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.

Stigma Rhetoric

I have always been skeptical of the value of the stigma concept in advocating for the rights of people with mental illness.  It seems to imply that a person with a mental illness is obvious to everyone and nothing could be further from the truth.  The usual advocacy groups certainly jumped on it and it was later picked up by professional organizations.  My basic problem with the entire argument is that nobody should know that you have a mental health problem anymore than people should know that I have asthma.  It is a problem of medical confidentiality rather than a problem with stigma.  Anyone who thinks that is not the case just needs to consider what prospective employers think about hiring people with back pain, asthma, or any pre-existing condition that potentially impacts their group health insurance coverage.  Any confidential medical condition is potentially stigmatizing and it certainly is nobody else's business.  If people want to disclose that information that is certainly up to them and as I have posted here in many cases it can be a useful public service.  And I do realize that health insurance companies force you to disclose pre-existing conditions using various methods but that does not mean that your employer should know.

The other problem is that there has been broad and systematic discrimination against people with mental illness and addictions at all levels of government and the business community.  These are the people who have access to protected medical information and make decisions about health care based on it.  That discrimination occurs with full knowledge of a diagnosis and often a recommended treatment plan.  Multiple posts here document that problem and yet nobody comes right out and attacks that issue.  If anything social activism with a stigma focus seems to cast a wide discrimination net rather than focusing on the few people and agencies that can make a critical difference.  It  suggests that the general public is the problem and that educating the general public will solve the problem.

This morning a friend of mine posted this link on Facebook and asked me for my impressions of the argument that neuroscientific explanations potentially lead to more stigma.  That is probably what has me fired up.  If you are trained in science, you realize that there are  internal politics but in general that is not the same as the politics of the barbarians at the gate.  The problem is that all types of science from climate science to neuroscience gets co-opted and interpreted by people who don't know what they are talking about.  I think that is illustrated by one of the summary points in this article:

"As this revolution gathers force, we need to be mindful that biogenetic explanations for mental health problems can have troubling implications for the people who suffer them."

I think it should be obvious that there will be "troubling implications" for anyone who is ignorant on either end of a "biogenetic explanation".  Further, it is really impossible to separate allegedly biogenetic explanations from decades of conditioning by governments, businesses, and the media.  Troubling implications start when you realize that your employer's health plan does not have coverage for mental illnesses or addictions and you have a family member that needs that insurance.


What are the take home points about stigma in all of this?

1.  Businesses that discriminate against mental illness by rationing current services and destroying any infrastructure necessary to treat mental health are stigmatizing.  The message is clearly that they can't be bothered to treat these problems seriously by offering much of anything beyond a crisis stay in a hospital and a 10-20 minute "med check" by a "provider or prescriber" in an outpatient clinic every 3 - 6 months.   No research proven modalities to treat mental illness and a severe push to send people with addictions and serious mental illnesses to county detox, jail, or the street.

But even the businesses not involved can get into the act.  Practically every local market has a business some who is offering "crazy deals."  If you doubt it, Google "crazy deals" or the equivalent "insane deals" and see what you come up with.  Don't forget to look at some of the images.

2.  Governments that ration and destroy the mental health infrastructure and collude with rationing by businesses are stigmatizing.  Examples include empowering insurance companies to decide how they can deconstruct the billing and services of mental health providers and clinics to their advantage (the arbitrary insurance company audit),  empowering business to discount services, legitimizing utilization review and prior authorization (tools for arbitrary denials), and allowing for proprietary business guidelines to dictate who can receive treatment and who can not.  What could be more stigmatizing than to have a business suggest that a person is not "dangerous" enough to be treated and use that as a basis for medical decision making?  Why aren't there any rules about admitting only the "dangerous" myocardial infarctions and sending everybody else home?

3.  Court systems that treat the mentally ill like they are criminals are stigmatizing.  This includes practically all court systems because as any forensic psychiatrist will tell you, despite the myths about the so-called insanity defense - it is practically impossible for anyone to get off with that defense.  There are significant numbers of people who are incarcerated for minor nonviolent crimes that were the product of mental illness.  Ask yourself if it is more stigmatizing to have a confidential diagnosis of a mental illness or be listed in the paper as being incarcerated or having been convicted of a crime?

