The Medical Cannabis Smorgasbord In Minnesota

I took in a CME course on Medical Cannabis: Clinical Applications and Evidence for Health Professionals on April 28, 2016 8 AM - 5 PM.  It was done as a collaboration between the University of Minnesota Center for Spirituality and Healing and The Minnesota Department of Health Office of Medical Cannabis.  Minnesota was the 22nd state to legislate a version of medical cannabis and this conference showcased the Minnesota version, the state and federal regulatory landscape, the available evidence to support the use of cannabis in certain conditions.  The politics of medical cannabis was also on display with viewpoints by some of the experts on the panel that represented scientific data, but also complementary approaches that had very little to do with science.

The Minnesota approach is an interesting one, because it may prove to provide the only cannabis products that offer a relatively standardized dose of tetrahydrocannabinol (THC), cannabidiol (CBD) or some combination.  In Minnesota there are two companies that are the exclusive providers of non-smokable cannabis products that are extracted from the entire plant - Leafline Labs and Minnesota Medical Solutions.  The extraction process is entirely carbon dioxide based and no hydrocarbons are used.  There are strict quality control measures.  There are no smokable or combustible cannabis products in the state.  According the statute, medical cannabis is available only as "oil, pill, vapor (oil or liquid but not dried leaves or plant form) or any other form approved by the commissioner excluding smoking".  These two companies supply state operated pharmacies that dispense only the cannabis products.  In order for a person to access these products they need to register with the state, pay a $200 annual fee, be certified as having an eligible condition by a physician who recommends rather than prescribes the product.  The patient discusses the actual product to be used with the pharmacist and pays for the product.  There are no insurance companies or state programs that pay for the cannabis.

The speakers at this venue were highly qualified.  Donald Abrams, MD is an adult oncologist with 32 years experience.  He gave lectures on "Medical Cannabis and the Endocannabinoid System" and "Clinical Applications of Cannabis: Cancer Care."  Both were highly informative.  He is one of the few people to access cannabis that is grown by NIDA (National Institute of Drug Abuse) and go through the regulatory maze that allows researchers to use it in clinical trials.  He discussed a concept that I had never heard of before called the entourage effect.  The entourage effect was defined as the benefits of using the whole cannabis plant rather than the more specific compounds.  The theory is that there are compounds in the broad mix that enhance the overall effect of the more active ingredients by both pharmacokinetic and pharmacodynamic effects.  He described this as one of the principles of Chinese medicine, which of course is not the allopathic medicine that we all practice in the US.  He emphasized the benefits of delivery as smoke or vapor rather than oral forms largely due to rapid onset of action and more rapid adjustment of the dose compared with oral forms.  He presented data to show that a particular volcano style vaporizer can consistently deliver therapeutic amounts of cannabis to the patient.  Once that was determined, that was the recommended delivery system for his patients.

Michael Bostwick, MD a Mayo Clinic psychiatrist gave two excellent presentations on "Medical Cannabis: Barriers, Myths, and Evidence" and "Medical Cannabis Statutes and the Role of the Federal Government".  One of the biases discussed by Dr. Bostwick in the seminar was the common observation that advocates see cannabis as a cure for everything when there is scant data that it is useful for the indicated conditions.  Of course that bias may also reflect the mixed agenda of recreational cannabis advocates seeking to legitimize cannabis as medicine and open the door for eventual widespread legalization.  In that endeavor, science would be an expected casualty.  The other bias was hysteria over the adverse medical and societal effects of cannabis use and how at least some of those attitudes may have resulted from racist attitudes in the 1950s.  Images from Reefer Madness were shown, as being emblematic of the spirit of the times.  That exercise does have a much different meaning today.  A good portion of the audience was all seeing and all knowing - eager to laugh at the ignorance of this archaic movie and applaud any speaker who advocated for the removal of all barriers to medical (and non-medical) cannabis use.  The problem is that I was sitting in an audience watching Reefer Madness in 1973 who were acting the same way.  The bottom line is that, these biases have clear effects on legislation and that led to cannabis going from being listed on the US Pharmacopeia for a hundred years to Schedule I on the DEA list of Controlled Substances.  A countervailing fact is that cannabis has been around for 5,000 years and has no clear medical indication.  That was mentioned as a historical fact, but not as a potential rationale for the Schedule I listing.  There was plenty of optimism that the discovery of the endocannabinoid system and getting cannabis off the most restrictive controlled substance category would lead to a whole new era of useful medicinal compounds.

Dr. Bostwick's discussion of the regulatory landscape of cannabis was superb.  I teach this subject myself and he was somehow aware of two more memos from the Justice Department than I was on the practical aspects of enforcing the Controlled Substances Act in the context of increasing legalization at the state level.  He described this as the states "going rogue" which I thought was humorous.  He also carefully laid out the FDA regulatory process and how it is not really set up the approval of botanicals or researchers interested in using cannabis for research purposes.

