Muhammad Ali - The Social Context Of A 15 -year old

I occasionally post in a local political forum in Minnesota.  I generally try to avoid it because politics in science is interesting at severals levels but the politics of American political parties is not nearly as interesting.  The biases and political responses are always predictable. It is always a mystery to me why there are so few reasonable candidates.  A few friends who have run for office and not made it on party ballots have given me their opinions, but this post is not about that.  The other aspect of politics as I have stated hundreds of times on this blog is how it gets transacted in academia and professionally.  The biases are again evident.  In science nobody seems to take complexity into account on reproducibility issues or the unconscious biases of the researchers.  In looking at conflicts of interest, nobody seems to take into account that in many cases (like the price of pharmaceuticals) that there are clearly some conflicts of interest that trump most of the others.  But again, this post is about one aspect of politics and that is connectedness to the candidate.

Today - I was reading my e-mails from the political forum and I came across a statement about how Barack Obama did not connect well to the middle class.  I think that the research shows no matter where you end up in life, your class identification stays where you were when you grew up.  That would place me solidly in the middle class - in the lower half if socioeconomic status means anything.  I have seen a lot of Barack Obama and can appreciate his charisma, intelligence, ability to communicate and personality.  As a small "i" independent I don't always agree with his politics, but there is no doubt that this is a guy who I can relate to and I have very high regard for.  I want nothing but the best for him.  In thinking about why that might be, I reflected on another prominent American in the news this weekend - Muhammad Ali.

Listening to a lot of news this weekend about his passing - I like George Foreman's comments the best.  This is an excerpt of a CNN video of George Foreman on meeting Muhammad Ali in New York City sometime after their fight in Zaire:  

"....Everybody falls in love with him.  You can't help it. He was one good looking, lovable guy.  I was excited to meet him and happy to be his friend." -  CNN - June 5, 2016.

I never came close to meeting Muhammad Ali.  I have never attended a boxing match and even if I did, by the time I could afford it he would have been retired.  My initial experience was as an early teenager in a remote outpost in northern Wisconsin.  The communication in those days was primitive - just newspapers, magazines, radio and television broadcasted out from Duluth over the airwaves to your antenna.  There were three television channels and on a good day - you could see two out of three.  My grandfather would often say: "They've got kids running those TV stations." to describe the predicament.  It was a long time before they could send a clear signal.  Even in those primitive pre-Internet days, Muhammad Ali could dominate a long news cycle with his comments and the press and others reacting to those comments.  There were a long series of controversies.  As a young guy he was probably the most exciting sports figure to watch.  He was verbose at times, articulate, and he had a great sense of humor.  When he was saying something that many considered to be outrageous, he was smiling and I had the sense that he knew exactly what he was doing.  He would also not back down from an argument even when he was being videotaped.  No matter what he was saying, I found myself nodding in agreement with him.  The  other sports heroes I had at the time were shallow by comparison.  No other sports figure could comment at length on American culture, religion, and philosophy.  There were no other sports figures who had such an active relationship with their fans.   

But the most striking thing I remember, is that older generations of men did not react the same way.  Most of what Ali did made them very angry.  And of course at times they characterized him in very ugly racist language.  Racism was rampant at the time, and it was everywhere.  In rural areas, it wasn't obvious because there were no black people.  My father was a railroad engineer and as a special day, he would take me to the roundhouse with him.  The roundhouse was the industrial side of the  railroad.  All of the engines were housed in a roundhouse, just off a large turntable that allowed them to be rotated 180 degrees and connected with the main line.  There was a very plain locker room with various signs encouraging adequate hygiene.  In the room at the far end was an area designated for porters.  I asked my father who the porters were, but I never got an answer and I never saw a porter.  Passenger traffic had just about ended by then and the only thing the trains were hauling was iron ore, coal, and large bundles of scrap paper for recycling.

As a 15 year old, I had to bite my tongue while the old guys in the room cheered for anyone to beat Ali or while they criticized his boxing skills or just made outrageous comments.  But it was the 1960s and the culture was rapidly changing.  Young people were getting louder and norms that had been in place for a generation were no longer accepted.  It was easier at first to publicly agree with Ali's stand as a conscientious objector, but it soon became obvious that you were a fan of the athlete and then the man.  I heard some commentators talk about the tumultuous times when Ali first grabbed the national spotlight, suggesting that had something to do with his fame.  I would see it as being the other way around.  A lot of young guys like me identified with him.  At some level it was teenage hero worship, but unlike the other sports figures - he did not go away.  He was an example of a sports legend who became a great man and on this weekend those stories abound.  I found a kindred spirit where I work and we have been exchanging Ali stories, pictures, and clips for the past few years.  Most of these stories are after his retirement from boxing and it is an impressive body of work.

Those were my associations to the notion that Barack Obama does not connect well with the middle class.  It is easy to identify with charismatic, intelligent, articulate, and empathic people.  I am sure that I am not the only 15 year old that had his eyes opened to that.  

And I won't be the last.

              

George Dawson, MD, DFAPA

Attribution:

1967 portrait of Muhammad Ali by Ira Rosenberg [Public domain], via Wikimedia Commons at: https://commons.wikimedia.org/wiki/File%3AMuhammad_Ali_NYWTS.jpg

In 1967, I was 15 years old.

Are Hallucinogens The New Miracle Drugs?

See Attribution 1 for full reference

Steve Jobs:  "Taking LSD was a profound experience, one of the most important things in my life.  LSD shows you that there's another side to the coin, and you can't remember it when it wears off, but you know it.  It reinforced my sense of what was important - creating things instead of making money, putting things back into the stream of history and of human consciousness as much as I could."  (ref 1)

Woodstock (Chip Monck):  "To get back to the warning that I received. You may take it with however many grains of salt that you wish. That the brown acid that is circulating around us isn't too good. It is suggested that you stay away from that. Of course it's your own trip. So be my guest, but please be advised that there is a warning on that one, OK?" (ref 2)




Warning: The final few paragraphs of this post contain language that some may find offensive.  I included it for a reason.   In 30 years of practice and in my real life - I have found that many people talk this way.  If profanity offends you don't read the end of this post.



Everywhere I turn these days - whether it is a blog or more traditional media I am struck by the same stories on hallucinogens.  If you believe what you read out there, hallucinogens are magical drugs in that they are almost totally benign, consciousness expanding, and they can treat your anxiety or your depression.  They have been actively discriminated against like other illegal drugs and that is the only reason we have not done the research to prove that they can treat many problems.  Back in the 1970's we would have said that "The Man" is restricting access to valuable consciousness expanding drugs and if "The Man" was overthrown - the world would be a much better place.  I have briefly reviewed the same lines of rhetoric that occur with cannabis.  I have not heard similar arguments with ketamine, probably because fewer people have experience with it and it is a more difficult drug to use, even in a medical setting where the drug has a known concentration and purity.

Hallucinogens are a diverse set of compounds with a number of analogues of the parent compounds for each basic structure.  The DSM-5 does very little in terms of organizing the category other than saying that it might make sense to classify the dissociative hallucinogens like PCP and ketamine as a separate category from more traditional hallucinogens like LSD.  The DSM-5 does very little to attempt to classify the wide array of hallucinogens that are available at this point in time.  Some authors (3-6) use the term serotonergic or classic psychedelics such as LSD, DMT, and psilocybin (and see above graph).  I think it makes sense to classify any drug taken for the express purpose of creating hallucinations - a hallucinogen.  Drugs with secondary hallucinatory effects like alcohol, cannabis, and stimulants remain in unique categories because they can all cause hallucinations but they are generally not taken for that purpose,  More scientific classification approaches that are generally based on chemical structure are available in standard addiction texts.

