Euthanasia And Other Ethical Arguments Applied To Psychiatric Patients

An article entitled Euthanasia and Assisted Suicide of Patients With Psychiatric Disorders in the Netherlands 2011-2014 caught my eye in this month's JAMA Psychiatry (1).  It wasn't that long ago that I recall being in the midst of a rather intense argument in a staff meeting about euthanasia in the broadest of terms.  Like many heated political arguments (I consider a lot of what goes on under the heading of ethics to be little more than politics) this one degenerated to personal terms.  The pro-euthanasia proponent ended the argument with: "Well if I am dying of terminal cancer and I want to end it, there is no one who is going to tell me that I can't do it.  Not you or anyone else."  In the dead silence that followed nobody brought up the obvious point that is the state of affairs currently.  Euthanasia proponents have always made that argument when in fact what they really want is to recruit physicians to provide them with euthanasia.  That is hardly the same thing as actively stopping them.  I would make the secondary argument that nobody really needs to be actively recruited these days.  I can't remember the last legal battle about whether a physician providing hospice care ordered too many opioids and benzodiazepines for a suffering terminally ill patient.  If I had to guess, the last time I saw that question raised in a court in the Midwest was about 20 years ago.

The concept of euthanasia in patients with psychiatric disorders is an even more complicated process.  Psychiatric disorders per se are not terminal illnesses, there is no protracted phase of increasing suffering and futile live saving measures with a fairly predictable death.  Death primarily due to psychiatric disorders occurs as a result of suicide, risk taking, comorbid medical illnesses, and severe disruptions in self care and homeostasis due to acute disorders like catatonia.  These are all relatively acute processes.  That does not mean that there are no people with chronic mood disorders, personality disorders, and psychoses.  Is the suffering in these situations acute and severe enough that euthanasia should be considered and if so, do any standards apply?

The authors of the Dutch study set out to study the characteristics of psychiatric patients receiving euthanasia or assisted suicide (EAS) in Belgium and the Netherlands.  The case studies of 66 cases were reviewed in the database of the Dutch regional euthanasia review committees.  There were 46 women and 20 men.  A little over half (52%) had made previous suicide attempts.  80% had been hospitalized in psychiatric units.  Most of the patients were aged 50-70 but 1/3 were older than 70.  Most (36) had depression and 8 of those patients had psychotic features.  The patients were described as chronically symptomatic and 26 patients had electroconvulsive therapy (ECT).  Two had deep brain stimulation - one for obsessive compulsive disorder and one for depression.  There was significant medical comorbidity.  The authors comment that there was very little social history to the point that they could not reconstruct the persons current living situation from what was abstracted.  Some of the reports contained fairly subjective data - as an example: "The patient was an utterly lonely man whose life had been a failure."  There was extensive treatment but also treatment refusal in 56%.

Twenty-one patients had been refused EAS at some point and in 3 of these cases the original physician changed their mind and performed EAS.  In the other 18 patients, the physician performing the EAS was new to the patient.  In 14 of those cases that physician was affiliated with a mobile euthanasia practice called the End-of-Life Clinic.  In 27 cases a psychiatrist did EAS and the rest were general practitioners.  Physicians disagreed in about 24% of the cases and EAS proceeded despite the disagreement.  In 8 cases the psychiatric consultant did not think that due care criteria specifying "no reasonable alternative" had been met.  The Euthanasia Review Committee (ERC) found that due care criteria were met in all psychiatric cases referred except for one.  In another case the ERC was described as being critical but in the end agreed with the euthanasia decision. It was a case of a man who broke his leg in a suicide attempt and then refused all treatment and requested EAS.

The authors come to several conclusions.  The first involves the issue that in this study the ratio of women to men was 2.3 to 1 and that is the opposite of what is expected with suicide.  They suggest that the availability of EAS may make the desire to die "more effective" for women.  Although the overall psychiatric sample was younger than the non-psychiatric EAS cases, they argue that the fact that a significant portion have significant comorbidities and this may indicate that Dutch physicians tend to self regulate EAS to a specific patient profile.  They point out that more judgment is required in psychiatric cases than in the cases involving terminal physical illness - 83% of which involved a malignancy.  They note that decision-making capacity can be affected by neuropsychiatric illness and that medical futility is difficult to determine especially when care is refused.  There were no official EAS psychiatric consultants involved in 41% of the cases.  In 11% of cases there was no psychiatric involvement at all.  Their overarching observation was that EAS for psychiatric illnesses involved making decisions about complex disorders and considerable judgment needed to be exercised.  They suggested that the decision about EAS required "considerable physician judgment" and that regional committees overseeing euthanasia deferred to the opinion of the treating physician when consultants disagreed.  

I have never seen it discussed but conflict of interest issues are prominent in any decisions about the autonomy of people who are designated psychiatric patients.  At the first level, there is the wording of the policy or statute.  There are criteria that are thought to be very objective that are used to decide if a person should be subject to civil commitment, guardianship, conservatorship, or any of the laws involving competency to proceed to trial, cooperate with one's defense attorney, or a mental illness or defect defense.  In all cases, the wording of each state's statute would seem to determine an obvious standard.  Those standards are routinely compromised in practice by any number of political considerations.  In the case of not guilty by reason of mental illness, the compromise occurs any time there are high profile cases that involve heinous crimes.  No matter how severe the mental illness, there will be a raft of experts on either side and the verdict will almost always be guilty.  At the other end of the spectrum is civil commitment.  Observing any commitment court over time will generally show the oscillation between libertarian approaches to more strict standards where need for psychiatric treatment is the more apparent standard.  The libertarian approach often uses a standard of "imminent dangerousness" as an excuse to dismiss the patient irrespective of what the statute may say.  It also seems to coincide with the available resources of the responsible county.   That is why in Minnesota the land of 10,000 lakes and 87 counties we say: "On any given day there are 87 interpretations of the civil commitment law."  Despite that range of interpretations, it would be highly unlikely that a patient who broke his leg in a suicide attempt (a case presented in this paper) would not be a candidate for court ordered treatment rather than euthanasia.  On the other hand, I do not know anything about civil commitment and forced treatment in the Netherlands.