Ilo Leppik, MD is a long time neurologist and epileptologist in the Twin Cities.  Thirty three years ago when I was an intern on one of the neurology services in town and he was an attending physician.  At about that time, he noticed some basic science research about CBD having potential anticonvulsant properties.  He tried unsuccessfully to get pharmaceutical companies interested in this compound for years.  He discussed the currently available research and the single company that is trying to get FDA approval for a cannabis derived approach to treating seizures.  He is also an advocate for getting all of his neurological colleagues involved as registered certifiers of medical cannabis.  Epileptologists treat refractory seizure disorders that do not adequately respond to other measures and in this population Dr. Leppik would use medical cannabis and he presented the supporting data.

 The well known publicized case of the pediatric patient with seizures was discussed by Dr. Leppik.  This case is frequently cited by pro-cannabis advocates as proof that cannabis is a legitimate medication that needs broader use.  He pointed out that this patient not only did not have the seizure disorder that he was purported to have (Dravet Syndrome) but that he also had not seen the top epileptologist in the state where he resided.  He went on to present a case from his own practice where childhood epilepsy was misdiagnosed.  He made the correct diagnosis, but at that point, the patient's mother insisted that he stay on CBD along with the correct anticonvulsant for the condition.  The patient eventually ran out of the CBD, but the seizures remained in remission because he had been put on the correct standard anticonvulsant for the correct diagnosis - in this case valproate.

Angela Birnbaum, PhD is a pharmacologist and presented the most science of the day.  Straightforward pharmacokinetic principles and how they apply to treating patients with epilepsy.  Her approach also highlighted the advantages of using the Minnesota approach to medical cannabis and being the only way to assure steady levels of the drug necessary to treat epilepsy.  Dr. Birnbaum also presented a graphic similar to the one below on the product types available from the Minnesota companies.  More detailed information is available at the company web sites shown above.

Susan Sencer, MD presented medical cannabis from the perspective of a pediatric oncologist.  With the relatively new medical cannabis laws in Minnesota, her pediatric hospital has certified its use in 19 pediatric patients all with cancer diagnoses.          

To a guy who has been an acute care psychiatrist and an addiction psychiatrist all of his working life, there were clearly some biases operating at this conference that very few people seemed to be aware of.  Cannabis was discussed as a nearly benign product.  Sure we know the endocannabinoid system has something to do with brain development, and sure it could lead to psychosis and early onset of psychosis but probably only in people who were predisposed to psychosis.  There were remarks that none of the panelists who recommended medical cannabis and followed adult patients on that cannabis had ever seen any of them develop an acute psychosis.  There were jokes made about the implausibility of amotivational syndrome.  In the opinion of the panelists side effects were generally benign, even though data was presented from clinical trials suggesting otherwise.  As I looked at the clinicians represented on the panel who treated patients with cannabis there were two oncologists, a neurologist, and a psychiatrist who specialized in treating chronic pain.  Only the psychiatrist talked about treating some people with psychotic disorders and at one point there was a slide that suggested chronic psychotic disorders might be a contraindication to the use of cannabis.  The data presented and the description of the practices suggested to me that there was a strong selection bias present.  The panelists were not seeing psychiatric complications or problems with addictions because they weren't treating anyone with psychiatric disorders or addictions.  Guys like me see those patients and the last thing we want to see is somebody giving our patients cannabis.  I think that it will be a much different story if the list of eligible conditions is expanded to include insomnia, anxiety, depression, and posttraumatic stress disorder like it is in some states and the list of medical personnel authorized to certify the use of medical cannabis expands.  Just expanding the indication to chronic pain will bring in a patient population that is probably distinctly different from the patient base that the panelists are treating.

As I have written on this blog many times before, I don't like the idea of medical cannabis for the exact same reason that one of the panelists mentioned - it always has been a political manipulation for the legalization of recreational marijuana.  If you want to advocate for the legalization of recreational marijuana that is fine with me, but don't drag physicians into it and pretend it is an allopathic medicine.  That reference came out at the conference many times when it was referred to as a "botanical" and therefore very awkward in the FDA regulatory scheme.  At the same time, I have no problem with oncologists or neurologists telling their patients to use it.  But I am not going to pretend that there is not significant psychiatric morbidity that extends far beyond activating psychosis in those who are predisposed.  And I imagine that many of my colleagues will find this out when they discover that some of their patients now have cannabis added to their list of medications and that many of the panelists will discover this if they start seeing significant numbers of patients with psychiatric problems and addictions.

Despite all of the politics and bias - there is some underlying science that supports medical cannabis and Minnesota has the most rational approach toward implementing it.  Addiction and the psychiatric side effects of these compounds will always be a limiting factor for some.   In that case - as in the case of every other addicting medication - the best solution is to avoid it and try something else.


George Dawson, MD, DFAPA

References:

1: Bostwick JM. We need to reschedule cannabis. A sane solution to an irrational standoff. Minn Med. 2014 Apr;97(4):36-7. PubMed PMID: 24868930.