As an addiction  psychiatrist, my experience is that hallucinogens are problematic drugs from a number of perspectives.  It is rare to see a pure hallucinogen user, at least until someone discovered that using high dose dextromethorphan (DXM) reliably produces hallucinations and delirium, is widely available, and inexpensive.  To that subgroup of patients many of them have a very difficult time stopping DXM.  The other problem with that drug is that excessive use of DXM in the predisposed person is common and the margin between the hallucinatory experience, toxicity and lethal overdose is not well characterized probably due to pharmacokinetic variability among subjects.  Reports of lethal ingestions in the medical literature are rare (5).  The hallucinogenic effect of DXM is from NMDA and PCP1 receptor antagonism.  DXM is metabolized by hepatic CYP2D6 so that other drugs that are inhibitors and poor metabolizer status may lead to unexpectedly higher levels of the compound in the plasma.  DXM  is also a serotonin reuptake inhibitor and a 5-HT1 direct agonist and can cause serotonin syndrome another potential cause of death when used with other serotonergic drugs.  PCP is another exception.  In my experience both PCP and DXM users are much more likely to use those drugs in an uncontrolled manner and addictive manner than other types of hallucinogens. There are seemingly rare but significant and in some cases fatal side effects from hallucinogens.  From a mental health standpoint, addiction specialists and general psychiatrists encounter patients with significant ongoing panic symptoms and perceptual disturbances that they attribute to the side effects of these medications.  The question is what is the frequency of these side effects and their significance?  An associated question is have there been any definitive studies?

Most of the recent epidemiology of hallucinogens has come from Krebs and Johansen.  Their 2013 study in PLOS was widely quotes in the news media as illustrating that classic hallucinogens are benign substances with little health risk.  Their work is based on the annual NSDUH survey of drug use in Americans.  They look at two small (N=192, N=156) cohorts of pure hallucinogen users in the NSDUH survey.  They outline the limited nature of this investigation based on the survey questions and the fact that this is a survey.  They cite other literature looking at people given LSD in clinical trials and other research and conclude that there is very little evidence for lasting side effects.  As an example, they could not corroborate that at least some people who taken hallucinogens have persistent problems with anxiety, panic attacks, or perceptual disturbances.  These are familiar themes in the new research on LSD noted in several of the additional references.  As a starter,  I read the articles (7-10) and came up with several unanswered questions.  Some are obvious in a technical sense and some are not so obvious.  Rather than get into a detailed critique of this and other papers, I thought I would outline what I see as missing in the claims made for the benign side effects profiles and efficacy of these drugs and look at more details in subsequent posts.


Efficacy for what?

These drugs in the broadest sense are not used to treat any specific collection of symptoms or syndromes.  Their popular indication for use has changed very little since the 1960s (3) and that is "mystical experiences, curiosity, and introspection."  At that level there is no medical indication for use.  They are being used to produce an altered state of consciousness like alcohol or any other recreational drug.  At that level the issue resembles in many ways medical cannabis, with the exception that cannabis seems to have some very preliminary evidence that it might be useful for some medical problems.  No such data exists for hallucinogens and psychedelics, but that is not for a lack of effort.  A recent meta-analysis discussed in Nature suggests that alcoholics treated with LSD are more likely to stay abstinent than those who are not.  The original experiments done in the 1970s, found no such correlation.  A recent paper in Lancet Psychiatry discusses application for the existential anxiety of the terminally ill and to facilitate psychotherapy.    So far the medical indications seem to be a bit of a stretch.  Using cannabis as the prototype, it seems that many parallel arguments are being made for hallucinogens.  From a rhetorical standpoint it is interesting that a common antipsychiatry criticism is that psychiatry has medicalized life in order to proliferate diagnoses and make more money for pharmaceutical companies.  Nobody seems to have any problems with cannabis or hallucinogen proponents medicalizing life in order to provide a useful venue for cannabis or hallucinogens.

As an adjunct for psychotherapy? 

There is a new recent review (14) of psilocybin and MDMA as assistive modalities in psychotherapy.  My read of this review is that the authors are proponents of these therapies.  They cite the lack of useful current therapies as a reason for exploring the therapeutic aspects of psychedelics.  That may be true to some extent but the usefulness of current therapies also depends on how broad the access is.  When I do a new assessment, I don't get the same global acceptance of therapy that some in the popular press suggest.  The impression I get is that the psychotherapy experience that most people get is suboptimal at best - and not because of the therapeutic modality.  It is often the technique of the therapist, economic considerations, managed care constraints, and/or the lack of any results.  The authors suggest that exploring psychedelics in these settings might offer better results and faster results.  I can't help but think about how therapy in real life, doesn't resemble what the psychotherapy in clinical trials is like.  Many people in managed care settings get two or three cursory sessions and they are discharged as doing better.  What happens if psychedelic assisted psychotherapy occurs in a managed care setting?  My guess is that the complex therapy is eliminated and the sessions where the drug is administered is emphasized.  The conditions for therapy reviewed include cancer anxiety, addiction (alcohol, tobacco and cocaine) and obsessive-compulsive disorder for psilocybin and PTSD, anxiety from life-threatening situations, and social anxiety in autistic adults for for MDMA.  There is minimal detail on the psychotherapeutic technique apart from some lengthy sessions.  Problems with blinding in controlled trials are discussed as an issue.  Lower dose psychedelics as the active placebo don't work.   Preliminary successes and speculation about the effect of the psychedelics and what they might be doing are discussed.  The main argument seems to be that there is ample reason to continue research in psychedelics.    


What can be measured?

All clinical trials in psychiatry lack objective measurements of both illness and improvement.  In the case of psychedelics some of these standard problems are still there.  Standard rating scales for anxiety and depression are used in some of these trials.  There are additional instruments such as the Altered States of Consciousness Questionnaire (ASQ) and the Psychotomimetic States Inventory (PSI).  It seems that an interest in purportedly consciousness expanding drugs may finally get some psychiatrists interested in consciousness as a dynamic multidimensional entity independent of syndrome definitions.  The problem of course is that these states are all highly subjective and resistant to classification.  It also highlights the question: "Is the psychedelic drug +/- psychotherapy supposed to target a typical syndrome of anxiety or depression or is there some other purpose, like altering the conscious state in some fundamental way?".  If that is true, we really have no idea how that can be measured or translated into therapy.  I would also suggest that it is outside the purview of physicians and psychiatrists.  If it is effective, the one aspect of psychedelic assisted therapy that I thought would be very useful was that the patient only takes two or three doses of the drug over the course of psychotherapy and does not require a maintenance treatment.

Quality of subjective measurement aside, there is nothing more annoying to me as an interested reader than reading about a rating scale or questionnaire that is not readily available.  I need to know what the specific questions are on those instruments.  The statistics of the instrument is a secondary consideration.  As far as I can tell neither the ASQ or the PSI is readily available in a readable form.  I would go so far to encourage editors to suggest that in the original analysis of rating scales, questionnaires, and inventories include the scale as it was used with all of the direct wording and how it was rated.  If that data is not included the article is essentially worthless to any clinician who talks to patients.


Are we measuring dimensions of consciousness?

I have addressed the general lack of concern over human consciousness in psychiatry and medicine in general.  Human consciousness is generally regarded as a brain determined state, but we have no idea how that state arises from the underlying neurobiology.  There are plenty of theories and there is a scientific society dedicated to the study of human consciousness.  Consciousness is a highly subjective state and that makes it very difficult to study.  Even a basic consideration of experiencing the color red can be as complex as considering that each human being (every human being has a unique conscious state) can experience the color red in a unique way.  We all may be able to agree on a basic task that requires selecting the color red from other colors,  but beyond that we can never be completely sure of how other people experience colors or other physical properties or more complicated states like pain, depression, aging, or the opposite gender.  If all that is true about human consciousness - what would we expect to happen if we are taking a drug that alters our conscious state.  For research purposes, if we alter a conscious state and we really don't have a good way to measure a baseline conscious state - how can we detect what changes.  Are we going to depend strictly on self report of whatever comes to the person's mind?


Sweeping conclusions about the lack of toxicity?

Any pro-hallucinogen article will produce a steady stream of references looking at how benign these compounds are.  There are usually quotes about millions of doses consumed and no deaths from LSD or other psychedelics.  The authors generally assume that the methodologies being quoted are adequate indications of drug safety.  These arguments fail at two levels.  First, there is evidence in the literature from reasonable sources that LSD exposure is not entirely benign.  The 1986 Danish LSD Damages Laws is a case in point.  In this study, 400 patients treated with LSD between 1960 and 1973 were followed.  154 of these patients were compensated for long term harm with 2/3 of them having severe flashbacks.  There was also one homicide, 2 suicides, and 4 suicide attempts in the group (12).  There is the question of other sources such such as the DAWN system that looks at the number of emergency department visits (ED) per day due to substance use.  This system looks at annual use of substances by 18-25 years olds, how much they use on an average day and the number of ED visits per day due to a specific category of drugs.

