wtf? for real…

Posted on Friday 22 May 2015

see also:

In my Internal Medicine days, I read the New England Journal of Medicine from cover to cover every single week. I still pick it up in the doctor’s lounge and read it just like I used to. And when I changed to psychiatry, I lamented that there was no NEJM-analog. So my comment, "What is this doing in the New England Journal of Medicine?" in my last post about the Drazen/Rosenbaum articles [wtf?…], was as a long time reader.

Well, I reread the editorial and series this morning, and if anything, they were worse – bordering on polemics. I tried to cut them a little slack because they’re internists and not psychiatrists. Psychiatry has been on the leading edge of the kind of problems COI can lead to for decades. Maybe, I thought, they’re just naive and not so in touch with the kind of fire they’re playing with here. They’re civilians, whereas we psychiatrists are veterans – knowing first hand how this COI thing can grow into a metastacizing cancer. But then I was alerted to this story about the Vioxx debacle by Bioethicist Arthur Schafer [University of Manitoba]. Editor Jeffrey Drazen should be a veteran after Vioxx [see also in Wikipedia]:
Fortunately, rescue from company “spin” was at hand. Some alert scientists discovered that the VIGOR authors had failed to report several heart attack deaths in their NEJM publication even though they had supplied the correct data to the FDA… Even worse from the company’s point of view, the Vioxx deaths which had been suppressed from the NEJM article were deaths which occurred in patients with no history of heart disease. This fact kicked the legs out from under the company’s specious claim that only those with a history of heart disease were at elevated risk from taking Vioxx.

The investigators did not correct the scientific record. Their failure to do so was compounded when Dr. Jeffrey Drazen, esteemed editor of the NEJM, declined an opportunity to publish a letter submitted to the journal by independent scientists which would have alerted readers to the misleading nature of the data originally published. Years later, when the full extent of the harm done to tens of thousands of patients became undeniably clear, Drazen and his fellow editors at the NEJM justified their refusal to publish a timely correction with the intellectually [and morally] feeble excuse that it is the responsibility of authors, not journal editors, to correct data…

In sum, almost no one emerges with much credit from the saga of the Cox-2 inhibitors. The drug companies which massively marketed the drugs, both to doctors and directly to consumers, made billions of dollars; but, when the facts eventually emerged, the companies experienced a serious loss of public trust. Merck, in particular, is now facing a staggering number of expensive law suits. The company continues to insist that it took all reasonable measures to determine whether Vioxx carried undue cardiovascular risks and is defending its conduct in all of these law suits. Medical journals and their editors, in particular the NEJM and its editor Dr. Jeffrey Drazen, were seen by some critics as being incompetent at best and collusive at worst in what turned out to be a terrible human tragedy…


The University as Corporate Handmaiden: Who’re ya gonna trust?”, by Arthur Schafer in The Universities at Risk: How Politics, Special Interests, and Corporatization Threaten Academic Integrity, ed. Jim Turk. James Lorimer and Co, Toronto, 2008.

Note: Schafer’s chapter is well worth reading in toto for a thoughtful in depth look at this whole issue of the Corporate invasion of Academia.
It’s very discouraging to find an editor of the New England Journal of Medicine writing and commissioning a reporter to write something like this after the strong stand of editors who came before him [see we were warned… and these tainted articles…]:
by Relman AS.
New England Journal of Medicine. 1980  303[17]:963-970.
[partial text here]

The most important health-care development of the day is the recent, relatively unheralded rise of a huge new industry that supplies health-care services for profit. Proprietary hospitals and nursing homes, diagnostic laboratories, home-care and emergency-room services, hemodialysis, and a wide variety of other services produced a gross income to this industry last year of about $35 billion to +40 billion. This new "medical-industrial complex" may be more efficient than its nonprofit competition, but it creates the problems of overuse and fragmentation of services, overemphasis on technology, and "cream-skimming," and it may also exercise undue influence on national health policy. In this medical market, physicians must act as discerning purchasing agents for their patients and therefore should have no conflicting financial interests. Closer attention from the public and the profession, and careful study, are necessary to ensure that the "medical-industrial complex" puts the interest of the public before those of its stockholders.
[Update: see also comment re NEJM Editor Jerome Kassirer who was fired in 1999]
by MARCIA ANGELL, MD
New England Journal of Medicine. 2000 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…
And by the way, "What is this doing in the New England Journal of Medicine?"
Mickey @ 8:39 PM

