Sunday, December 11, 2016

Brandolini’s Law





There was an informative editorial in Nature this week by Phil Williamson - a scientific expert on ocean acidification.  I like the concept of bullshit and have referred to Professor Harry Frankfurt's classic essay on it many times.  I was not familiar with Brandolini's Law until I read the essay.  Simply stated:

Brandolini’s Law: “The amount of energy needed to refute bullshit is an order of magnitude bigger than to produce it.”

It is also more simply known as the The Bullshit Asymmetry Principle.

Williamson uses a political example from a libertarian web site.  The central piece of that article was that ocean pH was not decreasing and that climate change would lead to reduced carbon dioxide in the oceans.   Because the climate is not changing there is no worry that the ocean pH would change.  The original publication denied Williamson's rebuttal.  An opinion piece in a professional journal led the author of libertarian piece to write online that his work should be "squashed like a slug".  Nothing like elite scientific dialogue is there?

In the UK there is apparently a press watchdog called UK Independent Press Standards Organization (IPSO).  Williamson filed a complaint with them about the factual accuracy of the piece and is awaiting their verdict.  He goes on to illustrate how Brandolini's Law comes in to play in this situation.  The original author these days can essentially be anyone from a journalist to a blogger.  He points out that online journalism "seems to be subject to few if any rules."  That leaves anyone in the position of responding to a factually inaccurate claim at a distinct disadvantage.  There may not be any formal complaint procedure and there is probably no editorial hierarchy.  Many web sites count on bloggers and writers to produce content that they can attach advertising to and this content seem to have very little oversight in terms of accuracy.  Much of this content on social web sites makes up what has been referred to as fake news.

Williamson's position is very clear.  He thinks that these inaccuracies need to be responded to and corrected.  He accurately points out that the audience for the correction is not the authors, but readers who are interested in accuracy and science.  I don't think that the division is that clear for a number of reasons.  A large number of people really don't care.  They are involved in the emotion generated by the issue and don't make decisions based on facts.  That general attitude is promulgated by the political process in most countries.  This is rarely a rational discussion of the main issues of the day.  I think this goes a lot deeper than generating rebuttals.  There needs to be education on the difference between science and everything else.  A good example is Creationist based rhetoric and the denial of evolution.  Creationist advocates do not seem to recognize that they are engaged in a process that is nothing like science and therefore cannot scientifically prove anything.  They fail to recognize the basic issue that science is a process and not an immutable collection of writings written by ancient prophets and subject to many interpretations.  That failure of recognition also leads to a failure to recognize that they are  completely outside the field of science. They fail to recognize where they are and that the best critics of a scientific theory are the scientists in the field.

This failure of recognition is much wider than Creationists.  Journalists produce many examples, not the least of which is a consistent bias against psychiatry.  That bias is present whether or not there is editorial oversight.  A great example is the journalistic tendency to propose what psychiatry is and then proceed to attack that straw man.  And interestingly these outsiders with no training in medicine or psychiatry are often joined by insiders pushing the same arguments.  In one case a prominent journal editor came out and endorsed an anti-psychiatry book, proclaiming legitimate criticism when in fact the book was rhetorical.  I would not presume that medical editors are without common biases.  There are many forces producing misinformation.

I diverge a bit with Williamson's approach on refuting the misinformation and hoping for the best.  I think that there are additional considerations.  One thing is very clear - the head-in-the-sand approach taken by physician professional organizations in response to misinformation is clearly not a good idea and is sure to lose in the current propaganda war of misinformation and political corruption.  If there is a lesson with the current Presidential campaign it is that there is a very small margin between a typical fact less campaign and one where anything at all can be said whether it is true of not - and nobody seems to care about it.

That is foreboding for all levels of public policy, especially when the political spoils includes being able to appoint agency heads with not only a lack of basic footing in science but also a lack of knowledge about what constitutes science.  For the country to run and maintain some standards in science, technology, and engineering there needs to be a basic understanding of these fields in all branches of government and at the highest levels.  There is currently no better example of what happens when the unscientific manage the store than what has happened to American medicine.  We are not only cursed by work rules that are made up as we go and have little to do with the practice of medicine, but we we have to live with pseudo-scientific management practices that affect our work flow and and detract from the lifelong task of learning the science of medicine.  A few strategies I can offer as a blogger follow.  I also have additional strategies that I am going to keep to myself until just the right time.

1.  Don't feel compelled to engage - Twitter is an excellent example of how this principle is applied. Suddenly you are being given the third degree by some poster. That turns into misinterpretations of your statements and positions and before you know it personal attacks.  But it doesn't stop there. A new account pops up and mysteriously continues the attack.  Call them trolls or whatever you like but recognize the tactic. They don't really care what you have to say and are quite happy to waste your time.  Don't engage. Twitter gives you the option to block them and that works the best.

2.  Present the facts but counter the rhetoric - It is important to recognize the common forms of rhetoric without being pedantic.  The best way to do that is by pointing out the erroneous aspects of the argument and the overall form without naming the fallacy.  This sounds easy and it should be - but physicians and psychiatrists seem to be spellbound at times by the simplest arguments.  One common example is anytime a business executive shows up and talks about "cost effectiveness" - everybody shuts down.  Nobody seems to understand that this is just business rhetoric.  It should be as obvious as the fact that with 30 years of intensive management and "cost effectiveness" - per capita health care costs are 40% higher than the country with the next highest per capita expenditures and health care is certainly no better.  In the case of treating mental illnesses and substance use disorders it is much worse.  Somebody needs to stand up and say: "We are doing our part - when are you going to start to do yours." or "Get out of the way and let us do our work." or "Give us the resources to provide the adequate service or shut it down."   Rationing is clearly a very ineffective and costly way to provide health care services.

3.  Recognize bullshit no matter where it comes from -  Many of the arguments for health care reform are just plain erroneous.  And why wouldn't they be.  We now have a continuous supply of what are essentially blogposts on the front of our most respected medical journals.  How could anyone expect that 12 or 52 health care reform ideas each year for years would be worth anything?  All of the top posts that they have been implemented like the electronic health record, managed care as business intermediaries for government purchasers, pharmaceutical benefit managers, creating various financial incentives - have all been progressively worse ideas.  Sifting through the misinformation to correct what is false, what are lies, and what is bullshit is a tedious but necessary task.  As long as medical journals legitimize this constant stream of unscientific information - countering it will remain an onerous task.  The sources of bullshit go far beyond blogs and traditional journalism.

4.  Don't let anyone define you - A common strategy these days is that detractors tend to jump in and set the stage with false criticism.  It was easy to see this in political debates.  In medicine and psychiatry the same process happens and I have pointed out the dynamic on this blog.  I also posted a recent summary of how the release of the DSM-5 was a major source of misinformation, lies, and bullshit in 2015 but there are many more examples in psychiatry.

5.  Don't let the barbarians at the gate get you down - I tell aspiring physicians and aspiring psychiatrists the same thing - don't let the detractors or in these days trolls - get you down.  Psychiatry is a tough field because there will always be a lot of people blaming you for their problems.  This is where Brandolini's Law really applies.  There are numerous dialogues on web sites available where the game is to post as much misinformation, bullshit and lies about psychiatry in particular.  Entire web sites exist for that purpose.  Entering into that discussion and taking the opposite side of the argument can be more futile than the Law suggests.  It may take several orders of magnitude of effort and even then it may be futile.  The best approach is to just get the information out there in cyberspace in an independent forum where you know that it can be safely viewed.   That is one of the reasons that this  blog exists.