See Attribution 2 for full reference.

         
In terms of drug safety and pharmacovigilance, there really has not been any with these drugs.  The side effects tend to be case reports, anecdotal, from settings where there is likely a bias to under report side effects, and from carefully run clinical trials.  In some cases researchers have a defined protocol for the safe design and running of clinical trials involving psychedelic drugs (15).

Medicine or recreational drug?

Cannabis legalization was basically dead in the water until the proponents adopted a political strategy that involved selling it as a medical treatment rather than a recreational drug.  The preferred path seems to be starting with terminal illnesses or illnesses for which there are no current good treatments.  Nobody ever seems to explore the question about why the legalization question doesn't seem to carry the argument on its own merit.  The arguments for the therapeutic use of hallucinogens seems to be following that same pathway.

More rights and politics?

Some of the pro-hallucinogen literature promotes the use of hallucinogens including the legal right of people to use hallucinogens.  I have no problem at all with activists trying to influence their favorite politicians in a way that they can more easily obtain their favorite intoxicant.  I do have a problem when activists start to write medical literature from that perspective.  I also think that an additional level of disclosure is needed at the editorial level.  Authors that argue for the availability of hallucinogens (or for that matter any recreational intoxicant) should disclose that as a potential conflict of interest by specific compounds.  An example would be: "Dr. Smith supports the widespread availability of LSD for both medical and recreational use".  Explicitly stating that potential conflict of interest, is every bit as important as stating that your research has been supported by a pharmaceutical company, but it is more difficult to track.    

Is there a better way to live?

There are always philosophical and ethical considerations.  As I hope to show in a future post, philosophers generally are not too interested in telling people how to live (although there are a few notable exceptions).  Psychiatrists certainly are not interested in that either no matter how much rhetoric is out there saying otherwise.  The arguments to use or try hallucinogens are of the general form that it may improve you in some way or offer you valuable insights.  It certainly may not or in the case of many leave them with a very negative residual memory of the personal experiment or some residual symptoms.  Much of the rhetoric is the old legalization argument: "If it really is that harmless, who shouldn't I have the freedom to use it?"  Add the corollary: "It is less dangerous than tobacco and alcohol!" and you have a full scale legalization argument on your hands.  This debate has become stereotypical these days and nobody seems to ever ask the question: "Is this a reasonable way to live?"  or  "Should people get high just because we can?"  Do you really have to take a drug to expand your consciousness or can you do something else?  Focusing on only the legal aspect and the freedom to use drugs short circuits that larger question and it is a very significant question.  Moreover - if your goal is expanding your consciousness how do you know that LSD is the best way to do that?  How do you know it is just not a complete waste of time - time that you may not have to waste?

There is a phrase that is popular in the drug using vernacular and that phrase is "fucked up."  It encompasses an entire spectrum from a highly desired state of intoxication to a very dysphoric state of toxic effects, withdrawal effects, and delirium.  Interview people at either end of the spectrum and they will declare: "I am really fucked up!" with varying prosody to suggest the end of the spectrum they perceive themselves to be at that given moment.  That is assuming that they are not too delirious to speak.  Use of the term highlights how subjective drug use is as well as the full spectrum of use.  It removes any pretense that a legal intoxicant will be used primarily in a therapist's office or a room full of intellectuals focused on expanding their consciousness.    We can't use a 10 point scale with the term on either end.  We are not really treating anything.  How many days during your life can you spend "fucked up" - whether or not the intoxicant is medically dangerous to you?  Probably not too many if you expect to have a work, a social and a family life where you depend on other people and they depend on you.  Probably not too many if you live in a dangerous environment like Minnesota and you have to decide at some point that you need to be wearing enough protective clothing outdoors to prevent frostbite, exposure, and death.

Hallucinogens or psychedelics are probably not the new miracle drugs simply because they have already been sold that way and it didn't work out.  As two authors (13) closer to the history of LSD put it:

"....In all likelihood acid will continue to ravage as many people as it liberates and deceive as many as it enlightens.  Whether it will play a more significant role in the future remains a matter of conjecture, for the psychedelic experience carries the impress of a constellation of social forces that are always shifting and up for grabs.  It's not over yet."  

My only qualifier is always that people with addictions will generally do worse.



George Dawson, MD, DFAPA



References:

1:  Walter Isaacson.  Steve Jobs.  Simon & Schuster.  New York. 2011. p 41.

2: Woodstock: Music from the Original Soundtrack and More. Cotillion Records. 1970.

3:  Glennon RA.  The pharmacology of hallucinogens and designer drugs.  in Principles of Addiction Medicine, Fourth Edition.  RK Ries, DA Fiellin, SC Miller, and R Saitz (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2009: pp 215-230.

4:  Domino EF, Miller SC.  The pharmacology of dissociatives.  in Principles of Addiction Medicine, Fourth Edition.  RK Ries, DA Fiellin, SC Miller, and R Saitz (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2009: pp 231-240.

5:  Pechnick RN, Cunningham KA.  Hallucinogens.  in Substance Abuse: A Comprehensive Textbook, Fifth Edition.  P Ruiz, E Strain (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2011: pp 267-276.

6:  McCann UD.  PCP/Designer Drugs/MDMA. in Substance Abuse: A Comprehensive Textbook, Fifth Edition.  P Ruiz, E Strain (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2011: pp 277-283.

7: Krebs TS, Johansen PØ. Psychedelics and mental health: a population study. PLoS One. 2013 Aug 19;8(8):e63972. doi: 10.1371/journal.pone.0063972. eCollection 2013. PubMed PMID: 23976938; PubMed Central PMCID: PMC3747247.

8: Johansen PØ, Krebs TS. Psychedelics not linked to mental health problems or suicidal behavior: a population study. J Psychopharmacol. 2015 Mar;29(3):270-9. doi: 10.1177/0269881114568039. Epub 2015 Mar 5. PubMed PMID: 25744618. 

9: Krebs TS, Johansen PØ. Reply letter: Mental health of people who have used classical psychedelics and no other illicit drugs. J Psychopharmacol. 2015 Sep;29(9):1036-40. PubMed PMID: 26649373. 

10: Krebs TS, Johansen PØ. Over 30 million psychedelic users in the United States. F1000Res. 2013 Mar 28;2:98. doi: 10.12688/f1000research.2-98.v1. eCollection 2013. PubMed PMID: 24627778; PubMed Central PMCID: PMC3917651.

11: Logan BK, Goldfogel G, Hamilton R, Kuhlman J. Five deaths resulting from abuse of dextromethorphan sold over the internet. J Anal Toxicol. 2009 Mar;33(2):99-103. PubMed PMID: 19239735.

12: Larsen JK. Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark. Hist Psychiatry. 2016 Jun;27(2):172-89. doi: 10.1177/0957154X16629902. Epub 2016 Mar 10. PubMed PMID: 26966135.

13:  Lee MA, Shlain B.  The Complete Social History of LSD: The CIA, The Sixties, and Beyond.  Grove Press, New York, 1985: p 294.

14: Mithoefer MC, Grob CS, Brewerton TD.  Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry. 2016 May;3(5):481-8. doi: 10.1016/S2215-0366(15)00576-3. Epub 2016 Apr 5. Review. PubMed PMID: 27067625.

15: Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008 Aug;22(6):603-20. doi: 10.1177/0269881108093587. Epub 2008 Jul 1. Review. PubMed PMID: 18593734.

Attribution:

1:  Krebs TS and Johansen PØ. Over 30 million psychedelic users in the United States [version 1; referees: 2 approved]. F1000Research 2013, 2:98 (doi: 10.12688/f1000research.2-98.v1)

Copyright: © 2013 Krebs TS and Johansen PØ. This is an open access article distributed under the terms of theCreative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2:  Figures 2 and 5 are from Substance Abuse and Mental Health Services Administration (SAMHSA) Emergency Department Data.

