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.

Live by the Customer Satisfaction Ratings and Die By Them

My original intent was to look at the problem of what happens to a group of physicians who are sailing along with very high patient satisfaction ratings.  Then for no particular reason, their ratings drop by about 20-25%.  At the high point they did not question the validity of the ratings.  They just assumed the satisfaction ratings reflected their high quality work.  The problem is that nothing they did changed and suddenly their ratings were significantly lower and people were looking for explanations.  Hence the title of this post.  If these ratings really mean something in the first place the physicians are suddenly thrown into a lot of self doubt.  If they believe the ratings are unscientific, designed by people who don't know much about survey design or sampling, and are actually biased because of the way the staff presents the surveys - they are much less worried.

I posted to above bar graph as an introduction to this post.  It is a composite of the opinions that several primary care physicians have given me about the correlation between benzodiazepine and opiate prescriptions and customer satisfaction ratings.  More prescriptions for controlled substances equals greater customer satisfaction.    Some clinics have adapted to this by letting patients know that they do not prescribe benzodiazepines or deal with psychiatric disorders.  That eliminates physician-to-physician variability in prescribing.  It also demonstrates that certain overprescribed medications are viewed as more serious than others.  I have not for example seen any similar clinic rules for antibiotics even though they are also widely over prescribed.

I hope it is not a news flash to anyone that highly satisfied customers in the health care system have the highest mortality and probability of hospitalization (1).  I know that at least some of the customers out there may be very surprised to hear that doctors can't be rated like a Toyota dealership.  Toyota dealers after all have a product that is high in quality, uniform, and the same irrespective of those pesky human factors that we all have to deal with in human encounters.    I am referring of course to things like communication,  interpersonal skills, thinking capacity, personality traits and personality disorders.  A Toyota dealer is out to satisfy all customer needs in the very circumscribed area of personal transportation.  Even then there will be bumps in the road.  A customer may not like the way the vehicle has turned out or some of the results from the service department.  But generally Toyota dealers have a great product and most of their customers are highly satisfied.

This may be hard to believe but the MBAs that currently run medicine in the USA decided to introduce management principles into the field that were designed for the auto industry.   The details and names of those management principles is irrelevant at this time, but when they were introduced it was a big deal.  I had to listen to several hours of lectures on Six Sigma.  Feel free to read about it and let me know how it possibly applies to the practice of medicine.  After those lectures it was obvious to me that the MBAs running medicine were completely clueless about medical care.  One small piece of evidence in what is now a mountain of evidence that the business emphasis in managing hospitals and doctors is completely off the rails.   Most business concepts are introduced to groups of physicians as a manipulation.  They have to be because no rational person would buy what appears to be Dilbert style management.  It goes something like this:

"Look - we know that physicians don't like the idea that they can measured.   We know you don't like that idea, but let's face it, this is a new era.  Things aren't like they used to be.  The day of the physician running things is over.  You are all going to have to be accountable now.  Some day your reimbursement is going to be tied to these satisfaction ratings."

Administrators like to seethe a little bit when they play the authoritarian act with physicians.  They think it gives them more credibility.  They could also be playing off the collective seething in the room.  The logical questions followed:

"Well what about clinicians seeing patients with cognitive impairment or who are being treated on an involuntary basis.  What can you say about the validity of those satisfaction ratings?"

That led to some laughter, but no explanations.  Everybody would be rated and that was the end of it.  There would be no exceptions.  The irrational authoritarian business model rules.

Before anyone gets too bent out of shape about my view of the business model let me illustrate with an second example of what I mean.  Earlier this evening I consulted with a colleague from another state on an inpatient problem.  When that was over I asked her how things were going in general and she told me:  "It's really kind of tough.  The patients are never really stable, they have multiple psychiatric, substance use, and medical diagnoses and they are very hard to stabilize."  She was thinking about moving on.  She was in a meeting and an administrator said:  "This patient has been here (x number of days) what is the plan?"   She said:  "What do you mean what is the plan?  The plan is what the plan always is - stabilize the patient and discharge them."  Managed care administrators have the uncanny ability to blame the physician for any discrepancy with a pure business approach to medicine.  They apparently believe that hospital treatment and discharges are as predictable as Toyotas rolling off an assembly line.  That is as true for customer satisfaction ratings as length of stay outliers.  It give the administrators leverage against physicians, especially any physician who buys in to the idea that these are valid metrics.

