a pilot…

Posted on Thursday 2 April 2015

Living in the UK in the1970s practicing in an a US Air Force Hospital near one of the UK’s primo Hospitals [Addenbrooks, in Cambridge] was interesting. Suffice it to say that our systems and expectations are very different. I never quite ‘got it‘ – except to say ‘very different‘ and ‘interesting.’ I think I understand the term, ‘service users‘ in the papers I’m about to discuss. It means, ‘people who rely on the National Health Service‘ for their health care – according to Wikipedia, that’s 92%. If I understand correctly, NICE [National Institute for Health and Clinical Excellence] sets treatment guidelines one of which is to offer CBT [16 sessions] to service users with Schizophrenia, but it’s not really available through the NHS. That adds a commercial element to the issues brought up by the BPS report [or I could’ve misread the whole thing].

Three years ago, there was a hot and heavy debate about including the Attenuated Psychosis Syndrome in the DSM-5. There were two major groups working on trying to identify ‘prepsychotic states’ and preventing ‘overt psychosis’ – Patrick McGorry in Australia and Anthony Morrison in Manchester UK:
At the time, I felt this was a worthy endeavor, but like most worried that it would open a door to even more over·medication. As it turned out, this move died out primarily because the initial excitement about identifying "prepsychotic" patients just didn’t pan out. But I recall thinking that Dr. Morrison was giving it a yeoman’s try with CBT and CBT+Medications.

Flash Forward: A few weeks ago, the ISPS [THE INTERNATIONAL SOCIETY FOR PSYCHOLOGICAL AND SOCIAL APPROACHES TO PSYCHOSIS] held a Conference in New York. It was the site where the British Psychological Society launched the report [Understanding Psychosis and Schizophrenia] we’ve read so much about. Here are a couple of overviews from Mad In America – What I Learned at ISPS 2015 and Towards a New Understanding of Psychosis – ISPS 2015. From the latter:
There was the phenomenal work of Anthony Morrison, who is the first researcher to empirically show that psychotherapy can be effective with individuals diagnosed with schizophrenia, even when they choose to not take psychotropics. Although many know this intuitively, the scientific community is not really interested in intuition; for him to show this repeatedly through empirical data is profound.
Recognizing the name, I thought I’d take a look:
by Morrison AP, Turkington D, Pyle M, Spencer H, Brabban A, Dunn G, Christodoulides T, Dudley R, Chapman N, Callcott P, Grace T, Lumley V, Drage L, Tully S, Irving K, Cummings A, Byrne R, Davies LM, and Hutton P.
Lancet. 383[9926]:1395–1403