Medical Treatment Is Never A Zero Risk Decision

Harvey W. Cushing, MD

Ever since Medical Errors - the Third Leading Cause Of Death came out the media and bloggers have been abuzz with the headline.  It is only a matter of time before we hear about how many full 747s crashing would equal the number of patients that are killed by physician errors each year.  There are any number of articles in the press each day about how there are algorithms or checklists from some committee or government agency that will eliminate risk in medical diagnosis and procedures.  There are an equal number of stories about how machine intelligence or will eliminate all of this human error.  There was a story a few weeks ago about a robot that could suture up operative wounds from surgery.  After seeing that robot in action, I would not want it anywhere near me or anyone I cared about.  There is often palpable conflict of interest involved in the news stories.  Stories designed to generate interest or influence politicians.  Stories to express a political viewpoint.  Even in the professional literature, much of what is written is a political viewpoint often to develop leverage against physicians and force them to do things in a certain way.  The selling point to the public and their elected officials is that medicine, particularly physicians would perform better and more uniformly if they would adhere to certain protocols and that these protocols need to include the input of people who have never been trained as physicians - most notably business managers.          

I can illustrate why these analyses are absurd based on an experience I had about 6 years ago.  At that time my wife was struggling with intense ear pain and the provider she was seeing wanted to start her on another course of antibiotics for ear pain.  I had her see an ENT surgeon instead, who performed an examination that only an ENT physician can do and then read the CT scan that he ordered.  That CT scan was read as normal by the radiologist.  This ENT physician not only read it as abnormal, but got additional imaging studies to demonstrate that my wife had a pituitary tumor.  Referral to an endocrinologist confirmed that it was a growth hormone secreting tumor, further explaining additional symptoms that she had described to various physicians over the years.  I went to work at that point and found the neurosurgeon who was one of the pioneers in transsphenoidal adenoma resections in the world.  Although not malignant, the prognosis of these tumors is not benign with disfigurement from acromegaly, progressive endocrine abnormalities, and eventual congestive heart failure all from the effects of excessive growth hormone secretion.  There were also complications of inadequate excision and secondary procedures like gamma knife irradiation in an attempt to obliterate the tumor.  We were sitting in the consulting room of the neurosurgeon as soon as we could arrange it.

He had pulled up a coronal section of the MRI scan showing the tumor wrapped around my wife's right internal carotid artery.  He made the following statement:  "This is the tumor and this is the artery (pointing to areas on an MRI coronal view of the pituitary gland and surrounding anatomy).  I am going to try to remove as much of the tumor as possible.  If I accidentally nick the carotid artery in this area, there is nothing that can be done about it.  That complication happens and I know good neurosurgeons who have had that happen to them.  I can assure you I will remove only as much tumor as possible.  I will remove only as much as I would remove if you were one of my family members."

This is the unspoken truth about medical errors and whether they are preventable or not.  In this case doing nothing results in an inevitable slow death and severely compromised quality of life.  The procedure is not without risk.  In this case the risk was minimized by selecting the most skilled neurosurgeon in the area, but he openly acknowledges that nicking the carotid artery in a place that cannot be repaired is not only a possibility, but it happens to the best neurosurgeons.  Any cursory analysis should illustrate why.  We are talking about an operation that occurs in about a 1 1/2 inch space at the tip of an endoscope on a tumor that extends away from that tip into a small crevice between the carotid artery and sphenoid bone.  Anyone really interested in this can go to YouTube and view several videos of the procedure from the view of the surgeon.  In this case our neurosurgeon explicitly talked about the issue of how much tumor could be removed.  He was acutely aware that the risk involved in removing too much tumor may be unacceptably high.  Incompletely removing the tumor involves the risk of continued exposure to excessive growth hormone and the secondary gamma knife procedure.     The fact that this surgery can be done at all seems like is a miracle to me.  Early in my  career, I had treated a patient who underwent a transtemporal approach to the same kind of tumor and that had resulted in significant postoperative disability.
                                                               
In the decision to proceed my wife clearly found the risk acceptable because acromegaly and a slow death from endocrine complications and further procedures were not.  The operative procedure went perfectly and 6 years later her growth hormone, IGH levels, and serial MRI scans show no tumor recurrence.  I don't have to speculate about what might have gone wrong in my wife's case because Henry Marsh (6) writes about it in his compilation of neurosurgical complications Do No Harm.  In the chapter "Pituitary Adenoma" he did a transphenoidal procedure on a man with acromegaly.  His description of the relevant anatomy: "There are however, two major arteries next to the pituitary gland that can, if the surgeon is exceptionally unlucky, be damaged during the operation."  His patient did well until post-operative day number 3, when suddenly his right arm was paralyzed and he could not communicate.  Brain imaging confirmed a major left hemispheric stroke.  Having no actual operative complications Marsh concludes: "This must have been caused in some unknowable way by the operation."

But let's take a look at what would have happened in my wife's case if there had been a complication or series of complications using the methodology cited by the authors in the studies.  First off, in the case of a complication where does the chain of errors begin.  The misdiagnosis of otitis media and two antibiotic prescriptions?  The misread CT scan of the sphenoid bone?  It seems like those are two preliminary errors right there even though neither was immediately threatening.  Combined with a surgical error that would be three medical errors had a complication occurred.  And what about the self correcting aspects of this process?  Does the ENT surgeon get any credit here for correcting the misdiagnosis of otitis media or the misreading of the CT scan?  Any focus on medical errors never looks at the self correcting aspects - how many times they are caught and how many times standard second opinions from colleagues or trusted referrals modify the treatment plan.  How much morbidity and mortality would occur without this level of self correction?  How is it estimated?  The best example I can recall of the problems of error determination was in a NEJM editorial to address the first report on medical errors by the Institute of Medicine.

In that editorial (5), the lead author of some of the most quoted studies discusses the issue of the definition of errors, the definition of preventability, and the subjective nature of these determinations.  His preliminary analysis is that the IOM conclusion that 44,000 to 98,000 deaths caused by medical errors "create an impression that is not warranted by the scientific work underlying the IOM report."  That number has been inflated to more than 250,000 according to the recent quoted report (1).   He also expresses an opinion completely consistent with Marsh's observations and goes on to point out that the observation of error can not cannot be reliably made by third party observers:

"Even with the best surgical technique and proper precautions, however, a hemorrhage can occur. We classified most postoperative hemorrhages resulting in the transfer of patients back to the operating room after simple procedures (such as hysterectomy or appendectomy) as preventable, even though in most cases there was no apparent blunder or slip-up by the surgeon. The IOM report refers to these cases as medical errors, which to some observers may seem inappropriate." (6)

He goes on to elaborate on four important aspects of the IOM report, 2 of which have to do with politics and public perception.  The first is the idea that either nothing is being done about safety or that things are getting more dangerous.  In many ways this is analogous to the public perception that violent crime is high when it is at a 30 year low.  He gives an even better example of Harvey Cushing's accomplishments during his neurosurgical career.  In 1913, the mortality rate for craniotomies for brain tumors was 80%.  In twenty years it was reduced to 13%.  Currently it is 1%.  All of that without the IOM or any of the current federal or state regulators.  The whole idea that physicians are motivated more by adhering to what politicians or regulators want rather than what is in the best interest of their patients has always been an incredible one to me.  I guess it makes sense only if you are a politician or a regulator and you really believe that your naively designed incentives and disincentives have meaning.   The second complication is increased reporting requirements and all of the complications that involves including the impact on confidential peer reviewed complications.  Every physician has participated in some form of complications conferences or what surgeons used to call morbidity and mortality conferences.  The modern goal of these conferences is to try to identify procedures and interventions to improve patients safety.  Opening that system up to increased reporting and subjecting it to the "dead weight of the litigation system" is something the author cautions against, but is often explicit in the news headlines.

