NIH Director’s Blogby Dr. Francis CollinsFebruary 4, 2014
It would seem like there’s never been a better time for drug development. Recent advances in genomics, proteomics, imaging, and other technologies have led to the discovery of more than a thousand risk factors for common diseases—biological changes that ought to hold promise as targets for drugs…
There are some other stock phrases that come to mind: unmet·clinical·need and global·burden·of·disease. Both of these are used routinely in reports of clinical trials or in pleas for more research funding for some particular project. The latter was almost guaranteed to be in the introduction to the ghost written clinical trial reports that were so popular during the last several decades, the age of psychopharmacology. And unmet·clinical·need is all purpose – can either go in an article to introduce a new drug that’s being hawked as an advance or later when discussing how that last drug wasn’t really very good and we need to find a new one [it’s actually hard to think of a medical situation or grant proposal where you couldn’t throw in an unmet·clinical·need].
Scienceby Steven HymanMarch 14, 2014
Last month, the battle against four major diseases received some good news. The U.S. National Institutes of Health [NIH] and 10 of the world’s largest pharmaceutical companies decided that instead of working ineffectively in silos, they would work together to discover therapies for Alzheimer’s disease, type 2 diabetes, rheumatoid arthritis, and lupus. This initiative — the Accelerating Medicines Partnership [AMP] — recognizes that progress toward new therapies for common chronic diseases increasingly requires large-scale collaborative efforts that range from the need to grapple with heterogeneous polygenic disease phenotypes to the validation of biomarkers in large populations. What is disappointing is that, at least for the time being, the consortium dropped schizophrenia from its list, despite vast unmet medical need and substantial, albeit still recent, scientific advances. Was schizophrenia deemed too risky to pursue? If innovative partnerships such as the AMP are not willing to take on common and serious but otherwise neglected disorders such as schizophrenia, then the scientific community will have to find new ways of pooling intellectual and financial resources to address them…
Schizophrenia is a severe and disabling brain disorder that also creates enormous costs and challenges for caregivers and for society. Antipsychotic drugs that partially treat hallucinations and delusions were discovered in the early 1950s but have serious side effects and leave entirely untreated schizophrenia’s characteristic cognitive impairments and “negative” symptoms such as blunting of emotion, loss of motivation, and impoverishment of thought and speech. The past six decades have witnessed many commercially successful antipsychotic drugs, but no new mechanisms of action and no gains in efficacy since the early 1960s. Cognitive behavioral therapies show promise, but even when combined with current medications, individuals with schizophrenia live with profound limitations resulting from diminished control over thought, emotion, and behavior. Many pharmaceutical companies have exited psychiatry in recent years because of high failure rates in clinical trials, only rudimentary understanding of disease mechanisms, and the lack of treatment biomarkers. Under these circumstances, patients and families would have scant hope for the arrival of better drug treatments….
Much about this grim scientific picture has changed in the past 5 years. New genomic technologies, combined with global collaborations to identify study participants and collect samples, have permitted the identification of a large and rapidly growing number of alleles associated with schizophrenia, bipolar disorder, and autism. Molecular pathways involved in neuronal function are emerging from the data and are beginning to suggest drug targets. Animal and in vitro models in which to investigate hundreds of gene variants of small effect remain works in progress. However, promising tools have emerged here too. For molecular and cellular analyses, stem cell technologies make possible the generation of human neurons in vitro. When combined with remarkable new genome engineering tools, these approaches permit the study of individual risk alleles, multiple alleles in molecular pathways, and the correction of risk alleles in neurons derived from patient samples. Studies at neural circuit levels are yet more challenging, but one can even envision transgenic nonhuman primate disease models with the genome engineering tools at hand. Proposals to the AMP have focused on advancing the genetic analysis of schizophrenia; improving in vitro human neuronal models to study disease-associated alleles; and a project to identify biomarkers, modeled on the early stages of the successful Alzheimer’s Disease Neuroimaging Initiative.
Perhaps recent exits by companies from psychiatry made schizophrenia too great a reach for the AMP, despite continued strong support from NIH leadership. It is precisely when new knowledge opens challenging but real possibilities to make major advances in health that partnerships such as the AMP seem most warranted. The scientific community, including industry, academia, patient groups, and government, must find ways of sharing financial risk while developing effective and well-governed partnerships. Otherwise, important basic science investments will go untranslated while patients and society continue to bear painful and costly burdens.
by Hyman SE.Science Translational Medicine. 2012 4[155]:155.