There is no reason I can think of that a euthanasia standard can be interpreted any more logically. This Dutch study points to that.  It also points to another issue that is never really discussed when it comes to psychiatric diagnosis or the ethics and laws that apply to them.  The conscious state of the individual is never recognized.  Brain function is parsed very crudely into separate domains of symptoms, cognitions, and decisions.  The examiner or legal representative usually has some protocol by which they declare the person competent or not and the legal or ethical consequences proceed from that.  There may be a discussion of personality that is also based on this parsing process.  Very occasionally there is a discussion of the person's baseline, but that is about it.  That is a serious problem for any student of human consciousness.  Let me explain why.  I think that it is a universal human experience to experience a transient (days to months) change in your conscious state that might result in you not wanting to live.  The insult could be a physical or mental illness.  It would seem to me that at a minimum there can be multiple conscious states operating here that look like a request for assisted suicide or euthanasia.  The limits would be bounded by a completely rational decision based on medical futility and suffering on one side and an irrational decision based on the altered conscious state on the other.  The only way for any examiner to make that kind of determination is to know the patient very well over time to recognize at the very least that they are not themselves.  Doing an examination for the express purpose of determining if a person meets criteria for euthanasia in a short period of time is by contrast a very crude process.        

There is too much variability in the patient's conscious state and how that impacts treatment and ultimately recovery to consider psychiatric disorders as a basis for a decision about euthanasia and assisted suicide.


George Dawson, MD, DFAPA


References:

1:  Kim SH, De Vries RG, Peteet JR. Euthanasia and Assisted Suicide of Patients With Psychiatric Disorders in the Netherlands 2011 to 2014. JAMA Psychiatry.2016;73(4):362-368. doi:10.1001/jamapsychiatry.2015.2887.

2:  Appelbaum PS. Physician-Assisted Death for Patients With Mental Disorders—Reasons for Concern. JAMA Psychiatry. 2016;73(4):325-326. doi:10.1001/jamapsychiatry.2015.2890.


Supplementary 1:  I intentionally wrote the above post without reading the accompanying commentary by Paul S. Appelbaum, MD.  Dr. Appelbaum is an expert in forensic psychiatry and has written extensively on ethical issues in psychiatry.  Dr. Appelbaum's essay provides some additional facts, but his areas of  concern do not touch on my focus on the conscious state of the individual.

A Neanderthal - Further Confirmation And Much More On Personal DNA

I like the idea of getting my own DNA analyzed and studying the results.  In an earlier post, I described some results of an analysis through a National Geographic project, and the finding that 2.5% of my DNA was from Neanderthals.  The ability to sequence ancient DNA is a relatively new capability and in the few years that it has been done, it has yielded a number of significant findings.  The applicability to the field of psychiatry is limited at this time to 2 references (1,2).  An additional search on ancient DNA and psychiatry yields 4 additional references (4-6) looking at the early origins of mutation and how the associated disrupted regulatory mechanisms could lead to psychopathology.  One of the susceptibility markers for schizophrenia dates back to the last glacial maximum or 24,500 years BCE.  

After trying out the National Geographic site,  I decided to see if the 23andMe site had anything more to offer.  I pulled up their web site, paid the fee and they sent me a sampling kit.  Their sampling technology if different in that they use a tube of saliva as the sample rather than a scraping from the buccal mucosa.  They send you a number of e-mail updates and finally a notification that your DNA has been processed and the necessary reports have been generated.  There are 67 reports in all that focus on ancestry, carrier status, wellness, and traits.  Some reports are more useful than others.  For example it is interesting that a 4th digit on the hand longer than the second digit or a second toe longer than the great toe are inherited characteristics with certain probabilities.  Unless there are some additional health implications involved I don't really care about my longest toe or finger.  The data I am looking for is precisely the data that the FDA told 23andMe that it should not market in the first place.  That initial FDA warning looks at the testing that the company was offering.  In this document the abbreviation PGS is used for "Personal Genome Service":

"Some of the uses for which PGS is intended are particularly concerning, such as assessments for BRCA-related genetic risk and drug responses (e.g., warfarin sensitivity, clopidogrel response, and 5-fluorouracil toxicity) because of the potential health consequences that could result from false positive or false negative assessments for high-risk indications such as these. For instance, if the BRCA-related risk assessment for breast or ovarian cancer reports a false positive, it could lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity-inducing actions, while a false negative could result in a failure to recognize an actual risk that may exist......."

I am sure there are plenty of posts around the Internet on the regulatory aspects of DNA testing and what the FDA is doing to protect the American public.  23andMe does have consistent qualifying statements saying that none of the data is for medical purposes, only for research and education.  My interest is purely personal research and education.  What more can I learn about DNA, genetics, molecular biology and human diseases.  As noted in my original, what more can I learn about my ancestry and the fascinating subject of Paleogenetics and the associated big questions like why is Homo sapiens - the genus and species of all current human beings the only surviving Homo genus.  Why are all of the others extinct?  I also think that it is quite instructive to remind ourselves that as members of that species we all started out in East Africa and migrated all over the world.

Looking at the test results from the 23and Me analysis, there are four major categories and some are more useful than others.  Those categories include ancestry, traits,  carrier status, and wellness.  Since ancestry was the focus of the National Geographic experiment I took a look at that report first.  In terms of methodology the 23and Me technology looks at overlapping regions of DNA and homology with comparison regions of known ethnic groups.  I prepared the following table to look at the predictive value of the 23andMe approach compared with the National Geographic technique looking at the purported ancestries of my grandparents. (click on any graphic to enlarge)  

As noted in the above table, there is more coverage of ethnicities, using the 23andMe approach with  the best example being that it picks up Norwegian, Swedish, and Dutch markers that were not present in the NatGeo analysis.  There are a few problems that might not be obvious at first.  The test subject does complete information about ethnicities and populations of origin that may be incorporated into the algorithm that assigns probabilities of certain ancestry.  These questions reminded me of the clinical data required for quantitative electroencephalogram machines in the 1990s.  The algorithms were supposed to predict psychiatric diagnoses, but the clinical data that was required with every test, frequently interfered with what the machine was going to select.  I take a very dim view of what appear to be scientific decisions being made on the basis of added speculative data.   The ancestry interpretations also depend the level of confidence assigned to the analysis.  As an example, take a look at the following genealogy assessments - the top a conservative estimate and the bottom much more speculation.  Significant changes in the analysis occur just based on how speculative the analysis is.  All things considered, I am quite interested in the range of the analysis and all correlations at this point rather than precision, but is some cases precision is apparently available.         

