1 Boring Old Man

With the Institute of Medicine [Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk] and the National Institute of Health [Honoring Our Promise: Clinical Trial Data Sharing] joining the call for Data Transparency, we’re beginning to approach the details, wherein dwells the devil – what data? which trials? The whole notion of proprietary ownership of the raw dat from Clinical Trials never made any real scientific sense in the first place [see except where necessary to protect the public…, a crushing setback…, the end game… ] being justified by trade agreements. The main two arguments in this last year against Data Transparency have been protecting Commercially Confidential Information and Patient Confidentiality. But first, yet another review of the landscape:

what data?

In the discussion that follows, Summary Data refers to the CSR [Clinical Study Report] which does not necessarily or usually contain the raw data. It’s got means, standard deviations, summary tables, etc. But it doesn’t have the individual test scores or the actual clinical observations of adverse events. The IPD [Individual Participant Data] does have the raw numbers from the individual participants, but the clinical observations are in tabular form – transcribed from the CRFs [Case Report Forms] which is as close as one can get to being there. And one mustn’t forget the a priori Protocol – the plan for the study before it commenced.

which Trials?

There seems to be a consensus developing that, going forward, the more comprehensive data [IPDs and CRFs] should be available for independent review to qualified reviewers. It levels the playing field between the sponsors/investigators and the independents. But what about Clinical Trials from the past [called below legacy trials]? Here, Ed Silverman interviews one of the members of the IOM panel on that very point:

Sharing Older Clinical Trial Data Should be Judicious: Sim Explains

Pharmalot: WSJ

By Ed Silverman

January 20, 2015

Last week, the Institute of Medicine issued an eagerly awaited report about sharing clinical trial data that recommends government agencies and companies provide access from research studies that they fund. The agency suggested timetables for such things as summary results and complete data packages. The move comes after heightened controversy over sharing data, how much data and the best way to do so. Among the issues that remain unsettled is the extent to which data from older trials will be shared. We spoke with Ida Sim, a professor of medicine at the University of California, San Francisco and a member of the IOM committee that prepared the report, about reaching back to past studies. This is an excerpt.

Pharmalot: To what extent did the committee look at sharing data from older trials?
Sim: It is addressed. We did think about it. But there are special considerations for sharing data from legacy trials… The first distinction to be made is between summary level data and individual patient level data. The average result of the trial, which is the summary, is a sort of bottom line – that’s an average result. Advocacy groups like Alltrials are asking for the release of summary level data. But the report focused on some sense of the value of individual patient-level data, and sharing the specific numbers that go into the average is much more complicated, especially for legacy trials.

Pharmalot: How so?
Sim: The primary challenge is the issue of informed consent. Patients who participated in trials in the past were most likely in trials that did not include [a provision for] sharing data publicly. So if we want to now share data, ethically, investigators should go back to get informed consent from the participants. There’s another complication. Very often investigators and the staff associated with a trial have scattered. So it can be expensive and challenging to pursue a team of people, maybe years later, to have them pursue this.

Pharmalot: Should that preclude all older trials?
Sim: Well, that said, for major significant trials that do influence decisions for clinical care, we recommend that, on a case-by-case basis, legacy studies should be prioritized for data sharing. But we have to be pragmatic and realistic. These are issues that have been going on for a long time. I think the committee has been building on prior work [of others] and recognizing there were instances of cherry picking of results, which started the whole movement of registration disclosure [registering trials with ClinicalTrials.gov]. Now, we’re pushing for the next level. But it’s incremental.

Pharmalot: Do you worry that companies may be let off the hook?
Sim: They have been really. The real question is what to extent can we go back and put them on the hook. It’s a question of balance. There are studies from academic investigators, who also have not been upfront [about disclosure]. There are problems of transparency across the whole clinical trial enterprise and the concerns apply to all clinical trials. The ones from the pharmaceutical industry are just more apparent to the public…

But, as Dr. Sim says, those legacy trials are going to contain a lot of jury-rigged science. And as a scientist/physician, I feel betrayed, and I want it exposed in all its gory detail. I, and the rest of medicine, have been actively misinformed – on purpose. Our patients have been actively misinformed – on purpose. And I personally believe that the companies and their medical allies will just do it again if there’s not a truth and reconciliation period to mark what happened in stone.  But that’s my opinion, my bias that surely affects my logic supporting full Data Transparency for legacy trials. From my vantage, the operative saying here is, "Don’t do the crime, if you can’t do the time."

But there’s another good very reason for full Data Transparency for legacy trials, particularly in psychiatry. The drugs in question are now off-patent – widely available in generic form, inexpensive, and still in heavy use. Managed Care reviewers still hawk them as cost-cutters. And they’re not going to be replaced any time soon. Nor is it likely that Bill Gates, PHARMA, or the NIMH will finance any new trials to restudy them properly. But we can look at the raw data from the original trials. And fortunately, the sleight of hand occurred primarily in the analytic and publication processes that came after the blinds were broken. So those legacy trials are the very ones that need to be reanalyzed and meta-analyzed by independent investigators playing with a full deck. Without an accurate and very public re-appraisal, the problem is going to be perpetuated for decades.

