1 Boring Old Man

Insel Looks to Transformation of Diagnostics, Therapeutics

"From Psychiatry to Clinical Neuroscience"

PsychiatricNews

by Mark Moran

June 17, 2014

NIMH Director Thomas Insel, M.D., says that more people are getting more treatment, but outcomes are not getting better, so many of today’s treatments may not be sufficient to “bend the curve.” The field of psychiatry and neuroscience is haunted by four “inconvenient truths” about the diagnosis and treatment of mental illness, said National Institute of Mental Health (NIMH) Director Thomas Insel, M.D., in a lecture titled “From Psychiatry to Clinical Neuroscience” at APA’s 2014 annual meeting in New York in May. These are his four inconvenient truths: the field has failed to “bend the curve” in the prevalence and cost of mental illness; more people are getting more treatment, but outcomes are not getting better; the current knowledge base is insufficient to ensure prevention, recovery, or cure for too many people with serious mental illness; and a transformation of diagnostics and therapeutics is necessary to make significant progress in treating mental illness.

Insel contrasted the remarkable progress of the last several decades in reducing morbidity and mortality associated with major medical conditions such as stroke, heart disease, pediatric cancers, and AIDS with the stubbornly high rates for mental illness. He noted, as an example, that the suicide rate in the United States is as high as it has ever been. “I can’t tell you a success story as I can for pediatric cancer or AIDS when we talk about suicide,” he said. “It’s rather remarkable that over the last two decades the suicide rate hasn’t budged at all. With about 38,000 suicides a year, we are as high in absolute numbers as we have ever been.”

Knowledge of the brain, despite enormous advances in recent years, is still in its infancy, Insel pointed out. “The brain is a world consisting of a number of unexplored continents and great stretches of unknown territory,” he said.But he also described a promising future in which mental illness is reenvisioned as a disorder of brain circuitry that will be greatly advanced by President Obama’s BRAIN Initiative, announced in April 2013. Research is revealing how chemical imbalances can lead to circuit dysfunction, and in turn to behavioral symptoms, and Insel said the connections that are emerging can be used in the development of diagnostic tests for brain disorders that are today diagnosed late through observation of symptoms. “We can now study the mind with the tools of neuroscience,” he said. For instance, he presented evidence that is revealing attention-deficit/hyperactivity disorder to be a disorder of delayed cortical maturation. He also presented evidence of schizophrenia as a neurodevelopmental disorder with distinct risk and prodromal stages that allow for early intervention.

Finally, he described the NIMH Research Domain Criteria (RDoC) project, which he said will work in tandem with DSM. “DSM/ICD will continue to be the basis of clinical care,” he said. “RDoC is a framework for research in which NIMH will support researchers to deconstruct current diagnostic categories or identify dimensions that extend across categories. RDoC will develop through an information commons that integrates data from many sources, transforming the way we diagnose mental disorders in the future.”

National Institute of Mental Health Clinical Trials

New Opportunities, New Expectations

by Thomas R. Insel,MD and Nitin Gogtay,MD

JAMA Psychiatry. 2014 71[7]:745-746.

There can be little question that we need better treatments for mental disorders. The recent Global Burden of Disease Study demonstrates how neuropsychiatric disorders are a leading source of medical disability in the United States, increasing since 1990 despite a concomitant increase in pharmacologic treatments. Although there have been many commercially successful medications for anxiety, depression, and psychosis, few compounds have shown truly new mechanisms of action, and even fewer represent true breakthroughs in efficacy. For many of our most serious clinical challenges, such as anorexia nervosa, posttraumatic stress disorder, the core symptoms of autism, and the cognitive deficits of schizophrenia, to name a few, we lack effective medications altogether.

With this background, in 2010, the NIMH asked its advisory council for guidance on the best way to address the urgent need for new treatments. The National Advisory Mental Health Council’s report, “From Discovery to Cure,” recommended several changes to the NIMH clinical trials portfolio. Among those recommendations was a call to accelerate the development process, moving quickly into humans for proof-of-concept studies, and a request for trials that identify and validate new targets. From these recommendations, the NIMH has developed a focus on experimental therapeutics, in which interventions are used as probes of disease mechanisms, as well as tests of efficacy.

In February of this year, the NIMH released 4 new funding announcements to transform its investments in clinical trials. These new announcements can be summarized as calling for changes in “what” and “how” trials are conducted. What are we looking for in these new announcements? Each of the 4 covers a different phase or area of clinical investigation, but they all share a focus on learning more about the disorders, as well as the mechanisms of intervention. Each requires a demonstration of target engagement, in addition to assessing changes in symptoms. And each seeks to identify a critical dose and duration of intervention that would engage or modulate the target in addition to assessing symptom change, with a goal of informing further research or treatment strategies.

