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…
    Bernard Carroll
    April 30, 2016 | 4:02 PM

    Insel’s RDoC is a truly stupid idea. Does any other medical discipline have an RDoC – internal medicine? Or neurology? No. They still believe in clinical diagnoses, which Insel has abandoned. The right way to advance our nosology would be the iterative refinement of clinical diagnoses.

    The essential problem with RDoC is that it doesn’t have a handle on pathophysiology. So it throws together look-alike dysfunctions that have very different distal and sometimes even proximal mechanisms. In the RDoC search for dysfunctions that cut across diagnoses, it’s as if we were to place diabetes mellitus, anorexia nervosa, Cushing syndrome, hyperthyroidism, and pregnancy in a single diagnostic basin because they all can display impaired glucose tolerance.

    Allowing Insel and his lieutenants to carry off this travesty of top-down science management was a most unwise decision of the NIH. The damage will take years to undo because funding is now tied explicitly to the misbegotten RDoC matrix.

    May 2, 2016 | 7:24 AM

    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.

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