The Antidepressant Black Box Warning - A Better Solution

There were two opinion pieces in the New England Journal of Medicine this week on the antidepressant black box warning.  Richard A. Friedman, MD contends that the warning had an adverse effect on antidepressant prescriptions, a decreased rates of new depression diagnoses, increase in psychotropic drug poisoning (as a proxy measure for suicide attempts)  and that is reflected in an increase in the rate of completed suicides in people from 10-34 years of age between 1999 and 2010.  He argues for removing the warning entirely.  Marc B. Stone, MD points out that there is contradictory data showing that an increase in suicide rates and no good correlation with an increase in rate and the year of the boxed warning.   He discusses other factors that can result in fluctuating levels of depression diagnosis and treatment, including a change in antidepressant marketing because many antidepressant were becoming generic at the time and how that may have affected the prescription rates.  He cites CDC data on the rate of intentional versus non-intentional overdose as a more appropriate metric and points out that rate was lower both before and after the warning.  He concludes that despite many efforts there is no real correlation between the warning and suicide rates.  Disclosure forms will be available when the article becomes available online but for now Dr. Friedman appears to be affiliated with the Department of Psychiatry, Weill Medical College of Cornell University and Dr. Stone is affiliated with the FDA.

One of the central problems with the debate is the problem of looking at statistical significance in low rates on a longitudinal basis.  In all of the studies I have seen and in these debates, the longitudinal data is almost always interpreted as correlational (we seem to never be able to determine causality) and there appear to be endless number of correlations - and none of them are mathematical.  In these articles alone the authors looked at drug company marketing and sales strategies, the impact of the original warning, the impact of the revised warning,  the impact of the discussion in the media as opposed to the warning, the diagnostic patterns of physician, the impact of managed care and pharmacy benefit managers, and the prescribing patterns of physician (broad versus narrow) as possible correlates.  All of this is analyzed at a qualitative level and apparently not by anyone who is an expert in the analysis of longitudinal data.  The debate becomes a series of true or false statements based on snapshots.  That to me is essentially a political analysis of the data and it seems to lead nowhere.  It can be a question of "my data being better than your data" but it is not the kind a probabilistic analysis that physicians are trained to do.  The central question here is whether the original FDA meta-analysis of clinical trials showing a 4% to 2% ratio of "suicidality" in the treated versus placebo group is valid and what should be done about it, keeping in mind that suicidality did not confer any increased risk of completed suicide.  In this case Dr. Friedman agreed that something should be done based on that meta-analysis so both authors would agree that finding is significant.

They differ on what existing data mean and what should be done.  As a clinical psychiatrist  who deals with side effects at least as much as symptoms of depression and anxiety, I think a lot could be done to improve the awareness of side effects and improve treatment.  The solution is a lot less drastic but more comprehensive than a Black Box Warning.   After all, it is highly likely that most people are going to encounter more common and potentially problematic side effects than intrusive suicidal thoughts  or suicide attempts.   That is probably as true for medications without a black box warning as medications with a black box warning.  Even considering another class of medications with a warning about suicidal ideation - anticonvulsants, says nothing about whether a patient is more likely to experience those thoughts with the anticonvulsant or the antidepressant.  Depression is a common problem in people with epilepsy, what about people needing to take both an anticonvulsant and an antidepressant?

My recommended approach to the problem would resolve a couple of issues.  It would emphasize to the public that a choice to take a medication is not without risk and is not a guarantee of a cure.  That one cannot assume that an FDA approved medication is totally benign and will be completely effective for their problems.  The FDA is unique in terms of the efficacy, side effects, and pharmacosurveillance data that they collect.  They are also not transparent with it.  In that context they expect physicians to make sense out of what is presented to patients in the risk-benefit discussion of whether or not to take a medication.  That leaves the benefit discussion full of unnecessary guesswork about what does and what does not need to be discussed.  In that context a black box warning is just another rare cloud on the horizon.  Using the Back Box warning as a standard, a doubling of suicidality from 2% to 4% with no completed suicides with antidepressants is on par with a 1-6/10,000 chance of Stevens-Johnson's syndrome from carbamazepine.

The solution here is an FDA attachment to the package insert of what needs to be discussed with the patient to give them a better idea of the risks and benefits of a particular medication.  It makes no sense at all to feel forced into a discussion of suicidality from taking a medication when far more patients will experience fatigue, headaches, diarrhea, and discontinuation symptoms.  I have attached a sample of a general outline of what needs to be covered.  I think that Medline plus medication handouts could also be considered.  The FDA can specify what these points are for every medication.  If the psychiatric profession has not set a standard, it is time for the regulators to do more than issue confusing black box warnings and back it up with all of the data in an accessible format on their very confusing web site.  You can bet that the managed care industry does not want their psychiatrists spending an extra few minutes with a patient to have this discussion.  The regulator in this case has a unique opportunity to set a uniform standard for side effect discussions based on the priorities they establish from both clinical trials and pharmacosurveillance.   The solution to the debate of the toxic or non-toxic black box warning is as simple as that.

Most importantly the physicians having the discussion with the patient can document "The FDA recommended risk/benefit discussion for this medication was completed with the patient."

George Dawson, MD, DFAPA    


Friedman RA.  Antidepressants' black box warning 10 years later.  N. Engl J Med 2014;317;18: 1666-1668.

Stone MA.  The FDA warning on antidepressants and suicidality - why the controversy?   N. Engl J Med 2014;317;18: 1666-1668.

Peter Diggle, Patrick Heagerty, Kung-Yee Liang, Scott L. Zeger.  Analysis of Longitudinal Data.  Oxford University Press.  Oxford.  Second Edition 2002.

Non-adherence And Other Reasons To Doubt Clinical Trials

In a word - adherence or what we used to call compliance.  That is whether the drug is taken at all or whether it is being taken according the the prescription.  Adherence is an important aspect of the working alliance with any physician.  The only accurate way to determine a response to a medication depends on whether it is being taken correctly and the person taking the medication is describing a true treatment response and true side effects.   Many patients  do not take the medication as prescribed for various reasons.  The question of adherence takes on an equally important role in clinical trials.  If non-adherence is present it affects the statistical power of the study.  Sample sizes are often calculated to bring the study into a range where the sample is considered to have an adequate number of subjects.  Non-adherence rates can adversely affect that estimation.  There is also the question of whether non-adherence reflects another issue related to the medication like side effects.   The related research question is whether non-adherence is evenly distributed across the groups taking the study drug and the placebo group.  In previous discussions of the placebo response in drug trials of psychiatric drugs I have not seen adherence discussed as a critical factor.

A brief news report in Science this week by Kelly Servick provides a good discussion of the adherence issue from a number of perspectives.  The central graphic is from a paper by Blashke, et al (2) showing summary data of electronic monitoring of medication adherence from 95 clinical trials that shows decreased adherence rates in terms of taking the medication and taking the medication as prescribed.  Both fall off significantly over time.   By 100 days 20% of subjects have stopped taking the medication and about 30% are no longer taking it as prescribed.  Those are substantial numbers especially if the active drug can be identified by a specific effect or side effect and discontinued on that basis.  In a field where there is a significant placebo response among subjects with mild to moderate illness non-adherence can lead to significant problems in the final outcome and overall worth of the study.