2: Bostwick JM. The use of cannabis for management of chronic pain. Gen Hosp Psychiatry. 2014 Jan-Feb;36(1):2-3. doi: 10.1016/j.genhosppsych.2013.08.004. Epub 2013 Oct 1. PubMed PMID: 24091257. 

3: Bostwick JM, Reisfield GM, DuPont RL. Clinical decisions. Medicinal use of marijuana. N Engl J Med. 2013 Feb 28;368(9):866-8. doi: 10.1056/NEJMclde1300970. Epub 2013 Feb 20. PubMed PMID: 23425133. 

4: Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. 2012 Feb;87(2):172-86. doi: 10.1016/j.mayocp.2011.10.003. Review. PubMed PMID: 22305029; PubMed Central PMCID: PMC3538401.

5: Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther. 2015 Jun;97(6):575-86. doi: 10.1002/cpt.108. Epub 2015 Apr 17. Review. PubMed PMID: 25777363. 

6: Hazekamp A, Ware MA, Muller-Vahl KR, Abrams D, Grotenhermen F. The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms. J Psychoactive Drugs. 2013 Jul-Aug;45(3):199-210. PubMed PMID: 24175484. 

7: Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011 Dec;90(6):844-51. doi: 10.1038/clpt.2011.188. Epub 2011 Nov 2. PubMed PMID: 22048225. 

8: Carter GT, Flanagan AM, Earleywine M, Abrams DI, Aggarwal SK, Grinspoon L. Cannabis in palliative medicine: improving care and reducing opioid-related morbidity. Am J Hosp Palliat Care. 2011 Aug;28(5):297-303. doi: 10.1177/1049909111402318. Epub 2011 Mar 28. Review. PubMed PMID: 21444324. 

9: Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007 Nov;82(5):572-8. Epub 2007 Apr 11. PubMed PMID: 17429350. 

10: Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007 Feb 13;68(7):515-21. PubMed PMID: 17296917. 

11: Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs. 2004 May;7(5):464-70. Review. PubMed PMID: 15154108. 

12: Andreae MH, Carter GM, Shaparin N, Suslov K, Ellis RJ, Ware MA, Abrams DI, Prasad H, Wilsey B, Indyk D, Johnson M, Sacks HS. Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J Pain. 2015 Dec;16(12):1221-32. doi: 10.1016/j.jpain.2015.07.009. Epub 2015 Sep 9. PubMed PMID: 26362106; PubMed Central PMCID: PMC4666747.

13: Arneson T. Insights from a Review of Medical Cannabis Clinical Trials. Minn Med. 2015 Jun;98(6):40-2. Review. PubMed PMID: 26168662.

14:  Health Canada web page consumer information on cannabis.

15:  Health Canada Information for Health Care Professionals Cannabis (marihuana, marijuana) and the cannabinoids - a very highly regarded report by the panelists at this conference.  This is the 2013 version and a 2016 update is pending at this time.

16: Katona I. Cannabis and Endocannabinoid Signaling in Epilepsy. Handb Exp Pharmacol. 2015;231:285-316. doi: 10.1007/978-3-319-20825-1_10. Review. PubMed PMID: 26408165. 

17: Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8. doi: 10.1016/S1474-4422(15)00379-8. Epub 2015 Dec 24. PubMed PMID: 26724101. 

18: Reddy DS, Golub VM. The Pharmacological Basis of Cannabis Therapy for Epilepsy. J Pharmacol Exp Ther. 2016 Apr;357(1):45-55. doi: 10.1124/jpet.115.230151. Epub 2016 Jan 19. PubMed PMID: 26787773. 

19: Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6. PubMed PMID: 26800377. 

20: Blair RE, Deshpande LS, DeLorenzo RJ. Cannabinoids: is there a potential treatment role in epilepsy? Expert Opin Pharmacother. 2015;16(13):1911-4. Epub 2015 Aug 3. PubMed PMID: 26234319; PubMed Central PMCID: PMC4845642. 

21: Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and Epilepsy. Neurotherapeutics. 2015 Oct;12(4):747-68. doi: 10.1007/s13311-015-0375-5. PubMed PMID: 26282273; PubMed Central PMCID: PMC4604191. 

22: Kaur R, Ambwani SR, Singh S. ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target. Curr Clin Pharmacol. 2016 Apr 17. [Epub ahead of print] PubMed PMID: 27086601. 

23: Leo A, Russo E, Elia M. Cannabidiol and epilepsy: Rationale and therapeutic potential. Pharmacol Res. 2016 Mar 11;107:85-92. doi: 10.1016/j.phrs.2016.03.005. [Epub ahead of print] PubMed PMID: 26976797.

