Monday, November 17, 2014

How To Really Fix The Broken Mental Health System

A few weeks ago the Psychiatric Times posted an article called "How to Fix the Broken Mental Health System: Call For Suggestions."  I posted a link to one of my previous blogposts in the comments but decided to write a separate post here.  My reasons are several fold.  First off, any call for suggestions to me is really an invitation to generate web traffic to a particular site.  It is a standard tactic of bloggers.  For proof of that just Google the title and you will see hundreds of references in the last 2 years.  Second, I can do a better job and have done a better job here.  It gives me an opportunity to collect links under common themes.  Finally, it creates an opportunity to provide answers in one spot.  I may be wrong, but I think that the Psychiatric Times piece will be quickly forgotten.  Since hardly anyone reads this blog, that will probably also happen, but at least my thoughts are out there and include statements that you won't see posted by anybody else.   Here are  my point by point suggestions:

1.  Managed care and all that it involves including Accountable Care Organizations (ACOs), Pharmaceutical Benefit Managers (PBMs) and the Substance Abuse and Mental Health Services Administration (SAMHSA) must go.  It should be evident to anyone that these organizations have not contributed to cost effectiveness, innovation, quality or efficiency.  Instead they are largely responsible for an additional hidden tax on all Americans.  I am referring to the typical high deductible health insurance plans that results in thousands of dollars in copays and premiums before any health care has been received and the $250,000 in out of pocket costs that any 65 year old couple can expect to pay in additional health care costs.  Contrary to their advertising, managed care organizations disempower patients and their physicians and are the largest obstacle to care in this country.  Their disproportionate effect  on psychiatric and substance use disorder services has been well documented.

2.  Centers of excellence rather than collaborative care is the primary goal.  All of the managed care forces and their political backers in the first point above are making the argument that we cannot possibly produce enough psychiatrists to meet the need in this country.  They maintain that argument despite the fact that the US currently has about 1/4 the number of psychiatrists per capita as Switzerland, significantly fewer than 18 of 32 OECD countries, and is only 1 of 3 countries where the number of psychiatrists is decreasing.  Instead of developing a rational triage system, their solution has been to say that anyone can provide psychiatric services or that a psychiatrist reading screening checklists like the PHQ-9 is some kind of psychiatric care.   This is both an absurd characterization of psychiatry and a non-solution to the problem.  Psychiatric specialists need to be available to treat the most difficult to treat disorders.  They don't need to see everyone taking an antidepressant or everyone with insomnia.  They need to see people with difficult to diagnose problems and treatment resistant mood, anxiety, psychotic, neurocognitive, substance use, and psychotic disorders.   They need to see this population both for diagnostic clarification and treatment.  Centers of excellence need to be developed around these disorders and the associated treatment delivery.  There are current models that develop statewide systems of care around centers of excellence that seek to provide the highest quality of care to residents in that state.

3.  The administration of systems at the local level needs to be done from a clinical and not a financial point of view.  The split systems of care (administrative versus clinical) is one of many sources of poor quality care.   It has resulted in some situations as absurd as administrators believing that they can design systems of mental health care without input from clinicians.  This is especially problematic in treating patients who have  problems with aggression.  Psychiatric training needs to include specific instruction on how to clinically administer these systems of care.

4.  The psychiatric infrastructure needs to be rebuilt.  That includes both community and state hospitals.  Very clear criteria need to be established for admission to these facilities since state hospitals in recent times have been the only housing option for people with severe problems.  The concept of "treatability" has been inappropriately applied by federal regulators.  I worked for years as a Medicare reviewer and reviewed many state hospital records where I was asked whether or not the patient had achieved maximum benefit from hospitalization.  That would allow the administrative authority that I was working for at the time to deny any payment to the hospital from that point on.   The reality is that the patient was still severely disabled and could not live on their own, with their relatives, or in whatever residential facilities existed in the state.  Whether there was continued payment or not, there was no place to send the patient due to the presence of a chronic severe disorder.  That is still the problem today.  Rationing has resulted in a severely constricted infrastructure that does not match the needs of the patient population.  A state hospital system cannot exist in a vacuum.  There needs to be an established system of residential facilities apart from those hospitals that can accept people who may never acquire the skills to live in a group home setting or independently.

5.  An emphasis on independent living and competitive or supported employment needs to be the priority of any mental health system.  The community psychiatry movement introduced an important bias - that people with severe mental illnesses should always live independently rather than in an institution if possible.  That is a very important concept but it is time to move beyond that basic bias to a more comprehensive approach.  That includes not only the vocational rehabilitation aspects but a renewed emphasis on the cognitive and functional capacity aspects of severe mental illnesses.  We now have large detailed studies of cognitive deficits in groups of patients with schizophrenia, bipolar disorder and substance use disorders.  That knowledge has not been used to implement any innovative approaches to residential living or vocational rehabilitation.   Treatment rather than rehabilitative approaches to these deficits need continued emphasis and research.  The comprehensive treatment of any person with schizophrenia or a mood disorder should include an assessment of cognitive problems beyond the usual approach of treating symptoms.

6.  Increased availability of psychotherapy and case management services.  Medicalization has become a popular buzzword by journalists and critics of psychiatry.  If you ask any psychiatrist about the likely causes of increased prescribing and attempts to treat all problems with medications the likely response will be that there are no other resources left to treat the problems.  Many managed care systems have eliminated psychotherapists from their clinics or restricted access to available services.  Family and marital therapy is often not available at all.  Many counties have severely restricted the availability of placements for children with severe problems.   There are clear population based approaches that have not been implemented on a wide scale basis including computerized psychotherapy, brief cognitive behavioral therapies, mindfulness based therapies, basic behavioral approaches, and non-psychotherapy approaches like exercise.   These therapies can not only be applied to a wide variety of problems but also can be part of a rational triage system to reduce the prescription of medications and assure that psychiatrists are seeing only the most severe disorders.  This system would also be an asset to primary care physicians and provide them with viable options other than prescribing medications.

7.  Reform of the civil commitment process is necessary.  Civil commitment for involuntary treatment of mental illness and substance use problems is highly subjective and varies considerably from county to county within the same state.  That variance is largely due to variability in resources form county to county and interpretations of the statutes that generally are in line with the level of resources.  Civil commitment and associated legal functions such as conservatorship or guardianship can be life saving and life changing interventions.  A better infrastructure will give legal authorities more confidence that a viable intervention can be accomplished that will reverse the reasons why the person has entered the legal system.  But beyond that it has to be clear that managed care definitions of "dangerousness" and interpretations of "imminent dangerousness" are basically rationalizations to do nothing.  There also needs to be an avenue for preventing the incarceration of mentally ill and substance using patients for minor offenses and diverting them to treatment programs in the community.  Another area where legal interventions are critically needed is guardianship and conservatorship decisions for mentally ill patients in need of acute medical care.  Civil commitment, conservatorship, guardianship, and substitute decision makers all need to be rapid parallel processes done through the same probate court rather than different courts and different jurisdictions.  It is more likely that experienced judges and referees will be able to make better decisions.

8.  Better public health interventions for violence and aggression are needed.  There has been no progress in this area due to the political stalemate on gun control or gun access.  That never addresses the state of mind prior to the violent incident.  The necessary public health interventions need to come at that level and there needs to be centers where aggressive behavior can be addressed and treated before there are adverse outcomes.  Beyond that immediate need there is also very little dissemination of the information that is already known about childhood adversity and adult mental health outcomes.  There is so much critical information out there about the adverse impact of certain social experiences in childhood that are not public knowledge and that should be widely available.

