The Balanced Rhetoric Against Neuroscience

The New York Times editorial pages continue to be a place where anti-neuroscience rhetoric can be expressed primarily as decreased funding or more accurately portion of the available NIMH funding.  Maybe there has been some pro-neuroscience opinion expressed there and if there was I have missed it.  I recently posted an exciting development in neuroscience teaching for psychiatrists and psychiatric residents.  In that post I reference an opinion piece by Richard Friedman, MD a psychiatrist (1).  Dr. Friedman makes several arguments for psychotherapy as if it is unrelated to neuroscience and based on that premise concludes that there is no substitute for psychotherapy, that people are more than a brain in a jar, and that anyone benefiting from psychotherapy seems to prove  that.  I found that to be an incredible statement considering that (according to Koch in above graphic):  "The brain is the single most complex object in the universe." There is also the fact that with 7.4 billion people on earth - there are 7.4 billion unique conscious states - the vast majority of which are not accurately described by any DSM or psychodynamic diagnosis/formulation.  All the time that Dr. Friedman is mounting this critique he also discusses the importance of clinical research and suggests shifting the funding balance away from neuroscience.

In the recent case John C. Markowitz a professor of clinical psychiatry at Columbia has a more subtle form of the argument.  In this case and the previous opinion piece the authors both endorse the importance of neuroscience to a point.  In this case the argument is - yes neuroscience is important but let's reestablish balance between neuroscience and clinical studies such as looking at the efficacy of psychotherapies.  Breaking it down, Dr. Markowitz makes the following points:

 1.  Under the directorship of Thomas Insel, the NIMH clinical research budget was "strangled" and the resources were diverted to neuroscience research.  The author acknowledges both the need for neuroscience research and the primitive stage of psychiatric diagnostics based on clusters of signs and symptoms.  This was really the basis for Insel's RDoC initiative looking at more reliable markers of psychiatric syndromes.  Any practicing psychiatrist who has seen all of the iterations of the DSM realizes that we are as far as we can go with this manual.  That includes from the standpoint of validity but also in terms of the clinical examination by psychiatrists.  As long as we are all contained by this manual, the clinical method of psychiatry will remain stuck somewhere in the 1940s.  That should be extremely disconcerting to the profession and future psychiatrists.

DSM technology is extremely limiting in terms of the usual clinical trials.  The NIMH sponsored Star*D study is a decade and a half old at this point.  It has defined the response rates for both antidepressant therapies and provided a discussion point for psychotherapy trials of depression.  Clinical trials of antidepressants provide an equally varied result.  Any practicing clinician knows that these studies are all seriously flawed out of the gate by using DSM diagnoses and also an intent-to-treat analysis that does not resemble clinical practice.  The variation in diagnoses from depression to anxiety to depression plus anxiety as seen in clinical practice should point to the fact, that patient selection into clinical trials currently results in very heterogenous patient populations in terms of both therapeutic effects and medication tolerability.  We can continue to spend large sums of money on these trials of mixtures of patient populations and post modest positive results or we can attempt to identify patients who will respond specifically and not experience side effects from a particular therapy.  That is the real promise of neuroscience based research.

2.  The patients who need help are poorly served by current neuroscience research.  The helpful psychotherapies listed by the author like interpersonal psychotherapy (IPT), cognitive behavioral therapy (CBT), and other psychotherapies have been around for decades.  I happen to have copies of Interpersonal Psychotherapy by Klerman, Weissman, Rounsaville, and Chevron and Cognitive Therapy of Depression by Beck, Rush, Shaw, and Emery.  The publication date of the former is 1984 and the latter is 1979.  Both therapies have been out there for over 30 years.  At this point both have been studied hundreds of times.   Looking at clinical trials on Medline yields 1711 for CBT and 261 for IPT.  Not only that but some of the clinical trials that were successful (like IPT for cocaine use) have never made  it into clinical practice.  In fact, in most places getting a therapist who actually practices any of the specific research proven psychotherapies is impossible.  The problem does not seem to be a lack of psychotherapy research but a lack of access to practitioners who use research proven psychotherapies.  Mental health treatment is the most highly rationed treatment resource and additional studies that continue to prove that existing psychotherapies work seems superfluous at this point.  Any current studies are often compared to existing therapies and with the DSM problem contributing to diagnostic heterogeneity.  Any new trials should only be funded for serious conditions where the therapy might be useful.  There is no reason to expect that a new therapy applied using the current diagnostic system or clinical trials technology will lead to any enhanced treatment effects.