6.  The Internet is still the Wild West and that will probably never change in its current form - Williamson suggests that it may be possible to "harness the collective power of the Internet to improve its quality."  He suggests the global scientific community reviewing sites and rating them like film rating sites.  I am far less optimistic.  The first problem is the scope of that project.  The second would be consistency in ratings.  The third is that a rating in some sense is legitimizing.  It is a far better approach to ignore the ignorant.  The reality is that reputation protection web sites basically work by generating a lot of information designed to bury the obnoxious web site.  Most people find that if they contact a search engine about a web site that may be slandering them that they are met with a a relatively hostile response and a complete lack of interest in correcting anything.  That is true for even the largest search engines.  Google for example, clearly doesn't give a damn about your reputation.

7.  Brandolini's Law is a significant deterrent to keeping professionals engaged in educating the public - Physicians certainly find this out in a hurry if they decide to post a rebuttal in political or media forums that are populated by the ignorant, trolls, or those with a specific agenda.  That is more true of psychiatrists than any other specialty.  That has a dual effect of limiting feedback to those who might be interested and eliminating the most informed criticism.  It also has the added effect of adding professionals who may have legitimate criticism to antipsychiatry web sites where scientific criticism is clearly not the agenda.  It is a dangerous path of least resistance when legitimate professionals start posting on web sites dedicated to the destruction of the profession.

 These are just a few ideas about Brandolini's Law.  I did not write the most important one down and that is you can always just go off the grid.  Even then there are problems.  I talked with a psychiatrist about 10 years ago who was asked to give presentations at local churches on depression.  He eventually gave up because there were people in the audience who for various reasons were so disruptive that it prevented him from giving the interested people the information that they wanted.  Only psychiatrists could end up being heckled in church.  Bullshit can be presented in person just as easily as is can by typed online.

Williamson refers to a "rising tide of populism threatens the future of evidence-based government."  I don't think that we have ever had evidence based government in the US.  I see it as mostly a power dynamic here - influencing people by emotional ideas and shouting them down.

The only reason why that Brandolini's Law doesn't work in reality in the case of psychiatry is that at the end of the day, there are still people with severe mental illness - no matter who tries to deny it and a group of people called psychiatrists who are interested in helping them.  That is not necessarily enough to prevent the widespread demoralization of a profession.        


George Dawson, MD, DFAPA


Reference:

1:  Phil Williamson.  Take the time and effort to correct misinformation.  Nature 8 December 2016; 540: 171.


Supplementary 1:

My brother saw this post and commented that Brandolini's Law has "never been more true."

I reflected on that true statement and the continued widespread ignorance of science and came up with the following observation that might have been made by Casey Stengel:

"Good science cancels out bullshit and vice versa."

That probably captures why misinformation grows as exponentially as scientific information in any society.  It levels the playing field (to some degree) between the informed and the uniformed.


Friday, December 9, 2016

Is The FDA Contraindication On Bupropion Wrong?






Since moving to a strictly outpatient consulting practice, I have been amazed at the number of women who are taking bupropion despite the above contraindication.  I have probable seen 50 women who were under my care in this situation.  In other words, I did not prescribe the bupropion and before seeing this would not have considered prescribing against an FDA contraindication.  The patients I see often have additional contraindications including a history of seizures, sedative hypnotic drug withdrawal, or alcohol withdrawal.  Seizures are the final common pathway for this subset of contraindications.  I have never really observed a seizure from bupropion and the vast majority of the patients with the contraindications have never had a seizure.  I have certainly observed and treated seizures in inpatient settings and understand that there is a low but significant risk of mortality with seizures.  I have also not observed a significant complication of seizures, but at the time I worked in an inpatient hospital environment with rapid access to nursing staff, medications, and experts.  None of the patients that I have initiated treatment on with bupropion have reported seizures, but I was strictly following the contraindication as listed in the FDA package insert.

My dilemma in this situation is always whether or not to continue the bupropion, especially when the patient tells me that it is the only medication that has been effective for them.  Patients who are seen in their late thirties or later generally have been tried on numerous antidepressants from several classes and that complicates the clinical picture.  Most of them have never seen a  psychiatrist and all of the medication trials have been done by primary care physicians.  It is common to see SSRI and bupropion combinations initiated by nonpsychiatrists.   In my current capacity, I am not treating any of these patients long term.  I see them anywhere from 1 to 3 months and at that time they return to see their personal physician or psychiatrist.  I try to contact their personal psychiatrist about the issue but communication among physicians is often difficult to complete.

As I began to see more and more of these patients my first question was a scientific one.  I was aware of the the trials that lead to the decision about eating disorders.  There were all based on immediate release preparations rather than the sustained release (SR) or extended release (XL) versions.  It certainly is possible that I am only seeing the success stories and that the patients with seizure related complications never come to my attention, but the practice of prescribing bupropion to a population that the FDA considers high risk seemed to be on the rise rather than decreasing.  Is it possible that all of the other prescribers had also not heard of this complication.  I knew that most of the patients were never apprised of the contraindication.  I know that because I had them read the contraindication section of the package insert for themselves.  Most would say that nobody have ever told them about this especially the part about any prior diagnosis of anorexia nervosa or bulimia.  It is difficult to tell a 45 year old woman who had bulimia nervosa in college and recovered that the bupropion that she has been taking for the last 10 years without any side effects needs to be stopped because of this contraindication.  The psychiatrists I talked with all minimized the wording in the warning.  They ignored the part about "prior diagnosis".  In fact some initiated treatment as the patient was completing treatment in a specialized eating disorders program.

I turned to the FDA web site for additional guidance on the agencies definition of contraindication.  Was it as relative as these psychiatrists were telling me?  It turns out the definitions used by the FDA in package inserts are defined in the Code of Federal Regulations (CFR).  The section defining contraindications follows (p. 6 of 18):

(5) 4 Contraindications. This section must describe any situations in which the drug should not be used because the risk of use (e.g., certain potentially fatal adverse reactions) clearly outweighs any possible therapeutic benefit. Those situations include use of the drug in patients who, because of their particular age, sex, concomitant therapy, disease state, or other condition, have a substantial risk of being harmed by the drug and for whom no potential benefit makes the risk acceptable. Known hazards and not theoretical possibilities must be listed (e.g., if severe hypersensitivity to the drug has not been demonstrated, it should not be listed as a contraindication). If no contraindications are known, this section must state "None."

People seem to think that there is room for interpreting this definition of contraindication and it does beyond the APA Ethics Committee.  I got the same opinion from an attorney.  I also consulted a national expert on eating disorders.  That expert opined that the contraindication was relative in both  a history of eating disorders and acute eating disorders.  The expert also had inside knowledge of why the FDA might have issued the contraindication in the context of scant evidence.

I have previously posted that the FDA seems to exhibit some biases when it comes to psychiatric disorders.  In some cases they seem to not consider the severity of the the disorder in considering contraindications.  There should be no question that eating disorders and depression are very serious conditions, serious enough that therapeutic options may include some risk.

In the meantime, I have decided to take some action.  The FDA web site is a wall with no way in for people like me with a legitimate problem.  I sent letters out to the US Senators from my state to try to find a way in.  My goal is to get this contraindication taken out so it reflects current clinical practice and the experience of depressed patients with both a past history of an eating disorder or an eating disorder.

If you are a person with that history or a psychiatrist who prescribes bupropion in the face of this contraindication, please join me in advocating for this change.    


George Dawson, MD, DFAPA


References:

1: Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry. 1998 Jul;59(7):366-73. PubMed PMID: 9714265.

2: Horne RL, Ferguson JM, Pope HG Jr, Hudson JI, Lineberry CG, Ascher J, Cato A. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 1988 Jul;49(7):262-6. PubMed PMID: 3134343.




Sunday, December 4, 2016

Please Use That CPAP Machine!

