Quebec beer-drinker's cardiomyopathy revisited

In the 1960's a condition called Quebec beer drinker's cardiomyopathy was described in the medical literature.  Between August 1965 and April 1966 46 men and 2 women were admitted to 8 hospitals in Quebec with acute cardiomyopathy and congestive heart failure.  Twenty of them died.  During the epidemiological analysis it was determined that they were all heavy beer drinkers.  An extensive analysis of the this phenomena is available in full text at the initial link on this page.  For those of us trained through the end of the 20th century the clinical methods in the 1960s were not that far removed.  The mystery was solved then by a combination of epidemiology and pathology:

"Suspicion of cobalt as the toxic agent was aroused after examination of the thyroid glands removed at autopsy showed changes similar to those found in cobalt intoxication. Had cobalt been added to the beer? Yes"

Similar patterns had been observed in Minneapolis, Omaha, and Louvain (Belgium).  Why am I suddenly interested?   The New England Journal of Medicine Clinical Problem-Solving case of the week entitled "Missing Elements of the History."  In this case a 59-year old women who was previously in good health develops acute congestive heart failure and a cardiomyopathy is diagnosed.  She has a complicated course with an initial pericardial effusion.  After acute treatment no etiology of the cardiomyopathy was determined and she was assessed for heart transplantation.  Her heart failure worsened and she developed cardiogenic shock and needed a left ventricular assist device.  Three months later she received a heart transplantation and was discharged home in 20 days.

Was the patient in question a drinker of cobalt laced beer?  No - but she did have cobalt in her body.  She had bilateral DuPuy ASR metal-on-metal hip prostheses that had been placed 5 years and 4 years prior to the heart transplant.  She had learned about one year prior to transplantation that the prostheses were being recalled due to a higher than expected failure rate and a protocol for follow up was sent to her.  She was advised to get repeat hip imaging and serum cobalt levels done.  Pelvic MRI showed reactive areas with fluid collection and the cobalt level was elevated at 287.6 mcg/liter with a reference value of less than 1.0 mcg/liter.  The prostheses were removed 11 and 13 months post heart transplantation.  She had a complicated course but apparently recovered.  Serial cobalt levels were done and 16 months after transplantation remained at 11.8 mcg/liter a significant drop.  She also had a chromium level determined at 248.9 mcg/liter about 8 months after transplantation.

The NEJM article points out that about 1 million people had these prostheses implanted between 2003 and 2010.  The authors here strike me as being overly modest in saying that they cannot absolutely confirm that this is a case of cobalt induced cardiomyopathy, but there is just too much evidence to hedge around.  Read their timeline of events in Table 1. and see what you think.  It would certainly seem to have implications for regulatory bodies like the FDA.  The parallel regulatory body in the UK states that any patient there needs lifetime annual follow up including imaging and blood cobalt and chromium levels.   The FDA recommendations are much more nonspecific and they appear to be placing the monitoring burden on primary care physicians and  other specialists.

What does the New York Times report about this story?  They have a story in November 2013 about $2.5 - 3 billion being award to a group of about 8,000 patients in the US.  They have another story that the manufacturer seemed to know earlier about the high than expected failure rate and need for replacement.  In that same story they quote the total number of recipients as "93,000 people, about one-third of them in the United States" as opposed to the NEJM estimate of 1 million people world wide.  Most of the stories I could find (15 of 26) were in the business section.  There is an interesting quote near the end of the article about how taking it off the American market was strictly a business decision.  In other articles there is a hint of a cover up and a hint of doctors not speaking up to warn other doctors, but the story has been out there since March 2010.  Where is the outrage?

We have just gone through a several year period of bashing psychiatrists for daring to rewrite a diagnostic manual that they use by themselves.  Further that manual explicitly says that you really can't just read the manual.  You need to be trained in medicine and psychiatry first.  There was plenty of outrage then.  Critics of all types in the New York media writing an endless stream of negatives about psychiatry and the DSM-5.  Accusations of conflict of interest (more appropriately the appearance of conflict of interest).  Outrage over various parties not being to have enough input into the book (when in fact the web site designed for that purpose took in thousands of comments that were debated by the work groups).  Outrage over whether the manual was written to appease the pharmaceutical industry that ignored the basic facts.  I could certainly go on, but what is the point?  Everyone has heard these stories.  They are commonplace.

The DSM-5 came out and nothing happened.  Clinical psychiatrists did not blink an eye or make any major changes.  Nobody ended up with elevated cobalt or chromium levels.  Nobody ended up with needing  more surgery or congestive heart failure from cardiomyopathy.   I certainly do not want to minimize what all of these hip implant patients are going through but it seems that the press and the FDA are doing just that.  I think the lesson is certainly there when you look at how the media overreacts to psychiatry they end up appearing to be very tolerant of significant problems in other fields of medicine.

My suggestion for the psychiatry critical press is that it might actually be worthwhile to critique other branches of medicine where there are significant problems.  Hold them up to the standard that you apply to psychiatry and see what happens.