According to Servick the typical approach used in the past has been to recruit enough subjects to counter the low adherence rates.  This is problematic for a number of reasons.  Subjects these days are often from nonclinical samples.  On college campuses this can be a problem with some subjects volunteering for multiple studies.  With psychiatric drug trials, the recruitment criteria are subjective, obvious, and selection is often coordinated by non-physician research coordinators whose job it is to get the required number of volunteers  in a specified period of time.   In the drug trials that I am personally aware of only Alzheimer's disease trials asked for corroboration from sources other than the patients on how they were able to function on a daily basis.  It would be very interesting to obtain that kind of data on subjects recruited from University campuses who were still attending classes especially if some incentive was involved.  In a related matter, one of the investigators in this area created a database to identify potential subjects who came in for screening at various sites where he was an investigator.  Up to 7.78% of the subjects across 9 sites were identified as duplicates (3).   Because of the potential negative effect of duplicate subjects the authors suggest that a nation wide database of subject should be considered.

The article looks at a number of measures to determine the level of adherence in a study.  The first take home message is that pill counts are relatively meaningless.  I have certainly talked with research subjects who told me that their blister packs were empty because they just threw the pills away.  In a study that compared pills counts with blood levels of the drug the sample sample had an adherence rate  of 92% by pill count but only 70% by blood levels.  The author cites medication side effects as a reason for non-adherence, but in a complex sample of patients with varying levels of motivation and insight the reasons can be very complex.  Several electronic approaches to adherence have been devised that vary from a chip in the pill bottle cap that records when the bottle is opened and closed (MEMS system) to a chip in a pill that records when it is ingested.

Adherence measures are another dimension to look for when reading the results of clinical trials.   I don't recall seeing any commentary on this important issue in Cochrane reviews and probably with good reason.   Non-adherence rates this high are probably at least as important as what Cochrane typically discusses as technical problems like small sample size and measurement problems.  Blaschke is quoted in the Servick article that many of the researchers in this area feel that the problem is bigger than one that can be detected by surveillance and databases.  To me this comes down to the limitations of clinical trials and a problem that cannot be potentially solved.  Certainly the days of research units where subjects could be supervised in inpatient settings for months is gone.  In most cases, persons with severe psychiatric disorders can only get that kind of treatment if they can personally pay for it or the state they live in has a state psychiatric facility.  Even then they often have to undergo civil commitment.  A practical solution would be to eliminate the obviously non-adherent subjects and not include them in any intent-to-treat analysis and use a standard adherence measure such as blood levels where appropriate.  Ambivalence about taking a drug in a research protocol is not the same thing as stopping an FDA approved drug in a clinical setting, but that conscious state has not been adequately studied.

George Dawson, MD, DFAPA

Supplementary 1:  In researching this article I was very pleased to find the full text of Blaschke, et al online but also a reference to the National Academy of Sciences Committee on National Statistics.  That site contains a report The Prevention and Treatment of Missing Data in Clinical Trials that was references in the  original Science article.  The full article can be obtained at no cost form that site with registration.

1: Servick K. Nonadherence: a bitter pill for drug trials. Science 17 October 2014: Vol. 346 no. 6207 pp. 288-289  DOI: 10.1126/science.346.6207.288

2: Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol. 2012;52:275-301. doi:10.1146/annurev-pharmtox-011711-113247. Epub 2011 Sep 19. Review. PubMed PMID: 21942628

3: Shiovitz TM, Wilcox CS, Gevorgyan L, Shawkat A. CNS sites cooperate to detect duplicate subjects with a clinical trial subject registry. Innov Clin Neurosci. 2013 Feb;10(2):17-21. PubMed PMID: 23556138.

4: Czobor P, Skolnick P. The secrets of a successful clinical trial: compliance, compliance, and compliance. Mol Interv. 2011 Apr;11(2):107-10. doi: 10.1124/mi.11.2.8. PubMed PMID: 21540470; PubMed Central PMCID: PMC3109858.

5:  General search on adherence related articles

A Head Full Of Prior Probabilities

I read an article in Science recently that reminded me of why I am a subscriber.  The article had to do with a model of rational thinking based on the neurobiology of the several critical brain structures, the prefrontal cortex (PFC), dorsal striatum, ventral striatum, and anterior cingulate cortex.  The interesting aspect of this model is that is also takes into account Bayesian analysis and uses that to build a model for how the can make use of these unique neuroanatomical local structures and come up with novel solutions in uncertain environments.

For about 15 years I taught a course that was designed to minimize diagnostic errors when physicians consider the question:  "Is this a medical condition or a psychiatric disorder?"  On of the first cases I would use is a hypothetical case of a teenage girl admitted to a hospital for dehydration secondary to acute gastroenteritis.  In this case the psychiatrist is consulted because the patient began to manifest acute agitation.  This was an acute behavioral change and that was confirmed by family members who had never seen the patient like this before.  The consult to the psychiatrist read: "Please see to assess and treat hysterical behavior."

On the diagnostic side there are several prior probabilities to consider.  In medicine, I like to consider prior probabilities as those of a particular finding or condition that exists is a particular population in the wild.  In this case a few to consider would be:

1.  The prior probability of "hysteria" in teenage girls with no previous behavior problems.  What is hysteria?

2.  The prior probability of acute mental status changes in teenagers with no medical conditions.

3.  The prior probability of teenage girls with no medical problems being in a hospital bed being rehydrated with I.V. fluid therapy.

4.  The prior probability of acute mental status changes in teenagers with no psychiatric or substance use disorders.

Considering 1-> 4, it should be evident that all of the corresponding probabilities are very low.  It would difficult to rank order them on that basis and it suggests the need for more hypothesis generation or data acquisition.   As we examine the patient we realize that cannot produce any meaningful verbal response, she has opisthotonic posturing and decorticate posturing on the left in response to painful stimuli.  The next set of prior probabilities is more declarative:

1.  The posterior probability of a brain problem with opisthotonic posturing and findings 1 - 4.

2.  The posterior probability of an acute brain problem with decorticate posturing and findings 1 - 4.

Suddenly with the examination findings - one specific and the other not - the probabilities of a severe life threatening brain problem have gone through the roof.  The patient appears to be acutely encephalopathic with an impending brain stem herniation syndrome.  This is no longer a patient who should be in a non-acute care bed in the hospital or a patient who needs acute psychiatric care.  She belongs in an intensive care unit, hopefully one that specializes in treating acute, life-threatening neurological disorders so that the problem of increased intracranial pressure can be addressed.  That important decision is made with a two minute examination of the patient at the bedside.  She is transferred to a neurological ICU for more appropriate care.

Without going into too many details about Bayesian inference other than this example, I have never really seen it referred to from a neurobiological perspective.  The new paper by Donoso, et al makes the connection in the introductory paragraphs:

"Human reasoning subserves adaptive behavior and has evolved facing the uncertainty of everyday environments. In such situations, probabilistic inferential processes (i.e., Bayesian inferences) make optimal use of available information for making decisions. Human reasoning involves Bayesian inferences accounting for human responses that often deviate from formal logic (1). Bayesian inferences also operate in the prefrontal cortex (PFC) and guide behavioral choices (2, 3). Everyday environments, however, are changing and open-ended, so that the range of uncertain situations and associated behavioral strategies (i.e., internal maps linking stimuli, actions, and expected outcomes) becomes potentially infinite."