wtf?…

Posted on Thursday 21 May 2015

I know when I run into a blog post like this one that references no less than five articles without summaries, I frown because the author is implying that I should read all five of them. And that is what I’m implying. I’ve listed them chronologically as they’ve appeared, but you might do better to read Dr. Poses’ commentary on Healthcare Renewal first, before digging in to the four in the New England Journal of Medicine. When I read the first one, I found myself writing about the origins of Academe in ancient Greece [a contrarian frame of mind…]. I was looking back and forth at the Nizkor site [logical fallacies] the whole time. I decided not to write about Dr. Rosenbaum’s series until they were all published, because I wanted to use it as a lesson in fallacious arguments. And lo and behold, Dr. Poses beat me to it! But I’m glad he did because he found some I had missed, and he’s at his best when he’s in this mode. I’m going to leave that part to him, as a resident expert in that kind of analysis. You might as well go ahead and read them all. Everyone else is. And when you find yourself saying, "What is this doing in the New England Journal of Medicine?" Be comforted that you’re in a community of comrades who are asking the same question. And when you find yourself looking around for Dr. Rosenbaum’s COI declaration, all you’ll find is that she "is employed as a national correspondent for the New England Journal of Medicine.":
by Jeffrey M. Drazen, M.D.
New England Journal of Medicine. 2015 372:1853-1854.
May 7, 2015
by Lisa Rosenbaum, M.D.
New England Journal of Medicine. 2015 372:1860-1864.
May 7, 2015
by Lisa Rosenbaum, M.D.
New England Journal of Medicine. 2015; 372:1959-1963.
May 14, 2015
by Lisa Rosenbaum, M.D.
New England Journal of Medicine. 2015; 372:2064-2068.
May 21, 2015
Healthcare Renewal
by Roy Poses, M.D.
May 21, 2015
I’ll defer to Dr. Poses’ review of Rosenbaum’s logic. Earlier, I said that I couldn’t read Dr. Drazen’s editorial without having a contrarian inner voice constantly arguing with what I was reading [a contrarian frame of mind…]. And in spite of my attempts at reading what she had to say with an open mind, with each of Dr. Rosenbaum’s installments, that inner voice got louder and louder. She basically was proposing that the "moral outrage" at Conflicts of Interest was ingenuous, and reduced down to some kind of misguided politically correct anti-industry bias – a false and naive adherence to a utopian [but meaningless] standard. I was reminded of those Ayn Rand books like Atlas Shrugged where the brilliant movers and shakers are being held back by the self-righteous and mediocre masses. I’ve put the links up and it’s all on-line. I’m going to let it age for a day and reread it in the morning to see if it still looks like it does right now [which is pretty shameful]. And by the way, "What is this doing in the New England Journal of Medicine?"
Mickey @ 10:52 PM

tylenol deficiency and other headaches…

Posted on Wednesday 20 May 2015

There’s obviously more to say about Wunderink, but I wanted to stick in a few front burner items first:
The Globe and Mail
by ADRIANA BARTON
May. 17 2015

If serotonin is the “happy chemical,” then boosting our serotonin levels should keep depression at bay. After all, low serotonin brings on the blues, right? But the truth is, depression is not a serotonin deficiency. The idea that depression is caused by low serotonin levels is based on flimsy evidence dating to the 1950s. Pharmaceutical companies promoted the low serotonin story to sell Prozac and related antidepressants. They marketed a myth.

Today, the serotonin fallacy is as ingrained as the notion that drinking orange juice wards off a cold. Many of us still believe we are raising our serotonin levels to lift depression using wildly popular drugs known as selective serotonin re-uptake inhibitors, or SSRIS. But psychiatrists now say it is unlikely these drugs treat depression by simply increasing serotonin. While antidepressants help many patients, researchers have only a hazy idea of how they work. The consensus is that depression is a complex disorder with hundreds of potential underlying causes, said Dr. Roger McIntyre, head of the mood disorders psychopharmacology unit at the University Health Network in Toronto. “There’s really no scientific case to say that people who have depression have a deficiency in body and brain serotonin levels.”

The medical journal BMJ put the spotlight on the low serotonin doctrine in a recent editorial published in April and written by Dr. David Healy, a professor of psychiatry at Bangor University in Wales. Blockbuster sales of antidepressants such as Prozac are based on the marketing of the serotonin myth, Healy wrote. He added that pharmaceutical companies misled the public into putting too much faith in SSRIs.

Scientists never confirmed whether SSRIs raise or lower serotonin levels. “They still don’t know,” Healy said. Many of his peers suggest that Healy is not a respected figure in psychiatry, in part because of his stance that older tricyclic antidepressants are better than today’s Prozac-type drugs. His colleagues maintain that SSRIs are safer if taken in overdose than older antidepressants, and caution that patients should not switch medications based on Healy’s views. Nevertheless, most psychiatrists agree that depression is not a matter of serotonin levels being up or down. The role of serotonin in depression is best described as a “dysregulation” of the serotonin system, McIntyre said.

The serotonin system regulates aspects of behaviour, thought processes and mood. But it also interacts with other brain systems that may be involved in depression. Modern antidepressants block the re-absorption of serotonin in the brain. When researchers discovered that SSRIs helped depression in some patients, they concluded that low serotonin must be the cause of the disorder. But the assumption was no more valid than the notion that “having a headache means that your Tylenol levels are low,” McIntyre said. McIntyre described psychiatrists as being “guilty of exuberance” when they framed depression as a low serotonin problem.
David Healy’s editorial has gotten lots of play…
Maybe it was the just right time to put the Serotonin Myth to rest. Whatever the reason, it is long past due. And McIntyre’s line in this piece, ‘the assumption was no more valid than the notion that “having a headache means that your Tylenol levels are low,”‘ is an instant classic!

But on the darker side of the street:
AllTrials
18 May 2015
hat tip to Ferrell…  
The Guardian
by Sarah Boseley
18 May 2015

The long-fought battle for greater transparency in human drug trials is facing a major setback after a legal challenge against full disclosure from within the pharmaceutical industry. The Health Research Authority, which authorises trials and works to ensure the safety of patients taking part, has proposed that all drug trials must in future be registered. A judicial review has now been brought by a leading clinical trials company, challenging the plans for reform.

In the past, some drug companies have airbrushed out bad results by not publishing them, which could result in a drug appearing to work better and more safely than it does in reality. Many scientists, campaigners and health bodies have applauded the HRA’s proposals, which recently include a requirement on those running trials to ensure all previous studies they were involved in have also been registered – to try to bring historical data to light.

But Richmond Pharmacology, a company which conducts clinical trials on behalf of major pharmaceutical firms, has received permission to bring a judicial review of the HRA’s plans. Sense About Science, one of the organisations behind the AllTrials campaign for clinical trials transparency, says it is appalled that the issue is to be brought before the courts. “It is shocking that a company is using court action to try to stop transparency,” said Síle Lane, director of campaigns. “Hidden and unregistered trials are compromising patient care, and, rightly, causing public outrage.