 
The best way to start out this post is by taking a look at the above graphic.  This is the graphic of a 60 year old man with diagnosed obstructive sleep apnea who is using a continuous positive airway pressure (CPAP) machine.  CPAP creates an airsplint in the airway to prevent airway collapse and snoring but more importantly hypoxemia due to obstruction.  The bottom graph is downloaded from his CPAP machine and it shows the number of apneic and hypopneic episodes. What is not shown on the graph is that around October 12 this patient got an upper respiratory infection.  As the nasal congestion worsened he changed his CPAP mask from nasal CPAP  to a full face mask.  He had a number of air leaks from this mask and as he found out later - he experienced nightly air leaks.  Some of the air leakage was enough to wake up his wife who was sleeping in the same bed.  As the hypopneic episodes worsened - he started to wake up with palpitations in the morning.   The orange timeline shows that this patient developed atrial fibrillation for about 2 minutes on 10/28/2016 and 90 minutes on 11/15/2016.  At that point he went in to see his pulmonologist the the AHI index was downloaded.

Sleep is a central part of any psychiatric evaluation.  Many of my colleagues and residents have gone on to do sleep medicine fellowships and I think it is a logical career path for any psychiatrist.  General psychiatrists need to know quite a lot about sleep and how to assess and treat sleep problems.  During my assessments, obstructive sleep apnea (OSA) is a very common problem and it is a standard series of questions in my evaluation.  I am consistently impressed with number of people who have already been diagnosed with OSA by polysomnography and prescribed continuous positive airway pressure (CPAP) devices who either do not use them or who just gave up trying to use them.  There are a number of misconceptions about OSA and CPAP that I thought I might address in this post.

1.  OSA is a benign condition:

The best way to start this discussion is to look at a complex graphic of the association of OSA and CPAP with atrial fibrillation - a known comorbidity of OSA.  In this case we have a 60 year old man with a known diagnosis of OSA.  He has been on CPAP for about 8 years.  Before the OSA diagnosis he had an episode of paroxysmal atrial fibrillation while exercising.  After starting the CPAP he was asymptomatic for 5 years before getting an upper respiratory infection and changing the mask he was using with his CPAP machine.  The first papers on OSA and cardiovascular risk began appearing in the 1990s.  Since then further research has demonstrated cardiovascular, endocrine, and cognitive comorbidity.   Recent research suggests that severe but not mild to moderate OSA increases risk for all cause mortality (1).  In the case of the above patient 40-50% of  patients with atrial fibrillation have obstructive sleep apnea (2).  In addition  to clear disease states OSA puts people at increased risk for motor vehicle accidents and occupational hazards from both cognitive symptoms and excessive daytime somnolence.

2.  CPAP is an elective intervention:

I am always shocked by the number of men who view a sleep study and the use of CPAP as elective procedures.  I doubt that a lack of adequate explanation of the problem and its implications is the issue, especially once the diagnosis is made in a sleep lab.  During my assessments I am often discussing chronic fatigue, insomnia, hypersomnolence, cognitive problems, depression, attentional problems and anxiety as prominent features of the disorder.  The wish on the part of the patient is that I can give them a pill that will solve some of all of these problems.  There was a time in the early days of OSA (about 1985) when a specific tricyclic antidepressant was thought to treat be useful in treating the disorder but that was disproven early on.  

They have often been treated with sedative hypnotic or anxiolytic drugs for this same purpose.  In some cases they are also taking opioid medications or muscle relaxants.  Opioids have demonstrated dose-dependent respiratory ataxia (3).  All of these medications decrease respiratory drive and either prolong apneic episodes or directly interfere with other respiratory mechanisms.  Alcohol use is another complicating factor either by itself or in combination with other medications that adversely affect OSA or normal respiration.

3.  If I lost some weight I probably don't need to use CPAP any more:

Although high body weight is a general feature of modern American society and some medications that are prescribed for psychiatric disorders can lead to significant weight gain and metabolic effects - many patients undergo profound weight changes in both directions.  It is common to see patients with OSA who have had a significant weight loss and decided to stop using CPAP on that basis.  They have not reconsulted with Sleep Medicine or had repeat polysomnography.  They are placing too much value on the correlation between BMI and sleep apnea.  Losing weight can result in resolution of OSA, but it is also possible to have OSA without obesity- suggesting that at a minimum Sleep Medicine should be reconsulted on the issue of discontinuing CPAP.  The complex relationship between obesity and OSA was highlighted in a recent review (4).  The authors point out that obesity, weight loss and sustained weight loss are difficult problems.  Of the three controlled trials of a weight loss intervention there were improvements in AHI with weight loss and worsening of AHI with weight regained.  They also looked at more extreme weight loss with with bariatric surgery and concluded that a drop of 1 BMI unit was associated with a 2.3 unit improvement in AHI,  The authors compile a table of earlier studies that look at weight losses of 22% to 65% with accompanying improvement in AHI of up to 88%, but unfortunately in only 3 of those studies was AHI measured at < 5 or about 4% of subjects.  In 18/19 studies the subjects had a post-op BMI of > 30.  They conclude that the majority of bariatric surgery candidates remain overweight after the surgery and the many will still have moderate OSA and the need for CPAP.  Their overall thesis is that OSA is a complex disorder and therefore no single intervention (like weight loss alone) can be used.      

4.  If I am not snoring as much - I don't need to use CPAP any more:  

Snoring is caused by vibration of the same upper airway tissues that are involved in the obstruction.  Snoring can be caused by number of acute and chronic conditions as well as being an artifact of normal genetically determined anatomy.  More men and women snore than have sleep apnea.  In many people snoring is positional and occurs much more often in the supine than side sleeping position.  Snoring also depends on detection.  Snoring and apneic spells directly observed by a sleep partner are more diagnostic than self report of waking up gasping or snoring - although those reports should also be investigated.  Snoring - like body weight is an approximate correlate of OSA and the decision to stop CPAP should be made with the assistance of a Sleep Medicine physician.  Modern CPAP equipment can provide a significant amount of in home data to assist with that decision.  

These are a few considerations about the diagnosis of OSA and  prescription of CPAP.  Any person seeing me is strongly encouraged to do whatever is necessary to use their CPAP machine and reduce risk factors including any unnecessary medication that may affect respiration.  I may be reluctant to consider some therapies that while not directly impacting on respiration may have some effect due to synergies with other compounds (like antidepressant and trazodone combinations for sleep).  You can also count on hearing about comorbid conditions (like the atrial fibrillation in this case) that are clearly affected by OSA.

So if you have that diagnosis and had a CPAP machine - please use it.  The modern autotitrating machines are much easier to use and allow for direct patient access to the data.  It is now possible to download a smartphone app and get your relevant sleep data directly from the SD card on your machine in the morning.  That gives you immediate detailed information on how you slept, what your AHI was, how the mask performed and what corrective action might be required.  In some cases it allows your Sleep Medicine physician to adjust your machine setting remotely to optimize therapy and reduce the need for office visits for that purpose.

Sleep better and live better.


George Dawson, MD, DFAPA


References:

1:  Pan L, Xie X, Liu D, Ren D, Guo Y. Obstructive sleep apnoea and risks of all-cause mortality: preliminary evidence from prospective cohort studies. Sleep Breath. 2016 Mar;20(1):345-53. doi: 10.1007/s11325-015-1295-7. Review. PubMed PMID: 26779904.

2: Hohl M, Linz B, Böhm M, Linz D. Obstructive sleep apnea and atrial arrhythmogenesis. Curr Cardiol Rev. 2014 Nov;10(4):362-8. Review. PubMed PMID: 25004989; PubMed Central PMCID: PMC4101201.

3: Walker JM, Farney RJ, Rhondeau SM, et al.  Chronic Opioid Use is a Risk Factor for the Development of Central Sleep Apnea and Ataxic Breathing. Journal of Clinical Sleep Medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2007;3(5):455-461.