4.   The press has a very poor track record in the area of stigma.  It is well known that the press covers psychiatry more than other medical specialties and has a consistently negative view about the specialty.  How would you feel if you had an illness that resulted in you being seen by a physician whose specialty is consistently portrayed negatively in the media.   For the past two years the press has produced nonstop political arguments about a diagnostic manual that is practically little more than a guidebook for billing codes with many of the esoteric codes only of interest to researchers.  One of the main arguments in those articles was that the diagnostic manual led to arbitrary diagnosis and treatment for the benefit of the pharmaceutical industry.  For anyone with a serious mental illness, could there be a more stigmatizing argument?

5.  The entertainment industry never hesitates to make a buck off of mental illness.  The film Halloween is classic example of equating mental illness with an evil so unstoppable that the psychiatrist involved has to pack a .44 magnum.  That same message has been carried forward in recent television shows.  Some of the efforts in this area are so bad that it takes an incredible bias to justify the product as entertainment.

These are all much better examples than suggesting that science somehow stigmatizes people.  The associated problem is the misunderstanding of science.  We all understand that the media needs to sell stories and the truth about science is that it is a process and not the ultimate truth.  Every story about new fads based on an experimental finding that will never be replicated in the absence of a discussion of scientific method is corrosive to the public's confidence in science.  In this case using "chemical imbalance" as a scientific theory is about as ill informed as anyone could be about the neurobiology of mental illness or normal brain functioning.  At that level this story is more about press induced stigma than anything that neuroscience or neurobiology has to say.

The lesson for today is that the brain is not a sack full of neurotransmitters that is balanced or unbalanced.  If you believe that, you can either stay ignorant about the problem and talk about "chemical imbalance" as though it means something, educate yourself about neuroscience (there are many free sites on the Internet) or you can join any number of psychiatry bashing web sites that claim that psychiatrists believe there is a chemical imbalance.  Your first neuroscience assignment is to read about Eric Kandel and why he got the Nobel Prize.

And where does conflict of interest enter into the stigma equation?  In other words who benefits from mental health stigma as an operative social concept?  Advocacy organizations certainly do.  In many cases is it their raison d'être.  Interestingly concern over stigma has prevented some advocacy organizations from dealing effectively with the issue of people with mental illness who are violent.  They considered violence and aggression to be stigmatizing rather than a fact of some mental illnesses.  Professional organizations like the American Psychiatric Association benefit in that it enhances their credibility with the advocacy organizations but any counterattacks on the forces that ration and deny mental health services have been weak and ineffectual.  Those rationing entities including politicians, government agencies, pharmacy benefit managers and managed care companies benefit tremendously.  After all they have added hundreds of billions of dollars to their bottom lines by basically denying or rationing treatment and in many cases denying that there is any problem at all.

Stigma rhetoric makes it seem like this is a problem inherent in our society with no better solution than an enlightened public.  We will not be able to solve it until enough people are enlightened while the rationing schemes continue.

At that level you could say that stigma is a concept that can be spun for everyone, but let's agree that science has nothing to do with it.

George Dawson, MD, DFAPA



Supplementary 1:  I was asked by a reader to summarize the above post.  Here it is:

There are societal wide biases (business, government, legal, entertainment, etc) that stigmatize the mentally ill.  Some aspects of that process involve the distortion of science (e.g. "chemical imbalance theory").

Now what happens if I decide to run an experiment that asks people about how happy they would be if they had a biologically determined mental illness in that culture? Of course they would react strongly because:

a)  They are from a culture that stigmatizes people with significant mental illness.  They know how the various players would react if they found out that a person has a significant mental illness. Mental illness by itself does not produce a stigma. People are stigmatized by other people with biases and clear agendas.

b)  They really don't know what the scientific implications are because they have been hearing about false theories or reading overt propaganda or they don't know enough about the process or implications of science.