“The HRA has really led the way with its proposals to check that clinical trials aren’t kept hidden during the trial approval process. Hundreds of members of the public, patients, researchers, doctors and pharmacists have told the HRA that this is exactly what it should be doing. They want the HRA to help right the injustice done to the thousands of patients who have taken part in clinical trials that have been kept hidden. I find it deplorable that one company is trying to stop that”…

The campaigners want to ensure that negative results are just as available as those from trials that succeeded in showing a drug was beneficial. From antidepressants such as Seroxat to the flu drug Tamiflu, it has been publicly argued that some drugs have worrying side effects or work less well than the published data suggests. Richmond Pharmacology said it was not at liberty to comment at the moment, because the case was in the hands of its lawyers.
Things never go as smoothly as we’d like, and I suppose that this kind of thing is to be expected, but it takes its toll. The Abbvie/Intermune assault on Data Transparency with the EMA was a setback that took some of the fire out of the EMA’s Program. And this feels like "here we go again" [Company Challenges UK Clinical Trial Transparency Rules].
Mickey @ 2:13 PM

comments…

Posted on Monday 18 May 2015

I was gone all day Saturday. I’m the BAR-B-Qist for our community, and it was a beautiful day for it. When I got up Sunday, there was an email from a Statistician with a ton of work for me to do. And then I read the comments and the emails about the comments, and my mood sunk. So I turned them off, because I had other important things to attend to. There was nothing wrong with the things people said, but it was the tone. It got contentious again. Let me be clear, I, 1boringoldman, don’t like that. One can make a point without doing it. I’m not going to moderate comments. The reason is simple. I don’t want to. If one of those obviously crazy comments shows up, I’ll deep-six it. But for regular commenters, I’ve got plenty on my plate as it is, and comment-cop just isn’t on my top ten list of fun things to do. So I turned the comments back on and am leaving it up to those of you who comment to make it safe. It’s your space – not mine. If you’ve got something to say to me in private, use 1boringoldman@gmail.com.

Mickey @ 10:07 PM

a contrarian frame of mind…

Posted on Monday 18 May 2015

"Over the past two decades, largely because of a few widely publicized episodes of unacceptable behavior by the pharmaceutical and biotechnology industry, many medical journal editors [including me] have made it harder and harder for people who have received industry payments or items of financial value to write editorials or review articles. The concern has been that such people have been bought by the drug companies. Having received industry money, the argument goes, even an acknowledged world expert can no longer provide untainted advice. But is this divide between academic researchers and industry in our best interest? I think not — and I am not alone. The National Center for Advancing Translational Sciences of the National Institutes of Health, the President’s Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration are but a few of the institutions encouraging greater interaction between academics and industry, to provide tangible value for patients. Simply put, in no area of medicine are our diagnostics and therapeutics so good that we can call a halt to improvement, and true improvement can come only through collaboration. How can the divide be bridged? And why do medical journal editors remain concerned about authors with pharma and biotech associations? The reasons are complex. This week we begin a series of three articles by Lisa Rosenbaum examining the current state of affairs."
by Jeffrey M. Drazen, MD, Editor
NEJM 2015 372:1853-1854.

We are currently in the midst of a three part series of articles in the New England Journal of Medicine making the case that we’re overly concerned about medical experts having financial ties to industry – specifically, their being excluded from writing "editorials or review articles" in our medical journals. The series is introduced with an editorial [Revisiting the Commercial–Academic Interface] by editor Jeffrey M. Drazen, MD [excerpted above]. The thing is – I know from the outset that I’m guaranteed to disagree with what this editorial and the articles that follow are going to say before I read a word. We have taken such a massive hit in psychiatry along in this area that it’s hard for me to believe the NEJM is even publishing such a series. And when I read them, I find myself generating contrary-arguments, rather than following what the editor or author says with an open mind. I know I’m biased. But I come by that bias honestly. I already have a slant in my mind on this topic. For example, when Dr. Drazen writes…
    Over the past two decades, largely because of a few widely publicized episodes of unacceptable behavior by the pharmaceutical and biotechnology industry, many medical journal editors [including me] have made it harder and harder for people who have received industry payments or items of financial value to write editorials or review articles
I’m thinking…
    A few? You’ve got to be kidding me – they’re everywhere! And it’s not just editorials and review articles. How about all those RCTs that were really written by paid expert medical writers instead of the guest authors, the key opinion leaders, whose names appear on the by-line? Didn’t you read my last post? what Dr. Healy said "But perhaps an even greater shame will be seen to lie with the fact that, during this era, most publications on on-patent drugs in our best journals were ghost-written"?
Instead of thinking about my own bias, I’m wondering about Dr. Drazen’s bias. And earlier, when he gives this example…
    In the mid-1940s, Selman Waksman, a soil microbiologist, and his team discovered streptomycin, an antibiotic with action against the tubercle bacillus. Although he was able to show efficacy in the laboratory, Waksman realized that if his discovery was to be of value to the world, he needed a partner capable of manufacturing adequate amounts of the material under conditions that would make it suitable for use in humans. He therefore struck a deal with Merck to produce streptomycin for clinical use. Soon thereafter, the British Medical Association undertook a large randomized, controlled trial of streptomycin for the treatment of tuberculosis. The results, including a description of the utility of streptomycin and resistance to it, were published in the British Medical Journal. This partnership between an academic researcher and a drug company went on to alleviate substantial human suffering and should be a model for current behavior. Unfortunately, it is not.
I was thinking something like…
    But that’s not the rule. That’s an exception. Waxsman was one of those exceptions in science. He had ‘nailed’ the treatment of Tuberculosis. He didn’t have to sell us anything or refine any arguments.  We were eager to hear what he had to say. And we already knew about his industry connections. There weren’t any secrets or hidden motives to wonder about.
Editor Drazen mentions powerful groups that are encouraging greater interaction and cooperation between academic institutions and industry:
    The National Center for Advancing Translational Sciences of the National Institutes of Health, the President’s Council of Advisors on Science and Technology, the World Economic Forum, the Gates Foundation, the Wellcome Trust, and the Food and Drug Administration are but a few of the institutions encouraging greater interaction between academics and industry, to provide tangible value for patients. Simply put, in no area of medicine are our diagnostics and therapeutics so good that we can call a halt to improvement, and true improvement can come only through collaboration.
But once again, I’m thinking…
    That interaction and cooperation between academia and industry may well facilitate improvements in something. But what does that have to do with the question of bias when academics with a financial relationship to a company write a review or editorial about that company’s product in an academic journal? An academic can interact and cooperate without money changing hands…
Plato's Academy [Pompeii Mosaic]And so it goes as my bias generates contrarian counters to his arguments. Back in the days of the Academy in Ancient Greece, a time when they fell in love with the rules of argument and logic, they initially thought they could reach absolute truth with their debates. So they studied logic and cataloged wrong arguments as the fallacies. Then along came questions of bias, and motive, and later even unconscious motive. And the sacred olive groves of Plato’s Academe [and later Aristotle’s Lyceum] moved from the quest for dogmatic truth to becoming cloistered havens for skepticism and a questioning attitude. And Academia has been under siege ever since [with arguments not unlike the ones coming from this NEJM series].

