currently unsolved problem…

Posted on Wednesday 21 January 2015

PsychiatricNews
Paul Summergrad, M.D.
January 2015

It was APA, along with NIMH and academic psychiatry leadership in the latter part of the last century, that helped the field to develop to its current prominence. It is incumbent upon us to focus our attention on these issues so that our academic departments remain strong enough to allow care, new treatments, and education to move forward effectively at a time when our services have never been more essential or the potential for fundamental breakthroughs greater.
It is actually unfair of me to snip out this last paragraph from Dr. Summergrad’s most recent commentary. He’s the first thoughtful President of the APA in memorable history, and this piece appropriately focuses on a real problem. He lays out the forces involved reasonably well – until his last paragraphs where, from my vantage, he could’ve appropriately written…
    It was APA, along with NIMH and academic psychiatry leadership in the latter part of the last century that lead the field to its current dilemma.
… and been more accurate. Certainly, the problems psychiatry faced fifty years ago were daunting and needed to be addressed. The Community Mental Health Movement collided with changes in the collective American attitude towards government involvement in social issues, and it began to wane before it really got started. The psychoanalytic and other psychotherapeutic paradigms had reached a point of exhaustion, yet remained over-represented in the hierarchy of psychiatry. Long psychotherapies were being billed to medical insurance, a practice that had to change. And there were competitive wars with other mental health specialties. All were problems in need of urgent attention. While there was nothing so wrong with the manifest solution [the APA’s DSM-III], the method of change [post without an end…], the over-representation of the neoKraepelinian point of view in the background, and the major unmentioned forces [PHARMA and Managed Care] were  specters that would haunt psychiatry’s rise "to its current prominence" throughout.

Reading Dr. Summergrad’s summary of the problems faced by academic psychiatry today is a déjà vu for me – the quicksand I experienced during the late 1970’s directing an academic psychiatric training program. Put simply, there was no fiscal support in sight. Like the Kalahari Desert on a Discovery Channel special, the verdant plains of a forgotten rainy season had given way to a barren desert with no future promise on the horizon. Whether PHARMA or Managed Care was involved in bringing about psychiatry’s radical changes is immaterial now. But in retrospect, their involvement was an integral part of the story going forward. For PHARMA, it portended a large potential psychopharmacology market that was realized beyond its value. And for Managed Care, that dovetailed into a cost cutting windfall. For practicing psychiatrists, it ultimately became a reimbursable commodity – as medication managers. And there was a lucrative source of grant funds flowing from PHARMA ‘s good fortune into the embattled academic departments. Research in neuro-anything flourished, and the Clinical Research Industry grew like a weed with academic guest-authorship. The other mental health professions prospered – providing psychotherapy services with negotiated medical payment.

But now it’s the dry season again. PHARMA finally exited the picture three years ago, and the impact of its absence on the economy of academic psychiatry is obviously widely felt. The APA’s recent failed DSM-5 enterprise also did little for the current state of the specialty. There has been more than a quarter-century-long alliance among academic psychiatry departments, the APA, the NIMH, and the pharmaceutical industry. The practice of psychiatry has come to be centered on outpatient medication management, and many patients have been "left behind." Add in countless examples of scientific misbehavior and misrepresented authorship in the Clinical Trial literature, particularly with these psychoactive drugs. So while the controversies and some of the players may be similar, this is not the same psychiatry that faced that dry season in the 1970s.

It’s the comments in the penultimate paragraph of this essay that actually caught my attention…
Also, many in the pharmaceutical and biotechnology industries have shifted from clinical neuroscience research to lower-risk areas with more well-developed genetic targets such as oncology. The net result is that clinical research in departments of psychiatry is systemically challenged. The greatest impact of this change in industry funding is, of course, on patients and families. We are deeply in need of new pharmacotherapies and neurotherapeutics based on specific genetic and neuroscience processes. Highly specific treatments, as the physician and noted author Lewis Thomas reminded us, are not only more effective but generally less toxic. These changes in industry funding, when paired with reductions in the true dollar amount of NIH funding, impact the success and potentially the longer-term viability of academic psychiatry departments. All of this is challenging for the field at what should be a time of enormous promise…
  1. "We are deeply in need of new pharmacotherapies and neurotherapeutics based on specific genetic and neuroscience processes".
    It’s in the area of Major Depressive Disorders that the notion of "pharmacotherapies and neurotherapeutics based on specific genetic and neuroscience processes" have been most vigorously pursued. Yet:
    • There is no compelling or replicated evidence that what has been called "Major Depressive Disorders" since the DSM-III Revision is a discrete biological or even clinical condition, much less a disorder with either unitary genetic or neuroscientific roots.
    • There is no compelling or replicated evidence that the current psychoactive drugs are disease or disorder specific.
    • For these reasons, the NIMH has abandoned the DSM-system altogether and is now chasing other rainbows [the RDoC].
    • Studies claiming treatment specificity based on biological markers remain in the range of speculation in spite of intense and expensive efforts otherwise.
    This is the almost ubiquitous future-think – always looking for something just around the corner or down the pike, things that never seem to arrive.
  2. "These changes in industry funding, when paired with reductions in the true dollar amount of NIH funding, impact the success and potentially the longer-term viability of academic psychiatry departments."
    While the extent of the industry support of academic psychiatry departments has been widely known about for some time, here, Dr. Summergrad implies that their very "longer-termed viability" has depended on that industry support. He’s not talking about gravy, or even dessert, he’s talking about meat and potatoes here – basic sustenance. Thinking back, there was no way that the academic department I was a member of in the late 1970s could’ve survived long term once the government and private hospital support began to dry up. There is essentially no university institutional support or service derived income for post-graduate psychiatric education like there is in other medical specialties.
There are certainly lots of things that suggest that there’s more than a spiritual tie to PHARMA among academic psychiatry departments and the APA. It’s been more like Superglue, or maybe a Joint Account.
  • The APA bet their whole ship on the DSM-5 making a definitive transition to a biological paradigm with no solid evidence to back up such a shift in tow. Why? It was as bad a bet in 2002 [A Research Agenda for DSM-V] when they announced their plan as it was in 2011 when they had to call it off [Neuroscience, Clinical Evidence, and the Future of Psychiatric Classification in DSM-5].
  • When the scientific and financial misbehavior of ranking members of the APA or academic psychiatry have been exposed, we haven’t heard a peep out of the APA or, for that matter, the NIMH. Why not?
  • The NIMH under Stephen Hyman and Tom Insel have preferentially funded and supported innumerable large scale psychopharmacology trials.Why?
  • When it became apparent that PHARMA was abandoning CNS drug development, there was a collective wail heard from every rafter, followed by an all out [and ongoing] campaign to woo them back. Why so loud? so passionate?
  • The number of highly placed academics who have been willing to sign on to shaky industry funded clinical trials or industry speaker bureaus is  shocking  surprising. Why so many?
I think that I’ve been naive all along, quantitatively blind. We all know that PHARMA has been throwing money at academic psychiatrists and their departments since early on in this age of psychopharmacology, but I think I saw it as something like supplemental income, Before I read the phrase, "the longer-term viability of academic psychiatry departments," it hadn’t really occurred to me that the PHARMA money was the vital artery supporting the body of psychiatric education. The conflict of interest implications of an academic psychiatry that is dependent on industry funding for survival are obvious to anyone that looks – mind boggling.

I don’t mean to malign Dr. Summergrad in discussing his comments. I appreciate his candor and his commitment to education. He is both a Department Chairman [Tufts] and the President of the American Psychiatric Association, and he’s speaking from experience about a problem that is fundamental and has to be addressed – financing the academic psychiatry programs that teach medical students and residents in psychiatry. It was a front-burner problem in the 1970s when I was a part of it and experienced it first hand. And it’s apparently a big problem now. In the interim, it appears that the income from industry flowing in by various routes has kept the wolf away from the door. Unlike the way things work in most academic settings, in the clinical part of medical education, almost no one gets paid just to teach – no ivory tower. Except for a few administrators, the full-time faculty have clinical jobs [and also teach]. There are also huge volunteer physician faculties who teach for no pay except an academic credential [clinical faculty], a parking sticker, a library card, and maybe free access to the school gym. But there are still plenty of expenses, and the residents have to be paid. Grants may fund research but they don’t fund the necessary infrastructure.

I wish I could say something positive to industry for their generous support of medical education. Unfortunately, such lofty motives don’t come close to describing how all of this went down. It would be more accurate to say that PHARMA bought themselves a tract of academic psychiatry real estate, and parlayed it into an extremely profitable investment by hook or crook. Rather than lament PHARMA moving on, we would do better to celebrate the exodus and lock the door behind them – even though it leaves organized and academic psychiatry with a huge, currently unsolved problem. Perhaps we can find a less destructive solution this time around…
Mickey @ 8:00 AM

the fiction – and another thing…

Posted on Saturday 17 January 2015

Special Reports, Psychopharmacology, Suicide
Psychiatric Times
By Robert D. Gibbons, PhD and J. John Mann, MD
December 31, 2014
[full text on-line with free registration]

There has been much debate about whether certain classes of medications [eg, antidepressants] increase the risk of suicidal behavior and whether that risk is greater in children, adolescents, and young adults. In 2004, the FDA placed a black box warning on all antidepressants because of concerns that the medications increase risk of suicidal thoughts and behavior in youths; in 2006, the warning was extended to include young adults [up to age 26]. The FDA based its black box warning on results of its meta-analyses of randomized controlled trials [RCTs] conducted in pediatric and adult psychiatric and nonpsychiatric populations.