Let me illustrate by considering two different physicians Doc A and Doc B.  Both are very competent psychiatrists, but for some reason Doc A consistently scores lower on customer satisfaction ratings than Doc B.   From the research in this area, it may simply mean that Doc B gives his patients more of what they want than Doc A.  My speculation is that personality is a big factor.  A simple mismatch between extroverts and introverts can fuel a lot of dissatisfaction.  The extroverts on both ends (doctor and patient) like to be engaged and they like the conversation to have no dead air.  A doctor that is too reserved may be perceived as being disinterested or not giving them enough in the interaction.  Some patients want special treatment and others just want confirmation of their perceptions of other doctors and in:  "I was not really impressed with your colleague.  What do you think of him?"  Psychiatrists generally know better, especially psychiatrists who recognize that their organization is set up to facilitate splitting and chaos.  There may be a difference between the doctors in terms of prescribing patterns in terms of my previous analysis of the overprescribing problem.  In this case Doc A may be known for no sleep medications, no benzodiazepine prescriptions, no opiate maintenance prescriptions and no high dose amphetamines for narcolepsy and no stimulant prescriptions for adult ADHD when the patient is functioning well in school or work.  Denying those groups of prescriptions will not only result in low physician satisfaction scores but threats of violence and suicide.  That is not to say that other tests or medication would not result in and extremely dissatisfied patient.  There are thousands of scenarios where the patient does not take the physicians advice in the manner with which it is intended and that is - the best possible advice to diagnosis or treat a problem at a given point in time.

I did not write this post to "prove" that being satisfied with your physician is necessarily a good thing or a bad thing.  If I wanted to approach problems like that I could probably get my own TV show.  The whole point here is that any potential patient-customer needs to know what these things mean.  You may not want to keep hearing the word but politics is the major reason.  People trying to sell their business based idea about medicine versus physicians who have no similar notions.  People trying to sell their idea that medicine is just like making widgets rather than treating people who have tremendous biological variability.  You don't want your Toyota to have tremendous mechanical variability, but for human beings biological variability is both a fact of life and a distinct advantage from an evolutionary standpoint.

And finally what about news from your physician that you don't want to hear.  Certainly there is widespread fear of a dreaded incurable diagnosis.  There is the concern of diagnoses associated with disability and loss of function.  But there is also straightforward advice on how to avoid fatal illnesses and disability.  The way that is presented varies considerably from physician to physician.  You have to ask yourself: "Would I rather hear that I am overweight and need to lose weight or that I should stop smoking or that I should stop using hydrocodone or alprazolam or would I rather be talking with a physician who would keep quiet on those issues?"

I don't think there is a good study of the issue and if somebody knows one please let me know so that I can post it here.  I can provide another anecdote.  I worked with a group of women once many of who consulted a female internist who was bright, attractive and wore very high fashion clothing (their characterization not mine).  Things were generally going along pretty well until this internist told some of them that they were overweight and needed to lose weight.  That elicited a very strong reaction and it seemed amplified by their perception of this physician as being "perfect".  When I thought about my experience with physicians - nobody has ever told me to lose weight even in situations where they should have.  I suggested it to a physician once and he said: "I concur with your recommendation doctor" but never told me that outright.  Social and cultural factors all play a part in the patients perception of the physician and their satisfaction ratings.

It is a good idea to keep all of those factors in mind in attempting to interpret physician satisfaction ratings especially since most consumer web sites focus entirely on these measures.


George Dawson, MD, DFAPA

1:  Fenton JJ, Jerant AF, Bertakis KD, Franks P. The Cost of Satisfaction: A National Study of Patient Satisfaction, Health Care Utilization, Expenditures, and Mortality. Arch Intern Med. 2012;172(5):405-411. doi:10.1001/archinternmed.2011.1662

From the reference:

"Patient requests have also been shown to have a powerful influence on physician prescribing behavior, and our findings suggest that patient satisfaction may be particularly strongly linked with prescription drug expenditures." (p. 408)

"While we do not believe that patient satisfaction should be disregarded, our data suggest that we do not fully understand what drives patient satisfaction as now measured or how these factors affect health care use and outcomes. Therapeutic responsibilities often require physicians to address topics that may challenge or disturb patients, including substance abuse, psychiatric comorbidity, nonadherence, and the risks of requested but discretionary tests or treatments. Relaxing patient satisfaction incentives may encourage physicians to prioritize the benefits of truthful therapeutic discourse, despite the risks of dissatisfying some patients." (p. 409)

Supplementary 1:  If you are a primary care physician I am very interested in your thoughts about how patient satisfaction scores correlate with prescriptions for benzodiazepines, opioids, and stimulant medications as qualitatively depicted in the above bar graph. 