4: Romero-Corral A, Caples SM, Lopez-Jimenez F, Somers VK. Interactions between obesity and obstructive sleep apnea: implications for treatment. Chest. 2010 Mar;137(3):711-9. doi: 10.1378/chest.09-0360. Review. PubMed PMID: 20202954; PubMed Central PMCID: PMC3021364.

5:  Phillips B.  Kryger MH.  Management of obstructive sleep apnea hypopnea syndrome.  In:  Kryger MH, Roth T, Dement W, eds.  Principle and Practice of Sleep Medicine, Fifth Edition.  St. Louis, Missouri: Elsevier Saunders, 2011: 1278-1293.   


Supplementary:

Some sleep medicine definitions used in the above post.  For more technical definitions see reference 5 above:

Apnea:  Cessation of airflow for at least 10 seconds.  The technical definition depends on the sensors used for this measurement such as a drop in thermocouple excursion by 90% for 10 seconds.  The thermocouple in this case would be measuring the temperature of exhaled air.  Obstructive apneas are present when there is inspiratory effort during the apnea and central apneas are present when there is none.  There can also be mixed apneas. 

Hypopnea:  Shallow breathing or a low respiratory rate for 10 seconds.  The technical definition again depends on the equipment usually defined as a drop in nasal pressure excursion and a percentage of hemoglobin saturation.

AHI:  Apnea Hypopnea Index - an index of severity of OSA defined as the number of apneic and hypopneic episodes per hour.  The general goal of therapy is to have an AHI of less than 5.

BMI:  Body mass index or weight in kilograms divided by the square of height in meters.  Several sites like the CDC offer BMI calculators and brief instructions on how to interpret these numbers.  Higher BMI and neck circumference increases the risk of OSA. 








Sunday, November 27, 2016

Mechanism Of Action Of Lithium - A Brief History




As a chemistry major and a psychiatrist Lithium has a special place in my consciousness.  During the years that I took organic chemistry lithium aluminum hydride was a favorite reducing agent when creating certain organic syntheses.  Most chemistry majors remember metallic lithium as one of those highly reactive metals that was packed under oil to prevent contact with water or even moisture in the air.  Lithium's reactivity is why the free metal does not exist in nature.  The most common form used as a medication is lithium carbonate in various preparations.

There has been a lot of speculation about the mechanism of action of lithium since its discovery.  Early in my career the definitive source of information for all things lithium-related was the Lithium Information Center at the University of Wisconsin Department of Psychiatry.  It was possible to call them and ask them anything about lithium and get the relevant references sent to you.  They also produced the Lithium Encyclopedia for Clinical Practice.  The mechanism of action was described as unknown at the time but ongoing research was cited (p. 7) in "ion substitution with subsequent effects on amine metabolism, membrane transport, glucose metabolism, and neurotransmitter synthesis and degradation."  An entire chapter was dedicated to mechanism of action.  In that chapter, the review of what was known about the mechanism of action at the time is interesting.  The major neurotransmitter systems being studied at the time were catecholamines, serotonin, and acetylcholine.  Animal studies showed acute changes on norepinephrine turnover that was only slight to non-existent with chronic use.  Results on serotonin turnover were conflicting, but it prevented hyperaggressive behavior resulting from a serotonin depleting compound that blocked tryptophan hydroxylase (parachlorophenylalanine).  Acute administration did not alter dopamine turnover.  Chronic administration resulted in increased turnover in mesolimbic and striatal areas but not the cortex.  These observations led to theories that lithium worked by altering post synaptic receptor sensitivity including decreased beta adrenoreceptor effects, stabilized opioid receptors, and preventing dopamine receptor hypersensitivity.

There was some speculation about endocrine mechanisms since it was known that lithium blocks release of thyroid hormone (T4).  It was also believed to reduce testosterone levels as a possible role in the anti-aggressive properties of the medication.  Studies at the time showed that in patients treated for aggression and closely followed, they had increased levels of luteinizing hormone but normal testosterone levels.  A significant theory at the time was that lithium worked by reducing T4 levels and this reduced beta-adrenoreceptor potentiation in mood disorders.  Lithium was also thought  to possibly work by the effect it had on the intracellular concentration of other ions like sodium, calcium, potassium, and magnesium in neurons. The 1980s was a decade when research interest on cell signalling was becoming more widespread after Sutherland's Nobel Prize for the discovery of cyclic AMP (cAMP).  Lithium was noted to inhibit adenylate cyclase the enzyme that produces cAMP.  Specific forms linked to beta-adrenoreceptors and prostaglandin-E1 were noted to be blocked leading to speculation that these mechanisms were related to mania.  

Another definitive source of drug mechanisms over the same era was The Biochemical Basis of Neuropharmacology.  My collection of these texts starts in 1984 with the fourth edition of that text.  There was a single paragraph on the action of lithium and its effect on catecholamines.  They used the term facilitated recapture mechanism (2) suggesting that the overall block  of stimulus related norepinephrine (NE) release may be due to facilitated uptake of NE.  They also point out the difference in acute and chronic effects with supersensitive NE responses with chronic administration.  By the fifth edition of this text (3), the speculative mechanisms had expanded to include inhibiting inositol-1-phosphatase in the phosphoinositide pathway (p. 114), the same NE mechanism as the previous edition (p. 306), and a new observation that lithium facilitates tryptophan uptake initially but with chronic administration tryptophan production normalizes despite increased uptake due to decreased enzymatic conversion to serotonin (5HT).  Shifting the balance between synthesis and uptake was suggested as a more stable mechanism.  By the seventh edition, lithium was back to being mentioned on single page  as part of the larger discussion of deficits in the catecholamine hypothesis of mood disorders - a theme the authors started in the fourth edition.  By the eighth and final version of this text there was no mention of lithium at all.  Two of the authors were involved in a successive text called Introduction to Neuropsychopharmacology (5).  That text describes lithium as "one of the major achievements of psychopharmacology of the past 50 years (p. 321).  The authors acknowledge that the mechanism of action remained unclear but the theories included inhibition of inositol monophosphatase, inhibition of glycogen synthase kinase-β, and modulating g protein function (p. 321).

Another excellent source of the evolution of lithium theory was the American College of Neuropsychopharmacology's (ACNP) Generation of Progress series.  The series has been discontinued.  I have the third to the fifth editions and the most substantial section on lithium action was in the Fifth Generation of Progress (6).  This chapter begins with an overview of the time course of mood stabilizer action and how the focus had changed over the previous 20 years from changes in neurotransmitter release and regulation to changes in cell signalling and morphological changes consistent with "altered signalling in critical regions of the brain."  The chapter is an overview of the complex effects of lithium on ion transport, neurotransmitter release, signal transduction, circadian rhythm, gene expression, and neuroplasticity.  The data showing that lithium and in some cases valproate and carbamazepine can regulate gene expression via transcription factors is reviewed.  Some of the changes produced a neuroprotective effect against a number of factors and at about that time neuroprotection was considered a potential positive effect form both mood stabilizer and antidepressants.  It was very interesting to reread the section on neuroplasticity.  Lithium was known to be an inhibitor of glycogen synthase kinase-3 beta (GSK-3β).  This molecule is a component of the wnt signalling pathway (see diagram).  This inhibition results in reduced phosphorylation of tau protein and the overall effect of  increased microtubule assembly.  Phosphorylation of MAP-1β is also inhibited by lithium and this results in increased axonal spreading and increased growth cone area and perimeter.  Long term down regulation of protein kinase C (PKC) substrate myrisolated alanine-rich c-kinase substrate (MARCKS) via phosphoinositide signalling was also shown to MARCKS expression is high in developmentally important structures like neuronal growth cones necessary for brain development.  It is also high in limbic structures in the human brain that retain the potential for plasticity - like learning and memory.  The authors conclude that section by pointing out that by its action on PI/PKC and GSK-3β signalling cascades, lithium "may alter presynaptic and post-synaptic structure to stabilize aberrant neuronal activity in critical areas of the brain involved in the regulation of mood."  In the space of just a few years, lithium was suddenly implicated in neuroplasticity and neuroprotection.  Maybe the Decade of the Brain did produce some benefits?  

