey @ 12:31 PM
Filed under: politics
miles to go…

Posted on Friday 25 July 2014

Back in February when I first read about Pradaxa® [how many examples?…, foot-in-mouth disease…], I couldn’t help but comment even though it had nothing to do with psychiatry. Without even reading the articles, just the basic premise was suspicious – that Boehringer Ingelheim had introduced a "blood thinner" [anticoagulant] that didn’t have to be monitored with blood tests. After a medical lifetime of monitering people on Warfarin with monthly clotting tests, I couldn’t figure how one could achieve the same results with a medication that didn’t have to be monitored. And when I actually read the articles, I still couldn’t. To me, Pradaxa® is a nightmare. It is an anticoagulant that, unlike Warfarin, can’t be reversed if a person has a bleeding episode. Having spent plenty of nights in a former career pumping patients full of Vitamin K to reverse dangerous bleeding, I wondered what one was to do when a person on Pradaxa® slarted bleeding. I had a vision of the little Dutch Boy trying to stop leaks in the Dyke and running out of fingers.

So why would I put someone on a medicine to prevent thromboembolism that cost 60 times as much and seemed pretty dangerous just for the convenience of skipping monthly blood tests? I wouldn’t. It’s that simple. And as fate would have it, within a few weeks of reading those articles, a friend with Atrial Fibrillation was put on the medication. I did my best to dissuade him, but his doctor carried the day recommending the convenience of Pradaxa®. To my relief, a cardioversion was successful in reversing his Atrial Fibrillation, and he was taken off of anticoagulants.
by Cohen D.
British Medical Journal. 2014; 349:g4670.

by Cohen D.
British Medical Journal. 2014; 349:g4747.

by Charlton B and Redberg R.
British Medical Journal. 2014; 349:g4681.

by Moore TJ, Cohen MR, and Mattison DR.
British Medical Journal. 2014; 349:g4517.
This weeks BMJ hit the ground running on the Pradaxa® story, and good for them. It’s is full of detailed articles documenting the whole mess. There’s plenty of blame to go around: NICE, the FDA, Boehringer Ingelheim, and all physicians involved – including the one that recommended it for my friend, a Habitat for Humanity crew chief who jumps in to do the jobs other volunteers don’t know how to do. I can just hear the phone call that he fell from a ladder [again]. Around that same time he was started on Pradaxa®, a cardiologist from the same practice frowned with disapproval when I declined his recommendation that I take a Statin for my until-recently-normal LDL [although I did get a laugh when I added "I don't need a Mammogram either"].
Mickey @ 10:29 AM
Filed under: politics
nostalgic after all…

Posted on Wednesday 23 July 2014

    He who knows syphilis knows medicine
    Sir William Osler, the Father of Modern Medicine
some of the research subjects

Some years back, I saw a play, Miss Evers’ Boys, about the Tuskegee syphilis study. In 1932. 600 black men were recruited into a Public Healtrh Service study that went on for forty years. In return for participating, they were given free medical care and burial insurance. The back story was that this was a study about the natural course of syphilis and 399 of these men had the disease, but weren’t told. They were only told they had the bad blood [a colloquialism with many meanings]. When penicillin came along in the 1940s, the definitive treatment for the disease, it was neither used nor discussed. The play centered on the study nurse, the Miss Evers of the play, who "saw after" the participants all those years knowing they weren’t being treated. The study was finally leaked in 1972, and the aftermath brought many changes in the safeguards for human experimentation [see Wikipedia's Tuskegee syphilis experiment].
By the end of the study in 1972, only 74 of the test subjects were alive. Of the original 399 men, 28 had died of syphilis, 100 were dead of related complications, 40 of their wives had been infected and 19 of their children were born with congenital syphilis.
It’s a story of epidemiology; of racism; and of the origin of Informed Consent and Institutional Review Boards. The entire 1997 HBO Movie of Miss Evers’ Boys is available on-line [1:57:59]…

Eunice Rivers (the real nurse)