All together there are 3 ancestry reports and the most interesting report for me was the Neanderthal analysis.  The test looks at 1,436 traits across the genome and generates a report based on a map of all 23 chromosomes and a table that takes a more detailed look several markers.

The traits report was significantly less interesting to me.  It answered the question about whether or not a genetic markers for a trait existed.  For example, the length of the second toe on the foot and the length of the fourth finger on the hand.  The testing predicts that I have a 96% chance of lighter skin and very little chance of freckling.  That is true.

Carrier status was similarly not very interesting.  There was a major focus on congenital illness rather than risk of chronic illness.  Some of the carrier states mentioned include: ARSACS, Agenesis of the Corpus Callosum With Peripheral neuropathy(ACCPN),  Autosomal Recessive Polycystic Kidney Disease (ARPKD) and 33 others.  My carrier status for these relatively rare conditions was negative.  That was really no surprise considering my age, family history, and the fact that most of these are illnesses of infancy or childhood.

The wellness section contained 6 reports and a few were moderately interesting.  Caffeine consumption is regulated by variants near the CYP1A2 and AHR genes and I have those variants.  The prevalence of these variants in various populations are also estimated and it seem that these variants are high.  I do tend to consume significant amounts of caffeine and it is hardly noticeable.  It seems like I am drinking decaffeinated beverages.  I have the rs73598374 variant in the ADA gene that is associated with deep sleep.  I do sleep for short periods of time, but my activity monitor suggests that my sleep may be deeper than people who sleep more hours.  I also have the rs3923809 variant in the BTBD9 gene that predicts more movement in sleep.  The R577X variant in the ACTN3 gene is present and that is associated with a greater portion of fast twitch muscle fibers or what the site refers to as sprinter/power muscle type.  The final two wellness traits were lactose intolerance and the alcohol flushing reaction.  I knew that I had neither trait prior to the genetic testing.

Apart from the Neanderthal testing, the most interesting aspect of the this service is that ability to search your genome looking for points of interest.  I think that this will eventually be the most interesting aspect of these services as long as the users keep in mind that having a genotype, especially of a complex polygenic illness is a probability statement rather than a guarantee.  I am testing out two ways to do these searches.  The first strategy is based on protein analysis and I used a recent paper on bipolar disorder (I have a strong family history) to see if I could find any of these markers.  The original paper suggests that there are higher plasma concentrations of 6 proteins in bipolar disorder including GDF-15, HPX, HPN, MMP-7, RBP-4, and TTR.  A direct search yields a significant number of hits for HPX (5), HPN (14), and TTR (89) genes with specific information on markers, genomic position, possible variants and genotype.  In this case the original paper was a protein analysis and as far as I can tell there is no genetic analysis of the subgroup with higher levels of the identified proteins.  I have sent an e-mail to the lead author to see if I missed any papers on that issue.  An example of the data available searching on these proteins for the HPX protein is shown below:

The second option would be to search for known genotypes.  It is no secret from previous posts that I have asthma that was quiescent for most of my life that was reactivated about 3 years ago by a upper respiratory infection.  Asthma is an interesting disorder because the genetics are very complex just like psychiatric disorders.  For the critics who suggest that there are no tests of any sort for psychiatric disorders, these two sentences are from the latest chapter on the genetics of asthma from UpToDate (9) are instructive:

"Exploration of the genetics of asthma has also been hampered by the fact that there is no "gold standard" diagnostic test for asthma, and the clinical diagnosis is inconsistently applied.  To circumvent these issues, investigators have studied the distribution of asthma-related traits, including bronchial hyperresponsiveness and measures of atopy (eg, total serum IgE levels, skin test reactivity) in addition to the presence of an asthma diagnosis."

This same author reviews the genetic research on asthma to date and points out that prior to the retirement of the Genetic Association Database in 2014 there were over 500 genetic association studies on asthma that identified hundreds of candidate genes for asthma.  From those candidate gene studies, she gives the most replicated genes as filaggrin (FLG) - an epithelial barrier gene also important in atopic dermatitis,  ORMDL3 - a transmembrane protein, Beta-2 adrenergic receptor gene, and Interleukin-4 receptor gene.  Genome-wide association studies (GWAS) have supplanted candidate gene studies and over 50 GWAS have been done in asthma.  These studies have identified other candidate genes and generally shown that GWAS done in populations with European ancestry seem to have little applicability in more ethnically diverse populations.  ORMDL3 was identified in both types of studies so I searched for that in my own DNA and came up with the following:

            
In order to look at specific markers and asthma risk, I searched on one of the genotyped markers (rs8076131) in PubMed and came up with 7 papers on asthma susceptibility.  Searching more broadly on ORMDL3 showed 132 references that were less specific.

This ends my preliminary review on the availability of personal genomics for education and research purposes by individuals.  I hope to come up with more effective strategies to look at several additional disease phenotypes that I either personally possess or that were present in my first degree relatives.  For me, the paleogenetics and personal genome browsing were the most interesting aspects of this data.  For educational purposes, it highlights the difficulties of correlating genetics with disease phenotypes due in part to the fact that multiple genes and polygenes can produce the same phenotype and that makes the activity of specific genes difficult to determine in a DNA sample.



George Dawson, MD, DLFAPA

      



References:

1:  Srinivasan S, Bettella F, Mattingsdal M, Wang Y, Witoelar A, Schork AJ, Thompson WK, Zuber V; Schizophrenia Working Group of the Psychiatric Genomics Consortium, The International Headache Genetics Consortium, Winsvold BS, Zwart JA, Collier DA, Desikan RS, Melle I, Werge T, Dale AM, Djurovic S, Andreassen OA. Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biol Psychiatry. 2015 Oct 21. pii: S0006-3223(15)00855-0. doi: 10.1016/j.biopsych.2015.10.009. [Epub ahead of print] PubMed PMID: 26681495.