That brings me to the latest piece of the puzzle.  A paper from Molecular Psychiatry (7) this October further examines the role of these signalling systems and how everything comes together.  The authors propose that one common biochemical pathway that may confer susceptibility to psychiatric disorders is the Wnt/ β-catenin pathway.  This is a pathway that is critical in all multicellular organisms for cell differentiation, growth, proliferation and morphology across a number of organ systems.  At least part of the pathway has a direct influence on the cytoskeleton.  It has been implicated in human diseases especially tumors and the metabolism of tumors.  The pathway was discovered about 34 years ago.  The  authors also looked at DIX domain containing-1 (DIXDC1) as a cytoplasmic transducer of the Wnt/ β-catenin pathway.  DIXDC1 interacts with disrupted in schizophrenia-1 (DISC-1) gene that has been implicated in the genetics of schizophrenia, bipolar disorder, and autism spectrum disorder.  DIXDC1 also has a restricted distribution in the nervous system depending on developmental stages.

Like most modern papers this article has an intense experimental section.  The authors prepared a DIXDC1 knockout mouse model and looked at several experimental manipulations.  They used several behavioral pharmacology approaches to model anxiety, depression, and social interaction among the mice.  On these models the Dixdc1KO (knock out) mice showed increased depression, increased anxiety, and less socialization than the Dixdc1WT (wild type) mice.  These behavioral phenotypes correlated with histological changes and the Dixdc1KO mice had reduced spine density and an increased number of filopodial or immature spines on pyramidal cell dendrites.  The authors confirmed that these reduced spine neurons functioned in an electrophysiologically expected manner.  They analyzed the reduced spines in the Dixdc1KO mutants and found that there was a decreased density of glutamatergic synapses along the dendrites of pyramidal neurons.  In order to determine if the Dixdc1KO Wnt/ β-catenin pathway would be impaired by the loss of cytoplasmic signal transduction proteins.  They found that treating the KO and WT neurons with and activator (Wnt3a) - the  level of β-catenin rose as expected in the WT neurons.  Wnt3a also failed to effect spine maturity or glutamatergic synapse density on the KO type neurons.

Most importantly for psychiatrists, the authors hypothesized that lithium would correct both the behavioral phenotype and structural defects in the Dixdc1KO type mice by inhibition of GSK3.  Injection of lithium or the specific GSK inhibitor GSK3i corrected the behavioral phenotypes and spine density, spine morphology, and glutamatergic synapse density in the pyramidal neurons of Dixdc1KO mice.                        

In a separate experiment the authors looked at a large database of patients with psychiatric disorders.  The first database contained 6000 cases of autism spectrum disorder (ASD) and 7000 controls.  The ASD cases had a greater number of sequence disrupting single-nucleotide variants (SNVs) that were judged to be likely to disrupt DIXDC1 function.  They showed the same pattern in patients with bipolar disorder (BD) and schizophrenia (Scz) versus controls.  In the end they had 4 patient data sets totaling 9000 cases (versus 11000 controls) with significantly more rare sequence disrupting SNVs.

The authors also used a cell based Wnt/ β-catenin signalling assay (compared to WT) to test specific missense SNVs from both psychiatric patients (BD, Scz) and ASD patients.  They found that rare missense SNV from ASD patients either increased or decreased Wnt/ β-catenin pathway activation.  Rare missense SNVs from psychiatric patients did not rescue spine density and synaptic deficits but the WT did.  A number of Wnt/ β-catenin pathway hyperactivating SNVs cased the expected decreased spine density, decreased glutamatergic synapse density and increased immature spine density.

The authors conclude that there may be other mechanisms in play that they could have missed.  They cite a downstream mechanism that is independent of the Wnt/ β-catenin pathway that leads to the structural changes they monitored in this study.  There are also different isoforms of DIXDC1 - some more active than others.  They do a great job of summarizing 20 years of research in the following lines:

"Several different biochemical mechanisms have been proposed to underlie the anxiolytic, antidepressant and mood stabilizing properties of lithium, a drug whose systemic use in modern psychiatry began in the first half of the last century.  Lithium's best validated mechanisms of action are inhibitory on IMP and INPP1, central phosphatases in the phosphoinositide pathway and on GSK3, the central kinase in the Wnt/ β-catenin pathway and AKT pathways."  (p. 8).  

 The story of lithium is similar to a lot of stories in biomedicine.  Research on lithium reflects a lot of popular theories of the day rather than any particular unique theory by one scientist.  That says a lot about the difference between physical sciences and biological sciences.  The technique of applying the most popular theories and lab techniques at the time is still common in medicine and neuroscience.  Like most neuroscience there needs to be further testing, replication, and debate about this mechanism but it does seem to be a lot clearer now than at any time in the past.  If the mechanism does check out there may be more than the few applications that currently involve lithium.  A lithium like effect from safer medications is potentially a very interesting one.  Applications may be as diverse as treating addiction - where glutamatergic innervation is thought to be an important component of top down control from the frontal cortex to neurodegenerative disorders and neuroprotection of synaptic complexity.







George Dawson, MD, DFAPA



References:

1:  James W. Jefferson, John H. Griest, Deborah L. Ackerman.  Lithium Encyclopedia for Clinical Practice.  American Psychiatric Press,  Washington, DC; 1983.

2:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  4th ed. Oxford, England: Oxford University Press, 1982: 214.

3:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology. 5th ed.  Oxford, England: Oxford University Press, 1985: 115, 306, 319.

4:  Jack R. Cooper, Floyd E. Bloom, Robert H. Roth.  The Biochemical Basis of Neuropharmacology.  7th ed. Oxford, England: Oxford University Press, 1996: 490.

5:  Leslie L. Iverson, Susan D. Iverson, Floyd E. Bloom, Robert H. Roth.  Introduction to Neuropsychopharamcology.  New York, New York: Oxford University Press, 2009: 321-322.

6:  Robert H. Lenox, Alan Frazer.  Mechanism of action of antidepressants and mood stabilizers. In:  Davis KL, Charney D, Coyle JT, Nemeroff C, eds.  Neuropsychopharmacology: The Fifth Generation of Progress. Philadelphia, Pennsylvania: Lippincott, Williams, and Wilkins, 2002: 1139-1163.

7:   Martin PM, Stanley RE, Ross AP, Freitas AE, Moyer CE, Brumback AC, Iafrati J, Stapornwongkul KS, Dominguez S, Kivimäe S, Mulligan KA, Pirooznia M, McCombie WR, Potash JB, Zandi PP, Purcell SM, Sanders SJ, Zuo Y, Sohal VS, Cheyette BN.  DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/β-catenin signaling.  Mol Psychiatry. 2016 Oct 18. doi: 10.1038/mp.2016.184. [Epub ahead of print] PubMed PMID: 27752079.

8:  Saito-Diaz K, Chen TW, Wang X, Thorne CA, Wallace HA, Page-McCaw A, Lee E. The way Wnt works: components and mechanism. Growth Factors. 2013 Feb;31(1):1-31. doi: 10.3109/08977194.2012.752737. Review. PubMed PMID: 23256519


Attribution:

Wnt signalling pathway is from VisiScience and their ScienceSlides 2016 slide set.