Osler’s famous pronouncement came at the turn of the century [twentieth century] attesting to the many manifestations of syphilitic pathology. At the time, CNS Syphilis was the main disease found in the patients in our large mental hospitals. Osler was still quoted in the days of my Internal Medicine residency [for good reason]. Some snippets:
    [1964] I paid my room and board in early medical school by being the house manager for a medical fraternity house. That essentially entailed keeping up with the elderly black man who had actually run the place since the dawn of time. One day I returned from a lecture where I’d heard for the first time about Tabes Dorsalis [tertiary syphilis of the spine], and I noticed that his walk looked a lot like the film I’d seen in class that day. I asked him about it and he said he was just "getting old." I engaged an upper classman who went to the hospital and got his chart. Sure enough, he’d been treated with heavy metal injections as a young man [for bad blood], but nothing since. We escorted him to the neurology clinic where he was treated with Penicillin [and became a Grand Rounds case].
    [1967] The first patient I had as an Intern was an elderly man admitted after abruptly losing his voice. The next day, we got an emergency page and found him in extremis coughing up blood and he quickly arrested and died. That afternoon, his VDRL [lab test for syphilis] came back positive. At autopsy, he had a syphilitic aortic aneurism that had ruptured into his trachea. The hoarseness was from the compromised recurrent laryngeal nerve [that wraps under the aorta on its way to the vocal cord].
    [1973] When I was an Air Force Doctor overseas, an older civilian administrator was admitted with jaundice and delirium from liver failure. He had the physical findings of chronic cirrhosis though he was not a drinker. But he also had fever and signs of some acute process. He had a history of hepatitis in the South Pacific in World War II and we speculated he had Chronic Active Hepatitis. But then on the second hospital day, he developed a generalized rash, present on his hands and feet [a characteristic sign of secondary syphilis]. Scrapings of the rash revealed those little corkscrew Treponema pallidum organisms bending in the middle that I’d only seen in pictures [the organisms that cause Syphilis]. In spite of our starting him on a very low dose of penicillin, he had a Jarisch–Herxheimer reaction [toxicity from the sudden death of the organisms] requiring high doses of steroids. He had been infected by a dalliance with the wife of a ranking officer at a base in another European country [a delicate and touchy point]. He recovered nicely, but unfortunately we were right the first time. On a subsequent liver biopsy, he also had Chronic Active Hepatitis that had been complicated by the Syphilis infection.
So what’s with a Syphilis retrospective out of nowhere all of a sudden? I got to thinking about Miss Evers’ Boys and what Dr. Osler said after writing about Adolescent Depression [its origin…], about the Mild Neurocognitive Disorders [needs looking into…], about the Attenuated Psychosis Syndrome that was being considered for the DSM-5 – or the current front burner issue of the Statins. It’s all about prevention – preventing suicide, preventing Alzheimer’s, preventing psychosis, preventing heart attacks and strokes – in each case, requiring a precise baseline knowledge of the course of a disease, and identifying the early signs of coming trouble that may become irreversible.

William Osler was "the Father of Modern Medicine" in part because he exemplified the era of the grand clinician – physicians who spent their lives carefully mapping the signs and symptoms, the clinical course, the family and environmental histories of diseases. They collected detailed case histories extracting patterns that became syndromes, many of which still carry their names. Their treatment options were limited, but hard won advances informed by their clinical precision. As monstrous as it was to withhold the diagnosis in the Tuskegee Study early on, and even worse, to withhold treatment when it became available, the idea of gathering precise epidemiological data was consistent with the way medicine operated in the latter nineteenth and early twentieth century.

In our current era, there is a race to treatment based on small differences and speculation, both measured and hypothesized. Each evening, we expect our evening news to be accompanied by an announcement of some medical advance or breakthrough, punctuated by direct to consumer ads with their mumbled warnings. We’ve become used to questionnaires, rating scales, laboratory examinations, and loud whirring machines replacing the classic history and physical examinations of the past. My point here is not simply nostalgia for former days, it’s about the hurried pace with which we race into action, to treatment. The current Tamiflu debacle is an exempler. Billions have been spent on a medication to stave off a hypothesized global epidemic. Now it appears that that medication, while not inert, is hardly suited to the task. We’ve defined Mild Neurocognitive Disorder and the Attenuated Psychosis Syndrome without having a solid anchor that tells us that they are, indeed, the precursors we seek. We are subjected to recurrent studies that try to convince us to use SSRIs in teens with little evidence that they even treat adolescent depression itself, much less prevent anything, and with that come accusations of withholding treatment.