9.   Pharmacovigilance and pharmacosurveillance services need to be developed in the same way that access to controlled substances prescriptions have been developed in many states.  We have been hearing about "Big Data".  Managed care systems have vast amounts of data that they consider to be proprietary that is analyzed from a business rather than clinical perspective.  Any clinician prescribing medications should get a monthly report on their prescribing patterns relative to all physicians and fellow specialists and subspecialists.  Statistical models of conservative prescribing and polypharmacy need to be developed.  Prescribing patterns associated with the highest complication rates need to be identified.   Feedback needs to occur at the level of the individual physician and the reports need an adequate amount of detail.  Literature based on data mining large PBM data bases is not useful to individual physicians.  With current pharmacy databases there is no reason why this system can not be developed nationwide.  

10.  Better neuroscience training for psychiatrists and psychiatric trainees.  We are past the point where a focus on pharmacology can inform a psychiatrist about how a prescription might affect brain functioning.  A detailed knowledge of signaling systems including many systems outside of the nervous system and how they affect plasticity is a requirement for the future.  A detailed knowledge of these systems is necessary to understand brain functioning and normal and abnormal conscious states.    There needs to be an emphasis on teaching neuroscience in psychiatric departments and correlating neuroscience with currently observed clinical phenomenon at a practical and theoretical level.

11.  Medical detoxification from substances needs to be widely available.  A lot of people forget that substance use disorders are in the DSM and there is a psychiatric subspecialty in Addiction.  Even though we have more addiction specialists than ever, the quality of acute detoxification is worse than ever largely because it is another rationed service.  People with significant withdrawal states are often sent home with a bottle of benzodiazepines or sent to a "social" detox setting with no medical supervision.  There are specific goals for detoxification from addictive drugs including the prevention of withdrawal seizures, the prevention of delirious states, the prevention of psychotic states, and the prevention of suicide during acute withdrawal.  It is a common expectation of the current system to expect a patient or their family to be managing withdrawal at home.   The secondary expectation of detox is to assist the patient with transitioning to a safe setting where they can stop using the drug they were just detoxified from.  My estimate from talking with primary care physicians is that only about 20% of the emergency departments and primary care physicians in any locale can refer people to functional detox units.  The non-medical powers that be in the health care system decided long ago that detox was  an "outpatient procedure."  In most cases the translates to sending a person home and hoping they will make it to an outpatient appointment or an AA meeting.

12.  The gross mismanagement of physicians has been a pathway to physician burnout, mass dissatisfaction, and a dumbed down assembly line approach to the practice of medicine and psychiatry.  Physicians don’t need to be told how many people to see in a day, what to document, or how to treat people.  The current collaborative care approach can be seen as being due (in part) to a mind numbing productivity approach that was invented by the federal government and the business world in the first place.   When I was trained as a physician, our teams knew what the resources were, knew what our tasks for the day were, and we could make a local resource allocation on that basis.  It was an extremely efficient way to practice medicine.  At some point, administrators developed “productivity” standards where physicians were expected to apply a totally subjective billing and coding scheme to a patient interaction and do that repetitively all day long.  There were rarely two interactions that were alike, but for the past 20 years physicians have pretended that they were and that this productivity concept had some real meaning.   Administrators could simply increase “productivity standards” to make it seem like more and more work was being done.  In some clinics this process reached an absurd level – 40 or 50 patients a day.  People with complex problems were being seen for minutes and physicians were going along with it because their salary depended on it.   Productivity is another managed care concept that needs to go. 

That is my top twelve list for fixing the broken mental health system.  They are obvious problems supported by my clinical experience.  They are consistent with the frequent problems I have had advocating for the resources I needed to treat patients with severe mental illness.  The government and business partnerships in health care have been obstacles to care.  As long as these partners continue to ration health care and siphon off large profits while rationing care and resources to the patients who are paying for them nothing will change.  This pattern has been most noticeable in psychiatric services.  Contrary to a lot of rhetoric, the problem with the mental health system is not the pharmaceutical companies behaving like other businesses.  It is not the DSM.  It can't be organized psychiatry because organized psychiatry is politically weak and ineffective.  It is not physician conflicts of interest because they are plentiful and the more important ones on the business side are never discussed.

This so-called system was brought to you by the government and the health care companies that lobby all politicians.  The idea that a system of medical care run by business people and politicians who know nothing about medicine or psychiatry is somehow a good idea, is an ongoing American pipe dream.

It is time for the country to snap out of it.

George Dawson, MD, DFAPA

Supplementary 1:  The photo credits here go to Ruzica Vuskovic, MD.

Supplementary 2:  I will be adding in links to previous posts at some point but ran out of time tonight.

Supplementary 3:  I added on Monday 11/17/2014.

Friday, November 14, 2014

Scourge Of Prior Authorization Finally Acknowledged?

A copy of Minnesota Medicine, the journal of the Minnesota Medical Association (MMA) was delivered to my office this morning.  I stopped paying dues to the MMA about 20 years ago.  My rationale was that I was already paying significant dues to two professional organizations that were doing nothing to protect me from the repeated abuses of the managed care industry - why pay a third to do an equally poor job?  I was probably more steamed at the MMA at the time because I realized that managed care in Minnesota was more than just an annoying business practice, it was institutionalized in both the statutes and administrative practices of the state government.   I sent the President of the MMA a letter to that effect.  I don't have his response but it did not persuade me to send them another check.  I can only guess that this is a marketing idea to persuade the disaffected that the MMA is now a vital organization that appreciates medical practice in the state in many cases has come perilously close to being a living hell.  That living hell is courtesy of managed care and the various heads of that hydra.

Despite those reservations, on the front page just below the journal title was this headline:  The Prior Authorization Burden and just below that the subtitle: The process is frustrating, time-consuming and costly.  No kidding.  Any casual reader of this blog may recognize that this is probably one of the only sites where you can count on rigorous criticism and aggressive opposition to all managed care techniques.  At the top of that list is prior authorization.  I have gone as far as coming up with a "no-Rx" logo that I use to symbolize the problem.  That symbol is at the top of this post. It means that a managed care company (MCO) or pharmaceutical benefit manager (PBM) can deny prescriptions and therefore medication to the patient.  That denial is also a denial of the prescription of the physician and everything that involves.  State and federal governments have granted these organizations this power based on some loose idea that it would save patients and the governments money.  These governments are still enamored with that idea despite the overwhelming evidence that money is not really saved, it is merely redirected to the bottom line of MCOs and PBMs.  The only people who pay the price are patients and physicians.

So my first and primary question was "Does the medical society finally get it?"  They certainly missed the boat on utilization review and as a result managed care organizations in Minnesota generally make the discharge decisions on patients.  Will they also continue to make decisions about what medications can be prescribed based on their profit margins rather than what a physician in a treatment relationship with the patient decides?  The initial example seemed hopeful.  It was the story about a primary care physician trying to prescribe a rescue inhaler for his asthmatic patient.  He had taken a specific brand of generic albuterol for years.  The prescription was rejected.  He wrote subsequent decisions for identical medications in the same category Proventil and that was rejected.  He sent in a script for ProAir and that was rejected.  He was told to choose another inhaler but not given a name to choose.  He picked Xopenex or levalbuterol rather than albuterol and that was accepted.  What is the rationale for a PBM having a doctor guess about which inhaler will be approved for days while a patient with severe asthma goes through the weekend without a rescue inhaler? In a word money, the only rationale for picking a newer and (usually) more expensive inhaler is that the PBM has some kind of financial deal with that manufacturer.