BACKGROUND: Antipsychotic drugs are usually the first line of treatment for schizophrenia; however, many patients refuse or discontinue their pharmacological treatment. We aimed to establish whether cognitive therapy was effective in reducing psychiatric symptoms in people with schizophrenia spectrum disorders who had chosen not to take antipsychotic drugs.
METHODS: We did a single-blind randomised controlled trial at two UK centres between Feb 15, 2010, and May 30, 2013. Participants aged 16-65 years with schizophrenia spectrum disorders, who had chosen not to take antipsychotic drugs for psychosis, were randomly assigned [1:1], by a computerised system with permuted block sizes of four or six, to receive cognitive therapy plus treatment as usual, or treatment as usual alone. Randomisation was stratified by study site. Outcome assessors were masked to group allocation. Our primary outcome was total score on the positive and negative syndrome scale [PANSS], which we assessed at baseline, and at months 3, 6, 9, 12, 15, and 18. Analysis was by intention to treat, with an ANCOVA model adjusted for site, age, sex, and baseline symptoms. This study is registered as an International Standard Randomised Controlled Trial, number 29607432.
FINDINGS: 74 individuals were randomly assigned to receive either cognitive therapy plus treatment as usual [n=37], or treatment as usual alone [n=37]. Mean PANSS total scores were consistently lower in the cognitive therapy group than in the treatment as usual group, with an estimated between-group effect size of -6.52 [95% CI -10.79 to -2.25; p=0.003]. We recorded eight serious adverse events: two in patients in the cognitive therapy group [one attempted overdose and one patient presenting risk to others, both after therapy], and six in those in the treatment as usual group [two deaths, both of which were deemed unrelated to trial participation or mental health; three compulsory admissions to hospital for treatment under the mental health act; and one attempted overdose].
INTERPRETATION: Cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs. Evidence-based treatments should be available to these individuals. A larger, definitive trial is needed.
Throughout the article, Morrison et al caution that this is a Pilot study that needs to be confirmed with a full definitive study. And that’s to their credit, since there are a number of methodological problems along the way. The primary outcome variable was the PANSS total score [PANSS positive + PANSS negative]. There were two groups of 37 subjects each: CT – treated with weekly Cognitive Behavior Therapy and TAU - treatment as usual. I’ve summarized their results here [I don’t have their raw data, so my results are on the observed cases without the adjustments to deal with missing values]. The statistical tests are mine:
The rows labeled "POSSIBLE" require some explanation [and here’s a graphic that may or may not help]:
The CBT Treatment was in the first 9 months, however:
Participants allocated to cognitive therapy received a mean of 13.3 sessions [SD 7.57; range 2–26], with each session lasting roughly 1 h [these figures do not include the four booster sessions that were available]. Adherence to cognitive therapy was reasonably good, with no patients not attending any sessions, and 30 [82%] having at least six or more sessions.
The subjects weren’t all in the study for a year and a half. Here’s the explanation [see the graphic above]:
… 74 individuals were randomised to the cognitive therapy plus treatment as usual group [n=37], or the treatment as usual alone group [n=37]. We stopped before the target of 80 individuals in accordance with our recruitment timeline, on the basis of restricted resources, to ensure that we had the possibility to obtain 9 month data for all participants. Baseline characteristics were similar between groups.
That means that 68% were in the study for all 18 months, 81% were in the study for at least 15 months, 92% for at least 12 months, and 100% for at least 9 months. Looking back at the table, two of the significant differences are at 15 and 18 months as the cohort is dwindling. Now another graph:
On the left, the dropouts appear similar, but it’s the number remaining ÷ the number POSSIBLE, and it goes up[?] Then on the right, it’s the change in scores from BASELINE for the two groups, and it makes no sense at all to me. The differences between the TAU group and the CT group are because the TAU scores went up[?] I have no clue what that means. Why would the untreated group get worse after the treated group was through with treatment? Since the change is coincident with the premature cutoff of the study, I thought it might have something to do with that, but again I can’t figure how. They reported their results in a very different way in their Table 3, a single effect estimate that I didn’t understand:
It’s there for the looking for the stats-types among you. They also queried a categorical variable, responders [a fall in PANSS total > 50%]:
By examination of the proportion of participants achieving good clinical outcomes in each disorder [defined by use of an improvement of >50% in adjusted PANSS total scores], we noted that, at 9 months, seven [32%] of 22 participants in the cognitive therapy group, and three [13%] of 23 from the treatment as usual group had achieved good clinical outcomes. At 18 months seven [41%] of 17 receiving cognitive therapy and three [18%] of 17 receiving treatment as usual had achieved good clinical outcomes.
By my calculation: 9 months [p=0.30 Fishers 2 tail NNT=5.3] and 18 months [p=0.31 Fishers 2 tail NNT=4.3]. So while I can see that the CT scores are lower that the TAU scores, I can’t find much in the way of statistical confirmation that there’s a difference using the only tools I have without the actual data.  And so I’m going to have to go with his caution that this is a Pilot Project rather that the conclusion in the abstract: "Cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia spectrum disorders who have chosen not to take antipsychotic drugs." And speaking of antipsychotic drugs – there were some after all:
With regards to use of antipsychotic drugs throughout the lifetime of the trial, ten [4%] of 37 participants in the cognitive therapy group were prescribed antipsychotics after randomisation [eight during the treatment window and two during the follow-up phase] as were ten [4%] of 37 in the treatment as usual group [nine during the treatment window and one during the follow-up phase].
I apologize for the rough tools I’ve used here. But that’s the whole point of the AllTrials campaign. We can’t really know what we’re seeing in a published paper on a Clinical Trial without some access to the raw data prior to manipulation. Both the British Psychological Society and NICE have signed the AllTrials petition, and I would hope that when there is a definitive version of this study, Morrison et al will publish their full data as a data supplement so that all of us can see what they see.

So in-so-far as I’m able to vet this study, I would see it as a pilot project showing a signal that deserves repeating, but I can’t confirm the opening quote above, the article’s conclusion, or the commentary on the article. Here’s the thing of it, my bias is on the side of confirmation. I support psychotherapeutic intervention in Schizophrenia. I’m not sure I would’ve picked CBT, but I’m not an CBT-er, and from what I can read, Morrison et al have adapted the technique to be used in this condition.