Questions regarding a possible relationship between antidepressants and suicide were first raised in 1990 with the publication of a series of case reports in which the then newly introduced SSRIs were associated with the apparent emergence of suicidal thoughts and behavior. This led to FDA hearings in 1991, but no evidence of an increased risk of suicidal acts associated with antidepressants was found. In October 2004, concerns raised over paroxetine use in children and adolescents eventually led the FDA to issue a black box warning regarding antidepressants and suicide for children younger than 18 years…

This next report is from the testimony at the first FDA Hearing about suicidality with Prozac® held in 1991:
… My husband was given Prozac on January 24 of 1990. On the evening of February 8, 1990, he killed himself. I am told his death was instantaneous, but I believe his cleat actually began the moment he took his first dose of Prozac. Before Prozac, my husband was very involved with people, our family, and his work. He was very much in charge of his business. But within days after he started taking Prozac I noticed a personality change in him. He showed sign of restlessness, akathisia, agitation, pacing, and his appearance was very drawn. He developed severe insomnia, extreme fatigue, chills, racing heart, dry mouth, and upset stomach. His hands would shake uncontrollably at times. This really alarmed him. I would ask him what was wrong and his only reply was, "I don’t know, I don’t know."
In the article by Gibbons and Mann above, they talk about "suicidality" as if it’s an isolated phenomenon and address the question of whether it occurs with an increased incidence in depressed people on antidepressants. That’s common in articles that address this issue, but it doesn’t fit with my understanding of the question on the table, either clinically or with the Black Box Warning. What I think this is all about are cases like this one – a patient that develops what this man’s wife is describing [which I know by the term – Akathisia]. It’s another example of a confusion of tongues – people talking at each other without clarifying shared meanings.

My own experience as a low prescriber was that when Prozac® first came out, I had a couple of patients who took it for a day or two, then stopped saying, "That stuff made me crazy" and "I was coming out of my skin." I was told by colleagues that it was activating, but I stopped prescribing it anyway. Over the years, I had occasional new patients who described the same agita talking about being given an SSRI by someone else before I saw them. The Black Box Warning came after I retired, and I was oblivious. Not long after I started volunteering, I gave Celexa® to an adolescent, who had an extreme Akathesia reaction with suicidal thoughts. That’s how I learned about it. Since then, I’ve seen two suicides in other peoples’ cases that I’m sure were SSRI induced, and multiple others with the Akathisia syndrome who immediately stopped the medication and it cleared quickly [I warn all patients]. In both suicide cases, the people around them mentioned personality change as part of the picture.

Here are a couple of concise descriptive references to the SSRI · Akathisia · Suicidality connection:
When I read something like this Gibbons/Mann piece, my first thought is that they must not see many patients. They talk about suicidality with SSRIs like the question is, "Does the medication ‘turn up’ the usual suicidal thoughts of depression?" Maybe that’s a question some people think about, but I’m not one of them. What I’m talking about is a distinct syndrome with inner restlessness, agitation, aggressive thoughts and actions, disinhibition, and sometimes lethal violence. It’s distinct from the depressive syndromes being treated – something else. Far and away, the commonest outcome is for the medication to be discontinued abruptly by the patient and it clears quickly. My guess is that these are some of the early drop-outs in clinical trials [see Healy above]. And I doubt they make it into population studies often, if at all.

I don’t like being this blunt, but when I read these Gibbons/Mann papers, I don’t think they know what they’re talking about [literally]. In my mind, the Black Box Warning is about an infrequent, idiosyncratic syndrome that can be associated with aggression, suicidality, suicide itself, and even homicide; one that likely has a physiologic basis affecting the extrapyramidal nervous system. I can find no mention of the syndrome in any of their papers [cataloged in the fiction…]. It’s certainly not something you would go lookiing for in some health plan database…
Mickey @ 10:45 AM

the fiction…

Posted on Friday 16 January 2015

University of Chicago Statistician Robert Gibbons was a voting consultant on the 2004 FDA Pediatric Advisory Committee that elected to add the Black Box Warning to the labeling of the Antidepressants:
    Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children and adolescents in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Prozac or any other antidepressant in a child or adolescent must balance this risk with the clinical need…
Since that time, he and Dr. John Mann, a Professor of Psychiatry at Columbia, have challenged that Warning with a steady stream of articles occasionally joined by other groups. Here’s the summary from their most recent offering:
Special Reports, Psychopharmacology, Suicide
Psychiatric Times
By Robert D. Gibbons, PhD and J. John Mann, MD
December 31, 2014
[full text on-line with free registration]

Summary
The data show that in adults, antidepressants appear to protect against suicidal events. SSRIs are associated with lower overall suicide rates compared with other classes of antidepressants [eg, TCAs]. Antidepressants are effective in reducing symptoms, which, in turn, mediates suicidal events in adults and the elderly. This does not appear to be the case for youths, for whom antidepressant medications can reduce the severity of depression but appear to have no effect one way or the other on suicidal thoughts and behavior. Conversely to what is seen in adults, it may be that aggressive-impulsive traits play a more important role in youth suicide than does depressed mood. The impact of antidepressants on these traits remains unclear. Youth suicide may also be potentially related to illicit drug use and social factors, such as bullying, that are not directly affected by antidepressants.

The black box warning and the earlier public health advisory have shown that discouraging the medication treatment of depression in children is not an effective solution in preventing suicidal behavior. Careful monitoring and treatment of depression and monitoring suicide risk in children is clearly essential. Overall, the clinical evidence is that the majority of patients, young and old, benefit from antidepressants, without increased risk of suicide.

Ten years after the introduction of the black box warning, it is time that the FDA reevaluates this decision and that the results be made public. Moreover, the labeling language should be rewritten to clearly delineate the risks of treatment compared with the risks of no treatment.

Dr Gibbons is Professor of Biostatistics in the departments of medicine, public health sciences, and psychiatry, and Director of the Center for Health Statistics at the University of Chicago. Dr Mann is the Paul Janssen Professor of Translational Neuroscience in the department of psychiatry at Columbia University, and Director, Molecular Imaging and Neuropathology Division, the New York State Psychiatric Institute, New York. The authors report no conflicts of interest concerning the subject matter of this article.
You would think that as much time as they’ve spent on this quest, they’d at least understand the domain of the FDA’s power. After approval of a new drug based on proof of efficacy and safety, the FDA is charged with monitoring safety ongoing, even pulling drugs from the market that prove to be toxic. The obvious reason is to alert physicians to the risks using the drugs as new information becomes available. Drugs are only approved for specific conditions, and manufacturers are constrained from advertising for anything except the FDA approved uses. On the other hand, the FDA has absolutely no authority over how physicians actually prescribe the drugs. So first, there’s the simple matter of what Drs. Gibbons and Mann are asking the FDA to do, "the labeling language should be rewritten to clearly delineate the risks of treatment compared with the risks of no treatment." That’s not remotely an authority the FDA has or should ever have. The FDA doesn’t give opinions about risk/benefit ratios or treatment. That’s for the medical profession to determine with clinical use. The FDA simply certifies minimal efficacy based on a few short term clinical trials, and reports on the adverse events from the trials and later spontaneous reports. It’s actually an absurd request, well outside either the charge or expertise of the FDA. Surely the authors know that. So one has to wonder why they would even propose such a thing?

Then there’s a fundamental misunderstanding of the practice of medicine that runs throughout their ten year thread of challenges. The information about clinical decisions comes from many places: the doctor’s own experience, the experiences of others over time, clinical trials and other studies, the wisdom of the ages, the specifics of the patient being treated, etc. But at the end of the decision making process, it’s only the patient in front of the doctor that’s being treated – not some nameless group defined simply by age and diagnosis. Just that one patient. Gibbons et al argue that because antidepressant prescription rates fell [or didn’t continue to climb] with the Black Box Warning, kids are being deprived of necessary treatment. And they even propose motives. First, that "discouraging the medication treatment of depression in children is not an effective solution in preventing suicidal behavior" as if that’s what the FDA did or was tasked to do. Again, the FDA warned that these drugs can, at times, be associated with suicidality – as a drug effect! That’s their job – drug effects. What doctors do with the information isn’t the FDA’s business [or Dr. Gibbons’]. The FDA is supposed to help us by telling us what bad things can happen – and that’s what they did. And further, these authors propose to know the psychology and motives of doctors, that we were afraid to prescribe these drugs for inappropriate reasons [like getting sued] because of all the publicity about the warning – so we are withholding treatment. They ignore the much more obvious explanation that knowing of the danger, we became appropriately more cautious ["Anyone considering the use of Prozac or any other antidepressant in a child or adolescent must balance this risk with the clinical need…"]. And they imply an efficacy for antidepressants in teens that’s mythologic. Only two of the antidepressants were approved for teens, and they had anything but a robust effect. They apparently think that population statistics should determine the treatment of any given patient. If that’s the case, we don’t need doctors, we only need computers and statisticians.