In psychiatry, this kind of rationalizing away Conflicts of Interest has characterized the current era with disastrous results. We almost don’t have much we can call academia any more. When we look at RCTs, it’s hard to even locate an industry-funded Clinical Trial that isn’t ghost-written  with authors on the by-line with extensive financial connections to industry. The sacred olive grove full of scholars has been replaced with professional Key Opinion Leaders, professional Medical Writing companies, Clinical Research Organizations, and Pharmaceutical Marketing Departments.

I’m going to try to read the coming three part series with an open-ish mind, but this prequel feels a lot like the introduction to a polemic that will evoke a similar contrarian frame of mind…
Mickey @ 9:44 PM

why not also?…

Posted on Friday 15 May 2015

In a recent discussion about the origin of the chemical imbalance notion of depression [see guilding the lily…], I mentioned a BMJ Editorial by David Healy [available online]…
… that ends with "so long, and thanks for all the Serotonin" – an allusion to Douglas Adams’ So Long, And Thanks For All The Fish [the fourth book in the Hitchhiker’s Guide to the Galaxy Trilogy]. It’s what the Dolphins said when they disappeared from earth, knowing that the earth was about to be destroyed – for good. It’s the kind of finality he’s suggesting we put on the Serotonin Depression Myths…

In his response yesterday to various comments, Dr. Healy is much more direct and speaks to a very obvious point:
I wrote an almost identical editorial in 1991. Covering the marketing of serotonin in 1997, I cited Jerome Gaub’s 1767 opinion of Leibniz’s views on the relations between mind and body—it is a “fable whose novelty has recommended it, whose recommendation has spread it, whose spread has polished it, refined and adorned it with … a pleasing look of truth.”

I use selective serotonin reuptake inhibitors [SSRIs]. Nevertheless I believe the SSRI era will soon stand as one of the most shameful in the history of medicine. The shame does not stem from what drug companies have done, which is only what might have been expected, but from the failure of doctors to know as much as they should have done about drugs they dish out so liberally. A recent study showing how a dollop of neuroscience dressing can disguise otherwise meaningless material should be compulsory reading for doctors who are, after all, the true consumers of these drugs.

But perhaps an even greater shame will be seen to lie with the fact that, during this era, most publications on on-patent drugs in our best journals were ghost-written. In addition, during this time journals refused to demand access to trial data as the price for publication — this is most clearly demonstrated in the area of antidepressant studies on children. It has been an era when industry has controlled journals, by spending money on some of them and by intimidating others.
I heartily agree. And while this is one of the more important announcements we’ve heard recently [and I applaud the decision]…
by Elizabeth Loder and Trish  Groves
British Medical Journal. 2015 350:h2373

Heeding calls from the Institute of Medicine, WHO, and the Nordic Trial Alliance, we are extending our policy. The movement to make data from clinical trials widely accessible has achieved enormous success, and it is now time for medical journals to play their part. From 1 July The BMJ will extend its requirements for data sharing to apply to all submitted clinical trials, not just those that test drugs or devices. The data transparency revolution is gathering pace.2 Last month, the World Health Organization [WHO] and the Nordic Trial Alliance released important declarations about clinical trial transparency.

These announcements come on the heels of the US Institute of Medicine’s [IOM] report on sharing clinical trial data, which called for a transformation of existing scientific culture to one where “data sharing is the expected norm.” The efforts of industry, too, must be acknowledged, some of which caught many people by surprise. In particular, Medtronic’s cooperation with the Yale University Open Data project and GlaxoSmithKline’s leadership on data disclosure efforts stand out.

WHO’s statement on public disclosure of clinical trial results and the accompanying rationale reiterate the organisation’s support for registration of clinical trials. WHO declares that the main results of clinical trials should be posted on a clinical trial registry or other acceptable website and submitted for journal publication within a year of study completion. The expectation is that results will be “made available publicly at most within 24 months of completion.” The statement does not call for mandatory sharing of primary data from trials but instead “encourages” sharing of research datasets “whenever appropriate.”