Life Is Not A Randomized Double Blind Controlled Clinical Trial

Or  what is wrong with placebo controlled clinical trials and transparency?

I was in an imaginary meeting with a bunch of Internists and Psychiatrists.  We were debating the available and meager literature on the use of trazodone for sleep.  We got into one of my favorite topics - the double blind placebo controlled trial and that catch all "Evidence based medicine."  The dialogue went something like this:

Internist:  "The evidence from double blind placebo controlled trials is weak for trazodone....."

Me:  "Do I need a double blind placebo controlled trial to tell me to prescribe trazodone for sleep?"

Internist: "Are you saying you don't need evidence.  Oh wait, I was at a conference where the head of the society stood up and and gave evidence that clinical trials have their limitations.  Like they are subsequently proven to not be true...."

Me:  "That is not what I am talking about.  I am talking about all of the hype out there that only 40% of people recover from antidepressants or that they are no better than placebo........"

Internist: "But you do have the algorithmic approaches that show...."

Me:  "Yada, yada, yada - for every algorithm, there is somebody with a meta-analysis to show it is wrong.  No I am talking about the ridiculous notion that psychiatrists could stay in business or want to stay in business if only 40% of the people they treat got better.  If that was true I would have become a recluse 20 years ago and just walked away."

General laughter

Internist: "I would kill for a 40% response rate for some of the problems that I treat."

And so on........

This informal conversation among colleagues is illustrative of the recent arguments that focus on physicians and generally psychiatrists more than other physicians that treatments are ineffective.  They are based on an oversimplified view of placebo controlled clinical trials and conflict of interest.  Many times there are no clear points of demarcation between what is a scientific issue (the technical aspects of the clinical trial) and the ethical issue (conflict of interest issues that may compromise the scientific results).   You can read all about current technical problems with clinical trials, like the common observation that there is a lack of generalizability to clinical populations compared with the highly selected and trial sample that in the case of psychiatry generally has much milder forms of the illness being studied.  Here are a few of the concerns that I don't see being discussed anywhere, especially when it comes to clinical trials of psychiatric interventions:

1.  The crude state of clinical trials:  Clinical trials in psychiatry are tremendously unsophisticated. The trial result generally depends on rating scale or clinician global rating scale results that grossly oversimplify the condition and measure parameters that are irrelevant in clinical settings.  The best example I can think of is depression rating scales that list DSM criteria for depression and then apply a Likert dimension to those symptoms.  In clinical practice it is common to see hundreds of patients with the same score on this scale who have a full spectrum of disability from absolutely none to totally disabled.  Which population might be more likely to exhibit an antidepressant effect?  It is also common to see medically ill patients with insomnia who may score as mildly to moderately depressed who are physically ill and not depressed at all.   The same problems exist with clinical trials of schizophrenia, anxiety and Alzheimer's disease.   When this weak technology is combined with a selection process that eliminates clinical populations with the most severe illness, it should not be surprising that any treatment being studied has a weak effect.

2.  A weak clinical trials data base:  One of the clarion calls of so-called evidence based medicine is the Cochrane Collaboration.  I have looked up hundreds of their reviews and the majority of those reviews of both medical and psychiatric studies is: "insufficient results and methodologically unsound".  I suppose it is good to have somebody make that statement, but if you have proclaimed that you are an evidence based physician - you have nothing to go on.  In fact, at some point you stop going to Cochrane because the results are fairly predictable.   Even in the case where you have a result does it apply to the patient you are seeing?  I don't see many Cochrane studies depressed patients that have right bundle branch block, ventricular premature contractions, or complex atrial fibrillation - all common patients seen in clinical practice.  How many more research papers do I have to read that conclude that "more research is needed" while continued inadequate trials are being published and analyzed by Cochrane?  From the current trends and political correctness of evidence based medicine this will go on forever.  The practical aspects are the very large costs of trials.  That is the real reason that pharmaceutical companies (Big Pharma) sponsor these trials.  The political system in the US has decided to farm out clinical trials to private for-profit companies in the exact manner that the US government has farmed out management of the entire health care system.  In these systems Big Pharma absorbs a disproportionate amount of criticism relative to managed care companies.  Managed care has equated "medically necessary" care with care that can be provided in the form of a pill.