 The article does go on to explore that theme and references a study of six Minnesota Health Plans.  The researcher Barbara Daiker, RN, PhD found that there were 1,036 drugs that required prior authorization but only 6 were on the prior authorization list of all 6 health plans.  Only 26 more were on 5 of the 6 lists.  This level of variability suggests that the decisions are not based on scientific evidence or quality concerns but financial models.  It would have been very useful to know if any of these lists included generic drugs. Without a scientific or quality basis for these lists, the obvious model is a purely financial one.  That is also consistent with the tactics used by these companies that I have documented in this blog such as refusing to cover generic antidepressants that can be purchased for as little as $4.00 per month.

One of the facts about prior authorization is that  like most managed care tactics, the burden has fallen disproportionately on  psychiatric practice and patients with mental illness.  One of the first articles demonstrating the adverse effects of prior authorization was published in the New England Journal of Medicine in 1994 (2) showing that when prescription limits were imposed on patients with severe chronic mental illness it resulted in increased health care costs that exceeded the savings in medication by a factor of 17.  In a more recent study, Driscoll and Fleeter (3), estimated the adverse effects (hospitalization, lost wages, homelessness, incarceration, higher medical costs) of prior authorization applied to the population of Ohio residents with schizophrenia and bipolar disorder.  They used conservative estimates of the population at risk and treatment discontinuity as a result of prior authorization programs.  They determined associated indirect costs with these treatment discontinuities and summarized his results in the following table.

The Driscoll and Fleeter study replicates several other studies that illustrate the problems with the "cost savings" of prior authorization.  Those savings to an MCO or PBM are shifted to the patient and the taxpayer.  These studies are consistent with the recent concern about the mass incarceration of the mentally ill.  Nobody is paying attention to the fact that when this happens the cost of care is now paid by the correctional system and not the person's insurance.  If a person with a substance use problem is incarcerated any medication they take to maintain abstinence is generally discontinued resulting in more savings to the MCO.  In addition to the financial analysis, the psychiatric care of these persons is often severely disrupted because correctional systems are now imposing their own form of a limited formulary so that the patient may get a medication, but not one that has been carefully assessed to work.

These studies all demonstrate that "savings" from prior authorization is savings to a health care company and it does not benefit the patient involved.  The costs to the providers in the case of the above table were not even used but per my previous reference are considerable.  I would also add that since this study came out most of the original second generation antipsychotics are now generic drugs and that reduces the Annual Cost Savings considerably.  The estimates for Annual Additional Cost are much higher and don't include the paperwork costs for physicians.  In other words the net added cost of prior authorization for psychiatry is considerable higher in 2014 than it was in 2008.

With all of these considerations it is good to see the state medical society finally paying attention.  That doesn't mean anything will be done and the evidence for that is contained in this quote from Janet Silversmith, Policy Director of the MMA: "We are not trying to eliminate drug prior authorization.  We are just trying to add some sanity to the process.  As it's practiced now we believe drug prior authorization is an onerous, inefficient process that sometimes harms patients."

Why wouldn't any medical society want to kill that kind of process?

George Dawson, MD, DFAPA


1:  Howard Bell.  The prior authorization burden.  Minnesota Medicine. November/December 2014:  18-25.  PDF

2:  Soumerai SB, McLaughlin TJ, Ross-Degnan D, Casteris CS, Bollini P. Effects of a limit on Medicaid drug-reimbursement benefits on the use of psychotropic agents and acute mental health services by patients with schizophrenia. N Engl J Med. 1994 Sep 8;331(10):650-5. PubMed PMID: 8052275.

3:  Howard Fleeter, PhD.  Estimate of the Net Cost of A Prior Authorization Requirement for Certain Mental Health Medications.  Prepared by Driscoll and Fleeter for National Alliance on Mental Illness Ohio.  August 2008. (Table used with permission).

Supplementary 1:  The "No - Rx" logo simultaneously symbolizes no prescription for the patient, no acceptance of a prescription from a trained and licensed physician, cost savings for the insurance entity that contracts with the patient to cover their prescription medications, and increased costs for all of the providers, employers, governments and correctional systems that need to address discontinuities in care.

Saturday, November 8, 2014

Clozapine As A Fictional Murder Weapon On The Walking Dead

clozapine (Clozaril)
clonazepam (Klonopin)

When something doesn't fit my typical hypothesis testing interview style, I start to think that there are other things going on.  Things that might not be obvious and things that I will need to piece together with further evidence gathering and collateral information.  That is what happened when I was watching television last weekend.  It happens all of the time in real life.  I remember the day when I was a second year resident and my attending asked my: "Suppose that you are at a party and this person comes up to you and starts to act in a certain way.  Do you tell yourself: "I am off the clock" and try to react in a way other than a psychiatrist might act or do your think about that interaction like a psychiatrist would?"  There was some uncertainty there as a rookie, but not after 3 decades of practice.   You see the world as a psychiatrist.  That is why I suddenly became much more attentive when I heard the words clozapine and clonazepam mentioned in a very popular television drama last weekend.

Before any further consideration, this is about the implications of a purely fictional scenario.  This post is more about the motivations of the author or authors than psychiatric treatment.  At that level it is probably more about individual or cultural perceptions than reality.  I was watching the highly popular television series the The Walking Dead  last weekend.  This series is all about surviving a zombie apocalypse.  In this scene, a group of survivors is providing some kind of emergency medical care.  They are in a large hospital building.  I was surprised when the ragged physician gave the order to give a patient "75 mg of IM clozapine".  Any psychiatrist or psychiatric nurse knows that there is no IM form of clozapine and that according to the standard titration that dose is probably too high in any clozapine naive patient on day 1.  Apparently the writers of the show knew at least some of that because the actress who was working on the doctors orders had to take clozapine tablets out of a standard large pharmacy bottle and grind them up with a mortar and pestle so that they could be dissolved and injected.  She proceeded to inject the fictional patient with clozapine.  In a few minutes, the treated patient developed tonic-clonic seizures and dies.  She goes back to confront the original physician who gave her the order and is told: "No I said clonazepam and not clozapine."  Interestingly this combination is not on the list of look-alike, sound-alike or confused drug names by ISMP , but it is in this document about using TALL MAN font conventions to prevent mistakes among drugs that look alike.  On page three we learn that clonazePAM- cloZAPine-KlonoPIN are confused medications.  I think that anyone without experience in these medications might make that mistake.  Of course for the purpose of drama, we learn later that the physician giving the order actually knew that the deceased man was a physician.  They previously worked together in a hospital setting.  In the dog-eat-dog world of the zombie apocalypse, the ordering physician did not want any competition for his medical position.  He did not want to risk elimination by his more ruthless leader.  He intentionally ordered his assistant to give a clozapine injection and then lied and told her that he said clonazepam and not clozapine.