And then there’s this decade-long cascade of papers with arguments that keep changing as they attempt to prove their point using population statistics on large databases or a meta-analysis of other people’s studies [with no public access to the data]. There are at least fifty other posts on this blog looking at the details in these papers [just put "gibbons black box" into the search box below]. In particular, see persistence…. It’s about number 11. below, which has my letter [unpublished] and letters from two others that were ultimately published in the journal.
  1. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  2. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
  3. Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg
  4. Nakagawa A, Grunebaum MF, Ellis SP, Oquendo MA, Kashima H, Gibbons RD, Mann JJ.
  5. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ.
  6. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
  7. Brown CH, Wyman PA, Brinales JM, Gibbons RD.
  8. Gibbons RD, Segawa E, Karabatsos G, Amatya AK, Bhaumik DK, Brown CH, Kapur K, Marcus SM, Hur K, Mann JJ.
  9. Barry CL and Busch SH.
  10. Gibbons RD, Mann JJ.
  11. Robert D. Gibbons, Hendricks Brown, Kwan Hur, John M. Davis, and J. John Mann
  12. Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai
  13. by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA
  14. by Robert Gibbons and J. John Mann
  15. by Mark Moran
  16. by Richard A. Friedman, M.D.
  17. Robert D. Gibbons, PhD and J. John Mann, MD
As I said last week:
    I’m obviously not writing about this because I’m conflicted about the Black Box Warning. I’ve seen enough adolescent patients with the Akathisia syndrome from SSRIs to know it’s a real thing. And I know of completed suicides that I am sure were SSRI induced.
I’m suspicious that the six articles in 2014 [12.-17.] are harbingers of an effort to get the FDA to convene yet another hearing to revoke the Black Box Warning, now ten years after its adoption, based on the monotonous arguments in the articles listed here. Again from last week:
    They are proposing that warning the clinicians of a potential problem has lead to what they think is an error, so we shouldn’t warn the clinicians?? however rare?? They speculate that operating without being warned, they may ultimately help more people in their ignorance [or silence]?? And perhaps we shouldn’t warn our patients either, so they’ll follow our [proxied] advice?? There’s nothing I know about Medicine that supports that confusion of tongues. These highly placed doctors are not thinking like clinicians, and their group-think has no place in the hierarchy of Medicine as I know it. They’re not speaking the right language… Individual physicians have to construct an individualized risk/benefit estimate on every shared decision from a baby aspirin a day to dangerous and life threatening chemotherapy using known poisons. You can’t do that living in the dark about risk…
The majority of this four page Psychiatric Times piece is designed to bolster the fiction that the Black Box Warning was motivated to affect suicide rates rather than what it says: to warn doctors of Akathisia and suicidality – an idiosyncratic drug effect that afflicts some child and adolescent patients.
Mickey @ 8:00 PM

post without an end…

Posted on Wednesday 14 January 2015

    "After about two years on the job, the plans for change were becoming clearer in my mind. Some ideas about the Diagnostic and Statistical Manual of Mental Disorders [DSM] had begun to be formulated just before I came to the APA, as discussed in Chapter 10 ["Evidence Based Diagnosis and Treatment"]. The awareness of how the DSM and Practice Guidelines could radically effect the image of the field and its scientific status struck me as a powerful insight during my second year in office. The interaction of a new medical and scientific identity for psychiatry coalesced with plans to build coordinated Offices of Research, Education, Government Relations, Public Affairs, and Business Administration. This made sense in thinking how to achieve a newly clarified mission"…
    Dr. Mel Sabshin, in Changing American Psychiatry

Dr. Sabshin was the respected Medical Director of the American Psychiatric Association from 1974 through 1997 – both architect and long-running project director of the radical changes in the specialty that came to the stage in 1980 with the release of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition [DSM-III]. And at this point, no one would question that "the DSM and Practice Guidelines could" [and did] "radically effect the image of the field and its scientific status." There are still many versions of this story, but too many still carry a personal take on the journey to pull out the kind of summary we might get from some future history book surveying the 35 years between then and now. The main narrative is of a revolt against the dominant ideology of the time, psychoanalysis, and a move into the world of "Evidence Based Diagnosis and Treatment" – the scientific mainstream of medicine. A contrary version describes it as the unfounded assumption of a biological causality for mental illness and the primacy of medication in treatment, fueled by grossly inappropriate commercial interests. Surely that future history book will have a more nuanced version that parses the many other forces that have bearing on the topic. But this post isn’t about the a priori reasons or legitimacy of what happened in those days. And it’s not about the ad hoc consequences of the change itself [intended or otherwise]. It’s about the consequences of the method.

    "How could a professional organization engineer a scientific revolution that changed its core? According to conventional wisdom, organizations respond; they do not initiate. By the 1970s psychiatry in the United States had begun to undergo massive changes. The postwar glow had been replaced by the new pressure for accountability on all of medicine, Many leaders in psychiatry deplored the ideological rifts that had divided the field, and they called far a more unified, scientifically based profession. They deplored the "demedicalization" of psychiatry and its severe loss of credibility… The field’s ideological schisms had weakened us seriously, and psychiatrists bitter public disagreements were self-destructive. To cover up these differences or to act solely because of the criticism was not in itself sufficient; psychiatry had to adopt a genuine commitment to science rather than to ideology. It needed to change the profession fundamentally if it was to become a respected part of medicine. To accede to the pressures without radical modifications of the field would not have convinced others that the profession had changed. A new strategy was essential! Producing the DSM-III stated emphatically that psychiatry in America chose an evidence-based practice rather than ideology"…
    Dr. Mel Sabshin, in Changing American Psychiatry

At the time all of this happened, I was too otherwise-engaged to offer much wise commentary on the climate of those times [directing a psychiatric residency in a time of Cholera in Atlanta and in the middle of a psychoanalytic training program in New York]. What I recall was receiving copy of the DSM-III and being mystified by its thickness and content. By the time I finished my psychoanalytic training in 1984, I had already resigned from my academic position and was spending a lame-duck year setting up a practice. If asked about all of this back then, I would’ve had nothing much to coherent to say. I remember thinking about my parents’ lives, so heavily shaped by the Great Depression and World War II. I guess I saw what was happening in psychiatry as my turn to be swept along by forces too big to really understand and my job was to personally adapt as best I could. I do know that academic psychiatry, our journals, and the American Psychiatric Association [APA] quickly became foreign to me, and I gradually withdrew from that arena that had been central to my life for a few good learning years. The other personal thing to add is that I now think my first medical specialty, Internal Medicine, privately remained my primary identity, and my somewhat immigrant status added to my sense of viewing the changes in psychiatry from afar, an additional alienation of sorts [primary identities can be sticky]. In spite of all of those personal provisos, I still think that my impression that the APA became and remained the central driving force in the shape and course of the American psychiatry that followed 1980 is a valid observation.

Following the DSM-III publication, the APA seemed to quickly biologize, neoKraepelinize, and medicalize in its meeting agendas, its journals, its leadership, and the books that flowed from the APPI [its new publishing arm, also founded by Dr. Sabshin]. The speed of that change as I saw it may well have been partially a local illusion, because where I was, it coincided with the retirement of a long-standing [department-founding] Chairman, and the arrival of a young new DSM-III-etc convert. So it was abrupt for me. And the -izes I described weren’t the most obvious things at the time, more in the range of something seen through a retrospectoscope. What it felt like at the time was that psychiatry homogenized, and organized around a new religion. And while the DSM-III, DSM-IIIR, and DSM-IV may have remained etiologically neutral, the APA everything-else gradually became strongly biomedical. However things happened, after successfully taking over control of psychiatry with its publication of the DSM-III, the APA hierarchy continued to be a power-base unto itself that controlled the directions of the specialty – at least that’s how it felt to me. "The field’s ideological schisms" and "psychiatrists bitter public disagreements" miraculously seemed to evaporate – at least from the front burners. But as time passed, the APA, academic psychiatry, and the NIMH shared in their complicity with the growing influence of the pharmaceutical industry in the ways and means of psychiatry [though that wasn’t so apparent at the outset] – something I wouldn’t have even imagined [and didn’t]. The Managed Care industry and the Hospital Corporations were also part of that story. Yet, from my perspective as a semi-outsider, I’ve should’ve noticed that I never never saw the APA, academic psychiatry, or the NIMH take a strong ethical stand countering the growing misbehavior of industry or the participation of some of their own higher-ups [sometimes highest-ups], no matter how questionable the practices.

By 2002, the APA’s DSM-V [soon to be DSM-5] Task Force announced it was going to add biological correlates to the new Diagnostic Manual and initiated an elaborate series of symposiums in preparation [see dreams of our fathers VII…]. It was to be a paradigm changing revision, realizing the dream of at least some of its neoKraepelinian founders – some even called psychiatry Clinical Neuroscience. The Task Force sauntered along unopposed until it finally hit some blowback – ironically, from two strong, Robert Spitzer [architect of DSM-III and DSM-IIIR] and Allen Frances [Director of the DSM-IV revision]. Spitzer weighed in about the [secret] secrecy of the DSM-V Task Force in 2008, and Frances entered the fray in 2009 over multiple issues in the DSM-V process as well as some of the emerging changes [and omissions] as they became apparent [semi-apparent]. The APA response to the criticism was anything but pretty [see the summer of 09… and dangerous men…]. The premise of this post is that the APA’s power play with the DSM-III under Dr. Sabshin never really ended. What began as something of the emergency assumption of power and control in the wake of a crisis ["A new strategy was essential!"] became a chronic way of life.

An understanding of Crisis Intervention is an essential ingredient in the tradecraft of any mental health professional. We don’t intervene in crisis states just to eliminate painful symptoms, nor to solve the particular situation underlying the crisis at the moment. People resolve crises with or without any help to escape the pain and fear. Crisis Intervention comes under the heading of Preventive Psychiatry, so first it’s important to know what is being prevented. In crises, emotions maximize and can become the problem themselves – so people jump to their deaths instead of waiting for the fireman’s ladder being raised to save them. On the other hand, they sometimes solve the problem too well based on the moment, and set the stage for the next problem [that they didn’t anticipate]. So the point of crisis intervention is to make sure that the sense of urgency and fear doesn’t cloud the senses and create future not-so-hard-to-see-coming "unintended consequences." If the Crisis Interventionist solves the problem for the patient, all that’s learned is for the patient to return with the next crisis for some more magic. As an example, Robert Spitzer was, in my opinion, so worried that the psychoanalysts and psychotherapists would reframe any equivalent of the former "depressive neurosis" to fit their own models, that he left it out altogether. By lumping together widely diverse groups of patients into his Major Depressive Disorder [MDD] category, he created a category exploited to the tune of billions by industry, got many people overmedicated, shut down promising research avenues by dilution, deprived some people of the kind of "talking" therapy they could have used, and created a thirty-five year fiction. By my read, that was hardly Robert Spitzer’s intent. But it still happened [is happening].