The Tuskegee Study is a genuine example of withholding treatment – epidemiology run amok. But the Black Box Warning with antidepressants in youth, the push-back against the current recommendations about Statins, the bruhaha about Tamiflu, and urging caution about diagnoses like Mild Neurocognitive Disorder, Attenuated Psychosis Syndrome, or Disruptive Mood Dysregulation Disorder may well be the wise voice of Dr. Osler’s generation cautioning us across time to beware of therapeutic zeal, to be careful with our epidemiology, and to be conservative with treatments until we’re sure of what we’re doing. Maybe I am nostalgic after all…
Mickey @ 6:37 PM
Filed under: politics
needs looking into…

Posted on Monday 21 July 2014

Emil Kraepelin           Alois Alzheimer          Auguste Deter

In 1907, Alois Alzheimer working in the lab of Emil Kraepelin, presented the brain findings on his patient, Auguste Deter, a woman who had died after developing dementia at age 51. Besides general brain shrinkage, there were characteristic microscopic findings: plagues in the extracellular spaces and neurons with neuro·fibrillary tangles in the cytoplasm.

Plaques were known from cases of senile dementia, but the tangles were felt to be a unique finding in pre·senile dementia. Kraepelin immortalized his colleague after Alzheimer’s untimely death by using his name in his classification. When I was a medical student, I was taught that the term Alzheimer’s Disease was reserved for the pre·senile cases, but in recent times, that distinction has fallen by the wayside – so Alzheimer’s Disease is a progressive dementia with characteristic brain findings.

There are a number of neurodegenerative diseases with distinguishing features listed in the DSM-5: Alzheimer’s disease, Frontotemporal lobar degeneration, Lewy body disease, Vascular disease, Traumatic brain injury, Substance/medication use, HIV infection, Prion disease, Parkinson’s disease, Huntington’s disease, Another medical condition, Multiple etiologies, Unspecified. In the case of Alzheimer’s, the diagnostic feature has formerly only be seen at autopsy, though there are apparently scans and other tests becoming available for antemortem diagnosis. There is a rare form that runs in families with a genetic marker and the findings are seen in the dementia that can develop with Down’s Syndrome. Since there’s no sure diagnosis in life, the DSM-5 provides probable and possible variants.

The DSM-5 added yet another distinction – a syndromatic diagnostic pair: Major Neurocognitive Disorder and Mild Neurocognitive Disorder. So now there are four possible Alzheimer’s diagnoses:
    Major Neurocognitive Disorder, probable Alzheimer’s Disease
    Major Neurocognitive Disorder, possible Alzheimer’s Disease
    Mild Neurocognitive Disorder, probable Alzheimer’s Disease
    Mild Neurocognitive Disorder, possible Alzheimer’s Disease

I’ll spare you the various criteria. They’re as you imagine – Alzheimer’s and Alzheimer’s lite. Dr. Frances focused on this new distinction in his critique of the DSM-5 and when it was approved, he wrote:
APA approval of DSM-5 is a sad day for psychiatry.
Psychology Today: DSM5 in Distress
by Allen Frances MD
December 2, 2012

This is the saddest moment in my 45 year career of studying, practicing, and teaching psychiatry. The Board of Trustees of the American Psychiatric Association has given its final approval to a deeply flawed DSM 5 containing many changes that seem clearly unsafe and scientifically unsound. My best advice to clinicians, to the press, and to the general public – be skeptical and don’t follow DSM 5 blindly down a road likely to lead to massive over-diagnosis and harmful over-medication. Just ignore the ten changes that make no sense…
I felt sad too. I was as surprised as Dr. Frances that they never really engaged his [or anyone else's] campaign. They had agendas and they pressed ahead no matter what came along until they were forced to drop some of their more bizarre diagnostic changes.
The motives of the people working on DSM 5 have often been questioned. They have been accused of having a financial conflict of interest because some have [minimal] drug company ties and also because so many of the DSM 5 changes will enhance Pharma profits by adding to our already existing societal overdose of carelessly prescribed psychiatric medicine. But I know the people working on DSM 5 and know this charge to be both unfair and untrue. Indeed, they have made some very bad decisions, but they did so with pure hearts and not because they wanted to help the drug companies. Their’s is an intellectual, not financial, conflict of interest that results from the natural tendency of highly specialized experts to over value their pet ideas, to want to expand their own areas of research interest, and to be oblivious to the distortions that occur in translating DSM 5 to real life clinical practice…
That last paragraph is the place where I disagreed with Dr. Frances some. I wasn’t convinced that he was right. I’m still not. I think he was correct that the DSM-5 wasn’t composed of a gang of sociopaths. But I personally think that there was real industry influence in places in the Task Force, and one of those places I’m most suspicious about is the one I’m writing about right now – Alzheimer’s Disease.It was number 3. on his please ignore list:
[3] The everyday forgetting characteristic of old age will now be misdiagnosed as Minor Neurocognitive Disorder, creating a huge false positive population of people who are not at special risk for dementia. Since there is no effective treatment for this ‘condition’ [or for dementia], the label provides absolutely no benefit [while creating great anxiety] even for those at true risk for later developing dementia. It is a dead loss for the many who will be mislabeled.
We agree that adding Minor Neurocognitive Disorder gave us nothing except diagnostic sprawl and makes little sense [but it's unfortunately beginning to make more sense now]. When Cosgrove and Krimsky released their COI article in the lead up to the DSM-5 being approved is when my nose started twitching. I graphed their findings then:
PLoS Medicine
by Lisa Cosgrove and Sheldon Krimsky
March 13, 2012