2:  Mariotti M, Smith TF, Sudmant PH, Goldberger G. Pseudogenization of testis-specific Lfg5 predates human/Neanderthal divergence. J Hum Genet. 2014 May;59(5):288-91. doi: 10.1038/jhg.2014.6. Epub 2014 Mar 6. PubMed PMID: 24599118.

3:  Sipahi L, Uddin M, Hou ZC, Aiello AE, Koenen KC, Galea S, Wildman DE. Ancient evolutionary origins of epigenetic regulation associated with posttraumatic stress disorder. Front Hum Neurosci. 2014 May 13;8:284. doi: 10.3389/fnhum.2014.00284. eCollection 2014. PubMed PMID: 24860472; PubMed Central PMCID: PMC4026723.

 4:  Zhang W, Tang J, Zhang AM, Peng MS, Xie HB, Tan L, Xu L, Zhang YP, Chen X, Yao YG. A matrilineal genetic legacy from the last glacial maximum confers susceptibility to schizophrenia in Han Chinese. J Genet Genomics. 2014 Jul 20;41(7):397-407. doi: 10.1016/j.jgg.2014.05.004. Epub 2014 Jun 2. PubMed PMID: 25064678. 

 5:  Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat Commun. 2015 Mar 10;6:6404. doi: 10.1038/ncomms7404. PubMed PMID: 25752243; PubMed Central PMCID: PMC4355952. 

 6:  Toyota T, Yoshitsugu K, Ebihara M, Yamada K, Ohba H, Fukasawa M, Minabe Y, Nakamura K, Sekine Y, Takei N, Suzuki K, Itokawa M, Meerabux JM, Iwayama-Shigeno Y, Tomaru Y, Shimizu H, Hattori E, Mori N, Yoshikawa T. Association between schizophrenia with ocular misalignment and polyalanine length variation in PMX2B. Hum Mol Genet. 2004 Mar 1;13(5):551-61. Epub 2004 Jan 6. PubMed PMID: 14709596.

7:  FDA Warning Letter to 23andMe

8:  Frye MA, Nassan M, Jenkins GD, Kung S, Veldic M, Palmer BA, Feeder SE, Tye SJ, Choi DS, Biernacka JM. Feasibility of investigating differential proteomic expression in depression: implications for biomarker development in mood disorders. Transl Psychiatry. 2015 Dec 8;5:e689. doi: 10.1038/tp.2015.185. PubMed PMID: 26645624.

9:  Barnes KC.  Genetics of Asthma. In: UpToDate, Barnes PJ, Raby BA, Hollingsworth H (Ed), UpToDate, Waltham, MA. (Accessed on April 8, 2016)


Attributions:

All of the above graphics and tables with the sole exception the the ancestry table were generated with on site software at 23andMe based on my personal DNA sample.

Say What You Mean.........

I read an elegant editorial piece during breakfast this morning.  It was in the regular section in JAMA called "A Piece Of My Mind".  Amanda Fantrey, MD writes about some of the insights she developed as a family member in an ICU setting after her brother was involved in a motor vehicle accident and sustained a traumatic brain injury and coma.  She describes the pull on doctors to make statements that offer hope and frequently diverge from the realistic medical appraisal of the situation.  She describes this as "the seismic gap between what was said by staff (both physicians and nurses) and what was heard by family."  A common example is the staff remembering the one patient with a miraculous recovery and bringing that up in discussions with the family as a way to give them hope.  Dr. Fantrey points out the origins of this behavior as wanting to reassure a traumatized and grieving family.  She gives a clear example of how this plays out in a discussion between the neurosurgical team and her parents.  What seems like a grim prognosis is suddenly being moderated by qualifiers. With enough modification the initial grim prognosis becomes the expectation of recovery.  She also points out that another level this is self preservation - a bias toward recalling the miracle cases and saves.  That without it practicing medicine and surgery is just too grim to contemplate.  This is an excellent essay that I would recommend to any medical student or resident as an example of the power of affective communication, language, and interpersonal dynamics.

The interactions that Dr. Fantrey describes on medicine are common.  I think they form the basis for a number of commonly observed phenomenon.  Psychiatric practice is no exception.  The first thing that came to mind is the promise of the miracle drug that will take away all of your problems.  Many psychiatrists witness first hand patients who explicitly ask them for this kind of medication.  Many people become addicted to opioids because at the outset - it seems like these medications have the properties of an ideal medication.  There has been abundant criticism that new medications are oversold both by advertising and the way that advertising affects the pharmacology literature.  I am much less certain of that as there is more evidence accumulating that the pricing power of the companies themselves is the single largest factor driving much higher pharmaceutical prices and profits in the US.  There is the inescapable sense of hope being conveyed through both direct-to-consumer advertising and and the novelty of a new drug.  Although it has not been adequately tested, that new drug is a form of hope in a pill.  The interested people are all hoping for better therapeutic effects even in spite of the rapid delivery of a list of serious side effects "including death" at the very end of the commercial.

It also brought to mind some of the serious discussions that psychiatrists have with patients and how the biases might be a little different.  The most obvious one is lithium.  Lithium is one of the best medications in terms of therapeutic effects that psychiatrists prescribe.  The attitude of other physicians seems to be: "We will let them prescribe that medication almost exclusively" or "You psychiatrists sure do prescribe a lot of toxic medications."  Treating people with the most severe forms of mental illness almost exclusively for 30 years has caused me to witness many miracles of lithium therapy.  The commonest was the depressed bipolar patient not able to eat, barely taking in fluids, and certainly not able to function outside of a hospital setting.  After starting lithium, many of of these folks recover enough function within a week to be up in the daytime, eating and starting to care for themselves.  For me the miracle of lithium has been on the depressed side.  People who have failed antidepressants and whatever anticonvulsant is en vogue for bipolar disorder.

There is no other medication prescribed by psychiatrists that invokes fantasies and expectations more to patients than lithium.  Their expectations are generally very bad as in:  "That is some serious shit - dude..  Isn't that the medicine in that song......"  I have to remind people that the band was Nirvana and yes I am old enough to have watched them perform the song Lithium live on Saturday Night Live.  I have to explain calmly that it is a salt and that this makes it a unique kind of medicine with fairly unique precautions but that is can be safely taken.  I do point out that is if they end up taking it for decades or if they have repeated episodes of lithium toxicity - it can cause renal failure in some and the need for dialysis and renal transplantation.  I know this because of my experience with end stage renal disease that was attributed to lithium by my Renal Medicine consultants and the protracted course of dialysis, in some cases delirium, and ultimately renal transplantation.  I try to outline all of that, but it is hard to imagine how much information is getting through.  Like Dr. Fantrey's ICU experiences, nobody is more acutely aware of needing to provide hope than a psychiatrist talking directly to a depressed bipolar patient.  We are simultaneously assessing suicide risk - even in inpatient settings.  Acute care psychiatrists know that this is our job.  We have to keep this person alive so that they can recover.