Mel Sabshin, Robert Spitzer, and many others were pleasantly surprised at the positive reception they received with the DSM-III, which I’m sure felt like a reward for a job well done confirming the rightness of their path. That may well have even been partially true at the time. The turmoil abated – surprisingly quickly. The psychoanalytic and psychotherapy types either converted or went quietly elsewhere, and the evidence-based metaphor swept through the specialty, followed in a few years by drugs from an industrial pipeline. Many psychiatrists changed their spots and became evidence-based medication managers, treating patients referred by their other mental health therapists, from within networks constructed by managed care MBAs, prescribing drugs from the pharmaceutical companies, approved for specific DSM-III diagnoses by the FDA, based on evidence-based clinical trials with academic psychiatrists as principle investigators, advertised by articles with academic psychiatrists on their bylines, published in peer reviewed journals. And evidence-based came to mean statistical significance in a Randomized Clinical Trial of a drug or a treatment. The Clinical Trial was usually designed and financed by a pharmaceutical company on its own drug, conducted by a contracted Clinical Research Organization, turned into an article by a contracted medical writing firm, then submitted to a peer reviewed journal by guest-author psychiatrist[s] with academic credentials.

Crisis Intervention isn’t supposed to end up with a solution that’s that comprehensive. It’s supposed to get people thinking with all eight cylinders again, playing with a full deck, grappling with things that matter. It’s not supposed to bail people out [or in], just get things on track. The DSM-III solution taught psychiatrists to look to the APA itself to solve its problems. So the power and control of the direction of psychiatry and its practice has remained concentrated in the hands of the APA hierarchy ever since. That wasn’t Crisis Intervention. It wasn’t even a Revolution. It was a coups d’état that quickly brought the peace, but at what ultimate price? Since then, many in the the specialty have looked to the APA to continue to set the course. And the APA has continued to see that as its charge. This is currently a post without an end…
Mickey @ 9:30 AM

these tainted articles…

Posted on Saturday 10 January 2015

Sometimes, I’m asked why I keep looking at studies long passed – like GSK’s Paxil Study 329 [2001] or AstraZeneca’s Seroquel Study 15 [1993-1995: still unpublished]. The usual answer is that the only way I know to aim for a better future is to thoroughly understand the misadventures of the past. But there’s another simpler answer. These tainted articles, once in the literature, are not really in the past. They’re sitting there in a journal as if they’re hot off the press long after they’re published – still used as references. Here’s a prime example from a recent New York Times blog:
New York Times
By Richard A. Friedman, M.D.
January 8, 2015

…Dr. Helen Mayberg, a professor of psychiatry at Emory University, recently published a study in JAMA Psychiatry that identified a potential biomarker in the brain that could predict whether a depressed patient would respond better to psychotherapy or antidepressant medication.

Using PET scans, she randomized a group of depressed patients to either 12 weeks of treatment with the S.S.R.I. antidepressant Lexapro or to cognitive behavior therapy, which teaches patients to correct their negative and distorted thinking.

Over all, about 40 percent of the depressed subjects responded to either treatment. But Dr. Mayberg found striking brain differences between patients who did well with Lexapro compared with cognitive behavior therapy, and vice versa. Patients who had low activity in a brain region called the anterior insula measured before treatment responded quite well to C.B.T. but poorly to Lexapro; conversely, those with high activity in this region had an excellent response to Lexapro, but did poorly with C.B.T.

What might explain these different responses?
This post isn’t about Dr. Mayberg, a neurologist at Emory best known for studying brain stimulation in refractory depression, or her contemporary study reported here [Toward a Neuroimaging Treatment Selection Biomarker for Major Depressive Disorder: full text on-line], or even only about Dr. Friedman’s NYT speculative blog. It’s about this next reference he mentions:
It turns out that other clinical factors may also help patients get the best treatment. For example, there is intriguing evidence that depressed patients who have a history of childhood trauma, such as the early loss of a parent or sexual or physical abuse, do not respond as well to an antidepressant as they do to psychotherapy.

In a large, multicenter study, Dr. Charles Nemeroff, then a professor of psychiatry at Emory and now at the University of Miami, found that for depressed adults without a history of abuse, there was a clear ranking order of treatment efficacy: Combined psychotherapy [using a form of cognitive behavior therapy] and an antidepressant [in this case, Serzone] was superior to either treatment alone. But for those who had a history of childhood trauma, the results were strikingly different: 48 percent of these patients achieved remission with psychotherapy alone, but only 33 percent of these patients responded to an antidepressant alone. The combination of psychotherapy and a drug was not significantly better than psychotherapy alone…
And so begins our remembrance of things past…
2003…
If you read the referenced article [Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma: full text on-line], you’ll find that it says exactly what Dr. Friedman says it says – bolstered by this graph:
But if you look at that article in PubMed, you’ll notice this:
Erratum in
    Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16530.
2005…
And if you chase down that Erratum reference, you’ll find this…
Erratum in Proceedings of the National Academy of Science. 2005 102[45):16530.

MEDICAL SCIENCES. For the article "Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma," which appeared in the Proc. Natl. Acad. Sci. in November 13, 2003, the authors note the following. "Results of the analyses of variance comparing change in Hamilton Rating Scale for Depression scores as a function of treatment type and early life trauma histories as well as Fig. 1A reflect change relative to the first week of treatment instead of baseline. When change scores relative to baseline are used, the interaction effects between treatment type and childhood trauma histories are not statistically significant…
… which invalidates their conclusion in spite of their attempt to evoke a plan B.
This discrepancy is due to marked changes in depression scores during the first week of treatment. Note that all analyses comparing the more conservative outcome measure of remission as a function of treatment type and childhood trauma as well as Fig. 1B are correct. Thus, consideration of treatment response relative to baseline does not detect the effect of childhood trauma on final remission, whereas consideration of final response relative to first response does detect the effect."
2012…
… and in spite of  that Erratum, here’s that same graph used in a presentation Dr. Nemeroff made at NYU in 2012 [see has to stop…]. Does he think everyone will just forget?


2003                                           2012

I originally got onto this thread reading a posting on Healthcare Renewal [PROFESSOR NEMEROFF GOES TO LONDON] by veteran Nemeroff watcher Dr. Bernard Carroll as Dr. Nemeroff was about to redo his NYU Grand Rounds in London last year. But then I got curious about the origin of the data in Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma, and I found myself back at the turn of the century.
2000…
It came from a Serzone® Clinical Trial financed by Bristol-Myers Squibb:
by Martin B. Keller, M.D., James P. McCullough, Ph.D., Daniel N. Klein, Ph.D., Bruce Arnow, Ph.D., David L. Dunner, M.D., Alan J. Gelenberg, M.D., John C. Markowitz, M.D., Charles B. Nemeroff, M.D., Ph.D., James M. Russell, M.D., Michael E. Thase, M.D., Madhukar H. Trivedi, M.D., Janice A. Blalock, Ph.D., Frances E. Borian, R.N., Darlene N. Jody, M.D., Charles DeBattista, D.M.H., M.D., Lorrin M. Koran, M.D., Alan F. Schatzberg, M.D., Jan Fawcett, M.D., Robert M.A. Hirschfeld, M.D., Gabor Keitner, M.D., Ivan Miller, Ph.D., James H. Kocsis, M.D., Susan G. Kornstein, M.D., Rachel Manber, Ph.D., Philip T. Ninan, M.D., Barbara Rothbaum, Ph.D., A. John Rush, M.D., Dina Vivian, Ph.D., and John Zajecka, M.D.
New England Journal of Medicine. 2000 342[20]:1462-1470.

Conclusions: Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.
It’s not the Clinical Trial that grabs the reader’s attention. It’s the list of 29 authors and what we now know about their future. Among other things, we’ll see Martin Keller leading the Paxil Study 329 team the next year [2001]; we see the leaders of the TMAP project [Rush and Trivedi]; we’ll see four who will make Senator Grassley’s list of COI offenders [Keller, Nemeroff, Schatzberg, and Rush]; we’ll see the principals in an attempt to get into the PHARMA business [Corcept: DeBattista and Schatzberg]; there are three department chairs who stepped down early [Keller @Brown, Nemerroff @Emory, Schatzberg @Stanford]; and others of note. It’s a veritable convention of KOLs in the salad days of 2000 [the year clinicaltrials.gov launched] on a Serzone® Clinical Trial [Serzone®, an SSRI, was pulled from the market in 2003 because of potential fatal hepatotoxicity]. The COI declaration list was so long that the NEJM published it separately on their web-site. But it was also the dawn of something else. In the same issue, then NEJM Editor Marcia Angell wrote an editorial focused on this specific article and all of the Conflicts of Interest, the start of what would later become her general campaign against Conflicts of Interest. It began:
by MARCIA ANGELL, MD
New England Journal of Medicine. 342[20]:1516-1518.

In 1984 the Journal became the first of the major medical journals to require authors of original research articles to disclose any financial ties with companies that make products discussed in papers submitted to us. We were aware that such ties were becoming fairly common, and we thought it reasonable to disclose them to readers. Although we came to this issue early, no one could have foreseen at the time just how ubiquitous and manifold such financial associations would become. The article by Keller et al. in this issue of the Journal provides a striking example. The authors’ ties with companies that make antidepressant drugs were so extensive that it would have used too much space to disclose them fully in the Journal. We decided merely to summarize them and to provide the details on our Web site.

Finding an editorialist to write about the article presented another problem. Our conflict-of-interest policy for editorialists, established in 1990, is stricter than that for authors of original research papers. Since editorialists do not provide data, but instead selectively review the literature and offer their judgments, we require that they have no important financial ties to companies that make products related to the issues they discuss. We do not believe disclosure is enough to deal with the problem of possible bias. This policy is analogous to the requirement that judges recuse themselves from hearing cases if they have financial ties to a litigant. Just as a judge’s disclosure would not be sufficiently reassuring to the other side in a court case, so we believe that a policy of caveat emptor is not enough for readers who depend on the opinion of editorialists.