In a move that is particularly welcomed by Ben Goldacre, cofounder of the AllTrials campaign, WHO also recommends disclosure of previously conducted but unreported clinical trials in a searchable and free registry and says it is “desirable” that these trials should be published in a peer reviewed journal. Goldacre notes that this is important because “the overwhelming majority of prescriptions today are for treatments that came onto the market — and were therefore researched — over the preceding decades rather than the past five years”…
… why not also say, "NO GHOST WRITTEN ARTICLES ACCEPTED? If discovered after the fact, they will be retracted! noisily!"
Mickey @ 8:00 AM

persistence…

Posted on Thursday 14 May 2015

A commenter mentioned some studies, Harrow and Wunderink, and I was snappy. I have acquired snappiness writing this blog from instances where some piece of what I said is questioned and I answer only to find myself being asked to defend forced drugging, commitment laws, ECT, biomedicine, corporate greed, and any number of things that I really have nothing of worth to say anything about. I’ve identified when I feel it [my acquired snappiness]. It’s when I’m being cast in a role as a straw man. One would think I’d be used to it since transference is a central piece of the kind of therapy I did for a career. I think the difference is that being a straw man is just being a target [a narcissistic insensitive biomedical psychiatrist living in a mansion paid for with ill-gotten PHARMA profits]. Being a transference object as a therapist is in the service of learning something useful that might help understand and alter the course of a life. But I snapped  at this commenter, perhaps prematurely, because my post was actually opposing the maintenance drug meme.  Thinking about it later, as often as I’ve heard "Harrow and Wunderink" held up as a banner, I haven’t read either. So here’s one of them – Wunderink. The oft quoted paper is from 2013, but it’s a follow-up to an earlier study published in 2007:

Quantitatively, my experience with Schizophrenia was in a charity hospital in the mid-70s [the end of deinstitutionalization and the disappearance of Mental Hospitals]. Schizophrenia + Socio·Cultural deprivation is a hard way to live and that’s most of what I saw. Later, knowing my interest in the illness, I was referred some Schizophrenic patients along the way by former students. I had the idea that I could slowly aim for medication free life for them, but my experience wasn’t what I planned. I couldn’t bring it off. It was, instead, exactly what Wunderink et al reported in 2007:
by Wunderink L, Nienhuis FJ, Sytema S, Slooff CJ, Knegtering R, Wiersma D.
Journal of Clinical Psychiatry. 2007 68[5]:654-661.

OBJECTIVE: To compare the consequences of a guided discontinuation strategy and maintenance treatment in remitted first-episode psychosis in terms of relapse rates and functional outcome.
METHOD: The study was conducted in 7 mental health care organizations and the Department of Psychiatry of the University Medical Center Groningen in The Netherlands, covering a catchment area of 3.1 million inhabitants. A sample of 131 remitted first-episode patients, aged 18 to 45 years, with a DSM-IV diagnosis of schizophrenia or related psychotic disorder was included [i.e., all patients with a first psychotic episode from October 2001 through December 2002 who were willing to participate]. After 6 months of positive symptom remission, they were randomly and openly assigned to the discontinuation strategy or maintenance treatment. Maintenance treatment was carried out according to American Psychiatric Association guidelines, preferably using low-dose atypical antipsychotics. The discontinuation strategy was carried out by gradual symptom-guided tapering of dosage and discontinuation if feasible. Follow-up was 18 months. Main outcome measures were relapse rates and social and vocational functioning.
RESULTS: Twice as many relapses occurred with the discontinuation strategy [43% vs. 21%, p = .011]. Of patients who received the strategy, approximately 20% were successfully discontinued. Recurrent symptoms caused another approximately 30% to restart antipsychotic treatment, while in the remaining patients discontinuation was not feasible at all. There were no advantages of the discontinuation strategy regarding functional outcome.
CONCLUSIONS: Only a limited number of patients can be successfully discontinued. High relapse rates do not allow a discontinuation strategy to be universal practice. However, if relapse risk can be carefully managed by close monitoring, in some remitted first-episode patients a guided discontinuation strategy may offer a feasible alternative to maintenance treatment. Further research is needed to find predictors of successful discontinuation.
It was uncanny reading this earlier article. I had looked it up because the later article was confusing about how these two groups differed [Maintenance vs Dose Reduction/Discontinuation] and I thought it might be clearer in this original study. It wasn’t. It was clinician’s choice. They concluded what I had been taught in training in the 1970s, and what I retired thinking in 2003 from experience. In my practice years, I was seeing less world-weary patients, and a relapse was a big deal, putting a strain on relationships, family, employment, and, of course, finances. So I had a few patients who ended up living medication-free, but it was way on down the road [and there was medication always on hand if needed]. That wasn’t how I wanted it to be. It’s just how it was. I ended my time in grade more in the aiming-for-medication-lite camp. And to be honest, the advantage over the old neuroleptics of the gentler atypicals kind of  melts at lower doses – so I mostly ended up using the [generic] older drugs. Now on to Wunderink et al in 2013:
by Lex Wunderink, MD, PhD; Roeline M. Nieboer, MA; Durk Wiersma, PhD; Sjoerd Sytema, PhD; Fokko J. Nienhuis, MA
JAMA Psychiatry. 2013 70[9]:913-920.

IMPORTANCE: Short-term outcome studies of antipsychotic dose-reduction/discontinuation strategies in patients with remitted first-episode psychosis [FEP] showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before.
OBJECTIVE: To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction/discontinuation [DR] vs maintenance treatment [MT] trial.
DESIGN: Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR.
SETTING: One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million–population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission.
PARTICIPANTS: After 7 years, 103 patients [80.5%] of 128 patients who were included in the original trial were located and consented to follow-up assessment.
INTERVENTION: After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician.
MAIN OUTCOMES AND MEASURES: Primary outcomewas rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy [MT or DR] was controlled for baseline parameters.
RESULTS: The DR patients experienced twice the recovery rate of the MT patients [40.4%vs 17.6%]. Logistic regression showed an odds ratio of 3.49 [P = .01]. Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates.
CONCLUSIONS AND RELEVANCE: Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice.