I posted the structures here to illustrate that before there were administrators focused on the confusion between names there were chemists to show that each of these compounds is unique.   Studying pharmacology and those technical details adds another layer of appreciation.  Psychiatry adds another layer of meaning on top of that.  I have seen the benzodiazepine trends and concluded like many psychiatrists after years of practice that clonazepam and other benzodiazepines might be useful for the first months of treating anxiety or panic.  As an add-on for anxiety in people with severe problems they don't add much.  In the end there are still the same problems and an additional addictive medication.  When I think about clonazepam, I am also reminded that even the professionals can be confused.  I used to work at a place where it was not considered a benzodiazepine and not sunject to the same security precautions - even after I pointed that out.  Clozapine on the other hand can be a life changing medication.  People with refractory psychosis and mood symptoms become clear and function at a much better level.   If clozapine did not have significant limitations from toxicity, I doubt than there would be a need for any other antipsychotic.  It is the only one with clear advantages in terms of symptoms relief, improved function, protection against suicide, and it even treats tardive dyskinesia and other movement disorders.  But the way it stands there are significant side effect limitations and  it is the antipsychotic that psychiatrists worry about the most.  

We have a case of homicide by injection of 75 mg clozapine.  Does that hang together as being plausible?  It also triggers and entire series of question about: "Why clozapine?"  Clozapine is a fairly esoteric second generation antipsychotic.  It is indicated for treatment refractory schizophrenia and a lot of experts believe it is underutilized because of its superior efficacy in this population.  It also is the only medication that has been shown to have anti-suicide properties in a double-blind clinical trial.  Those superior effects occur in the context of a wide range of toxicities that require close monitoring including weekly to monthly complete blood counts with differentials (depending on the time course of treatment)  for the length of treatment with the drug.  In addition to hematological side effects the drug can cause seizures and a number of other organ specific toxicities like myocarditis.  It should only be prescribed by experts familiar with its use and registered to prescribe it and follow the white blood cell counts.  If the white blood cell counts fall below a certain parameter, the clozapine must be discontinued and not restarted.  Clozapine can cause fatal agranulocytosis.  I view clozapine as one of the most beneficial drugs in psychiatry and one of the most toxic.  Clonazepam on the other hand is a benzodiazepine.  It can be used to treat anxiety and panic attacks.  It can also be used to treat seizures, but I have rarely seen it used for that purpose.  The main toxicity is excessive sedation and the main clinical problem is that it can be addicting.  But in terms of toxicity, it is generally well tolerated.

My first question is why clozapine would be available in the post apocalyptic pharmacy?   In any shorter term situation the medications that run out first are maintenance medications for chronic conditions.  In this case, the survivors are supposed to be in Grady Memorial Hospital, one of the largest hospitals in Atlanta.  I suppose it is possible that they would have a larger supply of clozapine since they are a metro hospital and if psychiatric services were as bad before the apocalypse as they currently are they would typically have a significant number of people in the emergency department that may be taking clozapine.  The second question is - can it be given intramuscularly?  It turns out it can be.  A 1999 reference from Lokshin, et al describes their use of parenteral clozapine in 59 patients.  They are using the drug for acute stabilization of inpatients and they do not describe whether or not their patients are taking other medications or are medication naive.  They do not specify dosing but in one case described the problems with giving large intramuscular injections of up to 300 mg in injectable clozapine when  patient refused the same oral dose.  They had surprisingly few side effects, no fatalities, and no seizures.   Unless I missed a reference somewhere this may suggest that the author of The Walking Dead episode believed that clozapine is a lot more toxic (and lethal) than it really is.   Or do they have access to other information?  That also brings up the question, if you were a physician with access to the post-apocalyptic pharmacy would there be more toxic and more lethal medication that could be used for that purpose.  Most probably, but I will not be speculating about that here.

There are a large number of questions that come up if you think about the possible intentions or biases here that involve the use of clozapine in a fictional plot.  In situations like this, I prefer to contact the author directly and ask them what they were thinking.  After a significant amount of time searching, I learned that there may have been some controversy with the writers of this series, but I could not find a single e-mail or snail mail address where I could send them that question.  I would certainly prefer to get an answer from the author or authors.  How did they first hear about clozapine?  Why did they decide to use it in this case?  Do they have a medical advisor who suggested it?  Do they have a personal relationship with anyone who takes clozapine?  Do they have an opinion about the medical treatment of psychiatric disorders in general?  There is really a long list of questions.

And finally there are also the practical treatment implications.  Up to 17.3 million people watch The Walking Dead, a large percentage of them 18-49 year olds.  I am sure that  has implications for informed consent conversations between psychiatrists and patients and their families.  We live in a country where 21% of 18-29 year olds get their news about Presidential campaigns from The Daily Show.  After hearing the name from a psychiatrist somebody is bound to say:  "Wasn't that the medication that we heard about on The Walking Dead?"  The standard reply is that medical conventions and treatments are not immune to artistic interpretation and all areas of medicine are similarly affected.

I may be missing something but it just seems like an unusual choice for this medication in this plot to me.

George Dawson, MD, DFAPA


1: Lokshin P, Lerner V, Miodownik C, Dobrusin M, Belmaker RH. Parenteral clozapine: five years of experience. J Clin Psychopharmacol. 1999 Oct;19(5):479-80. PubMed PMID: 10505595.

Thursday, November 6, 2014

The Shadow State Hospital System

Up until fairly recently, every psychiatrist at some point in their career was aware of a state hospital system.  The state hospitals were at one point the only available resource for long term care for most residents in a state.  They were also the facilities designated to care for people who were mentally ill and in some cases designated as dangerous to society.  That includes a population  with severe neuropsychiatric illness who have disorders that do not respond well to treatment and always represent some risk in terms of chronic aggressive behavior.  There is a population of people who are adjudicated as mentally ill but criminally culpable - that is they have failed a Not Guilty By Reason of Insanity (NGRI) defense.  This same group can be in a state facility being treated to the point where they are competent to proceed to trial or the minority group of NGRI defendants who have been adjudicated as not guilty but still need treatment before they can be released.  There is an assumption at some nonmedical level that psychopaths and people with antisocial personality disorders associated with aggression can be separated from the mentally ill persons and sent to the correctional system while some of those same definitions result in indefinite stays in specialized state mental hospitals.  The legal systems of some states designate certain forms of psychopathy or other criminal behavior a mental illness in order to allow for indefinite detention of people who are considered to have committed more heinous crimes like violent sexual offenses or sexual offenses against minors.

 At one point there were very large numbers of persons in state mental hospitals.  Two historic movements resulted in large numbers of these patients being released.  The first was the deinstitutionalization movement.  Historian Edward Shorter attributes the start of deinstitutionalization to psychopharmacology - specifically the invention of chlorpromazine that was FDA approved in 1954.  According to Shorter, the total number of patients in state and county mental hospitals declined from a high of 559,000 in 1955 to a low of 107,000 in 1980 or an 80% decrease.  In reality, many of the discharged patients did not take the medication reliably or developed side effects.  Shorter credits the "antipsychiatry movement" with providing continued impetus for state hospital discharges by suggesting that the institutions could be replaced by ""therapeutic communities" - a romanticized version of welcoming friends and neighbors clasping the mentally ill to their bosoms."  He also credits the National Institute of Mental Health with promoting this view.  The movement led to large numbers of mentally ill persons being homeless, not cared for medically or physically,  and  with dwindling resources for outpatient medical care when Community Mental Health Centers started to focus on providing psychotherapy for people without severe mental illnesses.  The Treatment Advocacy Center looks at available bed per 100,000 population as a rate.  They put the minimum acceptable figure at 50 beds/100,000.  In 1955, there were 344 beds per 100,000.  In 2005, that number had dwindled down to an average of 17/100,000 with a range of 7.1 to 50.  According to that same report 42 of 50 states had less than the minimum recommended number.