But as we spoke with research psychiatrists about writing an editorial on the treatment of depression, we found very few who did not have financial ties to drug companies that make antidepressants. [Fortunately, Dr. Jan Scott, who is eminently qualified to write the editorial, met our standards with respect to conflicts of interest.] The problem is by no means unique to psychiatry. We routinely encounter similar difficulties in finding editorialists in other specialties, particularly those that involve the heavy use of expensive drugs and devices…
She later came to be less forgiving, and saw psychiatry as the leader of the COI pack [see in the name of ethics…]. I see her editorial as an awakening, one that I wouldn’t have for a number of years [when Senator Chuck Grassley and right hand, Paul Thacker, woke up a lot of us with their investigation]…

And so to my favorite quote:
    We shall not cease from exploration 
    And the end of all our exploring 
    Will be to arrive where we started 
    And know the place for the first time…
    Little Gidding, 1942, T.S. Eliot
So we’re back around to Dr. Friedman’s blog in the New York Times last Thursday. It’s a perfectly reasonable topic, Treat Depression, Drugs or Therapy?, something of general interest. In the discussion, he evokes and links an older study, speculating on the meaning of the neuroimaging findings reported by Dr. Mayberg et al recently. A general reader following the link in the blog would find that study with no clue that the central scientific claim had been retracted [for what may well have been a bit of sleight of hand – discovered how?].
 
Should Dr. Friedman have known about all of that? or about the Conflicts of Interest in the original study? Probably. Even if he doesn’t keep up with the blogs here at the edge of the galaxy, quoting Dr. Nemeroff, particularly from a paper back in 2000 or 2003, is always risky business. And that’s a widely known bit of information in the psychiatric community and elsewhere. But that’s not my central point. A paper like that should have been retracted from the literature, or at the least, retrospectively annotated on the Journal’s web-site by the Journal itself. The medical literature endures. It’s one thing for a study to become outdated and replaced by newer information. But it’s quite another if the original paper is as seriously flawed as this one. As time passes and there’s more distance from the scene of the crime, such papers may even become more credible as the contemporary criticisms [and critics] fade away. In psychiatry, particularly in the realm of industry funded Clinical Trials with guest authors [and/or ghost writers], there are still a number of thoroughly discredited articles that occupy the exact same space as legitimate publications, and we owe it to future medical and general readers to make their presence obvious or eliminate them from consideration altogether. This is a clear example of why!
Mickey @ 11:01 AM

Beware of Shiny Objects!…

Posted on Friday 9 January 2015

During my forty years of an active medical career, I don’t recall thinking about the Food and Drug Administration [FDA] or, for that matter, the Clinical Trials of medications – even though they became obligatory about the same time I started medical school [1962] in the wake of the Thalidomide problem. Whenever there was a new drug I wasn’t familiar with, I opened the PDR and read the efficacy and adverse effects sections, assuming they were accurate. I generally stayed on the "trailing edge" of new drugs, preferring the familiarity of experience to "the latest." And, to be honest, my own prescribing from the late 1970s through retirement was minimal. Had there been an exam on the FDA approval process, I would’ve flunked it. That said, I’ve always been a medical literature junkie, but my reading has been focused on the things I was actually doing – and psychopharmacology wasn’t it. So there has been a lot of catching up to do in the last few years.

The idea of Randomized Clinical Trials [RCTs] for testing drugs makes perfect intuitive sense, particularly in psychiatry where the outcomes are subjective responses measured by standardized rating scales. Start with an a priori protocol describing the conduct of the whole study in detail – including the outcome variables, the analytic techniques, and criteria for the conclusions – and the trial should run itself. But looking at the process now fifty years later, things are anything but that simple. The story is one of recurrent regulatory reform to tighten the process countered by the creative exploitation of loopholes – a high stakes game played on the tables of medicine. And like any such gambling enterprise, it hinges on holding one’s cards close to the chest – on secrecy.

The idea of Clinical Trial Registration again makes perfect intuitive sense. If we know about the trial, its parameters, the changes along the way, and the results – how could it be jury-rigged? In oh so many ways is the answer. One way that has been front and center is to just skip the posting of results. There was no provision for enforcement, so the trialists just didn’t do it – shown in report after report. They just didn’t do it, so finally on to the next reform [see eyes wide shut open I…, eyes wide shut open II…, eyes wide shut open III…, eyes wide shut open IV…, and promises, promises…]. This is the NIH/FDA call for commentary [see Honoring Our Promise: Clinical Trial Data Sharing]:
by Deborah A. Zarin, M.D., Tony Tse, Ph.D., and Jerry Sheehan, M.S.
New England Journal of Medicine. 2015 372:174-180.

Broad access to information about clinical trials and their findings is critical for advancing medicine, promoting public health, and fulfilling ethical obligations to human volunteers. Traditional methods of information dissemination [e.g., presentations and publication] may nevertheless leave distortions and gaps in the knowledge base because the results of many trials are not published. Title VIII of the Food and Drug Administration [FDA] Amendments Act of 2007 [FDAAA] addressed some of these concerns by requiring the registration and submission of summary results information to ClinicalTrials.gov for certain clinical trials of drugs [including biologic products] and devices. The Department of Health and Human Services [HHS] recently published for public comment a proposed rule [or “Notice of Proposed Rulemaking [NPRM] for Clinical Trials Registration and Results Submission”] to clarify and expand [as permitted] the FDAAA requirements and ultimately facilitate compliance with the law. Separately, and in keeping with a long-standing principle that systematic dissemination of results is a critical step in realizing the value of the research investment, the National Institutes of Health [NIH] has issued a draft policy for public comment to promote registration and results submission to ClinicalTrials.gov. This policy is proposed to cover all NIH-funded clinical trials, regardless of study phase, type of intervention, or whether they are subject to the FDAAA requirements.

I’ve already had a say about my own response letter [why data transparency? I…, why data transparency? II…, and why data transparency? III…] after waiting for a new clinical trial to be published to use as an example. And I found one [Study Finds Olanzapine-Fluoxetine Combo Superior to Placebo for Bipolar Disorder in Children]. But I have a couple of other comments:
  • As intuitive as RTCs seem, even when they’re run and published in a pristine manner, they are anything but a gold standard for measuring the effectiveness or the safety of a drug or device. They’re short term. The subjects are carefully picked and more closely watched than in clinical practice. They are capable of detecting significant differences that are well below the threshold of clinical relevance. And particularly in the domain of adverse events, their getting on first results are often interpreted as a home run. And they have offered a conduit for some of the most egregious deceit in the history of medicine. For my money, the best treatise on this topic remains David Healy’s Pharmageddon.
  • The Results Database is a summary tool, not full Data Transparency. It can be helpful in vetting a Clinical Trial, particularly if the verbatim protocol is available. Many of the techniques used to distort results in published papers rely on the HARK technique [Hypothesis After Results Known] – poring over the numbers looking for something significant after the fact. But the more subtle techniques that play with data display or analysis can be buried in the summary just as in the published material. So it can be considered a step forward, but it doesn’t replace the kind of Data Transparency we really want – the raw data prior to any opportunity for manipulation [emphasis on any].
So I’m glad to see the NIH and FDA working on this, and particularly with their adding enforcement with punishment, but the operative message after fifty years of history is Beware of Shiny Objects!
 
Mickey @ 8:52 PM

boxes black are back II: a confusion of tongues

Posted on Wednesday 7 January 2015

I’m obviously not writing about this because I’m conflicted about the Black Box Warning. I’ve seen enough adolescent patients with the Akathisia syndrome from SSRIs to know it’s a real thing. And I know of completed suicides that I am convinced were SSRI induced. In addition, I am underwhelmed with the claimed efficacy of SSRIs in adolescents in Clinical Trials [I think I’ve read them all in the course of researching for this blog]. I would and have prescribed SSRIs to adolescents in situations where both the teen and some responsible adult will listen to the warnings and agree to being closely observed. The few cases where I’ve done that have been with habitual compulsive behaviors [bulemia, cutting, etc] with  success. So I am perfectly fine about the Black Box Warning staying exactly like it is. Good job FDA…

I am writing about this once again because of the confusion of tongues that swirls around this issue. The one solid fact that emerged from the population studies is that the prescription rate of antidepressants either leveled out or fell [instead of continuing to increase] in response to the Warning. In Lu et al, this was true for adolescents, young adults, and older adults – even though that initial warning only pertained to the adolescents. 

In the two articles in PSYCHIATRICNEWS [boxes black are back I…], Dr. Darrel Regier proposed that the reason for the fall-off in prescribing had to do with the widespread press coverage of the warning, scaring away doctors and patients alike [particularly primary care doctors who were prescribing the majority of antidepressants]. Regier proposed that the primary care doctors couldn’t follow the patients as closely as recommended, and were afraid of getting sued. He went further, saying that the drop in prescribing was not matched by referral for some other treatment modality [eg CBT], presuming that meant that depressed kids just weren’t being treated – a point echoed by Dr. Michael Thase in the article. Child Psychiatrist Dr. David Fassler [former APA Board member]  felt that the press coverage implied that the antidepressants increased the suicide rate, something unintended by the FDA – a point backed up by Dr. Thomas Laughren, team leader of the Psychiatric Drug Group within the FDA during the 2004 FDA hearings.

All of this speculation about the psychology of the primary care physicians strikes me as hyperbole. If I were to wax eloquent about Drs. Regier’s and Fassler’s own inner workings, I expect they would break out singing some evidence-based medicine anthem in three part harmony [and accuse me of being a loose cannon]. And they sure don’t paint a very flattering portrait of primary care doctors – fear of lawsuits, basing clinical decisions on newspaper reports, turning away depressed adolescents "untreated." And further, they’re assuming that the abrupt halt to the escalating antidepressant prescription rate was a bad thing, rather than something perfectly reasonable – slowing down an avalanche.