These changes are the result of the changing ecosystem of treatment development, the advent of new tools to look at mechanisms of change, and the advice of experts both within and outside of our field. They are also a response to many patient advocates who remind us that “time matters.” The current timetable for a clinical trial, which spans nearly a decade from proposal to publication, is not acceptable to families with a child with autism or an adolescent with psychosis. However, in addition to fixing the delay, these families need to know that we are doing everything possible to deliver treatments that are better than what is available today. New treatments will require a deeper understanding of the disorders and a new approach based on experimental therapeutics for pharmacological, psychosocial, and neuromodulatory interventions.

I first became aware that PHARMA was giving up on CNS drug development three years ago when Dr. Stahl let loose with a rant of cosmic proportions [myopia – uncorrected…]. Within a month, the DSM-5 Task Force admitted their planned "biological" DSM-5 wasn’t going to fly, the RDoC from the NIMH was brought to the fore, and Dr. Insel began to talk about brain wiring [class action in the air…] initiating any number of schemes to jump·start CNS drug discovery – all the while whining endlessly about the inadequacy of our current drugs. The timetable for his Clinical Neuroscience seems to have been abandoned around then, though the term is never far from his lips.

I’m so regularly moved to criticize everything he writes that I’m even tired of readng myself. So I thought that, for a change, I would take a moment and consider why I’m so negative whenever I read something from him. The first thing that was immediately apparent – he doesn’t stop and think himself. He doesn’t sit under a tree and consider the fact that the NIMH has been in a constant state of flux, mostly at his beckoning, and has essentially gone nowhere for years [his years]. He’s always coming up with new plans, programs, initiatives and they just flow from one to the other with little to show for the effort. My overused heroic graphic is borrowed from an old Russian Red Army poster, but when I first made it, I was looking for something else I couldn’t find – a picture I remember of Jeb Stuart from our Civil War. At least in popular lore, Stuart and his Cavalry were out racing pell-mell through the country-side with adrenaline flowing and the wind blowing in their hair, forgetting their assigned mission [intelligence], contributing to Lee’s loss at Gettysburg. That’s how I see Dr. Insel – bouncing from experimental medicine to translational science to personalized medicine to connectomes  to whatever-the-RDoC-is to experimental therapeutics without taking a long enough breath to take stock of the state of play.

I suppose another thing is that he seems to think he knows where we’re going and is frustrated that he can’t make us get there with his incentives [like in this JAMA Psychiatry opinion piece]. It’s easy to say all kinds of negative things about the pharmaceutical companies and their disreputable marketing ways, but they also happen to represent a massive, well financed, scientific consortium. They haven’t been able to find what they [and Dr. Insel] are looking for in decades – and they were looking plenty hard. CNS-anythings were selling like hot-cakes and they would have been as pleased as punch to find new targets and new animal models instead of watching those tired rodents floating in beakers eking out me-too antidepressants. PHARMA gave it their all and came up mostly empty handed. What makes Tom Insel think that he can beat their record by taking over their failed quest with his pea-shooter budget?

Were Dr. Insel able to transcend his fixation on Clinical Neuroscience and the as-yet-unfound-novel-breakthroughs-around-the-corner he’s chasing, and could sit quietly under the Bodhi tree beside the river, what faint music might he hear building in the stillness as he mused on his koans? "Why are the people who so embraced the DSM-III so turned off by its current incarnation? or his RDoC proxy?" "Why is there so much negativity about the drugs that were cheered as they flowed from the pipeline not so very long ago?" "Why have so many gurus of the past faded into obscurity, or retirement [or exile in Miami]?"

That music might just say to him that these are the signs and symptoms of Thomas Kuhn’s phase of paradigm exhaustion, a time when something once new and filled with such hope and explanatory power has all its warts showing in bas relief, a time when it’s hard to even recall the former glitter or even that there was such a golden time. All that shows are the exceptions and failings of the now tired paradigm. And the aging former messiahs seem like old men clinging to a dream past its time. What’s supposed to happen is that the passing era gets reconstructed through a more realistic set of lens than the the rose colored glasses that came with the passion of new discovery. But what’s supposed to happen rarely does happen. The proponents try to keep the dream alive, and in the process add a dark patina that increases and prolongs the depth of the period of disillusionment.