Makary thought the IOM missed the boat on the issue of how malpractice litigation is a risk against internally driven safety initiatives.  I think they and subsequent authors missed the boat on the issue of biological variability.  To some degree is it addressed by the subjective determination of preventability but not entirely.  If a neurosurgeon is observed to have performed an errorless operation and the patient sustains significant complications, what are all of the factors that go into calling that an error or not?  A lot of it may have to due  with the baseline state of the patient.  Are they already compromised by injury, illness or congenital variations.  Neurosurgeons after all are not operating on healthy people.  The example also applies to medicine and psychiatry.  As an example, I usually tell people up front these days that there is about a 40% chance that they will noticeably improve with an antidepressant if their symptoms are significant.  There is another 20 or 30% chance that they will feel somewhat better but not get back to their baseline state.  There is a 10-20% chance that they will get significant side  effects and not want to continue the medication and in a small number of cases (1-2%) there is a chance of really severe side effects from the medication.  Pharmacogenomics suggests that it can be invaluable in this process, but there is variability between predictions using the available analyses from the same manufacturer and between manufacturers.  Even with that warning there are a number of people who will consider it an "error" that they received a medication that caused them to get a rash or in the worst case serotonin syndrome.  I think that there is a natural tendency for some to see any medical procedure that does not go well to be attributable to error on the part of the physician.  I think that the personal experience of most physicians will bear that out.        

Another less well known intervention in psychiatry is the care of the chronically suicidal person.  Many of these persons have a history of serious suicide attempts and remain at significant risk.  The usual risk factor analysis of their suicide potential does not add very much.  There are frequently inadequate resources to treat them or they refuse to access what is available.  Frequent short term admissions to inpatient units adds nothing to their care.  The psychiatrist who accepts their care usually is seeing them more intensely and accepting more crisis calls from them than other patients.  Until a sufficient therapeutic alliance develops, there may be many sessions with a lot of depression and anger and very little objective information on what the patient is thinking.  The psychiatrist and patient in this case need to accept that the risk involved in this situation from suicide or a suicide attempt - is necessary to make progress and enhance the patient's ability to function and enjoy life.

My main point here is that people currently need to assume some risks in order to get better.  There is nobody more than physicians who would want medicine to be a no risk endeavor, but the reality is that is not going to happen anytime soon.   All patients realize this at some level, but that may do little to mitigate the anger or disappointment when it occurs.  Every family has a tale to tell about a medical miracle or a medical mistake.   In the situations like my wife faced with my support, people are clearly willing to take the risk in face of undesirable consequences.  The physicians involved see this as very serious work.  Should the classification of medical errors be refined and analyzed?  Of course they should - but the approach being used in the press invoking planes full of patients being sent to their death by physicians being equated to terrorists is not accurate or helpful.  The backlash is significant and impairs the ongoing error analysis and correction process.  Equating a heterogenous collection of complications classified by different methods as errors and listing them as a standard cause of death is also not accurate or helpful to the science of medical error analysis and correction.


George Dawson, MD, DFAPA


References:

1:   Makary MA, Daniel M. Medical error-the third leading cause of death in the US. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139. PubMed PMID: 27143499.

2: Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers AG, Newhouse JP, Weiler PC, Hiatt HH. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. N Engl J Med. 1991 Feb 7;324(6):370-6. PubMed PMID: 1987460.

3: Leape LL, Brennan TA, Laird N, Lawthers AG, Localio AR, Barnes BA, Hebert L, Newhouse JP, Weiler PC, Hiatt H. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991 Feb 7;324(6):377-84. PubMed PMID: 1824793. 

4: Localio AR, Lawthers AG, Brennan TA, Laird NM, Hebert LE, Peterson LM, Newhouse JP, Weiler PC, Hiatt HH. Relation between malpractice claims and adverse events due to negligence. Results of the Harvard Medical Practice Study III. N Engl J Med. 1991 Jul 25;325(4):245-51. PubMed PMID: 2057025. 

5: Brennan TA. The Institute of Medicine report on medical errors--could it do harm? N Engl J Med. 2000 Apr 13;342(15):1123-5. PubMed PMID: 10760315.

6:  Marsh H.  Do No Harm: Stories Of Life, Death, And Brain Surgery.  Thomas Dunne Books/ St. Martin's Press; New York,  NY; 2014.


Attribution:

Portrait of Harvey Cushing, MD by Edmund C. Tarbell [Public domain], via Wikimedia Commons at https://commons.wikimedia.org/wiki/File%3ADr_Harvey_Cushing_Edmund_Tarbell_1908.jpeg accessed on May 22, 2016.


Supplementaries:

Supplementary 1:  Another excellent example of biological variability is joint replacement surgery.  I see patients, friends and family members who have mixed experiences.  The majority turn out very well, in some cases extremely well.  In the case of extremely good joint replacement surgery, according to all of these people I talk to, the surgeon seems to discourage them talking to other people about how good the results were, generally by telling them that they had an extraordinary result in terms of how the replaced joint functions.

Supplementary 2:  A good example from a recent post about the aggressive treatment of pain and the risk of addiction and overdose deaths.  20 years ago when physicians were being criticized by various factions for not aggressive enough use of painkiller prescriptions and the use of opioids for chronic noncancer pain - the risk of death by overdose was minimized by those proponents.  Now that there is a clear cause of death from overuse of opioids and the rates of addiction have increased - physicians are faulted for not knowing how to prescribe opioids.  It seems like they had a better idea 20 years ago before yielding to the critics.  From the perspective of this post - there is always risk either way.  Only politicians and regulators can deny that.

Supplementary 3:  The Twitter graphic ( and yes I am serious).  The IOM did not start until about 1970.  None of these entities has a track record remotely close to Harvey Cushing in the 1920s and 1930s.

           

The NY Times Opinion On Congress and the Opioid Epidemic

The NY Times came out with an opinion piece of the opioid epidemic on May 16 (1).  In their opinion it was a good thing that Congress had finally decided to "get involved."  They emphasize the need to fund treatment and prevention programs.  But wait a minute, didn't Congress already approve the The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA).  That act was supposed to provide equal treatment for mental disorders and addictive disorders.  Here it is a few years later and we are supposed to be still trying to fund treatment despite a specific piece of legislation was was already supposed to provide funding?  In fact, this same editorial board came out with a very rosy assessment of the MHPAEA three years ago and they were wrong back then as well.  In that link, I posted reasons why the parity act would fail and of course - it did.  That failure is the only reason the editorial board is now calling for funding for treatment and prevention programs,  I criticized their original post because they lacked anyone with medical expertise on their panel and they did not seem to know how health care works or why Congressional intervention does not work. It looks like the same mistake has been repeated.  At some point we need to recognize that the opinions and legislation about health care aren't worth the paper they are printed on.  At least from the perspective of the prospective patient or the physicians who are trying to treat them.

This piece does reflect a dim grasp of the health care system in this country that is set up by Congress in the first place.  Some of the suggestions made me want to laugh out loud.

"The federal government can make the biggest difference by expanding high-quality treatment programs. States, which have more sway over doctors and hospitals, need to do more on the prevention side by placing limits on opioid prescriptions. States can encourage doctors to order alternative pain treatments, like physical therapy, and require insurers to cover those services." (1)

This seems to assume that the federal government is somehow interested in quality while they are setting up managed care organizations that really have nothing to do with quality.  Everything is set up to be cost-effective (translation = cheap).  There is nothing cheaper in the way of mental health care and treatment for addictions than refusing to fund it and that is a routine occurrence in spite of the MHPAEA, the bill that was supposed to put the care of mental illnesses and addictions on par with other medical conditions.  The second error in this paragraph is the idea of a bureaucrat somewhere placing limits on opioid prescriptions.  That will immediately alienate the majority of the physician workforce that currently prescribes opioids appropriately and of course the patients of these physicians.  And finally the idea that alternate treatments will be covered misses the cultural contributions to the opioid epidemic and the fact that Congress doesn't seem to be able to mandate insurance companies to do much of anything.  If they can't mandate equal coverage for mental illness and addiction, why would physical therapy be any different?