The Wisconsin Card Sorting Test (WCST), a well known neuropsychological measure of frontal lobe mental flexibility.  In the test the subject's task is to sort cards based on shapes, colors, or the number of objects per card.  The sorting paradigm is not made explicit and every time the examiner changes it, the test subject needs to figure it out and start sorting cards according to that new paradigm.  Results can be correct, exploratory, incorrect or perseverative.  Perseverative can be defined as a continuous repetitive sorting error that does not take into account the need for error correction - continuing to use a response that was at one point correct.

At this point there are many imaging studies that look at correlates between functional brain scans and performance on the WCST.  In this study the authors look at a custom variation of the sorting tests where subjects were looking for digit combinations by trial and error and produce a response that was exploratory, perseverative or correct based on feedback about the correctness of choices.  All subject were young (18-26 years old) and screened for medical, neurological, and psychiatric disorders).  There were a total of 40 test subjects equally split by sex.  The article contains a detailed discussion of the subjects response patterns relative to a theoretical model, but I am most interested in the brain imaging results and the implications of those results.

Working in the addiction field, it is fairly common these days to read research studies that look at activation of the ventral striatum.  There are also theories about which neural circuits are responsible for most aspects of addiction including the initial euphorigenic effects,  acute behaviors involving positive reinforcement, and chronic compulsive effects associated with negative reinforcement.  I think that there is an general conceptualization that there are varying levels of euphoria associated with activation of the ventral striatum whether that is from an addictive drug or what has been considered to be "natural" activators of the ventral striatum including food, water, sexual behavior, and social affiliation.  This is the first study that I have seen showing that activation of the ventral striatum is associated with the cognitive aspects of life.  In correspondence with the lead author Etienne Koechlin his group refers to this as the "Eureka Response".  He suggests that the ventral striatum adds and affective valence to a cognitive strategy that has been selected by the frontal cortex as a correct strategy and that  valence contributes to consolidation in long term memory.  He points out that the cognitive system needs the affective role of the ventral striatum to run properly.

If this paper can be replicated this is really landmark work.  It provides a neurobiological explanation for why we can choose among several prior probabilities in important situations.  In terms of clinical decision making it may be why senior clinicians have immediate associations to critical cases when they are involved in subsequent clinical decision making.  That process has been looked at in terms of pattern matching and pattern completion in the past but an affective valence adds another important dimension.

This is potentially one of the most important papers and theories I have seen in recent times.  It has broad implications for psychiatry, addiction, cognitive psychology, and many other fields.  An affective valence from the ventral striatum may make living with a head full of prior probabilities - a lot easier.


George Dawson, MD, DFAPA



Supplementary 1:  The following table lists the common neuroanatomical abbreviations used in this paper:

References:

1: Donoso M, Collins AG, Koechlin E. Human cognition. Foundations of human reasoning in the prefrontal cortex. Science. 2014 Jun 27;344(6191):1481-6. doi: 10.1126/science.1252254. Epub 2014 May 29. PubMed PMID: 24876345.


2:  Albert DA, Munson R, Resnick MD.  Reasoning in Medicine: An Introduction To Clinical Inference.  The Johns Hopkins University Press.  Baltimore. 1988.

"Our aim is to dig deep into the clinical mind and lay bare the processes of reasoning and inference that are (or can be) involved in arriving at and in justifying clinical decisions."

Nice Survey - Wrong Conclusion

There is a survey study of ease of getting and appointment with a psychiatrist in this month's Psychiatric Services.  The researchers called psychiatrists offices in three major cities in order to get an appointment.  They wanted to assess the degree of difficulty and whether or not payer source would be a factor.  Of the total calls only about 25% resulted in an appointment.  The reasons are listed in two tables in the article that is available on line.   Interestingly  there was no big difference  between private pay payer sources and insurance or Medicare in terms of getting appointments.  Given the movement of psychiatrists out of employee systems and Medicare based systems that was surprising and suggests to me a possible sampling flaw in the study or an artifact of the low return rate.  The flaw could be that the researchers looked at a Blue Cross Blue Shield (BCBS) web site and called lists of in-network providers in Boston, Houston, and Chicago.  The authors in this case do a reasonable job analyzing their limited data.  In their discussion of possible solutions they fall short of possible solutions.

In this case a key assumption is that the inability to set up appointments with psychiatrists implies there is limited access and this in turn means a shortage of psychiatrists.  We are hearing this argument at a time when managed care organizations like BCBS are basically saying that patients can receive psychiatric care in a primary care clinic.   In fact, BCBS was one of the early adopters of the PHQ-9 based Diamond project, where PHQ-9 scores formed the basis of a depression diagnosis in primary care clinics and the focus was optimizing antidepressant prescriptions based on those scores.  Where does an appointment to see a psychiatrist fit in that type of care?  Does collaborative care mean collaboration with a psychiatrist for every 500 or 1,000 or 10,000 primary care patients with an elevated PHQ-9 score?  Are patients in systems of mass care likely to seek psychiatric consultation?  In many algorithms of similar integrated care, some systems are set up to avoid psychiatrists completely, including the psychiatrist who is doing the psychopharmacological consultation.   How would such a system of care bias patients against psychiatrists and would psychiatrists be more dependent on other referral sources? And most importantly, wouldn't we expect limited access to a group of psychiatrists designated as in-network providers for a managed care company?  This is after all what managed care companies do.  They provide disincentives for physicians to see patients.  Managed care is a rationing mechanism.  It does not surprise me at all that physicians operating in that environment are difficult to see.

The authors propose that there are a number of ways to get medical students interested in psychiatry and that this would potentially solve the problem.  I don't know how that would work if there are already psychiatrists out there who are either working too hard or not interested in seeing new patients or referrals.  There was also the issue of psychiatrists being listed with incorrect phone numbers in over 10% of the cases.  It would also be interesting to note if the psychiatrist contacted agreed that he or she was actually in the network of care being described.  Many psychiatrists have told me they were in networks or panels that they had never agreed to participate in.

As I have previously stated, I don't think it is a question of recruiting more people in to psychiatry.  That approach ignores the state of crisis that the field is in right now.  That crisis involves the government and managed care companies dictating what psychiatric care is.  It also involves the American Board of Medical Specialties dictating what they think psychiatrists need to do for ongoing professional education.  It involves professional organizations - both the American Psychiatric Association (APA) and the American Medical Association (AMA) abandoning their member practitioners for what appears to be short term political gain.  The first thing lost to the politicians and businessmen  has been the practice environment.  Being a physician is more and more like being an assembly line worker.  Physicians are accountable to managers with no medical knowledge and no professional standards.  All of these developments have clearly demoralized physicians.

Taking a look at one of the suggestions, an interesting one was the suggestion that exposure to psychodynamic therapy increases medical student choice of psychiatry as a speciality field.  There are a few problems with that theory that are consistent with the deterioration of the practice environment.  It is certainly unlikely that any trained psychiatrist would make their expected productivity numbers for employees by doing psychodynamic psychotherapy.  It is currently practiced strictly in private settings or as supplementary activity once the productivity expectations are met in other endeavors.  Some psychiatrists have a psychotherapy practice "on the side" of their main employment.  It is highly unlikely that hospital or clinic environments are psychodynamically informed settings anymore or that residents learn how to manage those problems.  Many of those environments are a set up for split treatment.  Using psychodynamic psychiatry to sell residency to medical students seems like an informed consent issue to me.   Sure we will train you in it and supervise you doing the therapy but good luck practicing it in the real world.  I could put together a program that medical students would flock to, but they would never be able to use what they learned in a dumbed down practice environment.