My copy of Shorter's text was published in 1997 and it says nothing about the managed care era and the effect of managed care on state hospital systems and the community systems of care that were supposed to be there to treat the deinstitutionalized.  There were few of these systems at the outset.  In the 1970s and 1980s there was the beginning of a larger community psychiatry movement and some experts began to develop systems of care to support patients who had been in state hospitals in the community.  Those systems of care were by far the exceptions rather than the rule.  When managed care took over there was no longer an asylum or a containment function in community hospitals.  People with severe mental illnesses could no longer go to short term hospitals because they were no longer able to function or they had numerous problems that were too difficult to be managed in an outpatient setting.  The only reason for hospitalization was the managed care concept of "dangerousness".  Suddenly it no longer mattered if you were manic and squandering your resources, ruining your marriage and losing your job.  Unless "suicidality" was detected or there were threats to kill somebody, a person would be discharged from the emergency department.  Not only that but, anything said in the emergency department was now taken at face value.  A patient could have been tearing up their home, obviously paranoid and threatening a neighbor.   As long as that person said he or she had no intent to harm themselves or anyone else,  they would be discharged even if the family bringing them to the hospital was horrified with that decision.  That is the state of managed care and its impact on psychiatry even to this day.  The reason is quite clear.  Several studies have shown that adequate community treatment of some persons with mental illness may be no less expensive than state hospital treatment.  It is only by providing rationed or no treatment at all that a state or health care company saves money.  That is also referred to as "cost-effective" care by the people who are rationing care.

The other interesting twist is the spin put on deinstitutionalization.  I know one of the leading proponents of this process in the 1970s and had him as an individual supervisor.  I can still recall his presentation about why he became interested in community psychiatry and was one of the leaders.  It was a single black and white photo of a large gymnasium sized room in a state hospital.  There were about a hundred men in the photo and there was room enough to have all of their cots arranged edge-to-edge across the floor.  So never let it be said that state hospitals were luxurious places to begin with.  That fact alone was one of the main reasons that psychiatrists were interested in getting patients out.  

So what is the shadow state hospital system?  At the first level it is an administrative one.  The administrative systems for any state hospital systems have always been fairly intensive.  At some point, there is a predictable scandal and a political reaction to the fact that the many of  these hospitals were mismanaged by the political system in the first place.  It is another case of politicians reinventing themselves by reforming something that they mismanaged  in the first place.  Some clear examples include each of the following:

1.  People with psychiatric illnesses used to pack state hospitals and now they pack jails and emergency departments.  One of the primary goals of the shadow state hospital is to give the public the impression that this is more human and more effective treatment than real state hospitals run by psychiatrists.  It also effectively removes a large block of people with chronic mental illness from active treatment relationships with psychiatrists.  Any family advocates for these patients and psychiatrists themselves can unite to advocate for these patients but they are neutralized when the system is managed to allow a few 20 minute appointments with the psychiatrist per year.

2.  Rationing to the point of of the absurd is a theme that crops up on a regular basis over time.  That is true, whether you were an asylum psychiatrist seeing 500 patients or a hospital where serious injuries to staff and patients occurs.  Another goal of the shadow state hospital is to give the impression that no matter what, administrators somehow have special knowledge on how to run psychiatric services.  Nothing could be further from the truth.  The psychiatrists themselves end up jumping through a large number of administrative hoops since they are caught in this endless stream of bureaucracy and have less and less time for direct patient contact.  Bureaucrats with no appreciation of clinical medicine lack an appreciation for two critical factors in psychiatry.  Those factors are the quality of all assessments of a patient's problem depends on the time spent in direct contact with that patient.  The quality of any intervention including the prescription of medication also depends on time spent with the patient.  Together that time and relationship with the patient is the best predictor of outcome.  All administrative measures in the shadow state hospital seem to be designed to negatively impact that parameter, including the replacement of psychiatrists by "prescribers."

3.  The shadow state hospital doesn't really need psychiatrists.  Despite the fact that psychiatrists have (by far) the most training of any group of physicians or mental health professionals in hospital care and care of patients with the most serious mental illness, all of the administrative focus is the general elimination of psychiatrists.  I think it makes perfect sense from the administrative side.  If you are an administrator who is accountable to politicians or government bureaucrats - eliminating psychiatrists accomplishes two goals.  The first is taking out any professional opposition to any measures that you decide to implement from the perspective of a person with little to no training in the treatment of mental illness.  The second, is having a group of professional employees to scapegoat.  What better arrangement could there be than hiring people who are overworked to the point that they have little time left to muster any opposition to your plans and that same overworking in a dangerous environment puts them at risk for adverse events that they can ultimately be blamed for?  All of these events are the predictable outcome of people working in a split environment.

4.  Collecting data on citizens for reasons other than their psychiatric care.  To address the ongoing problem of gun violence by some of the mentally ill, many states have adopted legislation that allows a bureaucrat to collect data on people who have been committed for the purpose of putting them on a master list to prevent them from acquiring firearms.  The number of people denied in this manner is very small compared with domestic violence perpetrators or felons, but that doesn't prevent this false solution to the problem of gun violence at the cost of collecting this data.  In many states the only way to get into any existing mental health facilities is by civil commitment.  There is also a process for collecting financial data on the same population for the purpose of collecting money for the cost of hospitalization.  Is it ethically correct to forcibly collect fees from people with few resources who have been court ordered to get treatment?  I don't think so but apparently state and county governments do.

5.  Creating more administrative burdens to adequate treatment.  Some people who were previously treated in state hospitals are in foster care settings.  In Minnesota there was a recent ruling about developmentally disabled patients in a state hospital being secluded and restrained excessively.   That resulted in a long court ruling that applied to that incident and resulted in a financial reward to members of the class action suit, the closing of that hospital, and several administrative procedures that started to affect the providers of adult foster care.  In one case the administration of any "as needed" medication including sedatives for sleep, anti-anxiety medications, and antipsychotic medications - required a foster care provider to go online and complete a 7 page report.  Even a few extra doctor ordered doses of medication per week results in a tremendous paper work burden.  This burden was created for people who have been in stable foster care situations for years and who had been receiving excellent medical and psychiatric care.

6.  The prevention of violence and the care of the violent or aggressive patient in the community is a more bothersome situation.  Several years ago, a friend of mine told me that his son was involved in staffing a small group home that specialized in the treatment and support of violent mentally ill patients in their own adult foster care setting.  If the patient because aggressive, the staff would use pads to hold the patient to the floor until the aggression passed.  I was shocked to hear about this arrangement because there was no onsite supervision or training by anyone specializing in the treatment and containment of a physically aggressive person with mental illness.  Treating this behavior in a hospital setting with a well trained staff and clear support by the administration is difficult enough.  Now it seems that we have mini-facilities trying to provide some level of containment for aggression in residential buildings with a few staff on site.