24:  Volkow ND, Baler RD, Compton WM, Weiss SRB.  Adverse Health Effects of Marijuana Use.  N Engl J Med 2014; 370:2219-2227,  June 5, 2014;  DOI: 10.1056/NEJMra1402309

Supplementary 1: At this time (Saturday afternoon) - I am still waiting for the link to all of the presentations.  I do plan to add some detailed information at that point - the above information was only what I can recall from direct observation.  As soon as I have those links I will be able to list the actual medical cannabis products in Minnesota.  They are not available on the Medical Cannabis web site or one the sites of either of the manufacturers.  Stay tuned for a graphic containing all of that information.

Supplementary 2:  One of the jokes about addiction specialists at the conference was that they were like "orthopedic surgeons at the bottom of a ski hill."  The obvious implication is that they only see the train wrecks.  The other implication is that non-addiction specialists can prescribe addictive drugs with with no concerns about addiction and they will usually be OK - that is most people will make it safely to the bottom of the ski hill.  Of course by that time they had already presented data that "only" 9% of people who use cannabis get addicted to it, they are almost all young, and the panelists general impressions that their patients did not have a problem with addiction.  There has never been any disagreement that in terminally ill patients - addiction is not a concern.  Chronic pain patients without a terminal illness have a much different problem.   The ethical problem to me is that there may be an obligation to make sure that the skiers can negotiate the hill before you sell them the ticket.  There is also a recent precedent for declaring that prescribing practices were too conservative based on addiction risk.  That happened right before the current prescription opioid epidemic based on seriously flawed studies of addiction.

Supplementary 3:  If you want the best single reference on this subject - go to the Health Canada monograph (reference 15 above).  Read the currently available document and wait for the 2016 update.  It is a free download.

Supplementary 4:  Marijuana and Cannabinoids - an NIH sponsored neuroscience summit; March 22-23, 2016.  Link to the archived video recordings.

AMA versus CDC Patient Education On Opioids

CDC Poster On Opioids For Chronic Pain

The easiest place to start the critique of the initiative to stop opioid overuse in this country is the patient information products for both the CDC and the AMA.  The CDC poster on this subject is shown above and is public domain.  There is more detailed patient information from the CDC at Guideline Information for Patients.  The AMA page on the same subject is at this link.  AMA web site materials are copyrighted and I did not think it was worth the effort to attempt to get that permission.   It is available free online.  How do these guidelines compare with one another and are they likely to be useful to patients?

On inspection they both seem to warn patients that there are potential health problems including addiction and death from taking opioids.  The CDC graphic advises  the patient to actively collaborate with their physician around any potential opioid prescription.  It suggests that the physician in this case will present a number of non-opioid options and a receptive patient will decide how to use them.  Apart from the 1 in 4 statistic it is almost a fairy tale approach to the problem of addiction.  Keep in mind that direct-to-consumer advertising these days frequently end with a staccato-like recitation of side effects "including death" and pharmaceutical companies are not deterred from adding that qualifier.  That suggests to me that these dire warnings are really not a deterrent to people looking for what appears to be a "cure" - at least in some cases.  The more detailed approach from the CDC guideline seems more reasonable, but both do not take into account unconscious factors on the part of both the patient and physician.  The AMA version is seriously watered down, but both lack realistic information about addiction works.

The real issue with opioids is not that 1 in 4 people end up addicted to them.  That 1 in 4 number is after all an intent-to-treat number.  There are probably at least that many people who don't tolerate opioids at all, even on an acute basis.  Taking those people out, bumps up the number of potentially addicted to 1 in 3.  The real problem here is how the addiction occurs and the implications for primary and secondary prevention.  I can tell anyone who cares to listen that the secondary prevention aspect of opioid addiction is a long and arduous process, with no guarantee of a cure at the end of it.  Imagine that you have just started a family and started out in the workplace when the addiction occurs.  Contrary to all of the hype about medication assisted treatment with buprenorphine or naltrexone, this kind of treatment does not work well for everyone.  Addiction to an opioid may require that you participate in some form of education based treatment for up to three months or take long absences from your work and family to live in sober structured environments.  The structured environments are costly and the quality of these settings cannot be assured.  What the AMA and CDC references do not show is that if you have an addiction - you might be in a very expensive treatment program and still not be interested in stopping the opiate.  You may not feel ready to quit after one or more of these treatments.  The real danger of an addiction is that it alters your conscious state to continue the addiction, even in an environment where you are supposed to be learning how to get sober and maintain sobriety.

The AMA and CDC resources are short on this aspect of opioid addiction.  These pages should tell people a couple of other things aimed at preventing addiction rather than recognizing addiction and trying to treat it after it happens.  Here are the bullet points:

1.  Practically all people at-risk know it after they have taken the first few doses of medication.  The opioid makes them feel euphoric or ecstatic.  Contrary to the popular image of heroin addicts falling asleep, the at-risk population is energized and may feel like they have become more productive than they have ever been.  That response establishes a dangerous link between productivity and opioid use.  The at-risk population also has an enhanced perception of themselves.  They may suddenly perceive themselves as having become the person they always wanted to be.  That can include the perception of a number of positive personal qualities including confidence, intelligence, and creativity.  All of these reinforcing qualities disappear once tolerance to the drug occurs.