3.  The politicalization of clinical trials:  No clinical trials of psychiatric medications can be done these days without an eye to the politically relevant dimensions.  A new antidepressant needs to get as many FDA approved indications as possible in order to beat the political restrictions of utilization review by managed care companies.   That would include indications not only for depression, anxiety, panic, and social anxiety but also chronic pain and possibly attention deficit-hyperactivity disorder (ADHD).  The best way to beat utilization review is to have the only FDA approved indication in the class.  That is also applied to atypical antipsychotics and that fact seems to escape the critics who focus on the number of prescriptions and what that implies.  Physicians are pawns in a game when there are no suitable tolerated medications for bipolar disorder depression and there are atypical antipsychotics for that indication.  These current political factors in clinical trials preclude a focus on cognition, functional capacity, and endophenotypes - all potentially much more valuable than a focus on diagnostic criteria or rating scales based on those criteria.

4.  A characterization that the average physician is ignorant - at best:  Any political movement is associated with ugly rhetoric.   There has clearly been an effort to stampede any physicians with reservations about evidence based medicine into a Neanderthal category.  The irony is that the criticism often comes from sources like managed care companies, medical certification authorities and the press (bloggers) - all entities with their own high levels of conflict of interest.  Common rhetoric used against psychiatrists has been: "You just don't want to be measured".  If the criticism originates from a government, managed care company or administrative authority there is often the attached explicit threat: "Those  days are over!".  The obvious implicit observation is that medicine and psychiatry is now being run by people who don't know anything at all about medicine and there is plenty of evidence on this blog to back that up.

Many critics seem to get a lot of mileage out of the position that they seem to be particularly anointed to criticize the field.   That seems especially true if they happen to be a physician as in: "My colleagues certainly seem to be a bunch of chumps and therfore can be rejected on a wholesale basis or of course listen to me for enlightenment".  I have never witnessed that level of incompetence in any group of physicians where I have practiced across multiple settings.

5.  The use of statistics for rhetorical purposes:  At this stage after reading research for that past 35 years, I am convinced that you can come up with a meta-analysis that will show whatever you want it to show.  Several years ago in the New England Journal of Medicine there was a study that looked at how well meta-analyses predict the results of available large scale clinical trials.  That study showed 2/3 times.  It is common to see a result and then see a meta-analysis that "disproves" the clinical trials result.  Nobody seems very interested in looking in detail at how sound that meta-analysis was.

Today we have a large number of questionably valuable clinical indicators or quality care markers that are often based on the political rhetoric of the government and managed care organizations.   They may be invalid on the face of it, but there is a second equally important aspect.   These same organizations have no valid approach to looking at the statistics of longitudinal data.  They will look at clinic results or even results from the same physician and convert them all to a numerator and a denominator.  Whether that fraction means anything or not is anybody's guess, but there is an administrator somewhere who will be happy to tell you all about it.

6.  False assumptions about the expertise of physicians:  Much of the rhetoric above is focused on physicians.   Psychiatrists as the most politically disenfranchised group are a frequent target.  In the past years we have endured the ideas that medical treatments being prescribed are ineffective and overprescribed.  That brings us full circle to the opening imaginary conversation.  Physicians are trained to focus on several goals including acute treatment, treatment of chronic problems, and providing care for the dying.  The psychiatrists and physicians that I have had the pleasure of working with have been highly effective is achieving those goals.  When I look at the modest results of poorly designed clinical trials all I can do is shake my head.  I would have quit a long time ago if my diagnostic or treatment capabilities were accurately described in clinical trials and most physicians would have.  Informed clinical treatment is a series of often rapid changes in course, rejecting poorly tolerated treatments and looking for things that work better along the way.  I can change the course of treatment depicted in a clinical trial in one day.  In the trial that result is carried to the end as a failure.  How is it that a clinical trial or this evidence would predict my treatment results by mean?  If a treatment is ineffective or not tolerated in my practice, I don't stop treatment and call that person an unsuccessful intent-to-treat subject.  I work with them to establish effective treatment - often in the same time frame as a clinical trial.  Is it quite literally absurd to suggest that clinical trials accurately describe what will happen in clinical practice and yet that is the state of discourse.

