Wednesday, August 13, 2014

The Stanley Center Grant

 The details of this grant and some of the history of previous grants are given in this press release from the Broad Institute.  A few of the details include the fact that the Broad Institute has about 150 scientists working on the genetics of severe mental illnesses.  That focus includes detailing the genetic basis of these disorders, a more complete elaboration of the the pathways involved and developing molecules that can modify these pathways as a foundation for more effective medical treatment.   The focus of this group is on severe psychiatric disorders including schizophrenia, bipolar disorder, autism and attention deficit-hyperactivity disorder.  It was also the single largest donation for psychiatric research - ever.

Any search on research grants over the past decade will produce thousands of research articles that were funded by the Stanley Foundation.  The press release details the fact that grants from the Stanley Foundation have been incremental and that they are obviously monitored for progress by the grantees who are satisfied with the progress being made.  That has not stopped some critics from suggesting that the money is basically either wasted, that it could be better used for symptom control, or that it would be more useful for research in symptom control.  My goal here is to question some of these arguments about basic psychiatric research in much the same way that I question the arguments that usually attack psychiatric practice and clinical research.    My speculation is that the underlying premises in both cases are very similar.

The basic arguments about whether it is a good idea to fund basic science research as it applies to psychiatry range from speculation about whether or not it might be useful to the fact there are more urgent needs to funding on the clinical side.  Many of these arguments come down to the idea of symptom management versus a more scientific approach to the patient.  There are few areas in medicine that have a purely scientific approach to the patient at this time.   The more clearcut examples would be locating a lesion somewhere in the body, performing a biopsy and making tissue diagnosis.  That is an example of the highly regarded "test" to prove an illness that seems to be a popular idea about scientific medicine.  But in that case the science can run out at several levels.  The  diagnosis depends on correctly sampling the lesion and that can come down to the skill of the sampler.  It depends on the agreement of pathologists making the tissue diagnosis.  The tissue diagnosis may be irrelevant to the health of the patient if there are no treatments for the diagnosed illness.

In many cases in medicine, treatment depends on symptom recognition and monitoring.  In some cases  there are tests of basic anatomy or function.  A good example is asthma.  As I have previously posted here (see Myth 4), the majority of asthmatics have inadequate control of asthma and the approach to asthma is generally symptom control.  The current basic science of asthma depends on identifying genes and gene products that will allow for more specific treatment of the underlying pathophysiology and there are surprising similarities with mental illnesses.  For example, there is no single asthma gene.  The genetics of the various aspects of asthma pathophysiology including the degree to which it can be treated is assumed to be polygenic in the same manner as the genetics of severe psychiatric disorders.  The only difference being that a larger portion of the human genome is dedicated to brain proteins (personal correspondence with experts puts that figure as high as 25%).   Genome wide association studies of severe asthma can have as much difficulty identifying candidate genes that reach statistical significance.   Any thought experiment comparing the reference pathway for asthma to any number of similar pathways that are operative for brain plasticity, human consciousness and the variants we call mental illnesses will show that there are surprising few specific interventions for asthma signaling and that signaling occurring in the brain is even more complex.  The reason why we have impressive brain function is structural complexity at cellular, structural and biochemical pathway levels.   And yet the rhetoric of critics usually considers asthma as a disease to be more legitimate than psychiatric disorders and the lungs are apparently considered a more legitimate target for research funding than the brain.

What are the critics saying?  Allen Frances, MD DSM critic has decided that neuroscience research may be so complicated that the $650 million dollar grant may be a drop in the bucket in sorting out the basic science.  He suggests:

"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."