2.  People at-risk may notice that long standing anxiety, insomnia or depression is suddenly gone.  As an example, there are many people with social anxiety in childhood and early adult life.  Social anxiety is a condition where the person is overly concerned about being judged when they are out in public.  The associated concerns may be that they will be embarrassed or humiliated.  There is often an associated performance anxiety in certain situations.  This part of the at-risk population may notice that all of those concerns are completely gone when they start taking opioids.  All of these reinforcing qualities disappear once tolerance to the drug occurs and anxiety, depression, and insomnia recur (often amplified) during withdrawal and detoxification.

3.   The concept that opioids are medications that can reinforce their own use whether or not they actually work for pain is a difficult one to grasp.  In other words, the at-risk population may want to keep taking opioids even in cases where they do absolutely nothing to alleviate pain.  In this case it is not a question of tolerance to the analgesic effects of opioids.  The opioids did not work in the first place.  Opioids are only moderately effective for chronic pain in the first place and those effects are on par with antidepressants and anticonvulsants like gabapentin.

4.  Opioids can change your baseline personality and cause you to do things that you ordinarily would never have done.   Once an addiction has been established decision-making is in the service of maintaining the addiction.  That can include any number of legal and moral decisions that that involve the people who are closest to the person with the addiction.  The repercussions of these acts are not fully appreciated until the person is detoxified and is sober from the opioid.

5.  Opioids are legendary in the American culture.  The American culture strongly reinforces the place of intoxicants in the lives of even average Americans.  Intoxicants are in the literature, the media, and even day-to-day conversations.  People tend to hoard their unused opioids, exchange them with their friends and family, and talk about the effect of these drugs with their neighbors.  To illustrate, an acquaintance of mine recently had arthroscopic surgery of the knee.  He was in a large post-op recovery area with 8 other people.  Nursing staff were approaching people and asking them what they wanted for pain relief.  The choices were hydromorphone (Dilaudid) - a potent opioid, oxycodone-acetaminophen (Percocet) - a less potent opioid, and ibuprofen - a non-opioid.  The vote in the recovery room was 8-0 in favor of hydromorphone.  That vote parallels the disproportionate increase in emergency department visits for complications from hydromorphone relative to all other opioids.   Of course there are many variables at play, but I am suggesting at least one of them is the reputation that hydromorphone has in American culture as a potent euphoria producing opioid.

6.  Part of the American legend is that opioids are the magic bullet for pain.  The corollary is that if the doctor would just give me enough of this drug - my pain would be gone.  The important distinction here is chronic pain.  Across large populations there is no medication that will get rid of chronic pain.  For many people, no treatment at all, treatment with a non-opioid medication, or treatment with a different modality like cognitive-behavioral therapy works much better.

There are all important points for people to know before they start taking opioids.  I think that a clinical trial is indicated to see if people with this information do better than those without it.  If I was designing that trial, I would have an intervention that advised people to stop taking the medication and call the physician immediately if they experienced any change in their conscious state like the ones I described in points 1, 2 or 3 above.

Stopping opioid addiction well before it is established is the preferred intervention.  There is certainly effective treatment once an addiction has been established but it can be long, expensive, difficult, and the outcome is never guaranteed.  Anyone who starts to take an opioid needs that level of transparency.



George Dawson, MD, DLFAPA         

Attribution:  The infographic at the top of this post is from the CDC web site and is reused per their general information about being in the public domain.  The poster is available at:
 http://www.cdc.gov/drugoverdose/pdf/guidelines_patients_poster-a.pdf

Ethics, Law, and Politics In Psychiatry

I just spent yesterday at the 2016 Minnesota Psychiatric Society Ethical Issues In Mental Health for 2016.  It was a long day, especially for a guy who wants lectures and information.  About 1 1/2 hours was dedicated to a group discussion of cases.  I am always more interested in what the experts have to say - that is my comfort zone at CME courses and meetings.  The first lecturer was Rebecca Weintraub Brendel, MD, JD from the Harvard Medical School Center for Bioethics.  She was also the Chairperson for the Ad Hoc Work Group for the American Psychiatric Association on Revising the Ethics Annotations.  That resulted in the document APA Commentary on Ethics In Practice from December 2015.  A complete listing of the members of that working group is available in the document.  She started out by talking about the Trolley problem and reviewing the various approaches to this issue.  The ethical theories that applied were briefly reviewed including deontology, consequentialism (utilitarianism), virtue ethics, and principalism.  She said that the field has evolved to the point where principalism is the dominant paradigm.  Principalism includes the broad areas of autonomy, beneficence, non-maleficence, and justice.  At this time any search on bookselling websites will pull up a number of references on principalism, including critiques of the concept.  I will probably pick up a copy of one of these books to see just how heavily  the justice component in medicine includes social justice and concepts like global warming.  I have always been amazed at why physicians would expend valuable energy on these issues when they have been unable to protect the integrity of their profession.