You cannot have a profession that allows itself to be defined by hack politicians and businessmen with their own for-profit agenda.  Unless organized medicine and psychiatry focuses on that basic element, everything else is rearranging chairs on the deck of the Titanic.  Successfully rationing care does not mean there is a shortage of doctors.  It may mean the doctors just find the cost of doing business with a particular insurance company so high that they would prefer to see fewer or no patients from that payer.

It is absolutely mind blowing to me that nobody else can see that.


George Dawson, MD, DFAPA

Ref:

Monica Malowney, Sarah Keltz, Daniel Fischer, J. Wesley Boyd; Availability of Outpatient Care From Psychiatrists: A Simulated-Patient Study in Three U.S. Cities. Psychiatric Services. 2014 Oct (early online release).

Being Honest Won't Save You - Lessons In Medical vs. Business Accountability

Every now and again I flash back to a surgical rotation that I was doing at an old county hospital.  It was quite run down.  We had a large surgical service comprised mostly of people with gunshot wounds, cancer patients, and people who were in long term care hospitals for mental illness who developed acute surgical problems.  Most of the patients who had gunshot wounds had been shot by the police and they had police officers posted outside of their doors.  On some days it seemed like there were a lot of police officers outside of every other door for quite a distance down the hallway. We did two sets of rounds - in the morning after the surgical procedures and another set of rounds at about 6 or 7 PM.  The evening rounds always ended under fluorescent lights in what is probably a long abandoned nurses station.  In this particular case we are rounding with a senior surgeon and a junior surgeon.  The senior surgeon has just demonstrated how much he knew and how little the residents knew about the effects and importance of gastrointestinal tract hormones.  After a few moments of uneasy dead air, the junior staff asks the intern: "What was Mr. X's calcium level this afternoon?"  The labs were typically run at 4PM and in those days we would have started to see results at about 5 or 5:30, but we were all rounding at that time and attempting to answer questions about GI hormones.  The conversations went something like this:

Staff MD:  "What was Mr. X's calcium level this afternoon?"
Intern:  "I don't know."
Staff MD:  "What?  I expect you to run this service.  How can you run this service if you don't know what Mr. X's calcium level is?"

The team got quite nervous in situations like that.  Training in medicine puts you directly in the line of fire or at least it used to.  These days commentary and affect like I witnessed that day might lead to some type of disciplinary procedure for the staff physician.  Something that could be passed down on credentialing forms and haunt a physician for the rest of his or her career.  A type of pseudoaccountability arranged by the bean counters essentially to manipulate physicians.  In this case, it was considered to be a learning experience and culturally appropriate.

In this case the intern in question seemed to recover.  Things went well for another few days.  And then he was gone.  The rumor was he was asked about another lab value, gave an answer that was slightly incorrect as in no physiological difference between the answers. He was fired for making up the answer.  Keep in mind that this incident occurred at a time when there were hundreds of lab values to track and the technology was at a primitive state relative to what is currently available.  The computers were slow and getting results took a lot longer.  Medical students, interns and residents had to write the labs down on cards using whatever shorthand they could devise.  In the process some data was memorized but not all or most of it.  But the difference here is that the integrity of the answer was called into question.  The assumption was that you either know the answer for sure  or you say you don't know.  There are no near misses.  The judgment is that you made something up and that is unacceptable.  In the years since, I have seen quite a few colleagues fall by the wayside as a result of similar incidents or what were considered to be errors in judgment by the senior faculty.

In recent times, I think there is a tendency to lump this behavior in the category of senior faculty being abusive toward physicians in training.  That certainly may be true, but it is also true that it draws a very clear line about what you need to be doing as a physician as opposed to what you may have done in your undergraduate major.  You can no longer make things up like you used to do in your philosophy and English literature classes.  You have to be brutally honest about what you know and what you don't know.  I don't think there is a physician alive who will not tell you that knowing this is one of the most critical aspects of training as a physician.  The ultimate test of whether you are patient centered is whether you will not try to protect yourself - but whether you can be brutally honest even in a situation that may put you at risk professionally.  Can you acknowledge mistakes, lapses in judgment and most importantly a lack of knowledge or expertise?  Patient safety depends on it.  That atmosphere also has the effect that you show up for work.  If you know that you are a target for any faculty who want to criticize you, you tend to want to know everything there is to know about the patients on your service.  In contrast to the events where the question does not get answered I have seen residents give tutorials on ventilator settings or pressure recordings by Swan-Ganz catheters.  They were motivated to some degree by knowing that teaching staff would be asking and their assessment depended on their answers.  

The reason for that introduction is that it frames the backdrop for a discussion from a financial thread with a very interesting title: Will Ebola Vanquish the MBAs Who Run Our Hospitals?  It is a title by a blogger and certainly eye-catching.  I have followed this blogger for a number of years and agree with a lot of what she has to say about the way financial services are managed in this country.  I have disagreed with her about some of her medical opinions, but this post is something that I can agree with.  I was recently e-mailed about my tendency to selectively find research that supports my opinions.  I consider this to be more opinion to support my opinion.  Research on how businesses manage medicine is as scant as research on management in general.  Business people tend to produce papers suggesting there are deficiencies and then say how they will correct those deficiencies.  There is really hardly any research to support business opinion.  The opinion in this case looks at a topic I frequently comment on - how can business people with no medical or scientific training manage physicians and medical facilities?  In my opinion they clearly can't but let's look at what is presented in this article.

The basis for the article is essentially opinion in the press and the opinion of a medical blogger.  The conflict-of-interest here that is usually glossed over is that any journalist, newspaper, or blogger wants the public reading their stuff.  It will be provocative or sensational.  A measured analysis is not typically seen.  For example the comparison of staff infection rates between the staff at Dallas Presbyterian Hospital (DPH) and Doctors Without Borders (DWB) in Liberia seems pointed, but the obvious question is whether the infections rates vary with experience.  For example did the DWB staff in the earliest stages of their involvement have infection rates as high as were portrayed in the DPH staff.  Can a direct comparison be done without that information?  The highlighted emergency department (ED) problems are similarly problematic.  If you pull up the Internet sites for the DPH system of care they are affiliated with a number of inpatient psychiatric units.  Is the wait time a reflection of a large pool of chronically mentally ill or poorly stabilised psychiatric patients being stuck in the ED?  If that is true it would still be consistent with some of the authors concern about the lack of public health concern and the fact that lower socioeconomic classes come face to face with the wealthy in such settings.  It is also an aspect of the mismanagement by rationing that is pervasive with systems of care managed by large businesses.