On the question of how much legislation must be written and how much money appropriated, the money figures quoted range from $600 million to $1.1 billion to address the treatment needs of 435,000 regular heroin users, 1.9 million people who are regular prescription opioid users, and 4.3 million people engaged in non-medical use of prescription painkillers each month.  Considering only the prescription of buprenorphine for medication assisted treatment of opioid use disorder and the $1.1 billion dollar figure, at about $1,000/month for buprenorphine, that figure would result in the treatment of 92,000 individuals and that is not including the cost of medical evaluation and administration of the drug.  That is less than a quarter of the heroin users and less than 10% of the painkiller users.  It also does not fund any of the additional treatment services including addiction counseling and a continuum of sober support and housing.

In situations like this, seeming to address the problem by political one upmanship is always tempting.  A Governor is quoted in the article giving her opinion that the cause of the current epidemic is the prescribing practices of physicians.  I am sure that many legislators take the same concrete approach to problems but this is a much more nuanced problem.  Technically speaking - all physicians leave medical school knowing how to prescribe opioids.  Not all of them are good at managing the relationship with the patient or telling patients what they might not want to hear.  The commonest errors I see in prescribing addictive drugs to people has nothing to do with technical expertise of the physician.  It has to do with the idea that the patient is in distress and that it is the physician's job to do something about it.  Many of these physicians have a difficult time balancing the decision to prescribe an addictive drug versus the potential harm of addiction or the harm of not treating a pain syndrome that does not respond well to opioids.  Many of these same physicians lack an understanding of addiction and the fact that it is possible to continue to take an addictive medication even though it is providing no symptomatic relief from pain.   The third problem is the patient's lack of insight.  There a lot of biases when it comes to addiction and assigning responsibility.  There are numerous arguments about whether addiction is a disease or not and these are generally arguments about who is responsible for the addiction and its treatment.  I don't think that there is any doubt that a person who is addicted to opioids will behave in a predictable manner to keep the addiction going.  They will not tell their physicians that they have an addiction and in some cases try to get extensions on prescriptions, escalate the dose of a prescription, get more opioids from non-medical sources (dealers or acquaintances) or use the opioid for a reason that it was not intended - usually insomnia, anxiety, or depression.  How do legislators address this complex problem?  Basically by blaming physicians and passing legislation that doesn't make any sense.

It is important to remember that this epidemic did not start in a vacuum.  There was an activist movement among some professional societies and regulatory bodies to treat pain more aggressively.  Looking at past  New York Times editorials, some of this was recorded and in at least one case, the opinion came down on the side of aggressive pain treatment.   Congress and the media seems to have come full circle on the issue of opioids and is ready to head back in the other direction.  The news can be a powerful source of influence in encouraging people to use public health measures to stop this epidemic.  That can be as basic an idea as not hoarding leftover opioid painkillers and discarding them.

Hoping that Congress will solve the problem, when they were supposed to 7 and 22 years ago, does not seem like the best idea.  If they went back to sleep - nobody would notice the difference.


George Dawson, MD, DFAPA



1:  The Editorial Board.  Congress Wakes Up To The Opioid Epidemic.  New York Times May 16. 2016.

2:  The Editorial Board.  Making the Pain Go Away.  New York Times.  March 4, 1994:

"The new guidelines, issued in detail for physicians and in brief for patients, call for treating pain early and aggressively, starting with the simplest options, like aspirin and acetaminophen, and progressing through mild opiates to more potent drugs like morphine."

And....

"But there are scant data from scientific studies to document whether or not marijuana is as effective as or better than other anti-nausea drugs. The same outdated attitudes that inhibit the use of narcotics for pain relief should not be allowed to suppress clinical investigations into the therapeutic uses of pot."

Pimavanserin

Pimavanserin

The first time I heard any details about this compound was in a course for movement disorder specialists.  I have been a long time member of the Movement Disorder Society and get their journal Movement Disorders.  From time to  time, a mildly recurrent theme has been antipsychotic agents that can be used in specific movement disorders that do not worsen the underlying problem primarily by their activity at the dopamine-2 (D2) receptor.  One of the research interests in atypical antipsychotics over the past 20 years has been to look for this property.  In studying atypical antipsychotics in  Parkinson's patients, it  turns out that only one of these drugs does not worsen Parkinson's and that is clozapine.  There are several target populations that a drug with no liability to worsen dopamine (DA) mediated movement disorders would be useful.  The first is patients who require antipsychotic medications for bipolar disorder or schizophrenia and develop Parkinson's disease or tardive syndromes from typical or atypical antipsychotic medications.  The second group is patients with Parkinson's disease who develop psychotic symptoms associated with the primary neurological illness.  Both groups are significantly represented in geriatric psychiatry practices and despite the widespread availability of atypical antipsychotics medications in the last 20 years, geriatric patients with bipolar disorder or schizophrenia and severe movement disorders - usually tardive syndromes still exist.  A medication that does not affect the DA mediated locomotion system is potentially of great benefit.

In the conference I attended, there was an entire lecture devoted to the Non-Motor Features of Parkinson's Disease.  Results from the Sydney Multicenter Study were presented.  The study followed a cohort of Parkinson's survivors for 15 and 20 years and discovered that by year 15 - 85% had cognitive decline and 50% were depressed.  By year 20 - 56% had hallucinations, 50% were on antidepressants, and 75% had dementia by the time of death.  Delusions occur but at a much lower rate.  The first step in treatment is to eliminate reversible causes including polypharmacy with anticholinergic and dopaminergic agents.  The treatment of moderate to advanced Parkinson's is by definition one that requires multiple medications.  Clozapine and quetiapine in low doses were suggested as the best direct treatments currently available.  At that time pimavanserin was discussed as a drug in Phase 3 trials.  It was presented as a serotonin (5-HT2A) inverse agonist with no activity at dopaminergic, adrenergic, histaminergic, and cholinergic receptors.  An abstract from ClinicalTrials.gov was shown of a study of 199 patients with Parkinson's Disease psychosis (PDP).  The primary outcome measure was a psychosis score on the Scale For Assessment Of Positive Symptoms adapted for Parkinson's (SAPS-PD).  Rarely used, qualitative, outcome measures are one of many limitations of geriatric studies.  On that measure, there was a more significant decrease in psychosis scores in the treated group.  The medication was fairly well tolerated with 10/95 subjects discontinuing it due to side effects compared to 2/90 in the placebo group.  No motor side effects were noted and there were no other safety concerns.  As noted in the supplementary sections there appears to be very little published data supporting the FDA decision to approve this drug in the marketplace.  It has been used to treat psychotic disorders but apparently only as an augmenting agent for antipsychotic medications and the preliminary study suggests it may work for augmenting an atypical medication like risperidone but not a typical agent like haloperidol.

There is data on file with the FDA indicating that a substantial amount of research is not published at this time.  The 173 page briefing materials for the Psychopharmacological Drugs Advisory Committee discusses the results of studies involving 1200 subjects receiving pimavanserin including 616 PDP subjects.  One of the interesting aspects of this document is that it includes the full text of the 20 - item Scale for Assessment of Positive Symptoms (SAPS) by Andreasen at the very end.  The SAPS-PD is a 9 - item modification that focuses on hallucinations and delusions.  Each of the 9 items is rated on the basis of increasing frequency with a maximum score of 5 indicating frequent daily occurrences.  The evidence footprint so far suggests the usual profile of a medication approved on a priority basis by the FDA.  The most important data - how it fares in clinical practice remains to be seen.  At this point it does not seem to be a first line or even second line drug for purely psychiatric applications and will probably be limited to PDP.

The pharmacodynamics of the drug are very interesting relative to all other available antipsychotic drugs.  The following table is from the briefing materials.

From Reference 1

The receptor affinities shown in the above table, indicate a unique profile for pimavanserin with essentially no affinities at histaminergic, muscarinic cholinergic, dopaminergic, and adrenergic receptors.  There are only two other antipsychotics with no activity in one class of receptors and in this case it has no affinity for four classes.  In theory this will eliminate a lot of side effects and the lack of dopaminergic activity should not lead to worsening Parkinson's Disease in those patients.

The other interesting aspect of the description of this compound as an inverse agonist.  Inverse agonists bind to the same sites as agonists but it has negative activity or efficacy at the site.  Antagonists have no intrinsic activity at receptors - they block the effects of agonists.  There are a significant number of inverse agonists in clinical practice and a number in current development or under study.