A lot of time was spent discussing professional boundaries with some focus on electronic media and communicating with patients.  The afternoon cases discussion focused on two psychiatrists with multiple ethical problems some of which included clear ethical issues involving both social media and electronic communication.  In Minnesota, the consensus is that e-mail communication with patients using typical insecure e-mail is not a good idea, but many psychiatrists are employed by organizations that use secure e-mail through a health system portal.  One of the hypothetical case examples given was membership on Facebook of group therapy members and all of the problems that involves.  One of the key aspects of treating patients like psychiatrists involves not just interpersonal boundaries but also boundaries around the therapy like contact and phone calls outside of the sessions.  Online contact with either frequent e-mail or social media creates the illusion that the psychiatrist is always online and available.  That every comment will be noted, analyzed and responded to.  This is not only unrealistic availability, but also unrealistic analysis.  Psychiatrists more than any other physician should know that typed statements online are very poor substitutes for analyzing the emotional content of communication especially where aggression, suicide, and other critical aspects of judgment are the focus.

The second lecture was given by Colleen M. Coyle, JD General Counsel for the APA and it was titled When Law And Ethics Collide....   Privacy rules, informed consent and substituted consent were the early issues.  A suggested authorization form that covers all of the contingencies was suggested.  I can recall signing several including the standard recredentialing forms that authorizes multiple unknown parties complete access to any and all information about me.  The coercive nature of these forms was not discussed.  I see even the most standard consent to treatment form as fairly coercive these days, especially the sections that cover requirements for disclosure by state laws.  A comparison of attorney-client privilege vs. physician-patient privilege would have been instructive.  I think it would point out the obvious - once again that physicians have done a poor job of protecting their profession and that lawyers have succeeded in making legal decisions (Tarasoff) part of the psychiatric code of ethics.  Some of the vague situations of disclosure under the more liberal HIPAA versus the more restrictive CFR42 were discussed.

The discussion ended on prescription drug monitoring programs, the ethics and the current legal landscape.  The legal landscape was most interesting in terms of who inputs the data and whether mandatory accessing of the database exists.  Thirty one states require that prescribers access the database and 11 of those also require a query.  Nineteen states do not require mandatory access.  There are criminal and civil penalties for not reporting controlled substance prescriptions in the database.  Twenty six states and D.C. provide some immunity from civil liability for not accessing and using the database.  Minnesota has a very reasonable approach.  Pharmacy data populates the database and accessing the database is not mandatory.  As a physician I can't imagine having to treat patients, do all of the necessary documentation and orders/prescriptions and then access a separate database and re-enter the prescriptions.  If that is happening to any extent in other states that is another serious abuse of physician time.  It is also part of the general trend of dictating how physicians practice medicine.  Learning what rules apply to you in your particular state is critical irrespective of how rational the process may or may not be.

Ruth Martinez, MA Executive Director of the Minnesota Board of Medical Practice was the third presenter.  Her emphasis was on documentation, boundary issues, informed consent, and response or lack of response to the treatment plan.  An important concept that I have always used is documentation of the informed consent process.  A written and signed document is not needed (with the exception of ECT and antipsychotic medications in the state of Minnesota), but documentation of the discussion is useful.  In situations where the discussion covers a lot of contingencies, it is useful to come back to that part of the document in terms of treatment planning and what the next step might be.  The only potential problem is that when everyone has access to your thinking, suddenly everyone is an expert as in: "I noticed in your note that if this antidepressant was not effective your plan was to change to antidepressant B.  I discussed this with the patient and he wants to try B now."

The part of the presentation that I was in disagreement with was the discussion of the power differential in the physician-patient relationship.  The rhetoric of power is an interesting one that I hear discussed much more frequently outside of medicine than inside.  In my experience social workers tend to discuss power in relationships.  To me,  power is a nonspecific word.  When I am obsessing about making the right decisions in very uncertain situations - being some sort of omnipotent authority figure is the farthest thing from my mind.  All of the psychiatrists I know operate from a therapeutic alliance model and that can be captured by two sentences:  "The therapeutic alliance means that you and I are working to solve your problems.  In that context it is my job to give you the best possible medical advice on how to do that and your job to decide about whether you want to use that advice or not."  Even in the cases where substitute consent is required like civil commitments or guardianships, the physician involved basically brings the problem to the attention of a judge who makes the determination.  Physicians do not want to run patients' lives.

Steve Miles, MD from the University of Minnesota Center for Bioethics gave the scientific part of the program on the epidemiology of gun violence.  It had striking similarities to some of the positions I have posted here on how to approach this problem that I plan to discuss that as a separate post.  He also reviewed the political timeline on how research into gun violence was eventually defunded courtesy of heavy lobbying by the pro-gun forces in Washington.  