I have first hand experience with infection prevention in hospitals and attempt to stop widespread outbreaks from respiratory viruses.  Keep in mind that the Ebola virus is not an airborne virus.  All of the remarks in this paragraph are about airborne viruses especially Influenza virus.    For a number of years I was extremely disatissfied with the epidemics of respiratory viruses that swept through the staff where I was working.  Employer rules about paid time off only worsen the situation because the incentive is to work when you are sick to prevent loss of vacation days.  But the most frustrating part of the problem (apart from being sick 3-5 times a year) was that the employer had no real interest in doing anything that might reduce the risk of infections.  The intervention I suggested was just improving air flow in certain buildings.  The standard reply that you get is "wash your hands and cough into your sleeve."  Those are certainly common sense measures but as far as I could tell had no impact on the rate or severity of infections each year.  Hospital administrators everywhere seem to be in denial of the fact that airborne pathogens exist and washing your hands and coughing into your sleeve will not protect you against airborne pathogens.  I was also a member of two different Avian Influenza task forces.  At the time there was much uncertainty about a widespread epidemic that could not be contained.  We were setting up for the worst case scenario of thousands of people (both infected and not infected) coming into EDs and how to triage and treat people.  After years on these task forces it became apparent to me that nobody was really interested in planning for the prevention of mass casualties from an airborne virus.  There was no planning for any additional negative pressure airborne isolation rooms and no planning for any additional bed capacity in the event of a widespread epidemic.  There was planning for what to do with the expected bodies.  In the end it seemed that all of our hopes were pinned on a rapidly disseminated vaccine or antiviral medication.  The specifics of the antiviral medication were murky.  We were shown a picture of a large pallet of oseltamivir sitting in a warehouse somewhere.  From a business administrator's standpoint, planning to use imaginary resources from the government is always preferable to more functional planning because it is free.  My personal experience in this area from volunteer work on respiratory viruses is entirely consistent with the notion that health care businesses are not administered in a way that is consistent with public health needs in the case of infectious epidemics.

The Naked Capitalism article contains analysis from Roy Poses, MD of the Health Care Renewal Blog.  He looks at inconsistencies in the media and concludes that this is another case of health care leaders being untrustworthy.  That appears to be a central theme of his blog and he goes on to criticize them for being inconsistent, suppressing information from employees that may be critical to public health, and having an inflated sense of self importance.  These patterns are easily observed by physician employees of health care organizations.  For at least a decade after passage of The Health Insurance Portability and Accountability Act of 1996 (HIPAA) it was impossible to get necessary information from health care organizations, even in the case of needing to provide emergency care.  I would routinely request information and even send a HIPAA compliant release signed by the patient and I would get a blank form the other hospital saying that my patient had to sign their form and fax it back.  Hospital administrators were a big part of that process.  It is common for the clinical staff to be buffeted by the next big idea from their administrator.  That can range everywhere from high school style pep rallies that are supposed to improve employee morale to a new productivity system that is guaranteed to get even more work from physicians.  In every case, the administrator in charge could be making 2-5 times what the average physician makes for considerable less accountability, practically no "evidence based" methodologies, and no measurable productivity.  As pointed out in the article, public relations is much more of a factor in the CEO's reputation.  From the article:

" On Health Care Renewal we have been connecting the dots among severe problems with cost, quality and access on one hand, and huge problems with concentration and abuse of power, enabled by leadership of health care organizations that is ill-informed, incompetent, unsympathetic or hostile to health care professionals’ values, self-interested, conflicted, dishonest, or even corrupt and governance that fails to foster transparency, accountability, ethics and honesty." 

There are additional lessons from the decimation of mental health care in the United States, especially care delivered at tertiary care and community hospitals.  There is perhaps no better example of low to no value service that is the direct result of non-medical management.  There is no coordinated public health effort either improve the care of psychiatric disorders or specific high risk behaviors like suicide or homicide.  The standard approach is rationing of both care that would result in stabilization but also bed capacity that would alleviate congestion in emergency departments.  There should be no debate on cost, inpatient psychiatric care is without a doubt the low cost leader and is set to match reimbursement from a high turnover low quality model.  Psychiatric services in clinics and hospitals have a lot in common with what Dr. Poses observes on the administrative side of many health care organizations.

Responding to the question of  "Will Ebola Vanquish the MBAs Who Run Our Hospitals?" - my answer would be no.  It is always amazing to consider how so many people in business with so little talent can end up running things and making all of the money essentially through public relations, advertising and lobbying politicians.  There is no shortage of self proclaimed administrator-visionaries.  The author here should know that their power is consolidated around the same strategies that have worked for the financial services industry.  Managed care business strategies based on no science or input from physicians are now in the statutes of many states and in federal law.  They have successfully institutionalized business strategies designed to return profits to corporations as the rules that govern healthcare.  The pro-health care business lobby essentially gets what they want and the professional organizations are weak and ineffective, but continue to browbeat their members for contributions.  Administrators have a lock on running health care and demanding whatever accountability they demand from health care professionals while having no similar standards for themselves.

I can't think of a worse scenario for addressing potential public health problems whether that is an infectious epidemic or the continued mental health debacle.



George Dawson, MD, DFAPA

Supplementary 1:  Kaiser Family Foundation brief PowerPoint and Infographic on the current Ebola out break.

Supplementary 2:  I decided to add the above table comparing the accountability of physicians with business administrators.  Certainly there may be some things I have missed on the business administrator accountability so if I missed anything please let me know and I will include it.  From what I have observed, health organization and hospital CEOs are typically accountable to a Board of Directors that has very little physician or medical representation.  Often the Board is stacked with people who rubber stamp what the CEO wants to do.  Like the web site referred to in the above post there is often an aura that the CEO and the Board have visionary-like qualities that are based on public relations and advertising rather than any academic work or actual results.  I have never really seen an administrator who was a visionary or knew much about medicine - but  you can certainly read their proclamations about how medicine should be reformed on a daily basis in many places on the Internet.  The usual argument for all of the physician accountability is that it is a privilege to practice medicine and therefore regulation of physicians needs to reduce the privacy rights of physicians and subject them to much closer regulation than other professionals.  Why wouldn't that approach apply to the people who actually determine whether a patient gets health care, medications or a specific benefit?  Why wouldn't that same logic apply to the people who really run the health care system?
  

University of Wisconsin 2nd Annual Update - Day 2

The second day of the conference was actually a half day that was as interesting as day 1.  The first speaker was Kenneth E. Towbin on Chronic Irritability and Pediatric Bipolar Disorder.  Dr. Towbin pointed out that all of the research discussed by him at the meeting was funded by the NIMH Intramural Research Program or the American taxpayers.  He briefly mentioned the advantages and disadvantages of working under those conditions including no usual conflicts of interest and working in an ivory tower with possible ascertainment bias.  The main focus of his discussion was to make a few points about the concept of bipolar disorder and how the overdiagnosis of this disorder came about.  The first point was that bipolar disorder is an episodic illness.  The word I like to use is phasic.  The second point sounds obvious to psychiatrists and that is that in order to make a diagnosis of bipolar disorder the patient has to have had an episode of mania or hypomania.

I am going to digress here a bit on my own before continuing the review of Dr. Towbin's work.  Much of what I do these days is correcting incorrect diagnoses of bipolar disorder.  When I try to reconstruct what happened patients will invariably tell me that they were given an "assessment" and told that they tested positive for bipolar disorder.  The assessment typically consists of a brief interview and then a battery of checklists and psychological tests.  Many are surprised when I tell them that the diagnosis really doesn't depend on any of those things.  It depends on whether or not they have had an episode of mania or hypomania and then I define those syndromes for them.  We try to reconstruct their history of mood disorders and whether or not they have ever had such an episode.   I also emphasize that these episodes have to occur when they are not using excessive amounts of alcohol or other intoxicants.  I ask them about the time before they developed a substance use problem and during their longest periods of sobriety.  In this day of overdiagnosis of Attention Deficit-Hyperactivity Disorder (ADHD) it is not uncommon to hear that a person who has developed a substance use problem using all of their Adderall in the first week or two.   When that is gone  they switch to alcohol for the second half of the month.  That combination can result in what appears to be a manic episode during the first week or two of the month followed by a 2-3 week depression.  That sequence of stimulant intoxication followed by stimulant withdrawal/alcohol intoxication followed by sustained alcohol intoxication is not bipolar disorder.