On the other hand, we’ve just been through a period where the Clinical Trial literature has been problematic to a fault, and many of the results have molded to the wishes of the sponsors rather than the data itself. The fight for Data Transparency has been long and hard, and is anything but over. And if we are to apply the standard of outside replication of analyses to the industry sponsored drug trials, we need to apply it to all trials, including a study like this. I’ve come the personal conclusion that a published article is only a proxy for the actual data [proxies…][see also Study Report, Study Reality, and the Gap Between].
hat tip to 1boringyoungman 
Mickey @ 11:15 AM

a clinical impression…

Posted on Monday 30 March 2015

David Healy has up a post about the Pilot Suicide/Murder last week [Winging it: Antidepressants and Plane Crashes]. There’s also one on his Rxisk site by Julie Wood [Pilots and Antidepressants]. Meanwhile, the Psych Listserves and Twitter feeds have been abuzz with speculations that this was an SSRI [or other Psych Med] reaction. David, who has done more than anyone to bring these reactions to our attention, does a yeoman’s job of laying out how this is likely to play out. So I’ll stay out of his way on that score, deferring to his expertise, but I do want to briefly comment on a statement he makes along the way:
There are likely to be a number of features to the current debate.
    First an impression will be created that we know more about these drugs than we in fact do.
We know almost nothing about what antidepressants actually do – we still don’t know what they do to serotonin. Rather than being effective like an antibiotic, these drugs have effects – as alcohol does. Their primary effect is to emotionally numb. Patients on them walk a tightrope as to whether this emotional effect is going to be beneficial or disastrous.
I’ve never actually read those bolded parts said that way – their primary effect is to emotionally numb – but that’s exactly what I have also concluded on my own that the SSRIs do – emotionally numb. It’s just confirming to read it in print. And I sure agree that We know almost nothing about what antidepressants actually do
Mickey @ 6:17 PM

clinician trumps ideology…

Posted on Monday 30 March 2015

Sometimes, frustration and impossibility are necessary components of learning. Try looking around on the Internet for something that captures the essence of the difference between legal and ethical, between the Rule[s] of Law and a Code of Ethics. There’s plenty to find, sure enough, but something about the last thing I found isn’t quite it, so I return to the search. As in the phrase, the letter of the Law, Laws cover a minimal definable and enforceable standard of behavior derived from Ethics, which are more felt than written, more the difference between wrong and not right. So it’s little wonder that the Case of Dan Markingson is finally being decided by a faculty senate, a panel from an accrediting agency, and a legislative body, instead of in a Court of Law. Equally telling, it has become a cause célèbre through the efforts of an academic department of bioethics.

It’s hard to imagine reading the details of Dan’s story without seeing how not right it was from day one to its tragic ending. In the narratives of most other problematic Clinical Trials, the misrepresented efficacy or de-emphasized patient harms are experience distant from the trial itself, showing up as impersonal statistics from later users of the drug. In this case, it was the conduct of the trial itself that did the damage, not just some mathematical trick in the analysis or sleight of hand in the presentation of the study’s outcome. This case is also unique in that the role of the particular academic institution involved is central to the publicity – the Department of Psychiatry, the Institutional Review Board, the Clinical Research Center, and the Administration at the University of Minnesota. And this story is populated – Charles Schultz, Stephen Olson, Eric Kaler, Dan Markingson, Mary Weiss, Carl Elliot, Leigh Turner, Mike Howard – actual people make the story more real. And of course, the fact that Dan killed himself in an altered state [making sense…] some six months after he was placed in this Clinical Trial is an indelible marker of its not rightness – un·ethical.