I have to cautiously present the information on lithium as part of the informed consent discussion, but at some point I also started to include a line about lithium being a "potentially life-changing medication."  I explain that the person may experience mood stability like they have never had on the endless series of antidepressants, atypical antipsychotics, benzodiazepines, various anticonvulsants and the drift toward an inaccurate schizoaffective disorder diagnosis that they have been experiencing for years or decades.  I am always concerned about whether they hear the word potentially in my description.   I provide them with a detailed handout on lithium and encourage them to do whatever research they would like to do on the medication and I will answer any further questions.  Is this just another example of hope enacted in the countertransference, me trying to convey it to a desperate patient?  It is hard to imagine that patients who view lithium as a toxin at the outset could have unrealistic expectations about the drug.  Am I coloring their expectations by my description of the drug?  Would it be unfair to not include that information about potentially changing their life?

I think there are problems with all complex informed consent discussions.  These discussions can't be devoid of emotional content.  Like the surgical patients, some people will do better and some will do worse.  It is difficult to determine that ahead of time.  Every patient I see needs to benefit from my experience treating other patients.  And with lithium it is very good.  


George Dawson, MD, DFAPA


References:

Fantry A. Say What You Mean, Mean What You Say. JAMA. 2016;315(13):1337-1338. doi:10.1001/jama.2015.18910.






 

POTUS Tweets Measures To Address Opioid Epidemic

In 2014, nearly 21,000 deaths in the U.S. involved prescription opioids. Here's what @POTUS is doing about it: https://t.co/M2HgnDDN6a

— The White House (@WhiteHouse) March 29, 2016

I happened to be on Twitter last night when I caught the above Tweet from POTUS.  Having a professional interest, I decided to follow the link at the White House blog to look at the proposed measures.  They were listed as:

1.  Increasing a key drug for medication assisted treatment.  That key drug is buprenorphine in a number of formulations for treating severe opioid dependence.

2.  Preventing opioid overdose deaths.  This appears to be $11 million in funding for various forms of treatment and increasing access to naloxone to reverse the effects of an acute overdose.

3.  Addressing substance use disorder parity with other medical and surgical conditions.

These are very modest and in some cases unrealistic proposals about about trying to stop a drug epidemic that is killing 20,000 people a year.  Let me tell you why:

1.  Increasing a key drug for medication assisted treatment.  That key drug is buprenorphine in a number of formulations for treating severe opioid dependence.

Buprenorphine as Suboxone and Subutex have been available for the treatment of opioid addiction in the US since 2002.  The current evidence suggests that buprenorphine has superior efficacy for abstinence from opioids and retention in treatment.  There is also evidence that patients on buprenorphine have fewer side effects and that they is a less severe neonatal abstinence syndrome in mothers maintained on buprenorphine versus methadone.   Buprenorphine is also used for acute detoxification and treatment of chronic pain.  One of the limitations of maintaining opioid addicts on buprenorphine is that a special license is required to prescribe it.  Physicians can obtain that license by by attending CME or online courses.  Even then, expansion to primary care physicians has been slow because they may have no colleagues in their practice with similar certification and that makes on call coverage problematic.  In addition, many clinics that are medically based are reluctant to provide this type of service to people who have opioid addictions.  Apart from the technical requirements of prescribing the various preparations of buprenorphine certain physician and patient characteristics may also be important.  Physicians have to be neutral and not overreact in situations where the patient exhibits expected addictive behaviors that may include relapse.  As an example, younger opioid users are frequently ambivalent about quitting and in some cases, use other opioids and reserve the buprenorphine for when their usual supply dries up.  They may sell their buprenorphine prescription and purchase opioids off the street.  It may not be obvious but physicians prescribing this drug need an interpersonal strategy on how they are going to approach these problems.    On the patient side,  there is the biology of how the opioids have affected the person.  Do they have severe withdrawal and ongoing cravings?  What is their attitude about taking a medication on an intermediate or long term basis in order to treat treat the opiate addiction?

In clinical trials, buprenorphine seems to be ideal medication for medication assisted treatment (MAT) of opioid dependence.  Like most medications, there are issues in clinical practice that are not answered and possibly may never be answered.  The issue of life-long maintenance is one.  Many people with addictions are concerned over this prospect.  Long term maintenance with buprenorphine has advantages over methadone in that it is easier to get a prescription rather than show up in a clinic every day to get a dose of methadone.  Most addicts are aware of the fact that withdrawal from both compounds can be long and painful.  This deters some people from trying it and relapse risk is high if a person attempts to taper off of it.  Despite the current consensus about use. there is still the problem of young addicts who feel that they are "not done using" and who go between using heroin and other opioids obtained from non-medical sources and buprenorphine.  

2.  Preventing opioid overdose deaths.  This appears to be $11 million in funding for various forms of treatment and increasing access to naloxone to reverse the effects of an acute overdose.

Naloxone kits that would allow for rapid reversal of opioid overdoses have been shown to be effective in partially decreasing the death rate.  At some treatment and correctional facilities opioid users are discharged with naloxone kits for administration in the event of an overdose.  Opioids are dangerous drugs in overdose because they suppress respiration and that can lead to a cardiac arrest.  There are several properties of opioids that heighten the overdose risk.  Tolerance phenomena means that the user eventually becomes tolerant to the euphorigenic and in some cases therapeutic effects of opioids and needs to take more drug.  If tolerance is lost when the user is not taking high doses for a while, using that same high dose can result in an overdose.  Taking poorly characterized powders and unlabelled pills acquired from non-medical sources compounds the problem.  The exact quantity of opioid being used is frequently unknown.  Adulterants like fentanyl - a much more potent opioid can also lead to overdoses when users do not expect a more potent drug.