7.  The use of limited state hospital resources for political purposes continues.  The best example is commitment for psychopathy or sexual offenses, both disorders that have no treatment and are not considered psychiatric disorders in most cases by the legal authorities.  How is it that people committing sexual offenses are hospitalized indefinitely and people with severe mental illnesses are refused admission to hospitals and eventually incarcerated for minor crimes?  Only through a shadow system.

8.  The large population of mentally ill persons who are continuously cycling between the emergency department (ED), very brief and ineffective stays on short term psychiatric units, and jail.  This constant churning is typically covered in the press as a reason for overcrowding of the ED, but the real travesty is that these patients never get their psychiatric and social problems resolved and that keeps them cycling in and out.  Discharging a person with a severe mental illness from a short term psychiatric unit or the ED does not solve anything for that person.  It is nothing more than an expensive time out.

9.  The family as hospital staff has always been with us but it has not been as prevalent since the 1950s or 1960s.  I can recall violent and aggressive patients cared for at home to the point that the entire home was trashed and family members and the patient in question had frequent severe injuries.  Short of that scenario, it is much more common today that a family becomes the default hospital staff in cases where a person with severe mental illness does not meet the managed care "dangerousness criteria" for admission.  That means the patient does not tell an emergency room physician or social worker that they are going to kill themselves or become aggressive.  Family members recognize the person needs supervision and monitoring 24 hours a day/7days a week.  I have really never met a family who could do that for more than a couple of days.  Of course they should never be put in that position, especially with the fees and taxes that every family pays for health care in this country.  Anybody who requires 24/7 supervision should be in the care of professional staff who can offer appropriate therapy and maintain a neutral relationship with the affected person.

10.  It is all about the money.  The war cry of managed care systems, government systems, and government systems managed like they are managed care systems is "cost effectiveness".  It has been known since the Hay Report that psychiatric and mental health systems took a disproportionate hit relative to all other areas medicine.  There has never really been an informed discussion of what  a reasonable budget for the provision of mental health services should be.   The cost of services is often impossible to find.  That is a bureaucratic recipe for transferring money somewhere else.  Even standard bureaucratic solutions like "a 5% budgetary cut across the board" will obviously hit the most marginally funded systems first and the hardest.  Those services are psychiatric services.  The Shadow State Hospital System can function as a funding source for other projects at the cost of providing treatment for persons with severe mental illness.

11.  Let's all pretend that there is a real State Hospital System.  The front end of this illusion usually starts out when a person actually meets managed care "dangerousness criteria" and the hospital case managers cannot discharge them.  In this case, the court usually assists the hospital in getting the patient out.  For example,  there used to be a system to commit patients with substance use problems to treatment.  Those patients are frequently released by courts on the basis that they "no longer do chemical dependency commitments".  In the case of severely disabled patients with mental illness, the court may ignore that standard in a state commitment statutes and release the person for not being imminently dangerous.  In both cases the patient is hospitalized for a few days longer than the 3-5 day managed care length of stay instead of being committed to a system of care.   It appears as though something has occurred but it really has not.  

The Shadow State Hospital System allows the state and its partners in private business to establish covert control over any mental health system of care - to the detriment of the professionals and patients in that system.  The exact number of administrative measures and facilities like the ones I outlined above are unknown.  Shadow systems thrive on a lack of transparency, at least until the next scandal happens.  At that point there seems to be some level of transparency, but it is always incomplete and the real story of what happened and why never seems to surface.

The real state hospitals systems were far from perfect, but it is time for medical accountability to replace government bureaucrats and the very weak standard of accountability of these bureaucrats.  Until the Shadow State Hospital System is recognized as the prime example of mismanaged care we will not be able to address the miscalculations of deinstutionalization or what Shorter called:

" of the greatest social debacles of our time."

George Dawson, MD, DFAPA


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

Supplementary 1:  The image used for this post is of Dexter Asylum attributed to Lawrence E. Tilley [Public domain], via Wikimedia Commons.  The original image was Photoshopped with a graphic pen filter.

Wednesday, October 29, 2014

The Antidepressant Black Box Warning - A Better Solution

There were two opinion pieces in the New England Journal of Medicine this week on the antidepressant black box warning.  Richard A. Friedman, MD contends that the warning had an adverse effect on antidepressant prescriptions, a decreased rates of new depression diagnoses, increase in psychotropic drug poisoning (as a proxy measure for suicide attempts)  and that is reflected in an increase in the rate of completed suicides in people from 10-34 years of age between 1999 and 2010.  He argues for removing the warning entirely.  Marc B. Stone, MD points out that there is contradictory data showing that an increase in suicide rates and no good correlation with an increase in rate and the year of the boxed warning.   He discusses other factors that can result in fluctuating levels of depression diagnosis and treatment, including a change in antidepressant marketing because many antidepressant were becoming generic at the time and how that may have affected the prescription rates.  He cites CDC data on the rate of intentional versus non-intentional overdose as a more appropriate metric and points out that rate was lower both before and after the warning.  He concludes that despite many efforts there is no real correlation between the warning and suicide rates.  Disclosure forms will be available when the article becomes available online but for now Dr. Friedman appears to be affiliated with the Department of Psychiatry, Weill Medical College of Cornell University and Dr. Stone is affiliated with the FDA.

One of the central problems with the debate is the problem of looking at statistical significance in low rates on a longitudinal basis.  In all of the studies I have seen and in these debates, the longitudinal data is almost always interpreted as correlational (we seem to never be able to determine causality) and there appear to be endless number of correlations - and none of them are mathematical.  In these articles alone the authors looked at drug company marketing and sales strategies, the impact of the original warning, the impact of the revised warning,  the impact of the discussion in the media as opposed to the warning, the diagnostic patterns of physician, the impact of managed care and pharmacy benefit managers, and the prescribing patterns of physician (broad versus narrow) as possible correlates.  All of this is analyzed at a qualitative level and apparently not by anyone who is an expert in the analysis of longitudinal data.  The debate becomes a series of true or false statements based on snapshots.  That to me is essentially a political analysis of the data and it seems to lead nowhere.  It can be a question of "my data being better than your data" but it is not the kind a probabilistic analysis that physicians are trained to do.  The central question here is whether the original FDA meta-analysis of clinical trials showing a 4% to 2% ratio of "suicidality" in the treated versus placebo group is valid and what should be done about it, keeping in mind that suicidality did not confer any increased risk of completed suicide.  In this case Dr. Friedman agreed that something should be done based on that meta-analysis so both authors would agree that finding is significant.

They differ on what existing data mean and what should be done.  As a clinical psychiatrist  who deals with side effects at least as much as symptoms of depression and anxiety, I think a lot could be done to improve the awareness of side effects and improve treatment.  The solution is a lot less drastic but more comprehensive than a Black Box Warning.   After all, it is highly likely that most people are going to encounter more common and potentially problematic side effects than intrusive suicidal thoughts  or suicide attempts.   That is probably as true for medications without a black box warning as medications with a black box warning.  Even considering another class of medications with a warning about suicidal ideation - anticonvulsants, says nothing about whether a patient is more likely to experience those thoughts with the anticonvulsant or the antidepressant.  Depression is a common problem in people with epilepsy, what about people needing to take both an anticonvulsant and an antidepressant?