Reading through references 1 and 2 suggest that main safety concern is prolonged QTc interval at higher than recommended doses.  That lead to recommendations to avoid use with other QTc prolonging drugs.  In the older adult with Parkinson's who may also be already on an antidepressant and an antipsychotic and have pre-existing cardiovascular disease, the usual clinical approach with baseline ECGs and in some cases serial ECGs may be required.  From a pharmacokinetic standpoint, drug-drug interactions based on CYP3A4 inhibition or induction can lead to accumulation or clearance of the drug in the expected direction.

In thinking about prescribing pimavanserin, if I was working in the Geriatric Psychiatry and Memory Disorders Clinic where I worked for over a decade I would be looking forward to it.  There are many PDP patients and patients with tardive syndromes that do not tolerate typical or atypical antipsychotics alone.  In some cases, the symptoms are mild and do not require treatment, but in many cases they are persistent and totally disabling.  This medication may be an option for some of those patients.  As a member of two Pharmacy and Therapeutics Committee, this medication explodes the formulary myths of drugs in the same class being equivalent and therefore allowing for the least expensive drug to be used.  Inspection of the above table shows this is not really the case for other atypicals, but it is definitely not the case for pimavanserin.  Initially, I anticipate a steep prior authorization burden for any physician wanting to prescribe it even for the indicated condition and in this case it is:

NUPLAZID is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

The critical question at this point is how it will work in clinical practice.  


 
George Dawson, MD, DFAPA



References:

1: Acadia Pharmaceuticals.  NUPLAZID™(pimavanserin); SPONSOR BACKGROUND INFORMATION FOR A MEETING OF THE PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE ON 29 MARCH 2016.

2: NUPLAZID™ (pimavanserin) package insert

3: Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases.  US patent: US 7659285 B2


Supplementary 1:  Current studies listed on ClinicalTrials.gov:


Study 1:

Title: A Study of the Safety and Efficacy of Pimavanserin in Patients With Alzheimer's Disease Psychosis
Recruitment: Recruiting
Study Results: No Results Available
Conditions: Alzheimer's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate|Drug: Placebo
URL: https://ClinicalTrials.gov/show/NCT02035553

Study 2:

Title: A Study of the Safety and Efficacy of Pimavanserin in Patients With Parkinson's Disease Psychosis
Recruitment: Completed
Study Results: Has Results
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: pimavanserin tartrate|Drug: placebo
URL: https://ClinicalTrials.gov/show/NCT01174004

Study 3:

Title: A Study of the Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis
Recruitment: Completed
Study Results: Has Results
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate (ACP-103)|Drug: Pimavanserin tartrate (ACP-103)|Drug: Placebo
URL: https://ClinicalTrials.gov/show/NCT00477672

Study 4:

Title: Expanded Access of Pimavanserin for Patients With PD Psychosis
Recruitment: Available
Study Results: No Results Available
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate
URL: https://ClinicalTrials.gov/show/NCT02762591

Study 5:

Title: A Study of Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis
Recruitment: Completed
Study Results: Has Results
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate (ACP-103)|Drug: Pimavanserin tartrate (ACP-103)|Drug: Pimavanserin tartrate (ACP-103)
URL: https://ClinicalTrials.gov/show/NCT00658567

Study 6:

Title: A Study of the Safety and Tolerability of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis
Recruitment: Active, not recruiting
Study Results: No Results Available
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: pimavanserin tartrate (ACP-103)
URL: https://ClinicalTrials.gov/show/NCT00550238

Study 7:

Title: An Open-label Safety Study of Pimavanserin in Parkinson's Disease Patients
Recruitment: Completed
Study Results: No Results Available
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: pimavanserin tartrate (ACP-103)
URL: https://ClinicalTrials.gov/show/NCT01518309

Study 8:

Title: Antipsychotic and Motor Effects of ACP-103 When Administered in Combination With Haloperidol and Risperidone
Recruitment: Completed
Study Results: No Results Available
Conditions: Schizophrenia
Interventions: Drug: ACP-103
URL: https://ClinicalTrials.gov/show/NCT00361166

Study 9:

Title: ACP-103 to Treat Parkinson's Disease
Recruitment: Completed
Study Results: No Results Available
Conditions: Parkinson's Disease|Dyskinesias
Interventions: Drug: Intravenous Levodopa|Drug: ACP-103
URL: https://ClinicalTrials.gov/show/NCT00086294

Study 10:

Title: Treatment of Hallucinosis/Psychosis in Parkinson's Disease by an Investigational Drug
Recruitment: Completed
Study Results: No Results Available
Conditions: Hallucinations|Psychoses|Parkinson's Disease
Interventions: Drug: ACP-103
URL: https://ClinicalTrials.gov/show/NCT00087542

Supplementary 2:  Published clinical trials of pimavanserin:

1: Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R,Ballard C. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014 Feb 8;383(9916):533-40. doi: 10.1016/S0140-6736(13)62106-6. Epub 2013 Nov 1. Erratum in: Lancet. 2014 Jul 5;384(9937):28. PubMed PMID: 24183563.

2: Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day. Schizophr Res. 2012 Nov;141(2-3):144-52. doi: 10.1016/j.schres.2012.07.029. Epub 2012 Sep 4. PubMed PMID: 22954754. 

 3: Ancoli-Israel S, Vanover KE, Weiner DM, Davis RE, van Kammen DP. Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. Sleep Med. 2011 Feb;12(2):134-41. doi: 10.1016/j.sleep.2010.10.004. Epub 2011 Jan 21. PubMed PMID: 21256805; PubMed Central PMCID: PMC3137254. 

 4: Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, Friedman JH. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson's disease psychosis. Neuropsychopharmacology. 2010 Mar;35(4):881-92. doi: 10.1038/npp.2009.176. Epub 2009 Nov 11. PubMed PMID: 19907417.

5: Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin C, Farde L, Vanover KE, Hacksell U, Brann MR, Davis RE, Weiner DM. PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Int J Neuropsychopharmacol. 2008 Mar;11(2):163-71. Epub 2007 Aug 21. PubMed PMID: 17708779. 

6: Vanover KE, Robbins-Weilert D, Wilbraham DG, Mant TG, van Kammen DP, Davis RE, Weiner DM. The effects of food on the pharmacokinetics of a formulated ACP-103 tablet in healthy volunteers. J Clin Pharmacol. 2007 Jul;47(7):915-9. Epub 2007 May 10. PubMed PMID: 17495279. 

7: Vanover KE, Robbins-Weilert D, Wilbraham DG, Mant TG, van Kammen DP, Davis RE, Weiner DM. Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers. J Clin Pharmacol. 2007 Jun;47(6):704-14. Epub 2007 May 1. PubMed PMID: 17473118.


Supplementary 3:

This is a blog so don't mistake my opinion for that of the FDA advisory committee or the package insert.  Read all package inserts like I do and let your patients know if you or anybody else is prescribing a medication for them that is off label.  I may discuss off-label uses, because I know it is going to happen and I am also discussing research applications that at this point are not even part of the FDA process.

News Flash From Channel 5: "There is a shortage of psychiatrists"

This was an actual headline from a local news channel.  Of course the first question is where have they been for the last 30 years?  That was about the last time Anoka Metro Regional Treatment Center (AMRTC) was adequately staffed by psychiatrists.  In fact, at that point some of the psychiatrists working there considered it to be a high point in the education of medical students from the University of Minnesota.  One of them told me that their clinical rotation was the highest rated of any in the department.  The gist of this story is that the shortage of psychiatrists has led to inconsistent staffing for patients who need consistency.  The reporter emphasis was on Minnesota Department of Human Services hiring three psychiatrists with disciplinary actions on record with the Board of Medical Practice.  They also make the point that many of their psychiatrists are flown in for a few weeks at a time to see patients and this disrupts continuity of care.  The mother of a patient and a State Ombudsman comment about the importance of continuity of care.  If you watch the entire clip, the end is rather anticlimactic as the reporter points out that Minnesota is really no different than other states.  They are all suffering from the shortage of psychiatrists.