Back when I first read this, I got it that the two most compromised workgroups were Sleep and Neurocognitive Disorders, but when I went back and looked today at the actual graph in the study, the Neurocognitive Disorders were the most changed from the DSM-IV. It looked to me like somebody had stacked the deck this time around.
And when I went back and looked at my forest plot of the results of the DSM-5 Field Trials, there was something really not quite right about those Mild Neurocognitive Disorder results:
And here’s a snippet from their table [see footnote]:
I didn’t spend all that time looking back at these things for no reason. All of a sudden, Alzheimer’s is quite the rage these days, more on the financial front pages than in our journals [yet] – but it’s where the action is right now. I’m obviously concerned that adding Mild Neurocognitive Disorder was a pre-emptive strike aimed at expanding the market for some future treatments. If they get any of the drugs in development approved, no matter how weak the effect size, people with Mild Neurocognitive Disorder are going to be clammoring to take it, whether it’s approved for Alzheimer’s lite or not, whether it’s known if Alzheimer’s lite is a precursor of Alzheimer’s proper or not. And some of the strategies are going to be dangerous biologics [like monoclonal antibodies to beta-amyloid], and will likely cost a fortune. So I’ve run out of room in this post for much more than speculation, but I think some information on the R&D going on in this area will be coming soon. Don’t get me wrong, if they can find a real way to halt the progression of Alzheimer’s Disease, more power to them. But I’m wary that this is an area that’s vulnerable to exploitation, and this target population is among our most vulnerable [and exploited] already. So this is a topic that needs looking into…
Mickey @ 6:05 PM
Filed under: politics
one of the predators…

Posted on Monday 21 July 2014

New York Times
July 15, 2014
Healthcare Renewal
by Roy Poses
July 17, 2014

Dr Herbert Pardes was once one of the best paid CEOs of a US non-profit hospital system. A new New York Times article reported that the hospital system continued to pay him millions after his retirement… In 2009, we first discussed the compensation given to Dr Herbert Pardes, the CEO of New York – Presbyterian Healthcare System, which appeared to make him one of the best paid, if not the best paid non-profit hospital system CEO in the US. His total compensation for 2008 was $9.8 million, according to the NY Post. While his compensation was lower in 2007, approximately $5.1 million, 9 other executives made over $1 million, and the 10 together made over $26 million. This amount was approximately 20% of the system’s total surplus, and 1% of its total budget. The Times reported that since then, Dr Padres continued to do very well financially,
    Dr. Pardes’s compensation has consistently been among the highest of any New York hospital C.E.O. His compensation in 2011, his last year as chief executive, was $4.1 million, including base pay of $1.7 million and a bonus of $1.8 million.
According to the Times, after Dr Pardes retired in 2011,
    The next year, Dr. Pardes earned $5.6 million, which included $1 million in base salary, a $1.8 million bonus for his final year as chief executive and more than $2 million in deferred compensation, according to hospital tax records. That exceeded the amount earned by Dr. Pardes’s successor, Dr. Steven Corwin, who made $3.6 million that year. Three years after retirement, Dr. Pardes is still employed by the hospital as the executive vice chairman of its board of trustees, a position that compensation experts say is rare in the nonprofit world,…
So the year after Dr Pardes retired, he made as much from what most people might have thought was his former employer as he did in 2007 as CEO, when he was one of the best paid non-profit CEOs in the country, and more than he made in 2011, the year of his retirement…
Herb Pardes From Wikipedia

Herbert Pardes [born c. 1932] is an American physician, psychiatrist, and the Executive Vice Chairman of NewYork–Presbyterian Hospital. He was previously president of Presbyterian Hospital; a few years after its merger with New York Hospital he became CEO of the combined entity, which was named NewYork–Presbyterian Hospital. He is a national figure in psychiatry and academic medicine. Prior to his retirement at New York Presbyterian, Pardes in 2008 was receiving compensation in excess of nine million dollars annually while CEO at the hospital along with other benefits.