My recommended approach to the problem would resolve a couple of issues.  It would emphasize to the public that a choice to take a medication is not without risk and is not a guarantee of a cure.  That one cannot assume that an FDA approved medication is totally benign and will be completely effective for their problems.  The FDA is unique in terms of the efficacy, side effects, and pharmacosurveillance data that they collect.  They are also not transparent with it.  In that context they expect physicians to make sense out of what is presented to patients in the risk-benefit discussion of whether or not to take a medication.  That leaves the benefit discussion full of unnecessary guesswork about what does and what does not need to be discussed.  In that context a black box warning is just another rare cloud on the horizon.  Using the Back Box warning as a standard, a doubling of suicidality from 2% to 4% with no completed suicides with antidepressants is on par with a 1-6/10,000 chance of Stevens-Johnson's syndrome from carbamazepine.

The solution here is an FDA attachment to the package insert of what needs to be discussed with the patient to give them a better idea of the risks and benefits of a particular medication.  It makes no sense at all to feel forced into a discussion of suicidality from taking a medication when far more patients will experience fatigue, headaches, diarrhea, and discontinuation symptoms.  I have attached a sample of a general outline of what needs to be covered.  I think that Medline plus medication handouts could also be considered.  The FDA can specify what these points are for every medication.  If the psychiatric profession has not set a standard, it is time for the regulators to do more than issue confusing black box warnings and back it up with all of the data in an accessible format on their very confusing web site.  You can bet that the managed care industry does not want their psychiatrists spending an extra few minutes with a patient to have this discussion.  The regulator in this case has a unique opportunity to set a uniform standard for side effect discussions based on the priorities they establish from both clinical trials and pharmacosurveillance.   The solution to the debate of the toxic or non-toxic black box warning is as simple as that.

Most importantly the physicians having the discussion with the patient can document "The FDA recommended risk/benefit discussion for this medication was completed with the patient."

George Dawson, MD, DFAPA    

Friedman RA.  Antidepressants' black box warning 10 years later.  N. Engl J Med 2014;317;18: 1666-1668.

Stone MA.  The FDA warning on antidepressants and suicidality - why the controversy?   N. Engl J Med 2014;317;18: 1666-1668.

Peter Diggle, Patrick Heagerty, Kung-Yee Liang, Scott L. Zeger.  Analysis of Longitudinal Data.  Oxford University Press.  Oxford.  Second Edition 2002.

Tuesday, October 28, 2014

Non-adherence And Other Reasons To Doubt Clinical Trials

In a word - adherence or what we used to call compliance.  That is whether the drug is taken at all or whether it is being taken according the the prescription.  Adherence is an important aspect of the working alliance with any physician.  The only accurate way to determine a response to a medication depends on whether it is being taken correctly and the person taking the medication is describing a true treatment response and true side effects.   Many patients  do not take the medication as prescribed for various reasons.  The question of adherence takes on an equally important role in clinical trials.  If non-adherence is present it affects the statistical power of the study.  Sample sizes are often calculated to bring the study into a range where the sample is considered to have an adequate number of subjects.  Non-adherence rates can adversely affect that estimation.  There is also the question of whether non-adherence reflects another issue related to the medication like side effects.   The related research question is whether non-adherence is evenly distributed across the groups taking the study drug and the placebo group.  In previous discussions of the placebo response in drug trials of psychiatric drugs I have not seen adherence discussed as a critical factor.

A brief news report in Science this week by Kelly Servick provides a good discussion of the adherence issue from a number of perspectives.  The central graphic is from a paper by Blashke, et al (2) showing summary data of electronic monitoring of medication adherence from 95 clinical trials that shows decreased adherence rates in terms of taking the medication and taking the medication as prescribed.  Both fall off significantly over time.   By 100 days 20% of subjects have stopped taking the medication and about 30% are no longer taking it as prescribed.  Those are substantial numbers especially if the active drug can be identified by a specific effect or side effect and discontinued on that basis.  In a field where there is a significant placebo response among subjects with mild to moderate illness non-adherence can lead to significant problems in the final outcome and overall worth of the study.

According to Servick the typical approach used in the past has been to recruit enough subjects to counter the low adherence rates.  This is problematic for a number of reasons.  Subjects these days are often from nonclinical samples.  On college campuses this can be a problem with some subjects volunteering for multiple studies.  With psychiatric drug trials, the recruitment criteria are subjective, obvious, and selection is often coordinated by non-physician research coordinators whose job it is to get the required number of volunteers  in a specified period of time.   In the drug trials that I am personally aware of only Alzheimer's disease trials asked for corroboration from sources other than the patients on how they were able to function on a daily basis.  It would be very interesting to obtain that kind of data on subjects recruited from University campuses who were still attending classes especially if some incentive was involved.  In a related matter, one of the investigators in this area created a database to identify potential subjects who came in for screening at various sites where he was an investigator.  Up to 7.78% of the subjects across 9 sites were identified as duplicates (3).   Because of the potential negative effect of duplicate subjects the authors suggest that a nation wide database of subject should be considered.

The article looks at a number of measures to determine the level of adherence in a study.  The first take home message is that pill counts are relatively meaningless.  I have certainly talked with research subjects who told me that their blister packs were empty because they just threw the pills away.  In a study that compared pills counts with blood levels of the drug the sample sample had an adherence rate  of 92% by pill count but only 70% by blood levels.  The author cites medication side effects as a reason for non-adherence, but in a complex sample of patients with varying levels of motivation and insight the reasons can be very complex.  Several electronic approaches to adherence have been devised that vary from a chip in the pill bottle cap that records when the bottle is opened and closed (MEMS system) to a chip in a pill that records when it is ingested.

Adherence measures are another dimension to look for when reading the results of clinical trials.   I don't recall seeing any commentary on this important issue in Cochrane reviews and probably with good reason.   Non-adherence rates this high are probably at least as important as what Cochrane typically discusses as technical problems like small sample size and measurement problems.  Blaschke is quoted in the Servick article that many of the researchers in this area feel that the problem is bigger than one that can be detected by surveillance and databases.  To me this comes down to the limitations of clinical trials and a problem that cannot be potentially solved.  Certainly the days of research units where subjects could be supervised in inpatient settings for months is gone.  In most cases, persons with severe psychiatric disorders can only get that kind of treatment if they can personally pay for it or the state they live in has a state psychiatric facility.  Even then they often have to undergo civil commitment.  A practical solution would be to eliminate the obviously non-adherent subjects and not include them in any intent-to-treat analysis and use a standard adherence measure such as blood levels where appropriate.  Ambivalence about taking a drug in a research protocol is not the same thing as stopping an FDA approved drug in a clinical setting, but that conscious state has not been adequately studied.

George Dawson, MD, DFAPA

Supplementary 1:  In researching this article I was very pleased to find the full text of Blaschke, et al online but also a reference to the National Academy of Sciences Committee on National Statistics.  That site contains a report The Prevention and Treatment of Missing Data in Clinical Trials that was references in the  original Science article.  The full article can be obtained at no cost form that site with registration.

1: Servick K. Nonadherence: a bitter pill for drug trials. Science 17 October 2014: Vol. 346 no. 6207 pp. 288-289  DOI: 10.1126/science.346.6207.288

2: Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol. 2012;52:275-301. doi:10.1146/annurev-pharmtox-011711-113247. Epub 2011 Sep 19. Review. PubMed PMID: 21942628

3: Shiovitz TM, Wilcox CS, Gevorgyan L, Shawkat A. CNS sites cooperate to detect duplicate subjects with a clinical trial subject registry. Innov Clin Neurosci. 2013 Feb;10(2):17-21. PubMed PMID: 23556138.