Tuesday, November 22, 2016

The Fake News





I have been watching the controversy about "fake news"with amusement.  The clamor is a direct product of the unexpected results in the Presidential election.  In search of somebody to blame, the media is currently pointing fingers at Google and Facebook as incentivizing a process where any group of people can write fake news stories, have them published and generate ad revenue from both of those services.  An expert in Big Data pointed out (1) that this is a problem with algorithms and suggested hiring human judges of fake news.  That will help until we hit the artificial intelligence singularity - a point at which humans will have access only to the news that our machine overlords want us to have.  But isn't the fake news about a lot more than just software?

Looking at the literal definition. there are different types of fake news.  Satire is the best example.  It is a staple of late night television comedy and satirical publications.  Implicit in this comedy is the capacity of the viewer to recognize immediately that it is fake and "get" the associated irony.  For various sub-populations who have difficult with social cues that may not be possible.  There is what used to be called propaganda or fake news with an agenda to control access to what information people have access to or how they think about it.   The implicit aspects of current fake news is that it is there to intentionally deceive but also profit by the structure of social media sites.      

Like most news cycles, this is another story that strikes me as absurd at several levels.  First off, how hard is it to look at your Facebook feed and realize that some of the sources being posted by people with too much time on their hands are the equivalent of an e-mail attachment from an unknown source?  The Wild West nature of the Internet prevents me from making up websites for fake news.  The first 5 that I made up apparently exist.  Suffice it to say that even a slight amount of Internet common sense should preclude a lot of these stories from consideration.

Secondly, is the concept of fake news really news to anyone?  I can recall arguing with my late father back in the 1970s about a book that was basically a collection of conspiracy theories about how one party or the other lost due to groups of powerful Kingmakers who were manipulating the electorate (sound familiar?).  But nothing slows down the outrage crescendo like publishing detailed and tedious theories in a book.  Immediate viewing by thousands of the outraged and outrageous creates a much better mob atmosphere.  The theme of a clueless electorate being manipulated in one direction or the other is a historical theme in America and probably most legitimate elections in the world.  Don't like my candidate - you must be clueless.  My candidate loses - I am going to ignore confirmation bias (among others) and write obsessively about why I think that happened.  I won't let any facts get in my way.  That basic process occurs whether or not there in an Internet or a Facebook or a Google.  The indignant losing side will always try to tip the landscape to their advantage in the future.  It is how we ended up with left and right wing media outlets in the first place.  It is basically why the United States has no politically viable third parties.

Thirdly, most of what passes for credible scientific news is in a way fake news.  Ioannidis has famously stated that most published research is false due to the inherent practical limitations of research scale and confirmation bias (3).  His observation matches my experience over the past thirty years and I have posted some famous examples on this blog.  A lot of this information is vetted more rigorously than anything that you will find in the popular press and of course the researchers are generally not conscious of the falseness of their research.  It turns out that is even true for the hallowed meta-analyses and what has become the cottage industry of statistics (4).  That same study estimates that only 3% of these studies are useful and there is a very large non-publication bias.

Fourthly, a lot of psychiatric fake news involves government spin to make the government and policy makers look good.  It coincidentally maintains a business structure that adds no value but extracts a lot of revenue from the system for "managing" care.  I have many posts that illustrate this fact.  Most recently, the Surgeon General's report would have you believe that the sad state of addiction treatment in this country had something to do with the fact that medical providers were ill equipped to treat addicts and they were just shuffled off to other community agencies.  That is very positive spin considering long standing policies by governments and their proxies to not pay for addiction treatment or in some cases the physical trauma effects of acute alcohol or drug intoxication.  That has been 30 years of rationing policies that were supposed to be stopped by parity legislation.  But that did not happen.

Fifthly, does it make sense to separate bullshit from lies in the fake news category?  Harry Frankfurt's essay on the matter ads some perspective.  Are the producers of what people consider to be fake news - liars or bullshit artists or both?  A relevant question from a technical perspective.  Is fake news just part of the abundant bullshit that Frankfurt suggests is "one of the most salient features of our culture."  Are the people who want to stomp out fake news just deniers of the level of bullshit that we each have to negotiate every day?  Frankfurt's observation, that I happen to totally agree with - is given below:

"The realms of advertising and of public relations, and the nowadays closely related realm of politics are replete with instances of bullshit so unmitigated that they can serve among the most indisputable and classic paradigms of the concept." (p. 22)

It may be that the indignant are just angry that somebody has found another way to make money off of bullshit that they did not think of or have access to.

Sixthly, psychiatry gets more than its fair share of fake news and again - a lot of that has been posted here.  I can say without a doubt that one of the largest fake news stories of 2015 was all of the fake news about the DSM-5.  Apocalyptic visions of what would happen when that book was released.  The horror of grieving patients being treated with antidepressants like they have been for decades by their primary care doctors.  The horrors of "medicalization" and "diagnostic proliferation".  The horrors of clueless psychiatrists and family physicians as helpless as Manchurian candidates against the hegemony of the DSM-5.  The philosophical horror of a manual with an implicit moral agenda about how people should live.  And it is written by (gasp) psychiatrists.  We cannot allow that to happen!   And of course the vast profits to be made on the diagnostic manual.  What really happened is best captured by a brief conversation I had with another specialist just  yesterday.

MD:  "Is there a reference that explains what happened to the personality disorders in DSM-5"
Me:  "Yeah there is a reference or two.  The organization is different but there is still a categorical approach to the major ones.  You don't really read the DSM-5 do you?'
MD:  "No - the codes are basically the same.."
Me:   "More importantly when you type "depression" into your EHR don't you get about 240 diagnostic codes..."
MD:  "At least - it depends what the default is set at."  
Me:  "That's my point.  Any general psychiatric diagnostic category in an EHR generates more diagnoses than are included in the DSM, even though the recent edition had fewer codes than the last edition.  And the only thing that counts are the ICD codes that phrase is attached to."

That is the reality of the fake DSM-5 news.  Just to be clear - no cataclysmic events. No moral collapse.  No willy nilly assigning diagnoses to people randomly on the street.  No primary care physicians changing what they do or even reading the new manual.  Pretty much the same unimpressive tome that should really be of interest only to psychiatrists and then briefly.  There are more exciting things to read about psychiatry.

Fake psychiatric news is some of the most abundant fake news in medicine.  It is a prime example of the types of fake news that exists out there and what some of the motivations are.  The number one read post of all time on this blog focuses on a Washington Post article, basically correcting what was said about the DSM-5, conflict of interest, primary care, and psychiatry.  Should that level of correction render it into the fake news category?  The fake news in psychiatry is so pervasive there are entire web sites dedicated to it.  Some of these web sites have an air of legitimacy until you read what is actually being said.  Some even attract psychiatrists who are apparently confused about the content or tenor of the site and don't seem to understand rhetoric.

Just a few things to consider about the current fake news category - especially as it applies to psychiatry.  Fake news is here to stay - it is not some new problem introduced by Google or Facebook.  It is all a part of how society works, with a person or group of people seeking advantages over others.  In the USA we like to fool ourselves into thinking that we live in a fair society where everyone is equal.  We like to think that conflict-of-interest can be eliminated or at least managed.

That is just more fake news.


George Dawson, MD, DFAPA


References:

1:  Cathy O'Neil.  Social Media Companies Like Facebook Need To Hire Human Editors.  NYTimes Nov. 22, 2016

2:  New York Times Opinion Pages:  How To Stop The Spread of Fake News.  NYTimes Nov. 22. 2016.

3:  Ioannidis JP. Why most published research findings are false. PLoS Med. 2005 Aug;2(8):e124. PubMed PMID: 16060722.

4: Ioannidis JP. The Mass Production of Redundant, Misleading, and Conflicted Systematic Reviews and Meta-analyses. Milbank Q. 2016 Sep;94(3):485-514. doi: 10.1111/1468-0009.12210. PubMed PMID: 27620683.