The time leading up to the 2004 Black Box Warning was the heyday of psychopharmacology when drugs continued to flow from the mythical PHARMA pipeline. Direct-to-Consumer ads for antidepressants blanketed the media. Drug reps detailing psychoactive drugs and KOLs speaker’s bureaus were focusing on primary care physicians, specifically because of the much broader market than that reached by psychiatrists. Rather than see the de-escalation of antidepressant prescriptions as ignoring depressed teens, it seems much more plausible to suppose that the Black Box Warning appropriately neutralized the hype that had bombarded the general practitioners in those days – leading to more rational prescribing.


And so to the confusion of tongues

  1. The arguments in the two articles are not primarily against the content of the Black Box Warning – the reported signal for suicidal thoughts or behavior in RCTs of adolescents treated with SSRIs or the case reports of suicides presented to the FDA Hearing. These arguments are focused on the decrease in prescription of SSRIs that followed actually adding the Black Box Warning – a reproducible finding in multiple studies – and suggest that the quantity and quality of the media reporting at the time inappropriately scared clinicians and patients alike; leading to a fall in prescription rates; meaning that many depressed adolescents were being deprived of necessary treatment or were not even being brought for treatment; meaning that they were therefore vulnerable to depressive suicide.
  2. The Randomized Clinical Trials of these drugs in adolescents have been the subject of intense scrutiny and many meta-analyses of both efficacy and adverse effects, specifically suicidality. Most of them have been reviewed in this blog along the way. The RCTs are industry funded, conducted by Clinical Research Organizations, and several are clearly ghost-written by agents working for the industry sponsor. A 2012 extensive Cochrane Collaboration Systematic Review concluded:
    by Hetrick SE, McKenzie JE, Cox GR, Simmons MB, and Merry SN
    Cochrane Database of Systematic Reviews. 2012 Issue 11. Art. No.: CD004851.

    The Abstract[abstracted]

    BACKGROUND: Depressive disorders are common in young people and are associated with significant negative impacts. Newer generation antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are often used, however evidence of their effectiveness in children and adolescents is not clear. Furthermore, there have been warnings against their use in this population due to concerns about increased risk of suicidal ideation and behaviour.
    OBJECTIVES: To determine the efficacy and adverse outcomes, including definitive suicidal behaviour and suicidal ideation, of newer generation antidepressants compared with placebo in the treatment of depressive disorders in children and adolescents.
    SEARCH METHODS:…
    SELECTION CRITERIA:…
    DATA COLLECTION AND ANALYSIS:…
    MAIN RESULTS: Nineteen trials of a range of newer antidepressants compared with placebo, containing 3335 participants, were included. The trials excluded young people at high risk of suicide and many co-morbid conditions and the participants are likely to be less unwell than those seen in clinical practice. We judged none of these trials to be at low risk of bias, with limited information about many aspects of risk of bias, high drop out rates and issues regarding measurement instruments and the clinical usefulness of outcomes, which were often variously defined across trials. Overall, there was evidence that those treated with an antidepressant had lower depression severity scores and higher rates of response/remission than those on placebo. However, the size of these effects was small with a reduction in depression symptoms of 3.51 on a scale from 17 to 113 (14 trials; N = 2490; MD -3.51; 95% confidence interval (CI) -4.55 to -2.47). Remission rates increased from 380 per 1000 to 448 per 1000 for those treated with an antidepressant. There was evidence of an increased risk (58%) of suicide-related outcome for those on antidepressants compared with a placebo (17 trials; N = 3229; RR 1.58; 95% CI 1.02 to 2.45). This equates to an increased risk in a group with a median baseline risk from 25 in 1000 to 40 in 1000. Where rates of adverse events were reported, this was higher for those prescribed an antidepressant. There was no evidence that the magnitude of intervention effects (compared with placebo) were modified by individual drug class.
    AUTHORS’ CONCLUSIONS: Caution is required in interpreting the results given the methodological limitations of the included trials in terms of internal and external validity. Further, the size and clinical meaningfulness of statistically significant results are uncertain. However, given the risks of untreated depression in terms of completed suicide and impacts on functioning, if a decision to use medication is agreed, then fluoxetine might be the medication of first choice given guideline recommendations. Clinicians need to keep in mind that there is evidence of an increased risk of suicide-related outcomes in those treated with antidepressant medications.

    from the Review:

    A U T H O R S ’ C O N C L U S I O N S
    Implications for practice
    The evidence for the effectiveness of newer generation antidepressants compared with placebo in the treatment of depressive disorder in children and adolescents is not compelling; the overall effects of antidepressants compared with placebo were not modified by drug. The methodological shortcomings of the trials make it difficult to interpret outcome data on the efficacy of newer generation antidepressant medications. This is a particularly unsatisfactory since large numbers of children and adolescents have participated in trials, and we are still unable to answer the important clinical question of whether antidepressant medications are effective in treating depressive disorders. The search for treatments that reliably lead to good clinical outcomes must continue. Even when there is evidence that newer generation antidepressants reduce depression symptom severity, it is unclear whether the difference in effect between antidepressants and placebo reflects a difference that is of clinical importance to patients…
    I would say this review is, if anything, too forgiving…

My borrowed title [the confusion of tongues] refers to two communications [1. and 2.] that pass on the street as strangers with neither mutual recognition nor resolution. The scenario in 1. describes a vital treatment which, if missed, may have dire consequences. Whereas, the evidence in 2. suggests that the same treatment for the same problem is borderline effective, if at all, and, if used, may have the same dire consequences. The Black Box Warning being challenged is backed by independent meta-analyses and numerous case reports. The opposition to the Black Box Warning proposes that the physicians and patients who responded to it by failing to continue an escalating usage pattern were swayed by the initial media response and are neglecting real medical and psychiatric needs out of fear, yet no credible evidence has been mustered to support that hypothesis after a decade of persistent trying. The argument [1.] still rests on unsubstantiated speculations about the motivations of a large, heterogeneous group of physicians and guesses about the original intentions of the FDA, rather than scientific evidence. And the burden of both commercial and ideological bias is clearly carried by those opposing the Black Box Warning.

There is a second confusion of tongues in this story. In my view, Medicine is practiced at the interface between the physicians’ learning from groups and the experiences of the physician and patient in the room. The groups are the history of Medicine passed through school, training, lifelong learning, journals, meetings, supervisors, colleagues, previous experience with other patients, mistakes and successes, life, etc. The patient brings their own learning, their life, and their complaint/dis-ease. So it’s at that interface where the knowledge from groups [evidence-based medicine, n=many] and the needs of the unique individual come together [n=1]. The point of meeting is to arrive at the best case path into the future for that patient – the real meaning of "personalized medicine." In this controversy [the Black Box Warning], we’re operating in an area where the group information has been contaminated by commercial interests and ideological struggles. The influential groups opposing the Black Box Warning represent an ideological group who are speculating about another amorphous group – clinicians. They are proposing that warning the clinicians of a potential problem has lead to an error, so we shouldn’t warn them?? however rare?? Operating without being warned, they may ultimately help more people in their ignorance [or silence]?? And perhaps we shouldn’t warn our patients either so they’ll follow our [proxied] advice?? There’s nothing I know about Medicine that supports that confusion of tongues. These highly placed doctors are are not thinking like clinicians, and their group-think has no place in the hierarchy of Medicine as I know it. They’re not speaking the right language in argument 1. Individual physicians have to construct an individualized risk/benefit ratio on every shared decision from a baby aspirin a day to dangerous and life threatening chemotherapy using known poisons. You can’t do that living in the dark about risk…

Added response to a queryThe term confusion of tongues originated in the initial fragmentation of human languages described in the Book of Genesis 11:1–9, as a result of the construction of the Tower of Babel. My "borrowing" was from the 1924 paper Confusion of the Tongues Between the Adults and the Child [The Language of Tenderness and of Passion] by Sándor Ferenczi about the resulting problems experienced by sexually abused children from that kind of confusion…
Mickey @ 9:10 AM

boxes black are back I…

Posted on Tuesday 6 January 2015

Earlier, I said, "I was not aware that the American Psychiatric Association [APA] had been so active in its opposition to the Black Box Warning in 2004 and going forward" [a restrictive interpretation…]. What a naive guy I am! A search of PSYCHIATRICNEWS reveals the history of APA opposition from before it was even decided. So these recent articles are just an extension of a long running story of objections spanning a decade:
PSYCHIATRICNEWS
by Mark Moran
November 2014

Abstract: This is the first of a two-part series on the 2004 FDA hearings on antidepressants and suicidality in adolescents. Part two will focus on the effect of the antidepressant label warning on prescribing and adolescent health.
In 1991, at the original Hearings on suicidality from Prozac, Darrel Regier was an invited Consultant as the Director of the Division of Clinical Research at the National Institute of Mental Health. In the above PSYCHIATRICNEWS article, they link to the documents for the 2004 FDA Pediatric Advisory Committee Hearing where the Black Box Warning originated – the second Hearing. By then, Dr. Darrel Regier was the Director of the APA Division of Research, and he’s nowhere in any of those 2004 documents that I can find. Since he’s mentioned as testifying in 2004 in both articles, I’ve written PSYCHIATRICNEWS author Mark Moran asking for his source, but haven’t heard back from him. Here’s the second article:
PSYCHIATRICNEWS
By Mark Moran
December 2014