7.  The false promise of transparency:  Anyone who followed politics knows that disclosing potential conflicts of interest  is meaningless in the case of politicians.  The general idea is that politicians would refrain from either accepting money from sources where they are involved politically or just not be involved in that area of legislation.  In reality that does not happen.  Sometimes the politicians involved will speak out against any suggestion that there is a connection between the money they receive and their legislative record even when their activities are consistent with a financial conflict of interest.  The sunlight of transparency that many of the critics talk about simply legitimizes ongoing involvement in areas of potential conflict of interest.   Disclosure is a stamp of approval for involvement.  All of that can be researched on Congressional watchdog sites.   The new CMS web site that posts payments to doctors is hyped as a way to appease all of the critics who seem clueless about transparency.  For an eye opener take a look at their decision point on conflict of interest.  CMS seems much more charitable than the typical blogger, politician or journalist with this disclaimer:

"Sharing information about financial relationships alone is not enough to decide whether they’re beneficial or improper.  Just because there are financial ties doesn’t mean that anyone is doing anything wrong.  Transparency will shed light on the nature and extent of these financial relationships and will hopefully discourage the development of inappropriate relationships.  Given the complexity of disclosure and the importance of discouraging inappropriate relationships without harming beneficial ones, CMS has worked closely with stakeholders to better understand the current scope of the interactions between physicians, teaching hospitals, and industry manufacturers."

8.  A lack of appreciation of the regulatory environment:  In the rush to condemn Big Pharma and anyone associated with them, critics often have an idealized version of regulation in their minds.  If only they had access to all of the clinical trials data to analyze for themselves.  They would personally be able to hold Big Pharma's feet to the fire and only allow drugs to be approved that they deemed to be safe and effective.   They are smarter and more ethical than anyone doing the actual trials and certainly smarter than the regulators.  This is at the minimum a failure to recognize that pharmaceutical regulation is after all a political process.  Like all politically directed regulation there are broad goals of safety and efficacy but they are relative and the regulatory mandate takes that into account.  On this blog I have pointed out several cases of medications that not only I,  but the Scientific Committee employed by the FDA recommended against based on safety considerations, but that were approved by the FDA.   Many drugs that I approved as a member of a Pharmacy and Therapeutics Committee (P&T) were expensive but had minimal efficacy.  We approved it based on political considerations (small but vocal advocacy group and untreatable illness) rather than pure efficacy or safety considerations.  The regulatory environment is currently designed to get promising agents into the hands of clinicians for clinical use.  The limited exposure of patients in clinical trials means that rare but serious side effects will not be recognized until post marketing surveillance occurs.  Every person taking an FDA approved medication should realize that.  The regulatory process is not designed to provide perfect medications because there are none.

There is a lot more to say about this subject like a detailed analysis of how the politicalized version about how physicians work and think has nothing to do with the way physicians actually work and think.  But for today I am stopping here.

Life is not a randomized double blind controlled clinical trial and that is generally a good thing.

George Dawson, MD, DFAPA

Neanderthals - Real Human Differences and Stereotypes

That's right - I am 2.1% Neanderthal.  There have been some fascinating developments in human paleogenetics in the past decade including the characterization of genomes other hominins including the Neanderthals and the Denisovans from old remains.  It casts a different light on some of the stories based on stereotypes from the past.  For example, the common view of Neanderthals were that they were strong, but not very intelligent or sophisticated beings.  As as result Homo sapiens could easily outcompete these brutes and as a result modern day man is the only surviving species.  It was quite a surprise to learn that after the Neanderthal genome had been characterized portions of it could be identified in the modern human genome and that ancient DNA may have a role in the HLA (human leukocyte antigen) genes that play a central role in immunity.  There is the related question about whether incorporating the DNA of a new species could lead to certain autoimmune problems.   That fact compounded my interest in this area that was originally piqued by the first NatGeo Genographics project.  That project gave confirmation and graphics to the fact that at some point or another about 60-70,000 years ago, our ancestors walked out of the Rift Valley in East Africa and began their migrations around the globe.  Some of those folks migrating north through Europe encountered Neanderthals and Denisovans along the way.  Contrary to the conventional story that humans "outcompeted" them, they mated and produced offspring.