Neuron Perspectives in Neuroscience

Eric Kandel's thought, research, and writing have been a major source of inspiration to me ever since I read his neuroscience text and his classic article Psychotherapy and the Single Synapse in the New England Journal of Medicine nearly 34 years ago.  I was very pleased to see that he wrote the lead article in Neuron's   25th Anniversary edition entitled "The New Science of the Mind and the Future of Knowledge."  I read the article in the same spirit that I read the original NEJM article, guidance from a world class neuroscientist who was also trained as a psychiatrist.  At that level the article is quite exciting because somewhere along the line Dr. Kandel has clearly been following concepts that are far removed from the synapse and does a good job of summarizing the major points and the current deficiencies.  He also comes back to the idea that psychotherapy is a biological treatment as he proposed in the original 1979 article.

One of the most interesting aspects of the article is that Kandel does not apologize for psychoanalysis.  He is also not excessively critical.  I read an article about his residency class at Harvard and psychoanalysis was certainly prominent at the time.  Although it is fashionable these days to throw Freud under the bus, he points out that Freud and subsequent analysts were right about a number of issues that neuroscience has caught up with including:

1.  Unconscious mental processes pervade conscious thought.
2.  The importance of unconscious thought in decision making and adaptability.

The probable link here is that Freud, psychoanalysis, and current neuroscience is focused on the mind rather than descriptive psychiatry.  At some point the majority of the field got sidetracked on the issue of identifying a small number of pathological conditions by objective criteria.  The mind was completely lost in that process and those few psychiatrists who were focused on it were engaged in generating theories.  He criticizes the field for a lack of empiricism but recognizes that has changed with clinical trials of psychodynamic psychotherapy and recent interest in testing psychoanalytical theories with the available neuroscience.  He also points out that Aaron Beck was a psychoanalyst when he developed cognitive behavior therapy focused on conscious thought processes and became a leading proponent for an evidence based therapy.

It was good to see a discussion of the hard problem of consciousness.  I was on the ASSC listserv for many years until it eventually lost a home and was shut down.  Many of the experts in consciousness studies posted on that thread but there was very little neuroscience involved but plenty of discussion of the neural correlates of consciousness.

Information flow through the brain has always been one of my interests.  The idea that information flows through biological systems at both chemical and electrical levels is a relatively recent concept.  At the clinical level behavioral neurologists like Mesulam and Damasio discussed it based on cortical organization and information flow primarily at cortical levels.  I taught a course for many years that talked about the basic information flow through primary sensory cortex, association cortex and then heteromodal cortices.  The model had good explanatory power for any number of syndromes that impacted on this organizational model.  For example, achromatopsia made sense as a lesion in pure sensory cortex and posterior aphasia made sense as a lesion of heteromodal cortex.

Using this model, overall information flow from the sensory to the motor or output side could be conceptualized, but there were plenty of open boxes in the flowchart along the way.  The theory of how consciousness is generated from neural substrates was still a problem.  Social behavior was another.  Despite decades of descriptive psychiatry, the diagnostic criteria for major psychiatric disorders still depended on symptoms.  In many cases aberrant social behavior was a big problem and often a more accurate reflection of why patients were disabled, unable to work and had limited social networks.  Even though there were scales to rate positive and negative symptoms in schizophrenia, aberrant social behavior cut across a number of major psychiatric disorders.  In my first job as a community psychiatrist, we rated social behavior of the people in our community support program and it was a better predictor of disability than diagnosis or ratings of positive symptoms.  The neuroscience of social behavior remained resistant to analysis beyond the work done on cortical lesions and obvious comparisons to those syndromes.  But people with schizophrenia had no obvious frontal lesions.

Dr. Kandel points out the developments in these areas ranging from de novo point mutations affecting circuitry in the frontal cortex to mirror neurons to the neuroendocrinology and genetics of social behavior.  The review of Thomas Insel's work with voles and the extension of that work by Bargmann in C. elegans highlights the importance of specific systems in social behavior and how these systems are preserved across species.