I’ve shown their data looking at the traditional endpoint – relapse rate. It’s interesting. When they looked at the five years that followed their original two year study, a couple of years after that first study, the groups equalized. I’m not sure we can make a lot out of the difference in that last year where there’s a possible reversal so I’ll leave that to you to ponder.
No relapse occurred in 36 patients [34.9%], 20 of whom were in the DR group [38.5% of all DR patients] and 16 in the MT group [31.4% of all MT patients]. The number of patients with a certain number of relapses in the DR [range, 0-5] and MT [range, 0-8] groups did not differ significantly [Pearson χ2 6 = 4.96; P = 0.55].
But what happened in the two years after their initial study looks rock solid to me. However, the thing that distinguishes this study is that they had looked not only at relapse rate, but at parameters correlated with functional recovery. My added background colors show the phases in this follow-up study: violet, the original two year study; any-icky-green, the follow-up to seven years total; dark-icky-green, the period where they looked at their symptomatic and functional parameters. And here’s the part of this study that people are impressed with [in red]:
And it is impressive. They more than doubled the Recovery and Functional Remission Categories [Categories are not exclusive which is why the sums don’t add up]. So how did they measure these characteristics?
Symptoms were assessed with the Positive and Negative Syndrome Scale [PANSS]. The PANSS was used to measure observer-rated severity of symptoms during the preceding week, as well as during the past 6 months.

Social functioning was assessed with the Groningen Social Disability Schedule [GSDS], a semistructured investigator based interview measuring disabilities in social functioning in 8 domains [7 of which were included in this study] over the past 4 weeks, as well as during the past 6 months. The 7 domains are self-care, housekeeping, family relationships, partner relationships, relationships with peers, community integration, and vocational functioning. The parenthood domain was omitted because of limited applicability. A disability is rated by the investigator on a 4-point scale: none [0], minimal [1], obvious [2], and serious [3].

Definitions of Recovery, Symptomatic Remission. Relapse, and Functional Remission

Criteria for recovery were met when patients had symptomatic and functional remission for at least 6 months at the 7-year follow-up. Criteria for symptomatic remission were adopted from Andreasen et al. All relevant PANSS item scores have to be 3 [mild] or less on a scale ranging from 1 [not present] to 7 [severe] during an observational period of 6 months. Patients were assessed retrospectively for any symptomatic re- lapse occurring during this period. A symptomatic relapse was defined as an exacerbation of symptoms during at least 1 week with at least 1 relevant PANSS item score above 3 [mild]. Any relapse in symptoms during the 6 months preceding the assessment prevented the individual from being categorized as recovered at the time of the assessment.

According to generally accepted views, functional remission implies proper social functioning in the main domains of everyday life. The 7 domains of the GSDS included in the present study adequately represent these domains. A patient with functional remission should function adequately in all 7 domains with none or only a minimal disability in any of them [not allowing a score of 2 or 3 on any GSDS domain]. Patients were considered to have functional remission if, during an observational period of 6 months before assessment, all functional domain scores remained at 1 or lower.
I named this post "persistence" because [1] Wunderink et al persisted in following their cases and [2] you’re going to need to persist because I’m not done yet.

This is the part that’s hard to follow: What was the difference in medication use/dose between the DR [Dose Reduction/Discontinuation] and MT [Maintenance Treatment] groups? Complicated numbers, complicated analyses, complicated graphs. It’s available for all to read in full. Here’s the take home: During the two years at the end, in the DR Group, 11/52 [21%] were off all medications, and in the MT group, 6/51 [12%] were off all medications. Of those remaining on medications, the [Haldol Equivalent] doses were DR = 2.79 [2.21]mg  and MT = 4.08 [4.03]mg  with P=0.07 [there’s much more in the paper about this, but it’s not blogger-friendly].

There were some other things of interest. They looked at factors that might predict a good outcome in each of the categories [Recovery, Symptomatic Remission, and Functional Remission]. This is their table trimmed to only show factors with at least one significant correlation [in red; circled values were significant by step-wise logistical regression]:

Mostly, the usual suspects, but was interesting that the solid predictor of Symptomatic Remission was DUP [Days of Untreated Psychosis] – not Arm [DR vs MT]. I’ve had that thought myself – that if a person stays psychotic for a long time without initial treatment, they’re much less likely to respond to medication [as in Dan Markingson who was psychotic for months before his mother could get him home]. My guess is that with prolonged psychosis, paranoid beliefs set in and grow. Elaborate paranoid beliefs are the least treatable of the Schizophrenic symptoms.


I’m not going to paraphrase the author’s conclusions to this study. I think they do a fine job all by themselves, and I’m not interested in getting in their way. Hopefully this summary of their findings will stimulate your curiosity to read their thoughtful remarks. Remember, this paper and topic aren’t about ideology, mental health specialty, or anti-this-or-that. They’re about the best case treatment of First Episode Schizophrenia/Psychosis. For myself, I enjoyed this paper. I think I had felt a little guilty that my own bias in seeking the lowest possible antipsychotic dose [or none] had lead to some un-necessary psychotic breaks. One can always use a little reassurance along the way. I was also comforted that though my own cases were few, their experience was very similar to my own in carrying through with the Dose Reduction/Discontinuation mindset. It may be a goal, but in patient management, the clinical reality is always the compass that leads the way. And you don’t always get what you want

They ended with:
Of course, only one study indicating advantages of a DR strategy in patients with remitted FEP is not enough evidence in such an important matter. However, these results merit replication by other research groups.
Which is absolutely correct. I hope that’s happening somewhere. My own take on this is a more general and personal point. When I was in Internal Medicine, as much as I enjoyed the science of things, there was part of the practice that I didn’t like at all. The majority of the people that showed up with symptoms did not have a physical illness explaining why they came or were sent. And while most of them just needed some reassurance, there were a surprising number who obviously had something significantly wrong. And there would never be a future time when I could do anything about that as a busy Internist Specialist [which is what I was]. In those days, I was in a lull period – a military doctor on a [healthy] overseas Air Force base – and I did have plenty of time. So I started talking to those patients who had "negative" work-ups, and was amazed by what lay behind their symptoms. I didn’t know enough to always know what to do, but I could do a lot even in my psyche-naive state. I guess I got hooked. All those years ago, I decided that the essence of good medical care was providing someone to "follow along" and "think along" with any chronic illness, whether it be medical or psychiatric. And I still believe that forty plus years later.