Ioannidis concludes that despite the massive production of meta-analyses only 3% are "decent and clinically useful."






      

Saturday, November 19, 2016

An Unstated Developmental Milestone (or Two)





It is hockey season in Minnesota.

And like Little League seasons used to be, tens of thousands of pint sized hockey players are competing and practicing almost on a 24/7 basis.  Emotions run high as teams of widely varying levels of physical ability compete for the greater glory of their team.  Like most team sports that we all played as kids, there is a high emotional investment in winning.  None of the secondary goals of personal improvement, improved conditioning, and teamwork are generally considered.  Whether or not they can be realistically considered at a young age is an open question.  Clearly the adults carting all of these kids around and in many cases coaching them - want to see them win.  I don't know what impact the participation movement has had on winning.  In talking with some graduates of those systems, it offers limited protection.  At some point there is only competitive sports and a rude awakening that participation gets you so far.  At some point everybody does not get a trophy.

That realization is a game changing event for most people.  In your high school class of 300 people, you might be the fastest person in the quarter mile but you rapidly learn through a series of track meets that you will probably not be going to the Olympics.  The adaptation to that varies from just quitting the track team, to going to all of the meets and running as fast as you can, to questioning the coaching staff,  to trying performance enhancing drugs to see if that will give you the necessary edge.  It involves more than sports.  I have seen the same sequence of events play out in music and academics.  Being demoted from second to third chair in the orchestra section.  Not getting the perfect score or academic award in school.  In relationships, the break up of a first serious romantic relationship was the commonest reason I would see college aged students admitted to my inpatient unit and yet - none of them had a serious mental illness.  They were "suicidal" and emotionally distraught because they had not dealt with that kind of failure before.  My standard pep talk to them was that someday they would be as old and emotionally resilient as me and they would have scant recollection of ever seeing a psychiatrist in their life.  In many ways, relationships more than anything else highlights the developmental milestone I am referring to and that is dealing with failure - especially when that failure seems to have very high stakes.  A large percentage of the college students in crisis did not think that they would ever find a partner as ideal as the one they had just lost.

In Psychiatry School, they teach us all the normative models of cognitive and emotional development from various schools of thought.  Reading any modern text of child psychiatry (1) - the old developmental references based on theories by Freud, Piaget, and Erickson are gone.  They are now supplanted by specific emotion, cognitive, temperament, and attachment lines of development and their associated neurobiology. It is generally agreed that it is better to be resilient than not.  We now know that psychological trauma in childhood is a major cause of decreased resilience and that a fair number of children experience one of these traumatic events during childhood.   Apart from protecting children from these traumas as parents and society - what else can be done on an individual level?  During my career as a psychiatrist, I have made two observations that originated with other people that I think would be extremely helpful.

The first is the Sara Blakely story.  She is  the CEO of Spanx, a company that she started herself that became amazingly successful.  She has told her story repeatedly on a method that her father taught her to redefine failure as not trying rather than the outcome.  Her father took an active interest in his children and always inquired aboiut one thing they had failed at that week.  She said that he actually celebrated their failures at some point.  She discloses her failures at her company and encourages her employees to do the same thing.  Having survived several corporate cultures that thrived on blaming employees for various problems, I can imagine (if I try real hard) how refreshing that approach would be.  What would happen to all of these kids playing Minnesota hockey if they were able to just talk about what they were trying to do and how they failed at it?  Would it revolutionize the game?  If you are focused only on a win-lose outcome, you lose a lot of information along the way.  Information about yourself  and everybody else.  The starkest piece of information is that at any level of competition, the odds are stacked against you being the big winner.  You have to be able to see yourself as the Big Fish in a small pond at best.  You are probably not the one person in a million who is going to be at the top of that game.  In my estimation Sara Blakely's father was a genius when it comes to parenting.

I learned about the second genius father from of my coworkers before one of my morning inpatient team meetings.  We were the first ones there and she started talking about how she got into nursing.  Her father advised her to do volunteer work in the field when she was in high school.  She was reluctant to consider that idea.  At that point her father said her would pay her to do volunteer work in a field that would help her get into the health care professions.  At the time that struck me as pure genius.  I was talking with an extremely competent nurse.  I could also relate to not wanting to do much and not realizing why volunteer work as a teenager might be important.  That single idea by her father may have been the difference in her vocational choices.        

Those are my two favorite stories about parenting ideas that seemed like pure genius to me.  I am very interested in hearing what other people have discovered in real life that might have been useful in  improving resilience and getting to a more useful perspective on life - as opposed to the dry theories that we are all taught.  I would also like to point out that these issues are very difficult to study in a double blind clinincal trial, but I did encounter an experiment that was applied to a school class that also had very good results.  The study was highlighted by Ruth Shim, MD, MPH in her presentation Prevention in Psychiatry: A Public Health Approach given at the the University of Wisconsin 4th Annual Update in Psychiatry this year.  The research presented was on the Good Behavior Game (GBG), an intervention applied in the Baltimore City Public Schools in the late 1960s.  The game starts as three 10 minute sessions per week as a team competition.  The rules were focused on working quietly, being polite to others, getting out of one's seat with permission, and following directions.  Teams were rewarded with pencils and erasers if all of the members of the team followed the rules.  As the game went on the sessions got longer and students were given stars as rewards.  The games started with 1st and 2nd grade students and continued until the 6th grade.  Students were assessed up to the age of 19-20.  When the GBG classrooms were compared to standard classrooms there were significant reductions in alcohol use, smoking, and suicidal thoughts.  Looking at the males only there was less substance use and need for behavioral and substance abuse treatments.  The highly aggressive male strata had substantially less drug abuse, violent and criminal behavior (34% versus 50%), and diagnoses of adult antisocial personality disorder ( 40% versus 100%).

All of those results from the straightforward application of behavior therapy and peer pressure.  These are all good examples of basic ideas that seem to have had very good outcomes in terms of competent and successful adults.



George Dawson, MD, DFAPA


References:

1:  Anita Tharper, Daniel S. Pine, James F. Leckman, Stephen Scott, Margaret J. Snowling, Eric Taylor.  Rutter's Child and Adolescent Psychiatry (6th ed).  John Wiley & Sons, Ltd, The Atrium, Sounhtern Gate, Chichester, West Sussex, UK, 2015.  

2:  Embry DD. The Good Behavior Game: a best practice candidate as a universalbehavioral vaccine. Clin Child Fam Psychol Rev. 2002 Dec;5(4):273-97. Review. PubMed PMID: 12495270.


Attribution:

Hockey photo at the top is by y Ailura (Own work) [CC BY-SA 3.0 at (http://creativecommons.org/licenses/by-sa/3.0/at/deed.en)], via Wikimedia Commons at the following URL:  https://commons.wikimedia.org/wiki/File%3A20160416_AUTHUN_2883.jpg

The Surgeon General's Report on Addiction





Last week, the current Surgeon General Vivek H. Murthy, MD came out with the first report from that office on addiction.  The full text is available on line at this link.  The document is 428 pages long but it is full of a lot of unnecessary text.  As an example the first 64 pages are essentially an introduction and a listing of personnel who worked on the report as well as references.  The last 85 pages are references and appendices.  I don't know the chain of command but both the US Department of Health and Human Services (DHHS) and the Substance Abuse and Mental Health Services Administration (SAMHSA) have their imprint on it and that is not necessarily a good thing.  The Surgeon General came out with a letter earlier this fall about how to stop the opioid epidemic that I commented on.  That letter was brief, to the point, and could have been expanded into a more concise document than the current report.