One of the most interesting areas outlined by Dr. Kandel was the issue of art and the neuroscience of its creation and perception.  I have just posted on abstract art and was able to locate a quote from Kandinsky:

"The abstract painter derives his "stimulus" not from some part or other of nature, but from nature as a whole, from its multiplicity of manifestations which accumulate within him and led to the work of art.  This synthetic basis seeks its most appropriate form of expression which is called "nonobjective".  Abstract form is broader, freer, and richer in content than objective [form]." (Kandinsky Complete Writings on Art - p 789)

Kandel develops a narrative based on Viennese art historians and the importance of the aesthetic response to art.  That response is an emotional one based on the life experience of the viewer and the neuroscience of that response can be studied.  He looks at the inverse optics problem, facial recognition, and comes up with a flow diagram of the processes involved in viewing visual art.  I did not realize it until I read this article but he has a new book on the subject and ordered a copy to review at a future date.

Some of the conclusory remarks about neuroscience and what it means to society are the most important.  It is easy to be cynical about any scientific endeavor and it is also very easy to be political.  Neuroscience has to endure (although to a much lesser degree) than what psychiatry endures.   There are people out there commenting on neuroscience who don't seem to know much about it.  In many cases they are not scientists.  Even in the case of scientists, it is often easy to forget that the public will probably not hear the most objective and the most scientific.  They will typically hear from the experts who unambiguously support one side of the scientific argument as opposed to the other.  Kandel is cautious in his suggested applications of neuroscience to society.  He does not view it as a panacea or an explanation for behavior necessarily.  An example:

"Attributing love simply to extra blood flow in a particular part of the brain trivializes both love and the brain.  But if we could understand the various aspects of love more fully by seeing how they are manifested in the brain and how they develop over time, then our scientific insights would enrich our understanding of both the brain and love."    

Hopefully you will have time to read this paper.  I have highlighted a few more based on my reading about neuroscience over the past 20 years or so.  I will end with a paragraph on technical expertise.

When I was interviewing for residency positions 30 years ago, one of my questions that drew the strongest emotional reaction was: "Does your program have a reading list for residents?"  That question on average elicited shock or at least irritation from the average residency director.  The only exception was Johns Hopkins.  They handed me a neatly bound list of several hundred references that they considered key references that every psychiatric trainee should read.  I should have taken it as a sign and applied there, but my trajectory in life has been more random and circuitous than studied.  If I was a current residency director, I would have a list with a neuroscience section and the following articles from this volume of Neuron would be on it.  People often recoil when I talk about the technical expertise needed to be a psychiatrist.  Technical seems like too harsh a word for most psychiatrists.  Most of the media debate after all is essentially rhetorically based political discussions  I would say that if you read these articles, you can consider them to be a starting point for what you might need to know about neuroscience and psychiatry in the 21st century.

George Dawson, MD, DFAPA

A reading list for psychiatrists of the future (all available free online at the above link):

Kandel, Eric (2013) The New Science of Mind and the Future of Knowledge.  Neuron 80: 546 – 560

                             

McCarroll Steven A, Hyman Steven E (2013) Progress in the Genetics of Polygenic Brain Disorders: Significant New Challenges for Neurobiology. Neuron 80:578-587.

Südhof Thomas C (2013) Neurotransmitter Release: The Last Millisecond in the Life of a Synaptic Vesicle. Neuron 80:675-690.

Huganir Richard L, Nicoll Roger A (2013) AMPARs and Synaptic Plasticity: The Last 25 Years. Neuron 80:704-717.

Dudai Y, Morris Richard GM (2013) Memorable Trends. Neuron 80:742-750.

Shadlen Michael N, Kiani R (2013) Decision Making as a Window on Cognition. Neuron 80:791-806

Buckner Randy L (2013) The Cerebellum and Cognitive Function: 25 Years of Insight from Anatomy and Neuroimaging. Neuron 80:807-815.