If you can't there is clearly something wrong.  At the minimum I propose that outrage should be proportional to a real problem rather than the appearance of a problem.  Or better yet - it could just disappear and be replaced by a more rational analysis.

George Dawson, MD, DFAPA

Allen LA, Ambradekar AV, Devaraj KM, Maleszewski JJ, Wolfel EE.  Missing elements of the history.  N Engl J Med 2014: 320(6): 559-566.

Siegel E, Lautenbach AF.  Determination of cobalt in beer. Siebel Institute of Technology and World Brewing Academy.  Interesting historical document on why cobalt may be added to beer including the fact that the FDA apparently approved this application in 1963.

Clinical Note 1: I added this for the clinical psychiatrists out there who I know see a large number of people with hip implants.  Be on the lookout for pain, lack of follow up with their surgeon or signs and symptoms of congestive heart failure.  The FDA warning also suggests depression and cognitive changes.  MedlinePlus also has patient handouts.  It probably is also a good idea to remember that some people may be taking cobalt and/or chromium ionic forms as a supplement.  As an example poor quality information that can be seen on the Internet, there is some information on the that cobalt boosts erythropoetin (EPO) and athletic performance that is based on animal studies from the 1950s.  Trying that would obviously be an extremely bad idea.  A history of use of supplements is important for these reasons.

ADHD and Crime

There has been a lot of commentary on the NEJM article on the association between stimulant treatment of Attention Deficit Hyperactivity Disorder (ADHD) and less crime in a cohort of patients with ADHD.  Two of my favorite bloggers have commented on the study on the Neuroskeptic and Evolutionary Psychiatry blogs.  As a psychiatrist who treats mostly patients with addictions who may have ADHD and teaches the subject in lectures - I thought that I would add my opinion.

Much of my time these days is spent seeing adults who are also being treated for alcoholism or addiction. I also teach the neurobiological aspects of these problems to graduate students and physicians.  In the clinical population that I work with - ADHD is common and so is stimulant abuse/dependence and diversion.  Cognitive enhancement is a widely held theory on college campuses and in professional schools.  That theory suggests that you can study longer, harder, and more effectively under the influence of stimulants.  They are easy to obtain.  Stimulants like Adderall are bought, sold, and traded.  It is fairly common to hear that a feeling of enhanced cognitive capacity based on stimulants acquired outside of a prescription is presumptive evidence of ADHD.  It is not.  It turns out that anyone (or at least most people) will have the same experience even without a diagnosis of ADHD.

There is very little good guidance on how to treat ADHD when stimulant abuse or dependence may be a problem.  Some literature suggests that you can treat people in recovery with stimulants - even if they have been previously addicted to stimulants.  Anyone making the diagnosis of ADHD needs to makes sure that there is good evidence of impairment in addition to the requisite symptoms.  Ongoing treatment needs to assure that the stimulants are not being used in an addictive manner.  I would define that as not accelerating the dose, not taking medications for indications other than treating ADHD (cramming for an exam, increased ability to tolerate alcohol, etc), not attempting to extract, smoke, inject, or snort the stimulant, not obtaining additional medication from an illegal source, and not using the stimulant in the presence of another active addiction.  Addressing this problem frequently requires the use of FDA approved non stimulant medication and off-label approaches.

With the risk of addiction that I see in a a population that is selected on that dimension, why treat ADHD and more specifically why treat with medications?  The literature on the treatment of ADHD is vast relative to most other drugs studied in controlled clinical trials.  There have been over 350 trials and the majority of them are not only positive but show very robust effects in terms of treatment response.  The safety of these medications is also well established.

Enter the article from the NEJM on criminality and the observation that stimulants treatment may reduce the criminality rate.  This was a Swedish population where the research team had access to registries containing data on all persons convicted of a crime, diagnosed with ADHD, getting a prescription for a stimulant, and to assign 10 age, sex, and geography matched controls to each case.  Active treatment was rather loosely defined as any time interval between two prescriptions as long as that interval did not exceed six months.  The researchers found statistically significant reductions during the time of active treatment for both men (32%) and women (41%).      

I agree that this is a very high quality article from the standpoint of epidemiological research - but my guess is the editors of the NEJM already knew that.  This study gets several style points from the perspective of epidemiological research.  That includes the large data base and looking for behavioral correlates of another inactive medication for ADHD - serotonin re-uptake inhibitors or SSRIs.  There is a robust correlation with stimulants but not with self discontinued SSRIs.  They also analyzed the data irrespective of the order of medications status to rule out a reverse causation effect (treatment was stopped because of criminal behavior) and found significant correlations independent of order.

Apart from the usual analysis clinical and researchers in the field ranging from neurobiologists to researchers doing long term follow up studies do not find these results very surprising.  The Medline search below gives references of varying quality dating back for decades.  The pharmacological treatment certainly goes back that far.  The accumulating data suggests that where the disorder persists, it requires treatment on an ongoing basis.  A limited number of studies suggest that cognitive behavioral therapy (CBT) may be useful for adults with ADHD but not as useful for children or adolescents.  The practice of "drug holidays" prevalent not so long ago - no longer makes sense when the diagnosis is conceptualized as a chronic condition needing treatment to reduce morbidity ranging from school failure to decreased aggression to better driving performance.