There is a lot wrong with this report.  Just from an administrative side, it is clear that the report sends a strong public relations message about what the government is doing to advance the treatment of addiction and a lot of that message is flat out spin.  I am always interested in detoxification from addictive drugs so I naturally searched on that and found this paragraph:

 "Until quite recently, substance misuse problems and substance use disorders were viewed as social problems, best managed at the individual and family levels, and sometimes through the existing social infrastructure—such as schools and places of worship, and, when necessary, through civil and criminal justice interventions. In the 1970s, when rates of substance misuse increased, including by college students and Vietnam War veterans, most families and traditional social services were not prepared to handle this problem. Despite a compelling national need for treatment, the existing health care system was neither trained to care for nor especially eager to accept patients with substance use disorders." (p 1-19).

That is really not what happened.  It is not even close.  Services to treat addiction were rationed just like services to treat mental illnesses.  With the federal and state governments giving carte blanche to managed care companies - hospitalizations that required detoxification could be denied even if the patient had a significant psychiatric disorder.  Trauma surgeons were also affected by this discrimination.  People with serious traumatic injuries who also had positive toxicology for drugs or alcohol were denied payment for a hospitalization that required extensive surgery and prolonged hospital stays.  The very thin system of care for addictions and mental illness were outside of the funding stream of mainstream medicine because that is exactly where the government and the business world placed it.  In the entire document there is one reference to prior-authorization (p. 6-24) and then only to say that it is one of many strategies used by states to ration Medicaid resources used for treating addictions.

On the issue of training, in about 1992 I had accumulated a series of cases that involved inpatient detoxification that were denied payment by a managed care intermediary representing the state government.  All of these denials have appeal processes that are stacked against physicians and patients.  In this case I was told I would need to argue all of them in front of an administrative law judge.  I took a vacation day and was ready to do that.  On the day before the hearing, I was notified that the judge had made a summary decision in favor of the managed care company and I did not have to show up for the hearing.  This is obviously not a training issue when I am doing detoxification, a managed care company is telling me to discharge patients (2/3 of whom also have significant mental illnesses), and the state is backing them up.

In the entire document there are 4 paragraphs on detoxification - referred to as "Acute Stabilization and Withdrawal Management". (p. 4-12 - 4-13).  It really minimizes the medical aspects of detoxification and the potential complexity of the situation to the degree that it seems to have been written by a nonphysician.  The clear intent is to stress that detoxification by itself is not treatment for an addiction but only a necessary first step.  In the process it also minimizes the medical and nursing expertise necessary to get people through the detoxification phase.  After an entire chapter on neurobiology there is no mention of the craving and dysphoria that often prevent people from completing detoxification or cause them to immediately relapse afterwards.  There is no mention of the medical comorbidity that needs to be addressed along with the detoxification process.  There is no mention of the complexity involved in detoxifying people from multiple addictive substances - a common scenario these days.  There is no mention of why allowing people to detoxify themselves at home with addictive substances may or may not be a good idea.  There is no mention of why "social detoxification" in non-medical detox centers run by municipalities may or may not be a good idea.  There is no mention of the psychological aspects of detoxification and why it presents one of the most significant obstacles to care in the treatment of addiction.  In short, detoxification would seem to have a much more prominent role in a report about facing addiction than it does in this report.  The treatment of addiction would have been better served if all of these issues would have been addressed and the minimum medical requirements for detoxification could have been established.  

On the less wrong but not perfect side of things, there is a lot of neurobiology in the report, both in terms of basic science and medication assisted treatment.  The neurobiology is fairly intense for the average reader who is part of the target audience.  Even at the level of physicians who I lecture to and train the concept of the extended amygdala is comprehended by very few people.  I could probably say the same thing about the amygdala.  In fact, I attended a course of brain dissection by one of the pioneers of this concept Lennart Heimer, MD.  At the end of that two day course, in a room of highly motivated and interested people I think that few understood the importance of the concept.  My point in all of this is the old adage - you can know just enough neurobiology to be dangerous.  At some point all of these names just become pseudo-explanations, especially for people with a poor understanding of science.  I have talked with people who knew all of the jargon and started to explain their own addictions with it.  That was not a good scientific or clinical approach and I wonder if the public may have been better served by an approach that focuses on the conscious state of the addict.  We still do not know how that is derived from the underlying neurobiology - even though the neurobiological explanations make it seem like we do.  

Criticism aside, there are some things that the report does well.  It provides a fair outline of the NIDA based continuum of care guidelines for addiction treatment for people with severe addictions.  The specific section can be found starting on  page 4-13 and the section: Principles of Effective Treatment And Treatment Planning.  The average person or family interested in seeking treatment for someone with an addiction is often faced with a staggering array of treatment services and a lot of associated politics.  The news media is often a source of increasing confusion rather than clarity.  A recent example is the rise of certain treatment methods that claim very high rates of success, or that are critical of more traditional treatment approaches like 12-step recovery (AA, NA, TSF (Twelve-Step Facilitation Therapy) and residential treatment.  Managed care companies continue to ration residential treatment 1 or 2 or 5 or 7 days at a time.  From the report:

"A typical progression for someone who has a severe substance use disorder might start with 3 to 7 days in a medically managed withdrawal program, followed by a 1- to 3-month period of intensive rehabilitative care in a residential treatment program, followed by continuing care, first in an intensive outpatient program (2 to 5 days per week for a few months) and later in a traditional outpatient program that meets 1 to 2 times per month. For many patients whose current living situations are not conducive to recovery, outpatient services should be provided in conjunction with recovery-supportive housing."  (p. 4-18).

That recommendation on the continuum of care should be kept in mind by anyone who is seeing an addiction specialist from any discipline in their office on an outpatient basis and finds that they are not able to stop using drugs or alcohol.  That would include physicians or other prescribers who are providing medications and possibly making the situation more dangerous because of the combination of prescribed and addictive drugs.  There is a temptation to say that with new innovations in medication assisted treatments that all that is necessary is seeing a physician and getting medications to treat the addiction.  A close read of any of the FDA approved package inserts on these medications addresses the complexity and points out that psychosocial treatments like the ones in the above paragraph are necessary.  There is no strictly medical cure for addiction.

It is also fairly common these days to see Alcoholics Anonymous and their principles being bashed in various forums like the popular media or web sites that seek to aggregate professionals.  They appeal to people who don't like the model for various reasons, consider it antiquated, or claim more success using some other treatment.  Some of these sources are also confused, often by neurobiology or an ignorance of the treatment literature and claim that there is no evidence that 12-step recovery works.  The report provides solid evidence to the contrary.  TSF is listed as a treatment intervention with a solid evidence basis and results as good as any and it works as a stand-alone intervention or in combination with other treatment modalities (p. 4-28 to 4-30) that are often suggested as competing treatment models.

That's my overall take on the report.  Like most government documents it is a lot of unnecessary reading so I may have missed something and I can't comment on everything.  It is clearly the product of committees, meetings, and bureaucrats.  Documents like these serve a variety of purposes in addition to the stated purposes of educating the public and establishing public health policy.  As a person who lived through it, this is also a serious rewrite of history.  That history is decades of what has been called "health care reform".  In this country that means hiring proxies to ration healthcare.  When that happens the most disenfranchised patients get the most rationing.  Those patients have always been people with addictions and mental illnesses.   The real intervention needed in the addiction treatment landscape is establishing some controls on companies who are set to profit from denying care for addiction treatment and the governments that encourage it.

That is the single-most powerful intervention that we need in the addiction treatment field and it was nowhere in the report.


George Dawson, MD, DFAPA


References:

U.S. Department of Health and Human Services (HHS), Office of the Surgeon General, Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC: HHS, November 2016.


Disclosure:

I have no connection with any of the parties of agencies who wrote this report.  I am obviously a psychiatrist with a life long commitment to treating mental illness and addiction and extensive personal experience with the rationing of these treatment services.  I am currently employed at a treatment center that uses most of the treatment modalities specified in this report including medication assisted therapies (MAT).