It looks as if the idea of Data Transparency has finally become mainstream. Pharmalot is reporting on the report from the Institute of Medicine [Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk]. Johnson & Johnson has signed on to the Yoda Project at Yale [Johnson & Johnson Will Make Clinical Data Available to Outside Researchers]. Add in the NIH commitment to require the use of ClinicalTrials.gov as it was intended [Honoring Our Promise: Clinical Trial Data Sharing], the EMA’s new policies [EMA opts for trial data transparency], and that makes for an encouraging start for the coming year. But in every one of these moves towards Data Transparency, there’s a question of what can and will be withheld. What is Summary Data? What is Commercially Confidential Information? Who can look at the data? At this point, we can caution and question until we’re blue in the face, but we won’t really know until we actually see what’s released and to whom. So in as much as the idea of Data Transparency is beginning to bloom, the proof that we will actually be able to thoroughly vet and count on any given Randomized Clinical Trial lies in the future as these advertised modes of access become realities.

two chances…

So below, we’re offered two chances to comment on the coming changes in Data Transparency policy – with the Europeans Medicines Agency and the NIH. The last time the EMA asked, many of us responded and they actually changed what they were doing. And I got a note from the main poopah. And this time, I got a personal request to comment [well sort of personal as in "Dear all"]. But my point holds. If there were ever a right time to respond, this is our moment. Same with the NIH. We‘re on their radar now and it’s time to start being a blip. Please click the red underlined links…

Dear all, Please be aware that we have today launched a public consultation on how the transparency rules of the European Clinical Trial Regulation will be applied in the new clinical trial database.  More information on the consultation is available in our press release and full details and how to submit comments is available on our website, here. Given your expertise and interest in the area of clinical trials and transparency, we would highly value your input into this public consultation.  The deadline for comments is 18 February 2015. For a brief background: The European Clinical Trial Regulation aims to create an environment that is favourable to conducting clinical trials in the European Union, with the highest standards of safety for participants. The Regulation transforms the level of information publicly available for each clinical trial carried out in the European Union by requiring transparency on the authorisation, conduct, and results of the trial.  The Regulation will apply to clinical trials that are registered once the Regulation is in operation [not before 28 May 2016]. The key instrument to deal with clinical trials in a transparent way is the new clinical trial portal and database. It will be used for submission and maintenance of clinical trial applications and authorisations within the EU. It will serve as the source of public information on the clinical trial applications assessed, and all clinical trials conducted in the EU. According to the European Regulation, the European Medicines Agency [EMA] is responsible for the development and maintenance of the portal and database, while the authorisation and oversight of clinical trials will remain with the EU Member States. The document under consultation sets out proposals for the application of the transparency rules of the European Clinical Trial Regulation in the new clinical trial database for stakeholders to review and comment on.  The proposals aim to balance the right of patients and the public to access extensive and timely information on clinical trials, and developers’  and researchers’ need to benefit from investments. This will support the EU as a suitable location for innovative, cutting-edge research and development of medicines. Please note that this public consultation refers only to the practical application of transparency rules for the clinical trial portal and database that is established within the European Clinical Trial Regulation. The European Clinical Trial Regulation is distinct from EMA’s policy on the publication of clinical data, which has already come into force (January 2015). We look forward to receiving your feedback [here]. Many thanks and kind regards, Orla Ní Ógáin Press office Tel:  0044 20 3660 7904 Email: press@ema.europa.eu

Commenting on the NPRM and proposed NIH Policy

The public may comment on any aspect of the NPRM or proposed NIH Policy. Written comments on the NPRM should be submitted to docket number NIH-2011-0003. Commenters are asked to indicate the specific section of the NPRM to which each comment refers. Alternatively, written comments on the proposed NIH Policy should be submitted electronically to the Office of Clinical Research and Bioethics Policy, Office of Science Policy, NIH, via email at: clinicaltrials.disseminationpolicy@mail.nih.gov mail: at 6705 Rockledge Drive, Suite 750, Bethesda, MD 20892, or by fax: at 301-496-9839. The agency will consider all comments in preparing the final rule and final NIH Policy.

Protecting Academic Psychiatry

PsychiatricNews

Paul Summergrad, M.D.

January 2015

[full text on-line]

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 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.

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.

• 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 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.

The Relationship Between Antidepressant Initiation and Suicide Risk

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…

… 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."

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.

• APPENDIX 1 SSRIs & MECHANISMS OF SUICIDE: David Healy
• SSRI-Induced Akathisia’s Link To Suicide and Violence, Evelyn Pringle

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…

"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.

Treat Depression, Drugs or Therapy?

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?

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…

Erratum in

    Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16530.

Erratum in Proceedings of the National Academy of Science. 2005 102[45):16530.

[full text on-line]

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…

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."

2003                                           2012

A Comparison of Nefazodone, the Cognitive Behavioral-Analysis System of Psychotherapy, and Their Combination for the Treatment of Chronic Depression

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.

[full text on-line]

…

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.

Is Academic Medicine for Sale?

by MARCIA ANGELL, MD

New England Journal of Medicine. 342[20]:1516-1518.

[full text on-line]

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…

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

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 Proposed Rule for U.S. Clinical Trial Registration and Results Submission

by Deborah A. Zarin, M.D., Tony Tse, Ph.D., and Jerry Sheehan, M.S.

New England Journal of Medicine. 2015 372:174-180.

[full text on-line]

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.

• 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].

 

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:

   Newer generation antidepressants for depressive disorders in children and adolescents [Review]

   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.

FDA Actions on Antidepressants and Suicidality:
10 Years Later

PSYCHIATRICNEWS

by Mark Moran

November 2014

[full text on-line]

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.

Experts Debate Effects of Antidepressant Warning

PSYCHIATRICNEWS

By Mark Moran

December 2014

[full text on-line]

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.

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.

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.

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:

Antidepressants’ Black-Box Warning 

– 10 Years Later

by Richard A. Friedman, M.D.

New England Journal of Medicine 2014 371:1666-1668.

[full text on-line]

The FDA Warning on Antidepressants and Suicidality
– Why the Controversy?

by Marc B. Stone, M.D.

New England Journal of Medicine 2014 371:1668-1671.

[full text on-line]