Education and career
Dr. Pardes received his Bachelor of Science degree summa cum laude from Rutgers University in 1956 and his medical degree from the State University of New York-Downstate Medical Center in Brooklyn in 1960. From 1978 to 1984, he was director of the National Institute of Mental Health [NIMH], where he strengthened the Institute’s research program and emphasized the need to increase research support for psychiatry. From 1989 he was president of American Psychiatric Association [APA]. He is a former Dean of the Columbia University College of Physicians and Surgeons. Before becoming dean, Pardes was chair of Columbia’s Department of Psychiatry, where he remains a professor…
I don’t know Dr. Pardes or much about his contributions to medicine/psychiatry, except that he’s held all the prestigious positions there are to hold over the course of his career. And I don’t have much to say about the NewYork–Presbyterian Hospital being willing to pay him those absurd amounts of money. He may be a great fund-raiser and/or administrator, but what they’re buying is at least in part, his prestige. My only comment is about his willingness to accept that kind of compensation.

In his commentary about the New York Times article, Dr. Poses goes through the various rationalizations for Pardes being paid that obscene amount of money. They’re in his blog post. I want to skip all of that. That money has to come from somewhere and the only possibility is the pockets of the patients or their insurance carriers. Oh by the way, NewYork–Presbyterian is a not-for-profit hospital system. By accepting that salary, he’s making the statement that medicine is a business first and foremost, part of the system we now have that contributes to the wealth inequity in our country, that contributes to the ridiculous rising cost of healthcare, that contributes to the feeding frenzy of the hospital corporations, the pharmaceutical and medical equipment industries, and the insurance/managed care goliaths.

Independent of his contributions and/or prestige, he took the same oath I did at the end of medical school, Primum non nocere – "First, Do no harm." By accepting that amount of compensation, he plants himself firmly among those forces that are skies-and-away the most harmful elements in healthcare today. He’s become one of the predators [just like the KOLs we talk about] – a "bought doctor." It makes perfect sense that I read about this in a blog called Healthcare Renewal
Mickey @ 6:00 AM
Filed under: politics
our own eyes…

Posted on Sunday 20 July 2014

In the first post about the Lu et al study, I mentioned the CDC 1979-2007 suicide data [see a madness to our method…]. But in its origin…, my post had a broken link to the CDC YRBS [Youth Risk Behavior Study] in the Rapid Response by Barber et al. That was an unfortunate omission as it’s a center ring piece of information. First, here’s the CDC Suicide data [1979-2007]:
Here’s my graphing of the YRBS data [1991-2011]:
The Youth Risk Behavior Surveillance System [YRBSS] was  actually new for me. It’s an every other year survey querying dangerous behaviors in kids 16-19. It looks pretty solid to me and I was glad to find it. Take a look. It certainly doesn’t confirm the findings of Lu et al [in fact, most things don't].

I honestly don’t believe that the black box warnings lead to an increase in either suicides or suicide attempts based on scientific grounds, some of which are shown here. But that’s not what fuels my writing about this. What keeps me writing is what I do believe, not what I don’t believe. I’ve seen two completed suicides from SSRIs that I’m sure about. Thankfully, neither was a patient of mine, but I was privy to enough information to be unquestioning about what happened. I may fill this blog with graphs and population statistics, but as a clinician, I’m a one-person-at-a-time doctor. And people like me are at a loss because I can’t or won’t report why I can say that with such conviction. I also believe in Akathisia of the kind that’s described in patient reports, books, on RxISK, in blogs etc. I believe it because I’ve seen it personally in its very loud forms. I can’t or won’t report the stories that lead to that conviction either, so I can only say that I have no doubts. I think the black box warning is correct – the truth:


If someone actually did a non-jury rigged study that said that the black box warning is wrong, I wouldn’t change a single thing in the way I personally do things. David Healy says why best when he talks about getting doctors to "doubt our own eyes." See Akathisia once, a dramatic change in personality and the aggression that comes with the drug, that then disappears when the drug is withdrawn, and you’re on alert. See it the second time and that’s enough for this old man. It might as well be an epidemic. And given the fact that I’m an infrequent prescriber, that I’ve seen it often enough makes it real for me. I would bet it’s even under-reported because the patients stop that drug and don’t go back to see that doctor. I’ve prescribed SSRIs to adolescents and young adults infrequently, and only when I’ve said my spiel and am comfortable that I and competent others can keep close tabs. I can’t imagine anything ever changing that. There have been some successes, some failures, and much indifference. So I’m glad the black box warning slowed down the accelerating rate of prescribing – even in an HMO. And what I’ve seen with my eyes trumps epidemiology on large datasets.
Mickey @ 10:27 PM
Filed under: politics
retire the side…