So I gravitated to psychiatry. And just after I had finished my training, Psychiatry and Managed Care decided I shouldn’t take the time to do that anymore. Now they even want me to do Collaborative Care and not even see the patients. I said and say no thanks to all of that – and I’m glad I made that decision. In regard to the topic of this paper – First Episode Schizophrenia is a mega-big-deal in the life of a person and a family. These patients don’t just need Guidelines, they need a person to go along on the ride. It helps a lot if that person is not otherwise connected with their life and knows a whole lot about their illness. I had no interest in having some watchdog telling me what to do based on an accounting program, or some KOL premetabolizing medical information. So I never dealt directly with Insurance companies, and I adjusted my fees to fit the patient if I could. I dropped out of the APA from lack of interest [and relevance].

I think there’s a lot more to following a patient with Schizophrenia than just the medication prescription, more than something like CBT, or psychoanalysis, or anything that can be put down as a procedure. Whatever this condition is, it’s a hard way to be alive and the patients deserve whatever consistent ongoing benevolent interpersonal help they can rely on [and tolerate]. And it sometimes needs to be without an ending.

[3] So there’s my third reason to call this post "persistence"
Mickey @ 1:06 PM

prelapse: but there’s more…

Posted on Tuesday 12 May 2015

Recently, when I was reviewing two RCTs for Brexpiprazole, a derivative of Abilify®, I found that each study had only one academic author for each. The rest were pharmaceutical company employees. Both articles had "editorial assistance" [AKA ghost-writers] from the same firm and both were funded and administrated by the drug’s sponsor – Otsuka. Looking further, the two academic authors were from the same Department of Psychiatry at Hofstra and both were associated with the Feinstein Institute. And the two studies were spread over 117 clinical sites all over the US and World [the spice must flow…]. So everything about the studies was industry generated. But there’s more. One of the Brexpiprazole academic authors was also the senior author on a recent Abilify Maintena® RCT and both of them were part of a free CME about Abilify Maintena® [machiavellian medicine lives…]. Otsuka is certainly getting its money’s worth from the Department of Psychiatry at Hofstra. But there’s more. One of the authors on everything I just mentioned, Dr. John Kane, is the Principle Investigator on the NIMH RAISE-ETP [Recovery After an Initial Schizophrenia Episode] Project as well as being Chairman of Psychiatry at Hofstra. That was last week.

But there’s more. This week, I read Johanna Ryan’s article [The Once and Future Abilify: Depot Injections for Everyone?] and found that Dr. John Kane is Principle Investigator on the PRELAPSE study I’ve been talking about here using Abilify Maintena® in first episode Schizophrenia. The study is going to be done by a new CRO, Vanguard Research, at the Feinstein Research Institute. Watch the video to hear Dr. John Kane, founder of Vanguard, discuss this PRELAPSE RCT and hear how the Vanguard network arose from the NIMH study [RAISE?]. Now look at this Newsday article describing the $28M deal to do this study.
Vanguard will manage a clinical trial evaluating Abilify Maintena®, a once-monthly injectable version of a blockbuster drug made by Otsuka America Pharmaceutical Inc. Vanguard is majority owned by North Shore-LIJ. Dr. John Kane, the health system’s senior vice president of behavioral health services, owns a minority stake.
So Abilify® is about to go off-patent, and we have all of this activity – and every bit of it has Dr. John Kane plastered right in the middle of things. The rule is supposed to be that there shouldn’t even be a possibility of Conflict of Interest. In this tangle, Conflict of Interest is all there is to see. This is going to be a short post, because I can’t think of anything to say. The PRELAPSE study is designed to carve out a new commercial indication for Abilify Maintena®, not for any valid clinical reason that’s apparent to me. This is the Academic·Industrial·Complex with Dr. John Kane and Otsuka at the helm at its worst. I rest my case on the evidence as presented…
Mickey @ 10:45 PM

prelapse: prequel2

Posted on Tuesday 12 May 2015

Back in the 1970s, the depot injectable antipsychotics were around and much discussed as a solution to non-compliance in patients who had frequent relapses because as soon as they left the hospital, they stopped taking medications. There were Prolixin Clinics, and visiting nurses who took the medication to the patients. It seemed to me that it sounded like a better idea than it was, at least in the inner-city environment where I worked. Besides the Big Brother [1984] feel to the scheme, many of the patients were as unlikely to show up for their monthly injection as they were to take their oral medication.  In recent history, the Long Acting Injectable [LAI] Atypical Antipsychotics tend to be released late as the drugs go off-patent, presumably as a patent extension ploy [above].

The  PRELAPSE study that I introduced in prelapse: prequel1  is unique in my experience. I was alerted to it by Johanna Ryan of RxISK and Mad-in-America in her well researched post [The Once and Future Abilify: Depot Injections for Everyone?]. They are proposing to start off with a depot antipsychotic in first episode of Schizophrenia. I suppose the logic is to get off "on the right foot" by using a depot medication from the get-go to pre-empt any noncompliance problems. Their proposal is to divvy up clinical sites, half of which will use treatment-as-usual with oral antipsychotics of the clinician’s choice, and the other will use the injectable Abilify Maintena®. They plan to compare the groups at two years.