In addition to the pharmacology of the drugs being used there is also a psychological aspect to overdoses.  Users often get to the point where they don't really care how much they are using in order to get high.  They will say that they are not intentionally trying to overdose, but if it happens they don't care.

The available literature on making naloxone available suggests that it is effective for reversing overdoses in a fraction of the at risk population that it is given to.  I would see at as the equivalent of an Epi-pen in that the majority of patients with anaphylactic reactions get these pens refilled from year to year but never use them.  When they are required they are life-saving.  The problem with a naloxone kit is that it assumes a user or bystander can recognize an overdose and administer naloxone fast enough to reverse the effects of opioids before the user experiences serious consequences.  Unfortunately addiction often leads to social isolation and not having a person available makes monitoring for overdoses much more problematic.  Naloxone kits should always be available opioid users, first responders, family members, and anyone involved in assisting addicts.  Detailed long term data on the outcomes over time is needed.  

3.  Addressing substance use disorder parity with other medical and surgical conditions.

The is the most critical aspect of the President's tweet.  One of the main reasons for this blog is to point out how people with addictions and severe mental illnesses have been disproportionately rationed since the very first days of managed care - now about 35 years ago.  Some of the first major changes involved moving medical detoxification out of hospitals.  So-called social detoxification was available with no medical supervision.  These non-medical detox facilities were very unevenly distributed with only a small fraction of the counties in any state running them.  Any admissions to hospitals were brief and "managed" by managed care companies.  In the case of addictions some of the management practices were absurd.  A standard practice was to determine how many days a person could be in residential treatment.  That often required a call to an insurance company nurse or doctor who had never seen the patient.  They could determine that the patient could be discharged at any time based on arbitrary criteria.  In some cases that involved just a few days and the patient was leaving with active cravings and in some cases an an active psychiatric disorder.  This practice continues today, despite party legislation that suggests that addictions and mental disorders should be treated like any other medical problem.

This is where the President's tweet is on very shaky ground.  His legislation  focuses on large systems of health care and yet these systems don't seem to be able to supply adequate treatment with either buprenorphine or naloxone kits.  The President is fully aware of 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 illnesses and addictions that was on par with medical and surgical conditions.  I think it is no secret that special interests have shredded the intent of this bill to the point that it is useless.  Managed care systems still ration care for these disorders in their best financial interest.  The resources for treating these disorders are still not equal to the task. In the case of prescription painkillers the same system of care not providing adequate treatment for addiction is often where that addiction started.

All three of the President's points could be addressed by forcing health care companies to provide adequate care for addictions and mental illnesses instead of grants to provide services that they should be doing in the first place.  In an interesting recent twist the President (1) suggested that this discrimination was based on race.  He implied that as a result the police rather than doctors have been used to address the problem.

Let me be the first to say that President Obama is wrong.  There is no doubt that racial discrimination exists.  There is no doubt that it occurs in systems of health care (2,3).  There is also no doubt that all it takes is a diagnosis of addiction or mental illness to trigger highly discriminatory health care coverage - irrespective of a person's race.  It is all about how health care businesses make money in this country by rationing or denying treatment for these disorders.

To reverse that discrimination,  the government needs to take the MHPAEA seriously.  So far they have failed miserably and that is the problem on the treatment side in trying to address the opioid epidemic.  

George Dawson, MD, DLFAPA

References:

1:  Sarah Ferris.  Obama: 'We have to be honest' about race in drug addiction debate.  The Hill March 29, 2016.

2:   Eddie L. Greene, MD and Charles R. Thomas, Jr, MD.  Minority Health and Disparities-Related Issues: Part I.  Medical Clinics of North America July 2005; 89(4).

3:   Eddie L. Greene, MD and Charles R. Thomas, Jr, MD.  Minority Health and Disparities-Related Issues: Part II.  Medical Clinics of North America July 2005; 89(5).

  

Dr.Ghaemi on Dr. Spitzer

Nassir Ghaemi, MD has a commentary on Robert Spitzer, MD in this month's Clinical Psychiatry News.  After citing quotes by Shakespeare and John Adams to suggest that the dead are often idealized, he settles down to criticism based on whether or not the DSM-III helped or harmed the profession and Spitzer's role in that process.  Ghaemi comes down firmly on the side of harm because an unscientific approach to the diagnostic criteria for major depressive disorder has resulted in a lack of reliability and validity.  He uses the often quoted kappa score of 0.32 for diagnostic reliability of major depressive disorder in DSM-5 field trials as the main source of evidence, as well as the fact that the diagnostic criteria are unchanged since DSM-III.

Ghaemi suggests that his viewpoint is unique because unlike other eulogists, he had no personal connection with Spitzer and therefore can speak "in forthright recognition of fact from the impersonal perspective of another generation."  I am closer to Ghaemi's generation than Spitzer's and can make the same claim, but come to an entirely different set of conclusions.

I don't see Spitzer's efforts as being as corrosive as Ghaemi does, probably because I recognize the fact that there will never be a set of written diagnostic criteria that are perfect, based on science, and unambiguous.   But before I address the scientific, let me take on the rhetorical.  I would hardly blame Spitzer for the fact that the DSM criteria for depression have changed "hardly an iota" in the intervening 40 years since DSM-III.  Over that same time span there have been hundreds if not thousands of articles on the reliability of the major depressive episode diagnosis, as well as articles that analyze the symptoms according to that diagnosis.  There have been articles on standardizing various psychiatric and psychological instruments to detect major depression.  In fact, one of the rating scales basically copies the DSM criteria and asks the patient to rate on a 0 to 3 point scale - the percentage of days that they experience the symptoms. The PHQ-9 has become the standard for depression diagnosis in many primary care clinics.  There is also the fact that Spitzer's original DSM-III effort resulted in much higher reliability figures - a kappa of 0.72 to be exact (2).

There is also the issue that there have been two intervening Task Forces for DSM-IV and now DSM-5.   The Chair of the DSM-IV Task Force has since become a prominent critic of the DSM process and psychiatry in general.  I may have missed it, but at the time that Task Force was convened, I did not notice him or other members advocating for major changes to the major depression diagnostic criteria.  These are supposedly the top minds in the field.  Highly motivated academics with one axe or another to grind.  The idea that everyone would defer to Dr. Spitzer based on his original approximate efforts seems unrealistic to me.  More than a few people would have noticed his bungled and unscientific approach.