Posted on Sunday 20 July 2014

I will admit that it’s hard for me to write about this particular recurrent topic without sarcasm [I'll give it a shot, but will likely fail]. The topic is an NIMH Study called EMBARC [Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression] being conducted by Madhukar Trivedi [NIMH Project Number: 1U01MH092221-01] [ClinicalTrials.gov Identifier: NCT01407094]. This is part of a series of studies that date back to the TMAP program in the 1990s:
TMAP [Texas Medical Algorithm Project] was a program that began a push to medicate by algorithm. It was used by industry to get public funded systems to use in-patent medications rather than generics of equal effectiveness – and died a painful death when exposed by whistle-blower Allen Jones. But the idea of creating algorithms for treatment lived on in STAR*D with TMAP veterans John Rush and Madhukar Trivedi from UT Southwestern in charge. It was a complex scheme that had algorithms for sequencing antidepressants in an attempt to enhance the effectiveness of medicating depression. It was a $35 M NIMH project that generated hundreds of papers [now largely forgotten for good reason] and uninterpretable results. Dr. Trivedi had an NIMH Project of his own, supplying a computer program for clinicians to use picking treatments [IMPACTS], but that study was never completed because the clinicians wouldn’t use the computers [cost $2.7 M]. Failing at sequencing and computerizing, their next NIMH funded study tried various combinations of antidepressants [CO-MED]. It was a negative study.

In the first decade of this century, there was a preoccupation with the idea that more efficacy could be extracted from these antidepressants. By the end of the decade, sequencing, augmenting, and combining had each failed to produce the dreamed of enhancement, and so for a time, researchers had a love affair with "personalized medicine" – coming up with some test that would predict response to one or the other antidepressants. It would seem like sequencing and combining would’ve answered that question, but apparently not. At the time, it was thought that genotyping would be the key [but anything would've done]. The Australian Brain Trainer, Evian Gordon, gathered one group of KOLs and began the iSPOT study. And Dr. Trevidi was funded for an NIMH study, EMBARC, to look for biomarkers that predicted drug response. His study started with Placebo, Citalopram [Celexa®], and Bupropion XL [Welbutrin XL®], but the Citalopram was replaced for unknown reasons with Sertraline [Zoloft®] not long after the study began. It was funded from September 30, 2010 through June 30, 2014. The NIMH web site has the following data available for funds allotted:

That comes to $9,199,613 so far. The overall cost to the NIMH for the four funded studies in the figure above [STAR*D, IMPACTS, CO-MED, and EMBARC] exceeds $50 M. Some time back, I had added a note to my calendar that EMBARC ended on June 30, 2014. My prediction was that it would not be completed – based on Dr. Trivedi’s poor track record and my own conviction that it wouldn’t show anything of any value just based on reading the protocol. While that cynical prediction remains an open question, the study should now be completed and yet it is still listed as "recruiting."

I doubt seriously that there’s anyone on the planet waiting to have a biomarker test to decide between Zoloft® and Welbutrin XL® for a depressed patient, particularly with a ~$10 M price-tag. TMAP was a scam; STAR*D was a bust; IMPACTS never even got off the ground. CO-MED flat-lined. Can EMBARC live up to that record? [I warned you I couldn't contain the sarcasm]. It’s stories like this that account for my negativity about Dr. Insel’s NIMH. These people have been funded for a series of ill-conceived, badly designed, and poorly executed studies one after another for a decade and a half to the tune of $50 M. There’s just no need for that. STAR*D produced hundreds of forgettable papers, but never even really reported on what the study proposed to find out. Insel’s NIMH famously selects the directions for research rather than selecting from among the creativity of researchers own proposals. They chase things like personalized medicine, algorithmic medicine, measurement based medicine, translational medicine, RDoC, etc. – fads that come and goand genomics, proteonomics, neuroimaging, connectomics – shiny objects that have appeared in view. And the same people get funded over and over, like the examples mentioned above, independent of their track records.

These attempts to turn clinical psychiatry into algorithms for medications driven by symptoms, often gathered by questionnaires, have yielded nothing. Worse, they trivialize both the human experience of patients and the practitioners’ efforts to help them. Let’s hope that the chart up there has finally run out of iterations and we can retire the side…
Mickey @ 8:00 AM
Filed under: politics