A quick review on relevant taxonomy.  From zoology, the naming convention is Genus and species.  Modern humans are Homo sapiens.  Considering this convention there were about 16 different species of the genus Homo and apart from Homo sapiens all of the others are extinct.   That includes Neanderthals (Homo neanderthalensis) and Denisovans.  In historical terms, at one time or another there was more than one Homo genus walking the earth.  Looking at a graphic from the Smithsonian suggests that Homo sapiens, Homo floresiensis,  Neanderthals (Homo neanderthalensis), and Denisovans were all walking the Earth sometime in the time zone about 20-30,000 years ago.  Genetic technology has revolutionized this area of morphology based research.  There is a lot of speculation but no good conclusions about why Homo sapiens is the only surviving species.

I don't know if they still teach this in Medical School but in all of my major rotations I was taught to describe the patient in the first sentence by age, sex, and ethnicity based on outward appearance.  There were various rationales provided for that opening sentence but even in medical school (now a long time ago) they did not make a lot of sense to me.  Of course there were cultural and political influences on these descriptions.   The "38 year old black male..." became the "38 year old African-American male..." at some point and back again depending on the politically correct term of the time.  It was all very unscientific, but many physicians seemed to think that it was a more medically precise way to talk about the patient and condense relevant information about that patient.  I did not have to consider anything beyond "male-female" versus "man-woman" to decide that my notes would never start with these words.  The only facts that I capture in my opening lines is the actual age of the patient and whether they are a man or a woman.  Male and female are non-specific terms and don't reflect the fact that I am talking about a human being.  You could say that this is an old convention, but I still see it as present in most medical records that I review.  In fact, it has stretched so that in some cases the characterization of white people has progressed from White to Caucasian to European, even though the person in question and their family has not set foot in Europe in over three or four generations.  I guess I also missed the politically correct convention that white folks were now "European Americans" and yet I have seen that frequently in medical records.

I read a paper in Science about 20 years ago that there were no genetically significant differences based on race or skin color.  It what seemed like a surprisingly simple statement, the authors pointed out that all humans are much more genetically related to one another than to non-human primates.  Genetic differences based on skin color and facial features were trivial to non-existent.  If you look at it that way that opening line:  "24 year old Hispanic female..." becomes little more than an unscientific stereotype.  Why include it in the medical record?  Some might say that it provides the opportunity for the delivery of culturally appropriate health care.  If that is the case, I would suggest including a more accurate description of the patients culture (as described by them) rather than presuming their culture based on their physical appearance or a check off on a standard intake form.  Scientific rather than stereotyped descriptions of people should be the standard.

A related issue is how much people actually know about themselves and their family of origin.  On the average, most of the people I talk with about their family histories know the high points for about 3 generations.  Physicians are typically focused on heritable diseases but most third and fourth generation Americans in this country don't know much about how their families migrated to the US and where they were migrating before that.  The first humans migrated out of the Rift Valley in East Africa about 70,000 years ago.  That is 2800 generations ago, maybe more if we need to correct for the short longevity of prehistoric man.  The fact that we are all Africans to start with and that so-called racial differences were a byproduct of the migration is a huge fact that nobody talks about.  It has far reaching implications and it is why I like to talk about it.

The other issue is what happened to the Neanderthals?  The story used to be that the Neanderthals were typical cave men.  They were squat muscular, and not very bright.  Their fate was considered to be extinction because they were outclassed and outcompeted by Homo sapiens.  Paleogenetics has led to those assumptions being challenged.  An excellent Nova special called Decoding Neanderthals captures some of the surprise and excitement of some of the first scientists who discovered Neanderthal DNA in the human genome.  That program also looks at how inferences can be made about prehistoric beings based on both the archaeological evidence and the genetic evidence.  In the case of archeology, the complexity of Neanderthal flint tool technology was investigated.  They had a method of making flint tools with a broad sharp edge that could be resharpened.  It was termed Levallois technology and the complexity suggests a higher level of intelligence than is commonly assumed.  The second Neanderthal technology that was discovered was using a type of pitch on some of their implements.  To manufacture this early epoxy required mastery of a thermal process again suggesting advanced intelligence.  The final piece of evidence is the presence of the FOXP2 gene.  This gene is responsible for speech and language in humans.  There are FOXP2 variants, but when the Neanderthal DNA was decoded, it contained a copy of the FOXP2 gene identical to modern humans.  That technology and the fact that Neanderthals were also social beings makes it a little more difficult to explain how they were "outcompeted" by Homo sapiens.  I have not seen any theories about how that competition might have included direct incorporation of large numbers of Neanderthals directly into the Homo sapiens population.  What are the numbers of Neanderthals who could have been incorporated into the population given the current DNA percentages?  I suspect that it could have been large.   