All in all a very dramatic presentation of a problem that nobody wants to solve.  After all, I just pointed out that in the late 1980s and early 1990s staffing at this same hospital was excellent.  The psychiatric staff there was first rate and one of the best hospital staffs that could be found anywhere.  So what happened?   In a word that I have used frequently on this blog mismanagement.  At some point professional managers decided to ignore the once popular theories of Peter Drucker and manage professional workers like production workers.  They saw psychiatry as a production job and eliminated the systems aspects critical for a team approach to psychiatric treatment.  That team approach is also critical to the practice environment and the practice environment and patient care also suffers when governments and insurance companies start telling physicians what to do and what to prescribe.  The outcome is as predictable as the current failed state hospital system.

None of those basics are in this sensational piece from Channel 5 News.  The only narrative I can detect in this story is that there are long distance psychiatrists and problematic psychiatrists practicing problematic psychiatry at the state hospital - at least until the main reporter starts with a focus on the shortage of psychiatrists.  Psychiatrists in this story function only as scapegoats.  That is easy to do when you limit the practice and hire people who are willing to work in a compromised treatment environment.  It is also easy to do when you eliminate psychiatrists and experienced psychiatric nursing staff from the management and planning aspects of the system.   Just last week I pointed out that there were no psychiatrists on a Governor's Task Force on Mental Health.  There are no psychiatric experts discussing hospital care or what it will take to repair the system in the news piece.  It is as if we are in a parallel universe, pretending that politicians and bureaucrats can do the job of psychiatrists without any training.  They can turn around and ration access to psychiatrists and then blame psychiatrists for all of the problems they have created.    Luckily,  I have been writing about this curious set of circumstances here for a few years.  You can follow my commentary in the links below and see how it compares to the skewed news version.

The additional question any reader should ask is why psychiatrists are never consulted and why attorneys and bureaucrats with no psychiatric training are in charge of these facilities?  This the cultural trend that started 30 years ago.  Throw out the doctors and run the healthcare system with politicians and bureaucrats that tell the doctors what to do.  Make is seem like doctors in state hospitals can operate in a vacuum rather than on teams and have the bureaucrats tell them how to manage clinical problems.  For a good portion of that 30 year period the word on the street was that the State of Minnesota was shutting down state hospitals and they were going to shut down AMRTC.  Those rumors do not inspire the confidence or commitment from medical or nursing professionals that you need to build a first rate state hospital system.  Who wants to go through credentialing and all that professional applications involve to apply to a hospital that is rumored to be closing soon?

The problem in Minnesota is not about trusting psychiatrists, no matter how bad a media article attempts to portray them.  This article is about trusting the politicians and bureaucrats that run this system.  In 30 years those politicians and bureaucrats have done nothing to merit anyone's trust in managing the public system of mental health care.  The failed state mental health system in Minnesota is an excellent example of what happens when you leave the management of a profession up to amateurs.


George Dawson, MD, DFAPA



Previous posts on the management deficiencies in the Minnesota state mental health system (click on the last word in each line for the post):


Executive Order: No Psychiatrists On Governor's Task Force On Mental Health [ 5/4/2016 ]

Minnesota's Mental Health Crisis - The Logical Conclusion of 30 years of Rationing [11/2/2015 ]

Minnesota State Hospitals Need To Be Managed To Minimize Aggression [1/6/2016 ]

Minnesota Psychiatrist Workforce Shortage [12/2/2015 ]

The CMS Investigation Of Anoka Metro Regional Treatment Center [1/19/2016 ]

Minnesota Finally Rejects Managed Care [5/29/2015]

More On Violence And Aggression In Minnesota Hospitals [12/11/2014 ]

Minnesota Continues A Flawed Approach To Serious Mental Illness And Aggression [12/9/2014 ]

The Shadow State Hospital System [ 11/6/2014 ]

Conflict Of Interest, Primitive Defenses, And Celebrity Death

I don't think there is any good way to say it.  Minnesota's greatest celebrity died recently.  I am not going to use his name or picture on this blog.  It seems fairly obvious that he would not want that.  There was the expected and understandable outpouring of emotion from his tens of millions of fans.  And then he became a projective test for anyone who wanted to sell their idea or opinion or get exposure in the press.  Some of those ideas and exposures included:

1.  The opioid epidemic - he is another statistic.
2.  Opioids are bad drugs and they can kill you.
3.  We could have saved him if he went into treatment.
4.  We could have saved him with Suboxone.
5.  Public scorns buprenorphine (Suboxone) - a medication that could have saved him.
6.  We could have saved him with a treatment intervention.
7.  His problem wasn't addiction at all it was chronic pain.
8.  We could have saved him by treating his chronic pain.
9.  The doctors prescribing these medications need to be disciplined.
10.  The people designated to save him - should have saved him.
11.  His death was "pathetic".
12.  That publicity rights legislation that exceeds copyright protection is necessary for the heirs.

None of these ideas are my ideas and I am sure that by the time you read it - this list is incomplete and outdated.  This is what I have heard or read about his death since it happened.  Some of the dynamics are familiar to me.  The gossip columnists and sites trying to show that they have special contacts and insight and therefore may be more important than other gossip sites.  The insiders proclaiming special knowledge that only a person very close to the celebrity could have.  The very human tendency for some to celebrate the death of those with special talents and capabilities that none of the rest of us have.  Death seems like the ultimate revenge of the mediocre and personality disordered - the final verification that a high flying person dies just like the rest of us.  The entire debacle reminds of a sentence I read somewhere (the reference eludes me): "Only a primitive man celebrates the death of his enemy."  How primitive would the man need to be in order to feel elevated by the death of a superstar?  I realize that these more drastic formulations may be rare.  What fuels all of the controversy?  Some may say morbid curiosity.  They are compelled to look at adverse outcomes whether it is a car wreck on the side of the road or a celebrity death under various circumstances.  It still comes around to what one of my psychoanalytic supervisors described as the most primitive underlying and unspoken thought: "Better him than me!"  The first time an analyst told me that I was somewhat taken aback and then over time I noticed that he was right.  I expected to hear this kind of attitude from non-professionals but not from physicians.  It turned out that I could hear that attitude from a broad spectrum of people.

My biases tend to be at the other end of the spectrum.  I see special capabilities as a celebration of what human beings can do.  Whether that is in athletics, entertainment, art, or my co-workers doing the job in a way that nobody else can do it.  Individual talent and unique capabilities are there to be celebrated and not envied.  I discussed this in an earlier post where the concept is that even people who aren't soccer fans can appreciate the greatness of Pele and just by watching him realize that we are all lifted up by that performance.  Envy seems like a marker that we should all use to determine our own sense of self and our own boundaries.    

In today's conflict-of-interest morality analysis anyone wanting to capitalize on the reputation of the celebrity to sell their wares escapes criticism.  The people involved will say that this is the price of celebrity and if you did not want everything that went along with celebrity you should have avoided it.  You are protesting too loudly when your privacy is invaded in real life or after you die.  There is another argument that the fans are entitled to this information.  To me that would depend on who is dispensing it and what was their reason.  There are numerous analyses of this problem from the perspective of defense mechanisms and the study of life satisfaction based on the level of those defenses.  Defense mechanisms may be interesting to psychiatrists and other mental health professionals but I don't think that they have to be brought out for this discussion.  At some point in life everyone needs to take a close look at how they interpret both misfortunes and good fortunes of others.  What does it really mean to them?  What does it indicate about their philosophy of life?  What does it mean about their life satisfaction?  When you do that - I think that most reasonable people stop for accidents because they are there to help.  They are not spectators.  Human consciousness has the unique property of allowing us to imagine good and bad things happening to us without having to see the real thing happening to somebody else.

I hope that at some point the culture can move past the all too predictable sequence of self aggrandizement and the obvious conflict-of-interest that occurs when a celebrity dies.  Human life and human achievement is worth celebrating and just like a single person can make us all better or at least feel better - it doesn't take much to bring us back down.  In order to break out of these predictable patterns, it takes a conscious awareness of better ways to be or exist in life and that includes examining and rejecting reasons for continuing the old patterns.

I will personally remember his shining star and some of the accolades from the top performers in his field.  He was truly one of a kind and his art was uplifting to me.  


George Dawson, MD, DFAPA