3.  Existing treatments are not "good enough".  The author attributes this "good enough" statement to Insel himself.  I understand the point he is trying to make.  The author points to continued suffering, treatment failures and suicides as evidence that more is needed now.  The problem is that there is no assurance that clinical research will add any more at this time.  Certainly a focus on suicide as a stand alone problem (not suggested at all by DSM) and on serious disorders with no treatment like adult anorexia nervosa is warranted.  But even then we are left with a clinical trials technology that consistently produces modest results at best.  More multimillion dollar trials of psychotherapy that we already know is somewhat effective when patients have no chance of ever receiving it against a backdrop of "is this really depression or anxiety" seems like a waste of time and money to me.  It seems like a much better idea to develop a neuroscience method to determine who needs psychotherapy and who might benefit from medications.  But even then, the only treatments that will be readily available will be the medications and even then less than half of the affected patients will get access to treatment.  Good luck trying to find a psychotherapist and an insurance company willing to cover the cost of the number of sessions used in the psychotherapy research. Research proven therapies are only as good as the number of practitioners using them and access to those practitioners.

4.  The placing all of your eggs in one basket argument.  This is basically saying that if the ratio of clinical to neuroscience funding is 10% to 90% the risk is missing something big in the clinical research and not getting any useful results from neuroscience.  Given the history that I have provided, there needs to be a clear advance on the clinical side in order to fund large trials.  It does not make any sense to continue to  fund more of the same  or slight modifications of treatment for common disorders.  Our eggs have been all in one basket and I would call that treatment as usual.  In the 30 years that I have been in practice, there is nothing that I would call a major breakthrough.  Clinical research results come and go.  Effective psychiatrists are effective psychiatrists not based on breakthroughs but how they approach clinical practice.  Even that mode of treatment is threatened by widespread support for "collaborative care" that is being justified using the same kind of research that justified managed care in the first place.  In the end there has been nothing more destructive in terms of access to care for mental disorders than managed care.

In many ways these ongoing arguments resemble the arguments of the biological psychiatrists and psychotherapy psychiatrists that I trained under in the 1980s.  Many programs were split under this artificial division with the residents left to identify with biological or psychotherapy faculty.  It is interesting to note that this division occurred at a time when Kandel wrote a paper on how psychotherapy is neuroscience in action (3).  That may have been missed because the biologically based psychiatrists at the time were really focused on pharmacology and neuroendocrinology rather than a comprehensive neuroscience.  Neuroscience and the old diagnostic technology and clinical methods seem to be the current points of division.

A lot of the criticism is directed at Insel.  I have heard him talk about the initiatives and the rationale sounded clear to me.  I think that rationale is very similar to what I have discussed so far, but for clinical psychiatrists it is also the realization that as long as we live in an approximate world - we will get approximate results.  The inertia to stay in that place is always puzzling to me.

But - it is time to move out of the 1950s.

Clinical psychiatry the way it is currently researched and practiced holds no promise for understanding the most complex known object in the universe.  Neuroscience is one of the big ways out of that predicament.



George Dawson, MD, DFAPA      



References:

1:  Friedman RA. Psychiatry's Identity Crisis. New York Times July 17, 2015. p SR5.

2:  Markowitz JC.  There’s Such a Thing as Too Much Neuroscience.  New York Times October 14, 2016. p A21.

3:  Kandel ER. Psychotherapy and the single synapse. The impact of psychiatric thought on neurobiologic research. N Engl J Med. 1979 Nov 8;301(19):1028-37. PubMed PMID: 40128.

              

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.

DSM5 - NEJM Commentaries

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

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

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

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

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

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

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

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

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

George Dawson, MD DFAPA

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

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

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

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

17;366(20):1855-7.

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