Drug discovery is at a near standstill for treating psychiatric disorders such as schizophrenia, bipolar disorder, depression, and common forms of autism. Despite high prevalence and unmet medical need, major pharmaceutical companies are de-emphasizing or exiting psychiatry, thus removing significant capacity from efforts to discover new medicines. In this Commentary, I develop a view of what has gone wrong scientifically and ask what can be done to address this parlous situation…
The Dana Foundation: CerebrumBy Steven E. HymanApril 02, 2013[see whither the crisis…]
PsychiatricNewsFrom the Presidentby Steven Hyman, M.D. and Jeffrey Lieberman, M.D.October 17, 2013[see the monotony…]
by Steven E. HymanNeuropsychopharmacology Reviews. 2014 39:220–229.[see hope and hype…]
the·revolution: A lot of meanings here. One is the burst of discovery in the 1950s of medications that were effective in psychiatric conditions [lithium, antipsychotics, antidepressants, anxiolytics]. Another revolution was the coming of the neoKraepelinians and Robert Spitzer’s DSM-III in 1980. I think by the time Hyman arrived at the NINH, he might think of his tenure there as a revolution of sorts. By then, multiple classes of psychoactive drugs were flowing from the pharmaceutical pipeline at a steady rate. It was the decade of the brain, and the NIMH was front and center. Acadedemia and industry were collaborating [above and below the table]. And Hyman’s NIMH set out on a bold path to test the emerging drugs in mega clinical trials. During those years, the human genome project was completed and psychiatric genomics was becoming quite the rage. There was a feeling that the biological basis of psychiatry was just around the corner, and Hyman’s NIMH joined with the American Psychiatric Association to fund a series of symposia to plan for the next revolution, a biomedical DSM-V/5.
the·crisis: Another phrase with multiple meanings. After Hyman left the NIMH, his replacement, Tom Insel, came from a large academic/industry translational program and carried the banner of biomedical psychiatry, adding his psychiatry·as·clinical·neuroscience phrase to the base well laid by Hyman. But then came the crises. First there were a series of disillusionments as the misadventures of prominent academic psychiatrists became increasingly apparent, along with the exposure of widespread research misdemeanors in industry funded clinical trials. That culminated in Senator Grassley’s investugation of a number of high ranking psychiatrists for financial hanky-panky. Then came the legal suits exposing unmentioned adverse effects, accompanied by the release of documents that showed epidemic ghost-writing, the antics of the KOLs, the jury-rigged analyses of drug trials, and the deceitful marketing practices of PHARMA. And then there was another big crisis, the collapse of the grandiose wishes for the DSM-5 and its other foibles. But none of these are the crisis Hyman is talking about.
He’s referring to the recent·exits·by·companies·from·psychiatry that came in the summer of 2011, around the time Hyman left the Provost job for the Stanley Center – returning to the game, so to speak. The phrase I picked is Hyman’s, and it’s telling. Not recent·exits·by·companies·from·CNS·drug·development. He says recent·exits·by·companies·from·psychiatry. And I think that’s how it felt to the NIMH, to the APA, and to Steven Hyman – like they’d been abandoned by an essential ally.
"The scientific community, including industry, academia, patient groups, and government, must find ways of sharing financial risk while developing effective and well-governed partnerships."
There’s certainly another way to look at these phrases. It’s in all the papers. In the last thirty years, psychiatry has largely equated itself with drug treatment and colluded with the PHARMA advertisement that radically inflates efficacy and downplays risk. Psychiatry has largely taken the position that all mental illness is brain disease. Over the last thirty years of this monocular biomedical psychiatry, there has developed of a huge academic·pharmaceutical complex that has functioned like a symbiosis – operating on the the capital provided by PHARMA in return for lots of things. So the recent·exits·by·companies·from·psychiatry threatens this complex with financial collapse. This second view takes into account the scientific and financial misbehavior of PHARMA and the KOLs in psychiatry. It offers a more accurate view of the medications available. And it knows that PHARMA sees the recent·advances·in·genomics·proteomics·and·imaging as offering little that’s to their advantage – likewise seeing unmet·clinical·need as well as the global·burden·of·disease for what they really are, rhetorical gimmicks. PHARMA [and the rest of the world] also knows that just·around·the·corner is a fantasy that has run out of legs.
We want to make more people “eligible” for mental health interventions, and we never use the word “need.”
Steve Lucas
Dear Boring Old Man,
Your blog is anything but boring. It’s required reading for anyone interested in psychiatric research and practice. I appreciate your thoughtful writing.
I think you are overestimating the financial impact of Big Pharma. Community Mental Health Centers (CMHCs) continue to close and it is pretty clear that they are being choked out of existence by managed care and the government. Those same CMHCs provide an abundant amount of non-medical care in the form of case management services, Assertive Community Treatment, and psychotherapy. They can’t do it if the doors are closed. We all know that managed care companies (MCOs) are certainly not going to fill the gap. They are experts in shifting costs to CMHCs and county jails. We also know that concierge care psychiatrists in cash only practice are not going to be doing anything for people with chronic mental illnesses.
Psychiatric inpatient care has been decimated by the same forces. Neither depends on Big Pharma or a brain based model of psychiatry to function and yet they were gone long before the AMP initiative decided to not study schizophrenia.
I would take the message from AMP as just another government initiative to restrict resources for psychiatric care.
I would take the message from AMP as they’re going to describe the purported action of the same old drugs with genomics, proteomics, and imaging jargon.