 To use an example from my own ancestors, I constructed a table looking at the stated ethnicities of my grandparents.  My maternal grandparents had been in the US for a generation longer.  My paternal grandmother still spoke and read her native language.  My maternal grandfather knew just small bits of Swedish.  He taught me a prayer in Swedish but did not know the translation and neither do I.  Small customs usually having to do with celebrations and food persisted to a small degree but on the balance my family was Americanized.  Comparing the stated ethnicities of my grandparents to DNA markers results in a couple of matches, but as many question marks.

Will there come a time when genetics will allow for better probability statements about who might inherit what disease?  Given the fact that my haplotypes occur in less than 1% of the current NatGeo database of over 650,000 subject - maybe.  But that depends on a lot more study and a medical record descriptor about presumed ethnicity has very little to do with it.  There is a related issue about how the science of paleogenetics can be politicized like any other branch of science.  Chris Stringer wrote an excellent commentary about this in Nature.  He observed a trend speculating that some genomes were more "modern" than others based on their content of "ancient" DNA.  He summarizes this well in two sentences:

"Some of us have more DNA from archaic populations than others, but the great majority of our genes, morphology and behavior derives from our common African heritage.  And what unites us should take precedence over that which distinguishes us from each other."

The current evidence also seems to suggest that the migration out of Africa is only part of the story.  The identical FOXP2 gene found in both Neanderthals and modern humans, suggests a common ancestor long before the African migration.  There are currently 7 billion people on earth.  The processing power of the human brain means that there are 7 billion unique conscious states.  It should not be too difficult to imagine that isolated groups of humans in in recent times will result in different  appearances, customs and practices.  The all too human characteristic of promoting the interests of these groups even to the point of warfare against others seems to be a common element of human consciousness.

A more widespread appreciation that these distinctions are by convention only might moderate a tendency for groups to see themselves as different or "better" than other groups of modern humans.  That leap of consciousness will hopefully happen in future generations.


George Dawson, MD, DFAPA



Supplementary 1:  One of the most striking aspects of this project is the economics of it all.  Over 680,000 people willing to pay $200 apiece for this information.  Researchers take note.  This may be a new way to fund research and generate large amounts of data at the same time.  You probably need a willing department head,  IT department, and IRB.  There is also a question of collaboration.  Is there any correlate between mental illnesses and the genomes of the Neanderthals and Denisovans?  If I have a well characterized sample of research subjects with a specific problem does it make sense to look at that issue?

Supplementary 2:  There are currently only 19 references to the issues of ancient DNA in Medline at this time.  Seems like another good area for research.

Supplementary 3:   My old high school biology text was ahead of its time in another way.  I remember that it predicted that the human race would eventually appear to be uniform due to increased mobility and intermixing of different races.

Supplementary 4:  The infographic at the top of this post was generated by the National Geographic Genographic Project based on my DNA sample.

Supplementary 5:  The evidence of bias against Neanderthals in popular culture is significant.  My first thought was the Geico commercials based on the premise: " three pre-historic men who must battle prejudice as they attempt to live as normal thirty somethings in modern Atlanta".  Even the Wiki piece refers to them as "Neanderthal-like".  Wikipedia has interesting references on this page and also a separate page entitled "Neanderthals in popular culture."

Supplementary 6:  Updated NatGeo infographic accessed on April 9, 2016.  NatGeo knows how to make a world class infographic.  Note that the sample size has gone from 678,632 to 742,652.  The remaining details are about the same but there is more updated information on the web site.

References:

1:  Stringer C.   Evolution: What makes a modern human.  Nature. 2012  May 2;485(7396):33-5. doi: 10.1038/485033a. PubMed PMID: 22552077.