My experience in psychiatry is clearly much different from Dr. Frances. Although I am probably at least a decade younger, I can remember a time when there was no treatment at all.  As a child I heard the stories of my great aunt working in a county sanatorium full of patients with tuberculosis and severe mental illnesses.  This was state-of-the-art treatment before the era of psychopharmacology.  Large numbers of institutionalized patients went there and many never left unless they had a mood disorder that suddenly remitted or they received electroconvulsive therapy.  Those leaving often ended up on county "poor farms" for the indigent.  Contrary to Dr. Frances observations that was about 50 years ago. Going back earlier than that I consider Shorter to be definitive.  In his text he describes what describes what it was like to have a psychotic disorder before the asylum era in many countries of the world and concludes:

"In a world without psychiatry, rather than being tolerated or indulged, the mentally ill were treated with a savage lack of feeling.  Before the advent of the therapeutic asylum,  there was no golden era, no idyllic refuge for those supposedly deviant from the values of capitalism.  To maintain otherwise is a fantasy."  (p4)     

Even when psychopharmacology became available to people in institutions it took a long time to make it to Main Street. In the small town of 10,000 people where I grew up, I witnessed a generation of people with autism, schizophrenia, post-traumatic stress disorder (from WWII and the Korean War) and bipolar disorder being treated with amitriptyline and benzodiazepines by primary care physicians. They may have been home from the state hospitals but with that treatment the outcomes were not much better.

The only cruel paradox that I find quite offensive is the blatant discrimination of governments at all levels and their business proxies against anyone in this country with an addiction or a mental illness.  I don't understand all of the bluster about a diagnostic manual that clearly has not made a whit of difference since it was released or endless debates about conflict of interest that apply to a handful of physicians when this massive injustice exists and when clinical psychiatrists have to deal with it every day and many times a day.   I don't know who "we" refers to in the post, but I can say without a doubt that the technology and know-how is there to alleviate a significant degree of suffering for people with chronic and severe psychiatric disorders right now and at a very reasonable cost.  That cost will not be the few hundred dollars that it takes to see someone in 4 - 15 minute "med check" clinic visits a year and provide them with (now generic) medications.  No -  one year of care will cost about the same amount as a middle-aged person presenting to the emergency department with chest pain.  The reason why care for people with chronic severe mental illness is better in other countries is that there are no financial incentives in those countries for corporations to make money by denying care for the treatment of mental illness and addiction.  That is the cruel paradox in this country, not neuroscience research occurring at the expense of clinical care.  If a billion dollars was directed to clinical care in this country - my guess is that half of it would end up in the hands of the insurance industry rather than providing medical care.

The image of the "receding holy grail" of a future basic science breakthrough is certainly admirable rhetoric, but it is just that.   We have spent too much time rearranging the deck chairs of DSM technology.  Is there any informed person out there who thinks that it makes sense to keep rearranging diagnostic criteria, while clinicians basically focus on the same handful of disorders?  Is there any informed clinician out there who doesn't see the basic disorders as heterogenous conditions mapped onto unique conscious states?  With those basic premises there are just a couple of possible outcomes.   Continue pretending like the past two decades that everyone with these heterogeneous disorders can be treated the same way with a specific medication or type of psychotherapy.  The alternative is to look for specific subtypes based on more than clinical criteria that will produce better treatments with fewer side effects and better outcomes.  And since when is basic science research done in hopes of a clinical breakthrough?  Basic science research is hypothesis testing in the service of more science.  Science as the process that it is.  Any criticism that initially critiques terminology based psychiatry and suggests that it is a vehicle for the expansion of the pharmaceutical industry while suggesting that research funds should be directed at symptom control based on those crude definitions and research is internally inconsistent and defies logic.

I unequivocally applaud the past and current efforts of the Stanley Foundation.  At a time when mental health research and clinical services are subjected to intensive rationing efforts, it is inspiring when a private foundation comes forward in the face of all of those biases and makes an statement about how important this area of science is.  It is one thing to talk about stigma and quite another to come out and treat basic neuroscience and the associated disorders as seriously as any other major health problem.  Hopefully it will inspire others to provide grants for funding research and the development of clinical neuroscience programs that can be applied and taught to psychiatrists during residency training.