I have a question for anyone who understands this field. Doesn’t the fact that thousands of genes are being identified in association to schizophrenia and the fact that there appears to be genetic overlaps between schizophrenia,bipolar disorder, and autism make it less likely rather than more likely that we will develop anything therapeutically helpful from these findings?
It’s funny that you noted that he said exit from “psychiatry” and not “CNS drug development”. My boyfriend works as a chemist for pharma and has watched as his company (along with many others) put all of its efforts into oncology and out of neurology. Multiple Sclerosis is not getting a lot of attention right now.
Dr. Steingard,
The following group of people may be able to assist you. They generally stick to article topics, yet will discuss anything even marginally related to it that sparks their interest. You will have an advantage here in that you are also a physician. The owner and author of the blog is one as well as at least two of the regular commenters.
I have not seen any articles pertaining specifically to neuroscience. However, the subject of autism is frequently an article topic and often referenced in the comments; usually around refuting the idea that vaccinations increase its prevalence. Here is the latest autism specific thread I could find, but a new one could be up tomorrow:
http://scienceblogs.com/insolence/2014/03/14/autism-clusters-and-toxins/
For those Not Scientifically Inclined,
If you are visit this site and wish to challenge something in a comment, please come prepared. They are extremely intelligent, analytical thinkers with a seemly inexhaustible supply of scientific, historical and literary knowledge. If they disagree with you, they can insult you with such sophistication that it almost seems a compliment. But, if they find your argument lacks merit (factual evidence from reputable sources) and you try their patience, they are like sharks at feeding time.
To Sandra’s question yesterday: I don’t think your conclusion necessarily follows from your premise. It all depends on the pathophysiology. I give you 2 clear examples of medical conditions that are influenced by a large number of genes but for which highly effective treatments have been developed. The first is bronchial asthma – several treatments close to the final disease step are in common use with generally good effect, even though a large number of genes are somewhat associated with the disease.
The second example is pathologically short stature – this is associated with various primary conditions, and human growth hormone is used for their treatment. It is even used controversially for short stature where hormone deficiency is not demonstrated. Once again, the treatment is close to a final common pathophysiological target.
So, it doesn’t bother me that some psychiatric drugs are helpful in more than a single disorder. Actually, if there are some common features in the pathophysiology then that is what we would expect. Just think of the clinical varieties of epilepsy which respond to the class of anticonvulsant drugs.
Dr. Carroll-
I understand, I think, that disorders with complex genetic underpinnings can be treated effectively (wouldn’t we add type diabetes to this list?), but I am asking how the identification of these thousands of genes will enhance our search for effective treatments.
Well, there are a couple of ways I might respond to this, Sandra. First, until we look we cannot know whether it is thousands of genes or just a few. Second, if indeed it is thousands (which may be an exaggeration) then one take home message might be that genetic data aren’t going to inform the designing of new interventions. That would be another important realization.
I have no problem with exploratory genetic studies but at some point one has to ask if the geneticists aren’t flogging a dead horse.
This discussion of the utility of the genetic research reminds me of why this AMP business caught my attention. NIH Director Francis Collins is himself a famous geneticist. After several breakthrough discoveries, he headed the NIH genetics research and directed the program that defined the Human Genome. I wonder if much of this focus on genetics at the NIMH comes from his lead. I agree that genetic research is important, but it feels like it’s way over represented in the NIMH priorities.
I am referencing this statement:
“have permitted the identification of a large and rapidly growing number of alleles associated with schizophrenia, bipolar disorder, and autism.”
This is what I have read elsewhere. There are many genes identified. In one article the number 8000 was used. It looks like multiple alleles – often normal variants – are associated with schizophrenia. It also looks like there is talking of circling back to the 19th century concepts of the unitary psychosis since from a genetic vantage point schizophrenia does not separate from bipolar disorder. This is often discussed in Schizophrenia Bulletin.
This makes sense to me since I do not think of Schizophrenia as one thing. What does not make sense is why these findings have leaders in the field saying that we are just shy of making some major breakthrough. To me, it just leads to deeper complexity.
I am not anti-research. This may indeed be very interesting. What I am questioning is the cheer leading that this is getting us closer – very close – to some answer that will translate into therapeutics. That is what I do not understand.
Right. Schizophrenia is not all one thing. There have been credible signals for decades that some of it is due to environment insults in utero rather than genetically based. And even for the latter portion, the early Kety-Rosenthal genetic studies had to turn to a schizophrenia spectrum concept to make the numbers come out as hypothesized.
Some interesting new work from Canada (Anne Duffy and Paul Grof) suggests that the apparent overlap of schizophrenia and bipolar disorder is limited to the pedigrees where the bipolar cases have poor responses to lithium. They found almost no psychotic cases (schizophrenia or schizoaffective disorder) in the families where the bipolar cases had good responses to lithium. So, information like this discourages me from returning to the19th century idea of Einheitpsychose.
As for the pronouncements about imminent breakthroughs, that is just public relations talk if not propaganda in service of continued federal funding. For many in the business of research, the name of the game is to keep the game going.