I thought that politics was the important word that was left out of the ethics discussions.  As an example, the issue of torture was discussed and how the American Psychiatric Association came to the position that psychiatrists should not participate in torture.  That was a lengthy discussion that eventually came down to a line in the sand - psychiatrists should never participate in torture.  That is not true for two other ethical dilemmas discussed in this conference - managed care utilization review and collaborative care.  Instead hypotheticals were discussed.  If you were this managed care reviewer and your company wanted you to deny specific care that you knew was indicated - what would you do?  Similarly - if you were in this collaborative care arrangement and your salary and bonuses depended on what you were using to fund the "at risk" population that you were seeing - what would you do?   So basically being a military psychiatrist asked to perform torture there is a clear ethical guideline and in the managed care and collaborative care situations you are on your own.  You can call me concrete, but if I was king, the latter two situations would also be forbidden by the ethical code of psychiatrists.  In the case of collaborative care the APA recently announced (1) it received a federal grant to "train 3,500 psychiatrists in the clinical and leadership skills needed to support primary care practices that are implementing integrated behavioral health programs."  Instead of questioning the ethics of a practice that limits the direct assessment of patients by psychiatrists and potentially creates financial conflicts of interest - at the organizational level the APA celebrates this grant and making the practice it more broadly available to all psychiatrists!

Calling the APA Ethics Committee with your ethical dilemmas was encouraged and they clearly take it seriously, but I think these inconsistencies do not make the organization popular among clinicians who deal with these problems on a day by day basis.  They are as easily solved as the questions about physician participation in torture and executions.


George Dawson, MD, DFAPA


References:

1:  Mark Moran.  APA Receives Federal Grant to Train Psychiatrists In Integrated Care.  Psychiatric News - November 6, 2015.  v50(21): p.1.

The grant to train 3,500 psychiatrists was $2.9 million over 4 years or about $828 per psychiatrist.  Each psychiatrist is expected to support up to 50 primary care providers and consult on the care of 400 patients per year.  The ultimate goal is to support 150,000 primary care providers and consult on the care of a million patients a year.  Does anyone see the problems here?     



                     

More On Conscious States......

In my previous post, I concluded that the conscious states of human beings were far too complicated to allow an algorithmic decision on whether or not they are candidate for the euthanasia and assisted suicide.  The argument may not be all that clear to anyone who does not have psychiatric experience so I thought I would add more examples,  These are all fairly standard clinical scenarios but not specific case reports.

Scenario 1:  A 65 year old man with a long history of alcoholism presents for assessment of possible bipolar disorder.  He is euphoric, grandiose, and appears to be mildly intoxicated.  The psychiatrist performs a clinical interview that includes a standardized cognitive screen.  On the cognitive screen the patient performs perfectly for a person with his level of academic and occupational achievement, including on all tests of short term and working memory.  He returns two weeks later for follow up and does not recall ever meeting the psychiatrist or doing the cognitive exam.

Scenario 2:  A 42 year old woman with a history of bipolar disorder presents for follow-up from a recent hospitalization.  Her psychiatrist also works in the hospital and provided her care when she was in the inpatient unit.  During the follow-up visit the patient asks her psychiatrist if she recognized the fact that she was "not myself" either in the hospital or at the time of discharge.  When asked to be more specific she said that she was very angry and had attempted to drown herself while in the hospital but did not disclose that to the psychiatrist or nursing staff.  She criticized the psychiatrist for not recognizing that and suggested that she should never have been discharged.

Scenario 3:  A 50 year old woman is being seen for depression.  She has had recurrent episodes of depression following an episode of postpartum depression at age 28.  She has been on maintenance antidepressant therapy since age 28 and requested this appointment because it seemed like the maintenance therapy was no longer as effective.  In the appointment she appears to be mildly depressed.  She has some depressogenic thinking that does not seem much different from many other similar episodes in the past that generally required minor adjustments of medication and supportive psychotherapy with cognitive-behavioral interventions.  Those changes were made and suicide risk was assessed in a standard way by her psychiatrist.  She has no past history of suicide attempts.  Deterrents to suicidal behavior were discussed and she reminds the psychiatrist that she is very religious and her religion has a strong proscription against suicide.  A follow-up appointment is set.  Three days later, the patient's husband calls the psychiatrist to let her know that the patient attempted suicide and is recovering in a local hospital.