Well, out of the gate, that study doesn’t make much sense. First, do I want to commit a patient to maintenance antipsychotics the day I meet him/her? What about the patients whose psychosis is short-lived and may never return?  Brief Reactive Psychosis it’s called? What about at least giving the patient the chance to recover and remain medication-free if possible. The depot medications have traditionally only been used for patients who have a recurrent relapsing pattern and are medication non-compliant. And there are plenty of people who would see this scheme as "forced drugging." But my complaint is something else, and why I started with the Dan Markingson story in prelapse: prequel1. When you treat a case of a first episode of Schizophrenia, you pick a drug and a dose, and monitor the response – adjusting the dose or changing drugs based on the patient’s clinical response. Some patients are very sensitive to the EPS symptoms or other side effects of one drug, and you don’t know that until you try. The goal is the minimum effective dose and that’s determined by usage. Some patients don’t respond to one medication, but another works just fine. With a depot medication, you’re committed from the start.

That’s what I think happened to Dan Markingson. He was started on a fixed dose of a drug in a blinded study. I don’t think he ever fully responded. He needed a clinician who was on top of things and tried upping the dose, or changing drugs – the kind of medication tweaking that’s necessary with many of the drugs we use in medicine. With depot medication, that’s always going to be impossible. I’d never do what’s suggested in this study in the real world of clinical psychiatry. Since these depot medications have been around for at least forty years, why didn’t we think of doing this a long time ago? There must be some other factor in deciding to try this scheme in first episode cases.

Well we know what that factor might be. Abilify® is a blockbuster drug extraordinaire, topping the revenue charts with $5.7B in profits last year. And it’s about to go off-patent meaning that the generic version is just around the corner. We’ve already discussed the fact that Otsuka is submitting Brexpiprazole to the FDA for approval. Brexpiprazole is a kissing cousin to Abilify® that they hope will help them hold on to some of the Abilify® market share [see the spice must flow…, machiavellian medicine lives…, and chunk of change…]. And this push seems to be in that same mold, extending the use of Abilify Maintena® into the first episode cases. But there’s another big piece of this story that gets us into a Conflict of Interests realm. Stay tuned…
Mickey @ 12:00 PM

prelapse: prequel1

Posted on Tuesday 12 May 2015

It’s not easy to talk about the condition we call Schizophrenia these days. Much of the controversy is about long the term management, giving antipsychotic medication not to treat an existing problem, but rather to prevent relapses – the chronic treatment of the chronic patient. Our existing antipsychotic medications aren’t much fun to take – having side effects, and in some cases, irreversible and debilitating side effects. On the other hand, maintenance antipsychotics do significantly decrease the incidence of relapse. And the tendency of patients with Schizophrenic illness to spontaneously stop taking medications is legendary. Anyone reading this likely has an opinion about how to deal with maintenance antipsychotics, and mercifully, that’s not what this post is about so we can table that particular rhetoric and its usual discord for the moment.

One solution is to use depot antipsychotics meaning the patient gets a shot monthly rather than pill[s] daily. And in some instances, these depot injections have been court ordered – known as a form of the "forced drugging" bitterly opposed by many activists. Again, not exactly the topic here, but it’s getting closer. I think almost all of us agree that the first episode of Schizophrenia is a special case. While the course up ahead is  unknown, most feel that our best chance of preventing a downhill course of illness is in how we handle that initial episode [we’d like to keep a psychotic break from ever happening at all, but efforts in that sphere have yet to bear fruit]. And that brings us to a case most of us know pretty well by now – Dan Markingson [his story is here].

Putting aside all the tragedy of that story for the moment, Dan was in a study for patients having their first episode of psychosis [CAFE]. It was a fairly straight-forward trial. The patients were blindly assigned to one of three Atypical Antipsychotics and followed for a year. You left the study one of three ways: Completion; Voluntary Withdrawal; Removed by a clinician [non-response]. This study was a clone of an earlier NIMH study, CATIE, except CAFE was acute rather than chronic cases. But that’s a big difference. The chronic patients in CATIE were known antipsychotic responders put on medication to see how long they would take it – a tolerability study. I can’t imagine treating a person with a first break with an unknown medication and dose. Treating an acute episode means adjusting the dose or changing drugs based on the response. I wouldn’t mind the patient or rater being blinded, but not the clinician. Had I been on the IRB, I’m sure I would’ve voted "no."

By my read of Dan’s case, he didn’t ever really respond to the medication, and after six months, he suicided – a tragedy that might have been prevented had his doctors been more vigilant and done the usual playing with medication and dose until they found something that worked. While that might not have worked, it was certainly a real possibility that was never tried – and if he hadn’t been in that study, it would’ve surely been attempted. And that brings us to another study in the works – PRELAPSE – the real topic of this post. Here’s the blurb from Clinicaltrials.gov:

The goal of this project is to show that the best possible option for preventing relapses in patients suffering from first episode [<1 year of anti-psychotic medication] or early phase [<5 years of lifetime exposure to anti-psychotic medication] schizophrenia is by enhancing medication adherence. The study is designed to answer the question of whether the use of long-acting injectable [LAI] antipsychotics early in the course of treatment can break the cycle of frequent relapse that affects so many patients with early phase schizophrenia. The participating research sites [not individual patients] will be randomly assigned to either medication prescribed by their treating physician [with no restrictions] or to a regimen that involves a monthly long acting injectable antipsychotic. The sites will be assigned on a one to one basis to either of the arms taking into account types of patient population and geographical area. Patients enrolled in the study will participate in regular assessments either over the phone or in person and be followed for a period of 2 years. The primary outcome measure is time to first hospitalization.
The drug here is Abilify Maintena®, the depot form of Abilify® [Aripiprazole]. So the study brings up two semi-separate issues: the use of depot medications to deal with medication compliance and the treatment of a first episode of Schizophrenia with a fixed dose of depot medication. This is a stopping place, but there’s more to come…
Mickey @ 10:00 AM