Dr. Towbin went on to give his very interesting take on how some mistakes can be made from reading diagnostic criteria.  He focused initially on how there could be ambiguity in the DSM-IV-TR.  For example under the "A-Criteria" - how is the requirement of a one week episode of elevated mood determined?  Does it have to be every day or every hour?  Could it last for a short a period of time as an hour?  Under the "B-Criteria" - could some symptoms antedate mood symptoms and what does "present to a significant degree" mean?  I was familiar with Angst's work on following patients with various durations of mania and what the outcomes could be and had since incorporated a shorter period of time into my evaluations of mania.  The DSM-5 criteria sought to clear up these areas by stating that the mood symptoms had to be present most of the day and nearly every day and the symptoms had to represent a noticeable change from usual behavior.   After these discussions of the nature and importance of manic episodes he went on to look at some epidemiological data on the increasing rates of bipolar disorder in children (1, 2).  In the study by Moreno, et al the authors demonstrated a significant increase in office visits by adults and children.  Between the years of 1994 and 2002 the rates of visits increased 60% for adults and 4,000% for children, but the rates from that graphic increased from 0.01-0.4% in children and 0.3 to 0.5% in adults.  Between 1996 and 2004, the number of inpatient discharges with a principle diagnosis of bipolar disorder increased 296.4% in adolescents and 438.6% in children.

Towbin's explanation for the increase in bipolar disorder diagnoses in children was that a cultural change was advanced by two research groups.  That cultural change was operationalized by saying that episodes of illness were not required and the diagnosis could be applied to children with chronic illness.   That led to the idea that bipolar disorder in children is not the same as bipolar disorder in adults and that chronic irritability was synonymous with bipolar disorder.  Or as he put it another way: "If you were really angry you must have bipolar disorder."  The importance of bipolar disorder as an episodic illness was also emphasized in the area of "double counting symptoms."  As an example, could the psychomotor agitation and flight of ideas of bipolar disorder be the same thing as severe hyperactivity or distractibility of ADHD?  Only if bipolar disorder was not an episodic illness.

Dr. Towbin proceeded to discuss how the concept of Severe Mood Dysregualtion (SMD) was developed at the NIMH as an additional clinical phenotype that could be compared to bipolar disorder.  SMD was defined as chronic irritability, ADHD-like symptoms and significant impairment.  At about the same time he went on the one of my favorite topics - irritability.  I like it because it is used as a descriptor in many DSM diagnoses but never well defined.  Many people are surprised that it is listed as a symptoms in Generalized Anxiety Disorder (and in the criteria for 6 other DSM diagnoses and in the text for an additional 3 DSM disorders.)  He defined a two component model for irritability including a background of a grumpy, annoyed and irritable mood and a phasic component of briefer flashes of anger or explosive episodes.  That allowed for a clearer definition of SMD and the subsequents development of Disruptive Mood Dysregulation Disorder DMDD) diagnostic criteria.  He reviewed the evidence from longitudinal studies, family history studies and pathophysiology that SMD/DMDD is not the same as bipolar disorder.  Followed for a long enough period of time this population tends to develop depressions rather than bipolar disorder and have families with histories of bipolar disorder.  From a recent study by Sparks that he referenced: "Parental bipolar disorder increase the risk for multiple categories of childhood psychopathology and DMDD is no more on the bipolar spectrum than anxiety disorders, MDD, or ADHD." He went on to discuss treatment approaches to this population emphasizing the significant degree of disability the is usually not discussed in non-technical publications about this problem.

The final speaker of the day was Zachary N. Stowe, MD.  His presentation was: Treatment of Mood Disorders in Pregnancy and Lactation: Where Are We Now?  He made two observations at the outset that probably captured the imagination of at least some of the crowd.  The first was that any psychiatrist who specialized in the neuropsychiatric disorders of pregnancy would be unchallenged in any community they decided to practice. The second was that every psychiatrist treating women should treat all women of child-bearing age as though were pregnant and therefore needed clear conversations about whether they are using contraception and what the permutations might be with respect to prescribed psychiatric medications.  The method of birth control should be documented.  In terms of safe use of medications in pregnancy he made the point that is is all based on post marketing surveillance and there is no safety data for using 2 medications at a time.

He reviewed the frequent scenario that clinicians face when a patient who is being treated becomes pregnant.  He used an excellent graphic showing how pharmacokinetics and the timing of human development combine to virtually assure that the fetus will probably be exposed at some critical stage of organogenesis and how that factors into the decision to continue, discontinue, or change pharmacotherapy.  He showed survival curve data from both treated and untreated major depression and bipolar disorder on the proportion of women remaining euthymic at and several weeks following delivery.  As expected the rates of recurrence of the mood disorders was high and significantly higher for bipolar disorder.

When discussing the risks of medication he mentioned the current FDA Pregnancy Categories and the fact that there will be a new system that looks at more of the clinical aspects of making these decisions.   The old system will remain in place for existing ratings meaning that for the forseeable future there will be two FDA systems looking at medication safety in pregnancy.  He looked at a number of maternal and neonatal outcome variables for pregnancies associated with maternal depression and maternal antidepressant use.  There was a significant overlap and he suggested that a psychiatric illness diathesis and all that encompasses in terms of cormorbid medical illnesses and activation of the maternal and fetal HPA axis was a possible explanation.  In other words there  would be non-optimal outcomes whether the depression is treated or not.  He went on to discuss detailed basic science research in this area as well as fairly detailed treatment recommendations.  From a clinical standpoint, he pointed out that psychiatrists are more likely to discontinue antidepressants in pregnant women than OB-GYN physicians and attributed that to the American College of Obstetricians and Gynecologists treatment guidelines for depression in pregnancy.

Dr. Stowe's presentation covered all modalities of treatment including electroconvulsive therapy, medications, psychotherapy and exercise.  He was a participant in a workshop I attended on treating depression with exercise.  I think the single most important fact that he discussed in terms of medication was the need to avoid valproate and consider it to be the last drug used in women of child bearing age because of its effects on the fetus and subsequent development of the child.  I recommend that any psychiatrist who has the opportunity to see Dr. Stowe and who treats women of childbearing age take advantage of that opportunity.

That ends my brief review of the UW conference this year in Madison.  I felt fortunate to have been actively involved in all of the clinical work that these clinicians and researchers discussed over a day and a half.  I thought of all of the patients I had seen who could have benefitted from seeing this basic and clinical science applied.  As I listened to the translational aspects of Dr. Stowe's work, I tried to think of all the women I had treated who developed a severe post-partum affective psychosis at some point in their lives and never recovered from that.  I appreciated the quality of a conference that puts all of that information out there and tries to bring everyone up to the same speed as the top researcher-clinicians out there.