4: Czobor P, Skolnick P. The secrets of a successful clinical trial: compliance, compliance, and compliance. Mol Interv. 2011 Apr;11(2):107-10. doi: 10.1124/mi.11.2.8. PubMed PMID: 21540470; PubMed Central PMCID: PMC3109858.

5:  General search on adherence related articles

Sunday, October 26, 2014

A Head Full Of Prior Probabilities

I read an article in Science recently that reminded me of why I am a subscriber.  The article had to do with a model of rational thinking based on the neurobiology of the several critical brain structures, the prefrontal cortex (PFC), dorsal striatum, ventral striatum, and anterior cingulate cortex.  The interesting aspect of this model is that is also takes into account Bayesian analysis and uses that to build a model for how the can make use of these unique neuroanatomical local structures and come up with novel solutions in uncertain environments.

For about 15 years I taught a course that was designed to minimize diagnostic errors when physicians consider the question:  "Is this a medical condition or a psychiatric disorder?"  On of the first cases I would use is a hypothetical case of a teenage girl admitted to a hospital for dehydration secondary to acute gastroenteritis.  In this case the psychiatrist is consulted because the patient began to manifest acute agitation.  This was an acute behavioral change and that was confirmed by family members who had never seen the patient like this before.  The consult to the psychiatrist read: "Please see to assess and treat hysterical behavior."

On the diagnostic side there are several prior probabilities to consider.  In medicine, I like to consider prior probabilities as those of a particular finding or condition that exists is a particular population in the wild.  In this case a few to consider would be:

1.  The prior probability of "hysteria" in teenage girls with no previous behavior problems.  What is hysteria?

2.  The prior probability of acute mental status changes in teenagers with no medical conditions.

3.  The prior probability of teenage girls with no medical problems being in a hospital bed being rehydrated with I.V. fluid therapy.

4.  The prior probability of acute mental status changes in teenagers with no psychiatric or substance use disorders.

Considering 1-> 4, it should be evident that all of the corresponding probabilities are very low.  It would difficult to rank order them on that basis and it suggests the need for more hypothesis generation or data acquisition.   As we examine the patient we realize that cannot produce any meaningful verbal response, she has opisthotonic posturing and decorticate posturing on the left in response to painful stimuli.  The next set of prior probabilities is more declarative:

1.  The posterior probability of a brain problem with opisthotonic posturing and findings 1 - 4.

2.  The posterior probability of an acute brain problem with decorticate posturing and findings 1 - 4.

Suddenly with the examination findings - one specific and the other not - the probabilities of a severe life threatening brain problem have gone through the roof.  The patient appears to be acutely encephalopathic with an impending brain stem herniation syndrome.  This is no longer a patient who should be in a non-acute care bed in the hospital or a patient who needs acute psychiatric care.  She belongs in an intensive care unit, hopefully one that specializes in treating acute, life-threatening neurological disorders so that the problem of increased intracranial pressure can be addressed.  That important decision is made with a two minute examination of the patient at the bedside.  She is transferred to a neurological ICU for more appropriate care.

Without going into too many details about Bayesian inference other than this example, I have never really seen it referred to from a neurobiological perspective.  The new paper by Donoso, et al makes the connection in the introductory paragraphs:

"Human reasoning subserves adaptive behavior and has evolved facing the uncertainty of everyday environments. In such situations, probabilistic inferential processes (i.e., Bayesian inferences) make optimal use of available information for making decisions. Human reasoning involves Bayesian inferences accounting for human responses that often deviate from formal logic (1). Bayesian inferences also operate in the prefrontal cortex (PFC) and guide behavioral choices (23). Everyday environments, however, are changing and open-ended, so that the range of uncertain situations and associated behavioral strategies (i.e., internal maps linking stimuli, actions, and expected outcomes) becomes potentially infinite."

The Wisconsin Card Sorting Test (WCST), a well known neuropsychological measure of frontal lobe mental flexibility.  In the test the subject's task is to sort cards based on shapes, colors, or the number of objects per card.  The sorting paradigm is not made explicit and every time the examiner changes it, the test subject needs to figure it out and start sorting cards according to that new paradigm.  Results can be correct, exploratory, incorrect or perseverative.  Perseverative can be defined as a continuous repetitive sorting error that does not take into account the need for error correction - continuing to use a response that was at one point correct.

At this point there are many imaging studies that look at correlates between functional brain scans and performance on the WCST.  In this study the authors look at a custom variation of the sorting tests where subjects were looking for digit combinations by trial and error and produce a response that was exploratory, perseverative or correct based on feedback about the correctness of choices.  All subject were young (18-26 years old) and screened for medical, neurological, and psychiatric disorders).  There were a total of 40 test subjects equally split by sex.  The article contains a detailed discussion of the subjects response patterns relative to a theoretical model, but I am most interested in the brain imaging results and the implications of those results.

Working in the addiction field, it is fairly common these days to read research studies that look at activation of the ventral striatum.  There are also theories about which neural circuits are responsible for most aspects of addiction including the initial euphorigenic effects,  acute behaviors involving positive reinforcement, and chronic compulsive effects associated with negative reinforcement.  I think that there is an general conceptualization that there are varying levels of euphoria associated with activation of the ventral striatum whether that is from an addictive drug or what has been considered to be "natural" activators of the ventral striatum including food, water, sexual behavior, and social affiliation.  This is the first study that I have seen showing that activation of the ventral striatum is associated with the cognitive aspects of life.  In correspondence with the lead author Etienne Koechlin his group refers to this as the "Eureka Response".  He suggests that the ventral striatum adds and affective valence to a cognitive strategy that has been selected by the frontal cortex as a correct strategy and that  valence contributes to consolidation in long term memory.  He points out that the cognitive system needs the affective role of the ventral striatum to run properly.

If this paper can be replicated this is really landmark work.  It provides a neurobiological explanation for why we can choose among several prior probabilities in important situations.  In terms of clinical decision making it may be why senior clinicians have immediate associations to critical cases when they are involved in subsequent clinical decision making.  That process has been looked at in terms of pattern matching and pattern completion in the past but an affective valence adds another important dimension.

This is potentially one of the most important papers and theories I have seen in recent times.  It has broad implications for psychiatry, addiction, cognitive psychology, and many other fields.  An affective valence from the ventral striatum may make living with a head full of prior probabilities - a lot easier.

George Dawson, MD, DFAPA

Supplementary 1:  The following table lists the common neuroanatomical abbreviations used in this paper:

1: Donoso M, Collins AG, Koechlin E. Human cognition. Foundations of human reasoning in the prefrontal cortex. Science. 2014 Jun 27;344(6191):1481-6. doi: 10.1126/science.1252254. Epub 2014 May 29. PubMed PMID: 24876345.

2:  Albert DA, Munson R, Resnick MD.  Reasoning in Medicine: An Introduction To Clinical Inference.  The Johns Hopkins University Press.  Baltimore. 1988.

"Our aim is to dig deep into the clinical mind and lay bare the processes of reasoning and inference that are (or can be) involved in arriving at and in justifying clinical decisions."