George Dawson, MD, DFAPA

1: Reardon S. Gene-hunt gain for mental health. Nature. 2014 Jul 22;511(7510): 393. doi: 10.1038/511393a. PubMed PMID: 25056042.

2:  Adam D.  Cause is not everything in mental illness.  Nature.  2014 Jul 30; 511(7511): 509

3:  Shorter E,  A History of Psychiatry.  John Wiley & Sons.  New York, 1997.


  1. All medical illness discovered to date (in biology) can only cause Psychiatric symptoms that are not disease-specific. Drug use, infections, autoimmune disease, endocrine disorders, cancer, neurological diseases, genetic diseases, and malnutrition are some examples. Most diseases that can cause Psychiatric symptoms have nothing to do with the nervous system or neuroscience.

    Should Mental Disorders exist?

    Well, if they don't, then Psychiatry for 100 years may have isolated itself from the other medical professions, arbitrarily deprived millions of access to adequate medical care, and developed it's knowledge and treatments though forced medical experimentation (torture).

    As far as behavioral neuroscience goes, I sincerely hope they find what they are looking for (and that they can all agree exactly what that is), and that it absolutely translates to practice.

    I don't believe I will ever have another thing to say about it here, except just one thing.

    Either way though, there is one inherent problem with forcing ones beliefs on others; It returns and when it lands, words are due.

  2. "Either way though, there is one inherent problem with forcing ones beliefs on others; It returns and when it lands, words are due."

    Well Clark - you may have to say more because I don't have any idea about what that means.

    There are always people "trying to force their ideas on others." The topic I posted on right here is a good example. Many people would like the people involved in this grant to spend their money on other things. The only reason these people can spend it this way without any strings is that they have the ability to do that. No government or politicians of any kind in their way.

    I personally have practiced psychiatry in mainstream medicine for the past 30 years actively collaborating with specialists of all kinds. Practically all of the diseases we were treating had a direct impact on the brain. I don't know how medical illnesses cause psychiatric symptoms without affecting brain physiology.

    A disease example is trhis mechanism for SLE:

    The antibodies shown in the central part of the diagram are used by some clinics to monitor NPSLE (neuropsychiatric lupus) and the mechanism for cell damage results in vasculopathy around the brain and an often complex psychiatric picture. That happens directly in the nervous system.

    The direct effects of drugs of abuse and how they produce symptoms is also through specific CNS mechanisms:

    I have done research and served on Human Subjects Committees and have never seen research that was forced on anybody, much less torture.

  3. Behavioral Neuroscience research will never treat, cure, or prevent syphilis, lupus, or blood clots caused by heart disease. Roughly, you yourself said "suggesting that research funds should be directed at symptom control based on those crude definitions and research is internally inconsistent and defies logic."

    I wish you guys the best, unless the UN decides to rule the other way in the URL link I included above, in which case I don't know what that would be.

  4. "Behavioral Neuroscience research will never treat, cure, or prevent syphilis, lupus, or blood clots caused by heart disease."

    Why would it? There are very well funded research efforts for all of those diseases that are focused on the same pathophysiological processes that neuroscience needs to study for brain based diseases.

  5. People bandy about what should be done with "the" grant money. Should it be applied to basic neuroscience, or to symptomatic treatment, or to creating better resources for care? This question might make a difference if there were just one giant pool of money to be handed out to whatever is most deserving. But that's not how it works. There are multiple pools that don't necessarily overlap, so you might as well use money earmarked for basic science, for basic science, and do the best research you can.

    1. Agree - people also forget that handing out the money in all cases is a political process. There have been many problems with that process and many research careers hang int he balance. It continues to make no sense to me to think that clinical research is even worthwhile when the structure of the average mental health care in this country is so poor and getting poorer.

      Why worry about clinical research if everybody is filling out a PHQ-9 and taking and antidepressant? That approach negates the research of the past 10-20 years and yet it being hailed as some kind of great advance.