One of the typical criticisms of epidemiological research of this design is that association is not causality, I think it is time to move beyond that to what may be considered causal.  In fact, I think it may be possible at this time to move beyond the double blind placebo controlled trial to an epidemiological standard and I will try to pull together some data about that approach.

George Dawson, MD, DFAPA

Lichtenstein P, Halldner L, Zetterqvist J, Sjölander A, Serlachius E, Fazel S, Långström N, Larsson H. Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med. 2012 Nov 22;367(21):2006-14. doi: 10.1056/NEJMoa1203241.

Criminality and ADHD:  Medline Search

DSM5 - NEJM Commentaries

I highly recommend the two commentaries in the New England Journal of Medicine this week.  The first was written by McHugh and Slavney and the second by  Friedman.  Like Allen Frances they are experienced psychiatrists and researchers and they are likely to have unique insights.  I may have missed it, but I am not aware of any of these authors using the popular press to make typical political remarks about the DSM.  Those remarks can be seen on an almost weekly basis in any major American newspaper.

McHugh and Slavney focus interestingly enough is the issue of comprehensive diagnosis and opposed to checklist diagnoses.  It reminded me immediately that the public really does not have the historical context of the DSM or how it is used.  It also reminded me of the corrosive effect that managed care and the government has had on psychiatric practice with the use of "templates" to meet coding and billing criteria in the shortest amount of time.   Finally it reminded me of the bizarre situation where we have managed care companies and governments combining to validate the concept of a checklist as a psychiatric diagnosis and court testimony by experts suggesting that it is negligent to not use a checklist in the diagnostic process.

McHugh and Slavney summed up in the following three sentences: “Checklist diagnoses cost less in time and money but fail woefully to correspond with diagnoses derived from comprehensive assessments. They deprive psychiatrists of the sense that they know their patients thoroughly. Moreover, a diagnostic category based on checklists can be promoted by industries or persons seeking to profit from marketing its recognition; indeed, pharmaceutical companies have notoriously promoted several DSM diagnoses in the categories of anxiety and depression.” (p. 1854)

In my home state, the PHQ-9 is mandated by the state of Minnesota to screen all primary care patients being treated for depression and follow their progress despite the fact that this was not the intended purpose of this scale and it is not validated as an outcome measure.  The PHQ-9  is copyrighted by Pfizer pharmaceuticals.

The authors go on to talk about the severe limitations of this approach but at some point they seem to have eliminated the psychiatrist from the equation. I would have concerns if psychiatrists were only taught checklist diagnoses and thought that was the best approach, but I really have never seen that. Politicians, managed care companies, and bureaucrats from both are all enamored with checklists but not psychiatrists. They also talk about the issue of causality and how that could add some additional perspective. They give examples of diagnoses clustered by biological, personality, life encounter, and psychological perspectives. Despite its purported atheoretical basis, the DSM comments on many if not all of these etiologies.

Friedman's essay is focused only on the issue of grief and whether or not DSM5 would allow clinicians to characterize bereavement as a depressive disorder. That is currently prevented by a bereavement exclusion and DSM-IV and apparently there was some discussion of removing it. He discusses the consideration that some bereavement is complicated such as in the situation of a bereaved person with a prior episode of major depression and whether the rates of undertreatment in primary care may place those people at risk of no treatment.

There can be no doubt that reducing a psychiatric diagnosis to a checklist loses a lot of information and probably does not produce the same diagnoses. There is also no doubt that the great majority of grieving persons will recover on their own without any mental health intervention. Both essays seem to minimize the role of psychiatrists who should after all be trained experts in comprehensive diagnoses (the kind without checklists). They should be able to come up with a diagnostic and treatment formulation that is independent of the DSM checklists. They should also be trained in the phenomenology of grief and the psychiatric studies of grief and realize that it is not a psychiatric disorder.  If they were fortunate enough to be trained in Interpersonal Psychotherapy they know the therapeutic goals and treatment strategies of grief counseling and they probably know good resources for the patient.

The critiques by all three authors are legitimate but they are also strong statements for continued comprehensive training of psychiatrists. There really should be no psychiatrist out there using a DSM as a "field guide" for prescribing therapy of any sort based on a checklist diagnosis. Primary care physicians in some states and health plans have been mandated to produce checklist diagnoses.  The public should not accept the idea that a checklist diagnosis is the same as a comprehensive diagnostic interview by psychiatrist.

That is the real issue - not whether or not there is a new DSM.

George Dawson, MD DFAPA

McHugh PR, Slavney PR. Mental illness--comprehensive evaluation or checklist?

N Engl J Med. 2012 May 17;366(20):1853-5.

http://www.nejm.org/doi/full/10.1056/NEJMp1202555?query=TOC 

Friedman RA. Grief, depression, and the DSM-5. N Engl J Med. 2012 May

17;366(20):1855-7.

http://www.nejm.org/doi/full/10.1056/NEJMp1201794?query=TOC