My major problem is using a single reliability figure as the grounds for this criticism.  Every year outpatient based psychiatrists can see up to a thousand new people a year.  They may find that up to 50% of those patients have had a life-long sleep disturbance.  Many can recall nightmares and sleep terrors as children.  Another 20-30% will have generalized anxiety or social anxiety since childhood.  In some there will be a performance based anxiety that is comorbid with the social anxiety.  Another 10-20% will have post-traumatic stress disorder to some degree.  About one-third will have a significant substance use problem.  These percentages will vary by clinic location and referral base.  The majority will be referred for a diagnosis and treatment recommendations for depression.  A substantial number of people with depression have comorbid anxiety and anxious temperaments.  I don't think it is a stretch to say that on any given day, many of the identified depressives will identify themselves as primarily anxious.  It is not unexpected to find that many patients don't really understand the difference between anxiety and depression or they will overtly say that they are the same problem - indistinguishable from one another.  Unless there is a clear differentiating factor like a manic episode, the postpartum state, or psychotic symptoms I would not expect that anxiety and depression are distinct disorders for most people.  At the minimum anxiety might morph into depression, but in most cases they are coexisting chronic conditions.  A low kappa in this situation should be expected and not a shock.

Does that mean that psychiatrists should be wringing their hands and blaming Spitzer for it?  Neither response is appropriate.  Psychiatrists are highly successful in diagnosing and treating mental illness, not because of a DSM manual, but because of clinical training.  When it comes to anxiety and depression there are no known ways to parse all of the symptomatic possibilities.  The human brain is designed to realize all of the possible combinations of human experience.  Why would we expect it to be different when it comes to experiencing anxiety and depression?  The only chance that a psychiatrist has to make sense of the world is a number of patterns of diagnoses based on their training and practice experience that they can match against the patient they are currently seeing.  These patterns guide the diagnosis and treatment plan.  A clinically astute psychiatrist is not plowing through the interview to see if the patient "meets criteria".  A clinically astute psychiatrist carefully attending to the patient's conscious state and trying to figure out how they can be helpful.  That includes figuring out the real problems and prioritizing them in a complex matrix psychiatric and medical problems.  None of that flows from the DSM and none of that resembles research based on lay people interviews using DSM criteria.

In closing, any commentary on Dr. Spitzer should include his role in eliminating homosexuality from the diagnostic manual.  This detail and how it occurred is never taught to residents.  I had to learn it from public radio many years after residency.  This detail is significant any way you cut it.  It invites criticism that monolithic psychiatry is currently moving too slow in other areas or that monolithic psychiatry was just responding to public pressure.  There is also criticism directed at Dr. Spitzer for a paper based on self report that was withdrawn years later on this same issue.  There are always advocacy groups seeking publicity by their own spin on the issue.   In my opinion, none of that diminishes that significant achievement that put psychiatry four decades ahead of most people in the United States.  Say what you will about the DSM, that accomplishment alone is enough.  I am thankful that Dr. Spitzer was open minded enough to listen to the advocates and eventually side with them.              


George Dawson, MD, DLFAPA


1:  Nassir Ghaemi.  Commentary:  Dr. Robert L. Spitzer - An impersonal appraisal.  Clinical Psychiatry News.  March 2016. p 12-13.

2:  Riskind JH, Beck AT, Berchick RJ, Brown G, Steer RA. Reliability of DSM-III diagnoses for major depression and generalized anxiety disorder using the structured clinical interview for DSM-III. Arch Gen Psychiatry. 1987 Sep;44(9):817-20. PubMed PMID: 3632255.

Opiates And Moral Dilemmas For Physicians

I became aware of an article from Reason magazine written by a physician Jeffrey A. Singer titled Physicians Face A Moral Dilemma In Conscription on War on Drugs (1). In keeping with the main theme, the subtitle was “In the government’s new war on opiates, physicians and their patients find themselves caught in a crossfire.”  Physicians are generally in the crossfire of any number of government healthcare reforms. The opening lines of this essay should not surprise any physician.  We have been in the crosshairs for thirty years.  There is a tangible difference in the War on Drugs.  In the 1990s, I can recall a vague threat about incarceration for not doing my notes properly.  That wasn’t a threat to me specifically but an entire clinic of physicians than I belonged to at the time.  In retrospect it sounds absurd, but that the was pre-911 days when the FBI spent a lot of time reading physician notes and deciding whether or not they had committed health care fraud by not doing enough documentation.  These days physicians can be prosecuted and incarcerated for the way that they prescribe opiates. The threat is much more real.

Dr. Singer’s introductory paragraph points out that when any health crisis occurs politicians are eager to step up and offer their solutions and throw a lot of money at the problem.  In this case President Obama is building new drug addiction centers and “training” government physicians on opioids to the tune of $100 million.  Hillary Clinton is promising $10 billion as a criminal justice initiative as grant for drug treatment centers and training for first responders to administer opiate antidotes.  I have never seen a single politician or government bureaucrat acknowledge that the reason why the opiate epidemic exists has to do with policy initiatives that occurred right around the year 2000.  At that point, physicians were encouraged to treat pain more aggressively and with fewer checks and balances than they had in the past.  The cumulative effect of these policy changes was a lower threshold for prescribing opiates for chronic noncancer pain and a removal of some of the gatekeeper mechanisms – like getting second opinions from pain specialists on this practice.

The First War on Drugs was described as the initial prohibition of opiates and cocaine by the Harrison Act in 1914.  Singer describes a scenario where a physician who would prescribe an opiate to help a patient “cope with their addiction” as being in conflict with the law.  The Harrison Act prohibited physicians from prescribing opiates to maintain an addiction.  He cites this example as being the first moral dilemma.  It is more complicated than depicted.  There have always been a number of physicians who consciously or unconsciously maintained large numbers of patients in addiction and that was their medical practice.  That practice does not pass current conflict of interest considerations much less the ethical obligation of physicians to do no harm.  It is a given that legal interventions are generally blunt instruments for protecting people from their problematic decision-making and that a complete picture of all of the data (the number of people addicted by medical treatment versus non-medical sources) is never clear.  Is there a problem with suggesting that physician themselves should not be a primary source for creating and maintaining addiction?  The main problem is that even the most well-informed and well-intentioned physician can end up with a patient who is addicted to a medication.  There is currently no known way to prevent that.  Are those physicians criminals in any way?  I don’t think so.  At the same time, should there be a prohibition against physicians setting up a practice that maintains high number of patients in addiction, does nothing to facilitate their recovery from addiction, and has no other purpose – of course there should be such a prohibition. 