Abstract: Despite differences of opinion on the warning, there is agreement that better systems are needed to understand potential relationships among mental illnesses, their treatments or lack of treatment, and suicide attempts and completions. This is the second of a two-part series.
I want to give PSYCHIATRICNEWS writer Mark Moran credit for his handling of Lu et al. He acknowledges the glaring problem with this most recent assault on the Black Box Warning:
One recent study in the British Medical Journal linked the boxed warning to an increase in suicide attempts, as measured by “psychotropic poisonings.” But that study has been widely criticized for methodological problems, especially its use of psychotropic poisonings as a proxy for suicide attempts.
But what about the ten year campaign against the Black Box Warning by the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry? Here are their main arguments from the articles:
Darrel Regier, M.D., former director of APA’s Division of Research, who testified against the warning in 2004, noted that the original boxed warning came with explicit, highly prescriptive recommendations for the frequency of visits that should be made with children or adults started on antidepressants; these included weekly visits for the first four weeks, then visits every two weeks, followed by monthly visits… “Primary care physicians who rarely saw patients frequently considered themselves liable to suit if patients had an adverse effect from the antidepressant medication or died if the physician didn’t follow that protocol,” Regier said…
Regier countered that although the average severity of depression in patients seen in primary care practices is less than that seen in psychiatric settings, there are actually more people with severe depression treated in primary care settings than are treated by psychiatrists. “Although we now know from clinical trials that patients with mild to moderate depression do as well or better on CBT [cognitive-behavioral therapy] than on antidepressant meds, there is often a failure to treat those with moderately severe to severe depression in those settings because of a hesitancy to use antidepressant medications and the absence of referral sources for CBT or medications to specialists”…
“My own sense is that the extensive media coverage of the hearings probably had more of an impact on practice patterns than the black-box warning itself,” said child psychiatrist and past APA Board member David Fassler, M.D. “Front-page articles in major national publications and extensive TV and radio coverage created the general impression that the use of SSRI antidepressants actually increased the risk of suicide in children and adolescents. Although this was not the FDA’s conclusion, it was the coverage most people saw and heard. As a consequence, many parents and physicians became reluctant to use these medications”…
But from those interviews there did emerge consensus around a few points — that untreated depression is the most serious risk for suicide; that the FDA warning was never intended to discourage legitimate treatment of adolescent depression, a fact that may have been obscured by lay media reports that oversimplified a complex subject; and that better systems are needed for tracking risk factors for suicide and linking them to meaningful outcomes.
In spite of these decade long arguments, the only consistent finding from the multiple studies taking aim at the Black Box Warning has been a change in prescribing in response – a leveling off. Here’s the data from Lu et al [redrawn to a uniform scale] [see unsupportable and totally irrational…]:

Here’s another older version from Nemeroff et al [redrawn to full scale]:

And what a Nemeroff et al it was! "by Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg" – a rogue’s gallery of KOLs. The red authors are all Quintiles employees [the database used came from Quintiles] [see 2006…].

And just to broaden the scope, the New England Journal gave us a ten-year anniversary pro and con duo as Perspective pieces in November:

by Richard A. Friedman, M.D.
New England Journal of Medicine 2014 371:1666-1668.
by Marc B. Stone, M.D.
New England Journal of Medicine 2014 371:1668-1671.
Commentary to follow…
Mickey @ 1:36 PM

sleeping dog lie…

Posted on Sunday 4 January 2015

From the beginning, and in the decade since, APA has protested the warning, predicting that it would prevent parents from seeking care for their children – and clinicians from prescribing antidepressants – and insisting that by far the greater danger was untreated depression. “We are concerned that the publicity surrounding this issue may frighten some parents and discourage them from seeking help for their children,” child psychiatrist David Fassler, M.D., told the 2004 panel. “The most important point that I can make is that the biggest risk for a child with depression is to be left untreated.”

Shortly after the FDA issued the Black Box Warning of possible suicidality in adolescents on antidepressants, the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatry jointly established a website, ParentsMedGuide.org [Updated 2010], that said:
Do antidepressants increase the risk of suicide?
Suicidal thoughts and behaviors are more common during adolescence than at any other time, but suicide is more common among adults. In any year about 16 percent of high school students think about suicide and about 3-8 percent show suicidal behaviors. Fortunately, very few of them commit suicide. Children and adolescents with depression are much more likely to think about suicide and to attempt it than other children. Although not all suicidal children have depression, untreated depression increases the risk of suicide.

The Food and Drug Administration [FDA] described an increase in reports of suicidal thoughts and/or behaviors in children and adolescents taking antidepressants. But, there were no suicides in the cases they studied. Autopsies of teenagers who have committed suicide show that very few of them had traces of an antidepressant, making the link between antidepressant use and suicide even weaker.

Between 1992 and 2001, there was a large increase in the number of adolescents being prescribed SSRI antidepressants. But, during that time the rate of suicide among American youth ages 10–19 actually dropped by more than 25 percent. This was the first time in nearly 50 years that the suicide rate declined in young people.

What is a black box warning?
…The FDA did not ban the use of antidepressant medications for youth. The purpose of the warning was to alert physicians and parents to watch children and adolescents to see if their symptoms got worse, or if they showed unusual changes in behavior. The FDA also specifically said that “depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions”.

Why did the FDA issue a black box warning?
In 2004, the FDA reviewed 23 clinical trials involving more than 4,300 child and adolescent patients. These patients received any of nine different antidepressant medications. No suicides occurred in any of these studies. … A more recent study found that the risk was even smaller—around 3% in those on medication and 2% in those on placebo. Most of these events were increases in suicidal thoughts. Only a few were actual suicide attempts, and NONE were suicide completions.

Through careful monitoring, the development of a safety plan, and the combination of medication with psychotherapy, the risks for increased suicidal thoughts can be managed. For moderate to severe depression, there is benefit in the use of medication because of a higher rate of relief, and more complete relief, from depressive symptoms than not using any medication.

Since the FDA issued the black box warning, there has been a decline in antidepressant use, but an increase in completed suicides in adolescents in both the US and the Netherlands. Although it is not yet clear how these trends may be related, this has been the first increase in the adolescent suicide rate reported in over a decade.
And on the American Academy of Child and Adolescent Psychiatry website under the Depression FAQ, we read:
What should treatment consist of?
When possible, treatment for depression childhood depression should include both psychotherapy and medication. In milder forms of depression, it is reasonable to start with a psychotherapy, but treatment with a medication and psychotherapy should be considered for moderate to severe forms of major depression. Before starting treatment, a doctor will discuss it’s risks and benefits, as well as how the treatment should be monitored.

Are medications safe? Do they increase risk of suicide?
When prescribed and monitored carefully, medications are both safe and effective ways to treat of depressed youth. Fluoxetine or Prozac, a selective serotonin reuptake inhibitor, is the medicine that so far has proved most safe and effective. There are times, however, when other medications can and should be used. While medications have been associated with a small increase in thoughts of suicide, there is no evidence that antidepressants actually increase the risk of suicide. For moderate to severe depression, the potential benefits from medication treatment seem to outweigh the potential risks.
They get some credit for "Through careful monitoring, the development of a safety plan, and the combination of medication with psychotherapy, the risks for increased suicidal thoughts can be managed." But I’m afraid that, "the potential benefits from medication treatment seem to outweigh the potential risks" is actually a major flaw in this whole argument. Prozac® was approved early for adolescent depression, before the Black Box Warning was issued [top two graphs], but that was the only approval. Paxil® had the infamous Study 329 [lower left] and two other unpublished negative studies. And Zoloft® only eked out minimal significance at ten weeks by combining two negative studies [lower right]. So none of them support a claim of the kind of "potential benefits" their argument advertises [see tuning the quartet…]


So it’s hard to mount a rational explanation for why our two major professional organizations [APA and AACAP] are still making an assault on the Black Box Warning. Except for Prozac®, they’re advocating off-label prescribing for marginal efficacy at best. There’s unlikely much push from PHARMA now that the drugs are off-patent. In spite of the limitations, they’re still prescribing at a moderate pace. Seems to me they’d let this sleeping dog lie…

Review: See significant I…, significant II…, and significant III… about the NIMH TADS study…
Mickey @ 9:21 AM

a restrictive interpretation…

Posted on Saturday 3 January 2015

The campaign against the Black Box Warning has been relentless since it was added to the labeling of antidepressants in 2004. Here are a dozen major articles along the way opposing the Warning:
  1. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
    Arch Gen Psychiatry. 2005 Feb;62(2):165-72.
  2. Gibbons RD, Hur K, Bhaumik DK, Mann JJ.
    Am J Psychiatry. 2006 Nov;163(11):1898-904.
  3. Charles B. Nemeroff, Amir Kalali, Martin B. Keller, Dennis S. Charney, Susan E. Lenderts, Elisa F. Cascade, Hugo Stephenson, and Alan F. Schatzberg
    Arch Gen Psychiatry. 2007 Apr;64(4):466-472.
  4. Nakagawa A, Grunebaum MF, Ellis SP, Oquendo MA, Kashima H, Gibbons RD, Mann JJ.
    J Clin Psychiatry. 2007 Jun;68(6):908-16.
  5. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ.
    Am J Psychiatry. 2007 Jul;164(7):1044-9.
  6. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, Herings RM, Mann JJ.
    Am J Psychiatry. 2007 Sep;164(9):1356-63.
  7. Brown CH, Wyman PA, Brinales JM, Gibbons RD.
    Int Rev Psychiatry. 2007 Dec;19(6):617-31.
  8. Gibbons RD, Segawa E, Karabatsos G, Amatya AK, Bhaumik DK, Brown CH, Kapur K, Marcus SM, Hur K, Mann JJ.
    Stat Med. 2008 May 20;27(11):1814-33.
  9. Barry CL and Busch SH.
    Pediatrics. 2010 125[1]:88-95.
  10. Gibbons RD, Mann JJ.
    Drug Saf. 2011 May 1;34(5):375-95.
  11. Robert D. Gibbons, Hendricks Brown, Kwan Hur, John M. Davis, and J. John Mann
    Arch Gen Psychiatry. 2012 Jun;69(6):580-587.
  12. Christine Y Lu, Fang Zhang , Matthew D Lakoma analyst, Jeanne M Madden, Donna Rusinak, Robert B Penfold, Gregory Simon, Brian K Ahmedani, Gregory Clarke, Enid M Hunkeler, Beth Waitzfelder, Ashli Owen-Smith, Marsha A Raebel, Rebecca Rossom, Karen J Coleman, Laurel A Copeland, Stephen B Soumerai
    BMJ. 2014 348:g3596.
Now we have the first of an advertised two-part series on the topic in the PSYCHIATRICNEWS. I was not aware that the American Psychiatric Association [APA] had been so active in its opposition to the Warning in 2004 and going forward:
PSYCHIATRICNEWS
by Mark Moran
12/30/2014

Abstract: This is the first of a two-part series on the 2004 FDA hearings on antidepressants and suicidality in adolescents. Part two will focus on the effect of the antidepressant label warning on prescribing and adolescent health.