If you think this approach might interest you - mark your calendar for next October 23 and 24 and I hope to see you there.  In the two years that I have attended, Art Walaszek, MD and Ned Kalin, MD have an excellent method of picking presenters who can cover both the clinical and basic science of important disorders and treatment modalities that psychiatrists need to be aware of.  That information is presented well and there is ample time for discussion.

George Dawson, MD, DFAPA

1: Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007 Sep;64(9):1032-9. PubMed PMID: 17768268.

2: Blader JC, Carlson GA. Increased rates of bipolar disorder diagnoses among U.S. child, adolescent, and adult inpatients, 1996-2004. Biol Psychiatry. 2007 Jul 15;62(2):107-14. Epub 2007 Feb 16. PubMed PMID: 17306773.

University of Wisconsin 2nd Annual Update

I was in Madison Wisconsin for the Second Annual University of Wisconsin Clinical Update.  I reviewed the first conference last year.  For anyone unfamiliar with the conference it started last year as a replacement for the long running conference run by John Greist, MD and James “Jeff” Jefferson, MD.  They were acknowledged again this year for their contributions to psychiatric education.   This is a very good conference because it builds on that tradition.  The actual venue is the Monona Terrace Convention Center on the shore of Lake Monona.  It is an excellent modern facility with only one drawback - they charge for high speed wireless access.  I talked with many psychiatrists there who had attended the previous conferences for a long time.  They bring in speakers who are some of the top experts in their fields for in depth presentations and there is also a strong department at Wisconsin headed by Ned Kalin, MD.  The conference wraps up in in a day and a half and that seems like a very good length for working psychiatrists.  Combine that with very accessible speakers and an excellent course syllabus and it has what I consider to be the elements of a good educational experience.  The other bonus is that I have never really seen an unbalanced presentation at this conference.  The overarching message is that there are a number of interventions, that treatment is successful, and that there is a scientific basis for what psychiatrists do.

I thought I would make a few comments on day 1 and then move on to day 2.

The first lecture was given by Maria A. Oquendo, MD on the Neurobiology, Assessment, and Treatment of Suicidal Behavior.  Aleman and Denys have called for the investigation of suicide as a special problem apart from any particular diagnosis.  She began with a review of the epidemiology of suicide, including the fact that 90-95% of suicides have an psychiatric disorder.  She also discussed the converse of that statement - the vast majority of patients with psychiatric disorders never attempt suicide.  That statement is usually not discussed.  It is a parallel argument to violence and aggression in psychiatric disorders.  It has implications for any care based on dangerousness (threat of aggression or suicide).  She presented an interesting stress diathesis model of suicidal behavior that takes into account clinical features (impulsivity, cognitive inflexibility,  substance use,  family history, poor social support) and neurobiological features (low serotonin, decreased noradrenergic (NA) neurotransmission, inflammatory markers).  Her model links norepinephrine neurotransmission with pessimism.   She cited evidence that included a slide of CRH innervation of NA neurons and behavioral models that lead to NA depletion in animals.   She reviewed some of the evidence of inflammatory signaling related to childhood adversity, the mechanism of interferon-alpha induced depression and markers of inflammation in suicide attempters versus controls (increased interleukin- 6 (IL-6), tumor necrosis factor - alpha (TNF-alpha), elevated microglial cells, increased IL-4 in women, and increased IL-13 in men.  The tentative conclusion is that suicide occurs in the context of a stress response or at least it appears to have the same neurobiology of a stress response.   She concluded with a discussion of public health approaches to preventing suicide.  She had no specific recommendations for how psychiatry fits into that response apart from presenting data that increased antidepressant prescriptions led to decreased suicide rates in Sweden, Hungary, Japan, and Slovenia.   She also discussed specific psychotherapeutic interventions for suicide by name and presented a study of cognitive behavioral therapy that led to a 50% reduction in suicide attempts.   Dr. Oquendo also provided an excellent contrast in how the results of observational studies, meta-analyses, and double blind placebo controlled studies can differ and what biases may be in effect.  In the case of lithium preventing suicidal behavior, most clinicians are aware of the fact that only lithium and clozapine are consider medications that prevent suicide.  In the case of lithium, it turns out that data is from observational studies and meta-analyses but not double blind placebo controlled trials.  The two double blind studies do not suggest that lithium is more effective in preventing suicides than other agents.  She suggested one bias may be a tendency of clinicians to use lithium in people who can use it more safely and that led to fewer suicide attempts.          

I found the presentation on suicide and suicide assessment very interesting.  It is such a broad topic that a single lecture has to pick a focus.  The presentations on suicide that I have seen tend to focus on trying to figure out which people attempt suicide and interventions in those populations.    People with psychosis and suicidal ideation – a common clinical scenario for psychiatrists are generally left out.  It would definitely complicate the presentation at a couple of levels.  There is the issue of what happens to the usual risk factor analysis, especially in the case of subtle forms of psychosis.  Factors that are typically seen as reliable (deterrents to suicide, prevention plans) can be thrown out in that situation since the patient has had a marked change in their conscious state.  That is true whether or not the patient is clinically interviewed or given a structured interview like the CCRS.   In the case of psychotic individuals paranoia is also a risk factor for suicidal behavior.  The paranoia is focused on a particular situation where the individual believes that he or she will be tortured or killed by someone.  They develop a plan to kill themselves rapidly using a highly lethal method before that can happen.   A common scenario is to have a knife or handgun on the nightstand just in case it becomes necessary.  In both of these treatment situations, the preferred course of treatment is to address both the depression and psychosis at the same time.   Past studies of these populations also suggest very high levels of hypothlamic-pituitary-adrenal (HPA) axis activation, consistent with Dr. Quendo's model.

Roger McIntyre, MD followed with Practical Considerations in the Successful Treatment of Bipolar Depression.  There seems to be fairly widespread confusion about the diagnosis of bipolar disorder.  I think it is common for consulting and subspecialty psychiatrists to reverse the diagnosis of bipolar disorder more often than they make new diagnosis.  Dr. McIntyre made that point but said that misdiagnosis is still a problem even in an era of overdiagnosis.   He took the assessment up a notch to discuss the utility and limitations of the diagnostic issues of bipolar qualifiers in DSM-5 ( mixed features, anxious distress) and what they imply for diagnosis and treatment.  He also emphasized the need for time to do an assessment.  He appreciates the fact that primary care physicians may have as little as 6 minutes to make a mood disorder diagnosis but said that even in his specialty clinic he may not know the diagnosis of 25% of the patient after doing a lengthy assessment.  He made this point to illustrate that in many patients a single cross sectional view of symptoms in a clinic appointment is insufficient to make the correct diagnosis.

He presented an excellent graphic showing the DSM-5 continuum from manic to manic with mixed features to depressed with mixed features to depressed.  He also spent a fair amount of time discussing the treatment of comorbid anxiety as a significant morbidity in bipolar disorder.  He presented interesting data on how comorbid medical and psychiatric conditions in bipolar disorder were the rule rather than the exceptions.   His main focus was on metabolic syndrome, obesity, and migraine headaches.  He presented very good graphics on mechanisms associated with these comorbidities.  He made the point that the metabolic abnormalities (much like studies done in patient with schizophrenia who had never been treated with medications) were associated with a number of social, metabolic, and environmental factors.  He suggested that the obesity/major depression and obesity/bipolar disorder phenotypes carried specific risks including poor cognitive performance, anxiety symptoms, and in the case of depression a possible higher suicide risk.   He cited estimates of metabolic syndrome ranging form 20-66% in populations with bipolar disorder compared to a general population estimate of 23.7% from the NHANES III study.  He presented interesting data on the correlation between cognitive impairment in obese and overweight bipolar patients that can be demonstrated in first episode manic patients (obese versus non-obese).  At the molecular level it has been demonstrated that there is a gradient of inflammatory markers between obese and non obese bipolar patients.   He has a published paper that looks at the relationship between treatment response in depression and body weight.  Although he did not speculate on an exact mechanism he suggested there were altered brain systems involved in cognition in many of these patients.