The next argument in the essay has to do with the safety of opiates versus alcohol.  This is a common argument by people who see nothing wrong with the legalization of drugs.  I am not suggesting that Singer is making this argument; he is trying to point out that opiates are relatively safer than alcohol and alcohol is a legal drug.  I think that he is wrong on several counts in this argument.  The first point has to do with the overall toxicity of alcohol.  He cites a number of diseases that have to do with the long-term toxicity of alcohol.  Alcoholic cirrhosis for example is typically the fifth or sixth leading cause of death in middle-aged men.  The estimated dose required in most cases is 15-pint years or drinking one pint of whiskey per day for 15 years (2).  Doing a quick calculation shows that this is about 143.26 grams of ethyl alcohol per day.  The progression to cirrhosis will vary based on sex, genetic factors, and rates of metabolism.  The overriding point is that alcohol consumption at this rate is limited to a small percentage of drinkers and the population exposure to alcohol is relatively stable based on current legal and cultural factors.  A related issue is that if you are alcohol dependent tolerance and withdrawal phenomena may lead to a marked increase in consumption – up to 750-1,500 ml/day in order to maintain blood levels high enough throughout the day to prevent withdrawal.  The exposure of multiple tissues over time causes the damage.

The primary mechanism of injury and death from opiates is respiratory ataxia and arrest by the direct action of the drug on small clusters of cells in the midbrain and medulla.  Opiates have a direct effect on the center that determines respiratory rhythm and the center that responds to chemical changes due to oxygen deficiency and carbon dioxide accumulation.  Benzodiazepines, alcohol and sleep medications are often involved in these situations and have a combined effect.  Alcohol in high enough doses can have a similar effect in depending on the individual and their state of tolerance.

Looking at the acute mortality related to alcohol and opiates, I don’t think that there should be any doubt that opiates are probably more lethal than alcohol.  The CDC states that about 2,200 people die every year from acute alcohol poisoning (3).  The population at risk appears top be 38 million binge drinkers.  Men ages 35-64 are at highest risk.  In 2014, there were 18,893 overdose deaths from prescription painkillers and 10,574 deaths from heroin overdose (4).  In this case the estimated populations at risk include 1.9 million people with a prescription painkiller problem and 586,000 heroin users.  Furthermore the death rate from prescription painkiller and heroin use parallels the availability.  I am puzzled by the author’s suggestion that opiates are “much safer” and that there is “honest disagreement among health care practitioners over just how harmful long term opiate use can be…”.

I guess that I am one of those disagreeable health care practitioners.  Anyone can fact check the above argument for acute toxicity and I would encourage a close look at the trendlines over the past 15 years.  If you look at this lines, you will find that the rate of deaths due to heroin overdose was relatively stable for at least a decade before a sizable number of prescription painkiller users decided to start using heroin.  The decision is a strictly economic one.  The most commonly abused prescription painkiller costs a dollar per milligram on the street.  Addicts are typically using 120-240 mg per day.  The equivalent amount of heroin can be purchased for about ¼ as much.  The end result is that stable rate of heroin overdose deaths has quadrupled in the last 5 years.  It is stark to contemplate that the total opiate death rate is based on a population at risk that is about 10% the size of the drinking population at risk.

Dr. Singer describes the movement that led to increased opiate prescribing at the beginning of the 21^st century as “enlightened” and “compassionate.”  He uses the term opiophobia as the irrational fear that doctors and patients have about these medications.  I think it is very clear that these advocacy groups and bureaucrats had no clue that increased access would lead to an epidemic of addiction and overdose deaths.  The moral dilemma for physicians is not colluding with law enforcement in the War on Drugs and “cutting patients off.”  The moral dilemma is practicing sound medicine in a system that blames them for not prescribing enough opioids and then ten years later blames them for prescribing too many.  All of this occurs against the backdrop of a culture that has an insatiable appetite for intoxicants in a country that has one of the highest per capita opiate consumption rates in the world.  The moral dilemma for physicians is recognizing that they can’t predict who will or not become addicted to an opiate and that many physicians do not have the skills necessary to not prescribe to patients who either really don’t need the drug or are probably addicted to it.

There is more than one moral dilemma in the opiate epidemic.  On the patient side should you let your doctor know if you have an addiction before the opiate prescription is written?  Should you let your doctor know that the first pill from the prescription left you feeling euphoric, energetic, confident and like you have never felt before in your life?  Should you let your doctor know that you are continuing to take prescription painkillers even though they don’t work for the pain or because the pain is gone?  Should you tell your doctor or pharmacist know that you suddenly have access to all of the opiates from a deceased family member who was in hospice care and ask how to keep them off the street?

There are many moral dilemmas associated with opiates for everyone and very little moral guidance.

      

George Dawson, MD, DLFAPA


Supplementary:

To calculate the mg alcohol in a pint of whiskey:

1 pint = 473.18 ml

473.18 ml x 0.4 (percent alcohol) x 0.757 g/ml (specific gravity of alcohol) = 143.26 g ethyl alcohol

References:

1:  Singer JA.  Physicians Face Moral Dilemma In Conscription on War on Drugs.  Reason.com  March 23, 2016.  Accessed on March 25, 2016.

2:  Lefton HB, Rosa A, Cohen M. Diagnosis and epidemiology of cirrhosis.  Med Clin  North Am. 2009 Jul;93(4):787-99, vii. doi: 10.1016/j.mcna.2009.03.002. Review. PubMed PMID: 19577114.

3:  Centers for Disease Control and Prevention.  Alcohol Poisoning Deaths.  CDC Vital Signs, January 2015.

4:  American Society of Addiction Medicine.  Opioid Addiction 2016 Facts and Figures.  ASAM web site accessed on March 26, 2016.