From the beginning, and in the decade since, APA has protested the warning, predicting that it would prevent parents from seeking care for their children—and clinicians from prescribing antidepressants—and insisting that by far the greater danger was untreated depression.

‘We are concerned that the publicity surrounding this issue may frighten some parents and discourage them from seeking help for their children,’ child psychiatrist David Fassler, M.D., told the 2004 panel. ‘The most important point that I can make is that the biggest risk for a child with depression is to be left untreated…’

Darrel Regier, M.D., M.P.H., who is the former director of the APA Division of Research and testified at the hearings against the warning, noted that there were in fact no actual suicides among the thousands of teens treated in clinical trials reviewed by the FDA panel. Moreover, the FDA data on suicidal ideation associated with SSRI use was based on spontaneous reports, not on studies prospectively designed to systematically define and identify the incidence of suicidal thoughts or behaviors in teenagers taking the medications.

Regier believes the extraordinary media attention the hearings attracted is a case study in how data pertinent to public health can be obscured or distorted by overinterpretation of spontaneous reporting. “I think it calls into question the FDA’s entire system of spontaneous reporting,” he said. Regier said a promising step is the agency’s adoption, for use in future phase 3 clinical trials, of the Columbia Suicide Severity Rating Scale for any drug that is thought to have some potential for suicidal ideation [including dermatologic drugs such as Accutane].

‘I think the solution is more systematic reporting, which the FDA will start to move toward as the agency begins to have access to electronic health records used by large health systems and HMOs,’ Regier said. ‘This will give the FDA access to phase 4–type data on the long-term effects of medication side effects and associations with suicidal attempts and mortality from all causes.’
It’s unlikely that anyone reading this is neutral on the topic – one that has pervaded our literature almost from the time of the introduction of the SSRIs a quarter of a century ago. Those who support the Black Box Warning rely on individual instances – their own experience as patients and clinicians or the case reports of others. People who oppose the Warning point to studies in populations that show no effect either way on suicide, but confirm that the prescription rate of SSRIs either fell or stopped rising in response to the Warning. It’s hard to find a discussion of this issue that doesn’t also make ad hominem accusations of bias towards the other camp. With that as an introduction, I’m sure not going to revive my own usual arguments, refutations, or accusations. I’d rather talk about an article I read yesterday [sent by literature maven, James O’neill] that seems to fit my take on all of this:
by Fava GA, Guidi J, Rafanelli C, and Sonino N
Psychotherapy and Psychosomatics. 2015 84:1-3.
It’s a short two paged article best read as a narrative rather than viewed in a couple of sound bytes, so I’ll skip any attempt at summary. It’s an article that talks about clinical judgement taking precedence over the tenets of evidence-based medicine. It’s a hard argument to make as it can be instantly met with "How do you know that?" or "But that’s just what you think." And I’ve actually never heard any two people have this argument with even slightly changed minds as a result.

My own opinions are embedded in my narrative. I came into the world equipped for science – aptitude, interest, a father who taught chemistry and geometry. After a degree in mathematics, I headed to medical school intending a medical research career and, in fact, wound up my training in a lab bench based NIH fellowship. I lived and breathed evidence-based medicine [I would like to think I still do]. My first post-training posting was as an general internist in an Air Force hospital overseas [by special invitation from the US government – AKA drafted]. I had been well trained as a clinician, but what I quickly realized was that in training, I had always been located somewhere in the hierarchy of a team of some sort, and when it was just me and a patient, medicine was a different game altogether. What Giovanni Fava is calling clinical judgement is as good a way as any to describe the difference.

I think of that three years as the most important and intense period of my own medical training. I became so interested in the individual illnesses and unique experience of my patients that I returned to a psychiatry residency and added a psychoanalytic training program that ran in parallel. My post academic career was as an individual psychotherapist in a world where clinical judgement was on the front burner of every day.

There was another important and intense period of my own medical training after my psychiatry residency. I directed a psychiatry training program for a decade before leaving for practice during the storm in psychiatry that followed the coming of the DSM-III. And I noticed something in my dealing with my residents during those days. I often found myself preaching the gospel of evidence-based medicine – quoting studies, handing out articles, sending a resident to the library. But at other times, my sermon was equally passionate, but was much more in the range of Fava’s clinical judgement. When I noticed that contrast, I quickly realized that the theme of my message depended on which resident I was talking to, and what I thought that particular resident needed to learn. The point being that I don’t slightly see evidence-based medicine and clinical judgement as a dichotomy – in opposition. Medicine as I know it is practiced at the interface of group data and unique human experience [including  my own].

So how do I relate this little discourse to the issue of prescribing SSRIs to adolescents? First, I object to the "untreated depression" argument out of hand. The "depression" on the table here is, in my view, a symptom – not a disease. And there is no formula I know that says that the "treatment" of "adolescent depression" is "SSRIs" or, for that matter, medication. I see the drugs as symptomatic medications that may, at times, be helpful in the "treatment of a particular depressed adolescent." Second, I have no question that the SSRIs can occasionally cause a unique syndrome [called Akathisia by David Healy] characterized by agitation, aggression, disinhibition, and intensely lethal thought. I know that’s true because I did it to someone:
    I saw a seventeen year old who was very depressed with good reason. His mother had remarried a man who was a retired Drill Sergeant [really] and this kid and his step-father were oil and water – at war. The boy had an impending interview for a training program that would’ve paid his way to move 200 miles away and study something he had dreamed of all his life. His mother and I were both worried that he was so depressed that he wouldn’t "pass" the interview. So I prescribed an SSRI. In a few days, he developed the full Akathisia syndrome in spades, including being intensely suicidal [for the first time]. His mother stopped the medication, didn’t leave his side, and it cleared within 48 hours.
I’ve since seen other cases of Akathisia and know of two completed suicides from SSRIs, fortunately none cases of my own. But that first case was from around the time of the Black Box Warning and I hadn’t been warned. Worse, I hadn’t warned them. So for me, this issue started in the realm of evidence-based medicine, something I saw in person, and became part of my subsequent clinical judgement. Would I prescribe an SSRI to an adolescent now? I would and have done on some occasions, but with more than plenty of warnings, and only to those I was absolutely sure were going to be closely watched by someone I had talked to myself.

When I look at that dozen articles I listed above, or read what Dr. Regier has to say, I’m aware that I’m a total snob. There’s not anyone that I would consider to be a clinician on the bylines of the articles on the list, or speaking in the PSYCHIATRICNEWS article. They’re Statisticians, Academicians, Researchers, or Administrative types. Even putting aside all the Conflict of Interest and Methodological issues in those papers [which are prodigious], I’m sure that I still wouldn’t change my mind about this no matter how long that list of population studies gets. And, by the way, I sense that the PSYCHIATRICNEWS article is a harbinger of yet another assault on the Black Box Warning [as if what it says on a package insert defines the truth].

I personally take this issue as a microcosm of a much more general point. I most respect the opinions of people who are deeply steeped in the findings of evidence-based medicine, but who remain immersed in clinical medicine throughout their careers [and show the tell-tale signs of having developed clinical judgement]. I don’t think that’s a tall order – more a baseline requirement. Back in 1980, the people who brought the DSM-III revolution in psychiatry to my own neck of the woods saw themselves as the prophets of evidence-based medicine. I sure didn’t object to that, but they were specifically disdainful of anything that slightly smacked of clinical judgement [as in "How do you know that?" or "But that’s just what you think" ad nauseum]. They were followed by a second wave who were even worse, in the range of contemptuous – the generation that became what we now call the KOLs [some of whom inhabit those author bylines above in the flesh]. They came at a time when psychiatry may have needed an encounter over its reliance on matters subjective, but in the process they turned clinical judgement into an object of ridicule rather than one for examination and inquiry.

There’s a strong pressure pushing this same trend in medicine in general – simplifying medical practice into the rote application of large group findings to the care of individual patients based on averages and statistics. That pressure comes from third party carriers, pharmaceutical companies, hospital conglomerates, governments, even professional organizations, etc. – anyone who tries to quantitatively deal with the healthcare of populations. So the amount of allowed contact, the access to diagnostic tests, the available treatments, just about everything is regulated based on algorithms and guidelines derived from large group studies. Meanwhile, patients increasingly clamor for individual attention, and are driven to distraction along with their doctors by the hoops they have to jump through when they get sick. Dr. Regier’s comment is typical of this particular mindset, "I think the solution is more systematic reporting, which the FDA will start to move toward as the agency begins to have access to electronic health records used by large health systems and HMOs."

So while Dr. Fava’s comments appear in a mental health journal, I think they can be generalized to all of healthcare:
    The conceptual model that has generated EBM and guidelines clashes with clinical reality and fosters a dichotomy between medical science and clinical judgment. EBM has certainly made an important contribution to questioning unsubstantiated therapeutic claims. The time has come, however, to become more aware of its considerable limitations, including overall reductionism, disregard of patient-physician relationships and patient preferences, and insufficient consideration of problems related to financial conflicts of interest. As an increasing body of literature indicates, EBM offers only a restrictive interpretation of the scientific approach to clinical practice.
Mickey @ 8:00 AM