Scenario 4: A 22 year old man is being seen for heroin addiction and depression.  He is hospitalized following an accidental heroin overdose and contemplating transfer to residential treatment for substance use disorders.  During the interview he discusses his depression as the result of guilt and regret from some of the activities he has engaged in to have a steady supply of heroin.  He talks about those activities in detail including stealing from his friends and family, dealing drugs, and and in one case witnessing an episode where drug dealers severely beat up one of his acquaintances to the point that person nearly died.  He concludes that all of these activities are "not me - I wasn't raised this way.  I have values and I don't break the law.  Now I break the law every day and it is just a matter of time before I end up in prison.  I can't do this anymore."  The psychiatric consultant asks him about the decision to go to the rehab hospital so that arrangements can be made and the patient says: "I don't think that I am ready to stop using heroin yet"        

This is a short list of what I see as changes in conscious state that are not well captured or described in the current psychiatric nomenclature.  Part of that comes from the fact that psychiatry is a subspecialty of medicine and all medical classifications are by their nature imprecise, linear and somewhat static.  The ideal medical diagnosis implies a certain general course and prognosis.  That selection process will find static linear processes more ideal in terms of meeting those criteria than dynamic processes that can change minute to minute or hour to hour.  Human consciousness changes on that shorter time frame, is nonlinear and therefore unpredictable.  There certainly can be more drastic and persistent changes in consciousness that are more easily recognizable-like delirium or dementia.  Even the scenarios outlined above suggest significant disruptions in consciousness to the point that result in amnesia, unpredictable suicidal behavior and suicide attempts, and drug addiction.  Some would consider the alcohol induced amnesia or blackout  to be the more severe disruption, but that is purely a subjective judgment.  It is possible for people to have hundreds if not thousands of blackouts and appear to be functional during that time.  That is certainly a major problem and a high risk problem but no more risky than a suicide attempt that results in hospitalization or the decision to continue heroin right after an overdose as tolerance is waning.

Recognition that these conscious states exist makes a psychiatrist a far better clinician.  He or she is much less likely to get angry or upset about unpredictable events like suicide attempts and relapses to drug or alcohol use.  An appreciation of the fluidity of human consciousness, precludes any angry or blaming of the patient for something that happens outside of a limited standard evaluation.  There is a strong tendency of physicians who are unaware of this phenomenon to either get angry and think that the patient lied to them in the original assessment, adopt the fatalistic attitude that these events are all unpredictable and nothing can be done about them, or adapt a paternalistic attitude and sympathize that the person has a mysterious disease that they should not be blamed for.  None of these attitudes captures the true conscious state of the individual.

Are there any interventions that can be done to reduce the risk from these rapid changes in conscious state?  That is currently an empirical question.  A lot depends on the ability to detect persons with the problem.  There are certainly plenty of people who told a physician that they were not suicidal and who went on in a short period of time to attempt or complete suicide.  In some cases the survivors are available for interview.  In hospital settings interviewing survivors of self-inflicted gunshot wounds it is very common for the patient to recall pointing the gun at themselves but not recall pulling the trigger.  Survivors who have jumped off the Gold Gate Bridge almost all regret jumping when they were a few feet away from the rail.  At the minimum this suggests that the conscious state of the actively suicidal person is transient and impulsive as in unpredictably driven to act on the suicidal plan.  Young opioid addicts are very common these days and generally personify the Hijacked Brain Hypothesis or a brain that is biased to continue an addiction and the associated behaviors that are in stark contrast to their previous moral development and educational and vocational trajectory.    

Any clinician who is aware of these changes in conscious state can educate the patient about what is happening.  During an assessment of suicidal risk after a discussion of all of the risk and mitigating factors, I think that it is reasonable to have a discussion with the patient about their current conscious state and risk based on that conscious state as well as the fact that conscious states change in some cases to a high risk state.  Any psychiatrist who has interviewed survivors of suicide is often struck with what that person describes as a clearly different state of mind from the one being experienced in the interview.  In some cases that altered state is drug induced.  The DSM-5 catches a glimpse of these phenomena with two tables on Neurocognitive domains on Page 593 and Diagnoses associated with substance class on Page 482.  Both categories recognize that  changes can be transient and limited to intoxication or withdrawal states, but there are also some persisting states depending on the intoxicant.  The table on neurocognitive domains lists some subtle manifestations of known brain disorders.  The DSM-5 does not look at the more subtle changes as noted in the above 5 scenarios or even in everyday life.   Another limitation of medical diagnoses is that they work the best in extreme states where there are obvious problems.  Everyday life and the kinds of changes we all observe in our spouse or parents in any given environment are the most subtle yet.

I hope that these examples have made it clear that psychiatric practice is much more than categorial diagnosis and risk factor analysis.  If there is any hope for a 21st century psychiatry - this is where I would put my marker - not on the same diagnostic system and mental exam that we have been using for the last 50 years and certainly not on a checklist and mass medication approach being promoted as collaborative care.

A focus on consciousness is the best way to help our patients and the best way to learn how the brain is really working.




George Dawson, MD, DFAPA



Supplementary: 

The graphic at the top is part of one slide from one of my lectures on the neurobiology of addiction.  My emphasis to the students is human consciousness and why it is unique.  I try to get them to think outside of the DSM-5 box when considering how the patient changes on a practical basis day-to-day and how that relates to neurobiology.  

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.