The section of Dr. MacIntyre's lecture included an interesting graphic that had all FDA and EMA (European Medicines Agency) approved medications for bipolar-manic, bipolar depressed, and maintenance therapy.  Both agencies have approved quetiapine for bipolar and only the FDA has approved lurasidone and olanzapine-fluoxetine combination (OFC).  The number of medications not approved in all columns is about the same (4 for EMA and 3 for FDA).  He presented number needed to treat (NNT) and number needed to harm (NNH) analyses for OFC, quetiapine, and lurasidone and in that analysis lurasidone looked like the superior medication but that analysis is for specific side effects.  The NNT was nearly identical for all medications.  In terms of overall treatment he was in general agreement with the Florida Medicaid Drug Therapy management Algorithm.   One of the very interesting points he made during his presentation was that treating and preventing recurrent manic  episodes may reduce risk for Alzheimer's dementia but that is potentially confounded by the effect of lithium on GSK-3-induced tau phosphorylation.         

Lithium Pearls (From several lectures)

1.  The claim that lithium is one of two medications that can prevent suicide is based on observational studies and meta-analyses.  There have been two double blind studies looking at this issue and they have both been negative.

2.  Experts continue to use lithium and consider it to be one of the major treatments for bipolar disorder.  Lithium may provide more benefit to manic prone patients with long periods of stability and a positive family history.

3.  Once a day dosing was recommended.

4.  Lithium can be used in pregnancy given several specific precautions and informed consent issues; including precautions are the time of delivery to prevent elevated lithium levels in the newborn.

5.  Lithium may decrease the risk of Alzheimer’s Disease and minimal cognitive impairment.

   
After afternoon breakout sessions on various topics, the final presentation was by Ned Kalin, MD on the Neurobiology of Depression.  As a point of disclosure I know Dr. Kalin and was his first fellow at the University of Wisconsin back in 1984 and I completed my residency there.  He is a model of the clinical researcher who has seen patients his entire career and also been involved in basic science research.  There were several other department members at Wisconsin engaged in the same balance of clinical and scientific activities.   I learned that he was also President Elect of the Society of Biological Psychiatry.  The UW has always been active in primate research and Dr. Kalin discussed some important ethical and scientific issues about basic science research in non-human primates including the reason for primate research and the changes in standards and research settings over the years.  He has broadened his research over the years to include how depression and anxiety start in childhood and adolescence.   He posted an interesting graphic on deaths worldwide due to violence that suggested suicide was the top cause, followed by homicide and then warfare.  It was based on World Health Organization (WHO) data.  He showed experimental data on conscious regulation of the amygdala.  These interesting studies show that activity in the amygdala can be modulated by cognitive activity that either enhances of decreases the response to the feared stimulus.  The ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC) are critical associated areas with activity correlating inversely with activity in the amygdala (high vmPFC and OFC activity correlate with low activity in the amygdala).   Preliminary data suggests that depressed patients fail to suppress activity in the amygdala with vmPFC and OFC activity.  A similar change occurs in the ventral striatum when depressed individuals attempt to enhance their positive affect over the course of an imaging session.  Controls show a significant increase in left nucleus accumbens activity (LNAcc).

Dr. Kalin reviewed the genetics and environmental factors in depression using a graphic that cited 3 of Kendler's papers.  He reviewed the progression of hypotheses ranging from monoamine depletion to altered serotonin neurotransmission to serotonin alteration hypothesis to  stress diathesis to neurotoxins to inflammatory/cytokine theories.  One of the possibilities he discussed was a theory that at least some developmentally based depressions are based on frontal cortical-amygdala substrates that result in increased activity in the amygdala and associated neuroplasticity mechanisms that also lead to increased vulnerability.   Cognitive therapy for depression may strengthen the ability of the frontal cortex to regulate the amygdala.  One of his areas of intensive investigation has bee the HPA axis and its effect in depression.  He reviewed the important roles of CRF both as an endocrine modulator and a neurotransmitter.   He used a Vonnegut quote from Breakfast of Champions as a quick review of HPA axis physiology.  For anyone who had read the book (and forgotten some physiology) it was an interesting reference.   In the last quarter of the lecture he reviewed the issue of stress in separated infants, maternal stress, and adults in human and non-human primates.  The focus was primarily on neuroanatomy, neuropathology, neuroendocrinology and possible treatments that target these systems.  Earlier in his discussion he also posted a graphic on translational neuroscience and how neuroscience findings need to be able to correlate at the clinical level.  A detailed discussion of that approach is available in this article that is available online at no cost.              

The first day in Madison went as well as expected.  Lectures with very high quality content by researcher-clinicians who actually see patients and investigate clinically relevant topics.  Psychiatry taught, researched, thought about, and practiced the way it should be.


George Dawson, MD, DFAPA



1: Oquendo MA, Galfalvy HC, Currier D, Grunebaum MF, Sher L, Sullivan GM, Burke AK, Harkavy-Friedman J, Sublette ME, Parsey RV, Mann JJ. Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 2011 Oct;168(10):1050-6. doi: 10.1176/appi.ajp.2011.11010163. Epub 2011 Jul 18. Erratum in: Am J Psychiatry. 2012 Feb;169(2):223. PubMed PMID: 21768611

2: Lauterbach E, Felber W, Müller-Oerlinghausen B, Ahrens B, Bronisch T, Meyer T, Kilb B, Lewitzka U, Hawellek B, Quante A, Richter K, Broocks A, Hohagen F. Adjunctive lithium treatment in the prevention of suicidal behaviour in depressive disorders: a randomised, placebo-controlled, 1-year trial. Acta Psychiatr Scand. 2008 Dec;118(6):469-79. doi: 10.1111/j.1600-0447.2008.01266.x.

3: Fox AS, Kalin NH. A Translational Neuroscience Approach to Understanding the Development of Social Anxiety Disorder and Its Pathophysiology. Am J Psychiatry. 2014 Aug 26. doi: 10.1176/appi.ajp.2014.14040449. [Epub ahead of print] PubMed PMID: 25157566.

4: McIntyre RS, Rosenbluth M, Ramasubbu R, Bond DJ, Taylor VH, Beaulieu S, Schaffer A; Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force. Managing medical and psychiatric comorbidity in individuals with major depressive disorder and bipolar disorder. Ann Clin Psychiatry. 2012 May;24(2):163-9. Review. PubMed PMID: 22563572.


Supplementary 1: I thought it was very interesting that we are still talking about lithium as a very effective medication for psychiatric disorders int he same city that hosted the Lithium Information Center cofounded by Greist and Jefferson and the same location where the Lithium Encyclopedia for Clinical Practice was published.