There’s something else unique about this case. The usual suspects aren’t incorporating it into the constant bickering about bio·medicine or ideology. One of the problems with those arguments is that without a real case they’re carried on in the abstract, so the waring parties can [and often do] have different patient populations in mind and talk at cross purposes. I wish I knew more about Dan’s clinical course, because what I think I know is confusing:
  • When his mother visited him in California June 2003, he was floridly delusional, yet was still able to convince the police that he was fine [see The Deadly Corruption of Clinical Trials].
  • His September emails were again quite delusional, as was his presentation in Minnesota in November. But again, after 12 days on Risperdal®, he seemed to have cleared [see Study Visits p. 5], passing of his former symptoms as "lack of sleep." yet, whistleblower Nikki Gjere said that he was "too sick to be in the study" at that time [a paradigm…., INVESTIGATORS: Nurse questions integrity of U of M drug researchers].
  • Notes from various sources and Dan’s journal suggest that for the last several months of his life, he was getting worse [making sense…]. From the journal:
      Mar 23, 2004: "world walking, you were at a farm house and we’re getting presents from dogs who had presents fastened in plastic bags to their snouts… in the gloaming and breening, you were thinking of naming it gloaming and greening or gloam-green. That was someone brings a snowslide in summer or midsummer. It has been left behind…" [Olson 2007 p. 467].
    But from what I can find, it certainly appears that Dan was very ill either on-and-off or throughout the study.
Again, the information is sketchy, but it suggests to me that he needed either a different drug, a higher dose, or both because he was obviously not responding to the study meds [if he was even taking them]. My point here is that when discussing an actual case, the ideological wars melt and people from multiple sides of a debate can usually agree. "Clinican trumps Ideology." And in Dan’s case, we all seem to be of one mind about his care no matter our different perspectives or degrees. That may be simply a wish on my part, but I hope I’m right. Then today, someone sent me an article about how inconvenient it is to have the Clinical Trial program shut down at the University of Minnesota [Researchers chafe at halt of psychiatric trials]. If I’m right about Dan’s clinical state, no one was looking at him closely in that Clinical Trial program, and shutting it down was absolutely the right decision – even if it was eleven years late. Rather than "chafing" that it was suspended, a better topic might be, under what circumstances should it ever be allowed to be reopened…
Mickey @ 2:11 PM

the exposome…

Posted on Saturday 28 March 2015

NIMH
by Tom Insel
03/26/2015

… This update of our Strategic Plan is a commitment to take a fresh look at our horizons so that we can refine priorities and energize our path of discovery.

We know that some scientists reject the concept of “directed science,” believing that science rarely follows a plan. True, important discoveries often result from serendipity or side roads rather than a premeditated, carefully articulated strategy. On the other hand…

While the tools of genomics and neuroscience now permit rapid progress, equivalent tools and paradigms to study environmental influences are just being developed. Over this next 5-year period, we can expect this new approach to environmental factors, sometimes called the exposome, to yield more scientific traction in understanding the mechanisms by which environmental factors alter brain and behavior, from prenatal development through the process of aging…

Strategic Plan Strategic Objective 3
Director’s Message Strategic Objective 4
Introduction Highlights
Strategic Objective 1 Appendix
Strategic Objective 2 References
Strategic Research Priorities
After a number of years of reading someone’s writing, you sort of pick up on their rhetorical style. For example, when Tom Insel is discussing something he’s been criticized for [like being a control freak], he always puts the criticism first ["important discoveries often result from serendipity"], then says something like "On the other hand…" and carries on along the path he favored in the first place, ignoring the criticism altogether. In this case, it means continuing to be a control freak. And watch out for his neologisms – things like genomics, protenomics, connectome,  – or buzz phrases – personalized medicine, translational medicine, neural circuits, etc. This new one [the exposome] is particularly creative [not to be confused with the envirome or the the interactome]. At first, I thought that the exposome looked promising [are we finally going to recognize that there are factors outside the genetic endowment that effect the mental state?]. But, alas, these are terms generated after the Genome Project that have to do with speculations about how the outside world might shape biology. I was looking for something more like having nutty parents or life-changing events. Oh well… And don’t let the brevity of my quotes and links up there fool you. They connect to a labyrinthine Strategic Plan [insert and grandiose]. There’s really not going to be much room left for that serendipity he was mentioning. For example [in Objective 1: Strategy 1.1]:
To unravel the mechanisms that lead to mental illnesses and target novel treatments to those mechanisms, more comprehensive descriptions of the molecules, cells, and circuits associated with typical and atypical behavior are necessary. What classes of neurons and glia are involved in a given aspect of mental function? Which brain regions contribute to a single thought or action, and how are these regions interconnected? These questions will be answered by defining the cellular components of circuits, including their molecular properties and anatomical connections. New tools and techniques that span biological scales—from single-cell analysis, to macro-electrode arrays, to systems-level brain imaging — are needed to address these questions.
I think the thing that bothers me the most, besides the impossibility of serendipity in Insel’s NIMH, is that his grand plan is monomaniacal and based on hypotheses cum speculations that have yet to be anchored in the reality of solid science. I’ve spent my days with the simple idea of a Hardware/Software dichotomy for mental illness [Hardware «Melancholia, Manic Depressive Illness, Autism; maybe Schizophrenia, etc» and Software «most everything else»]. So a lot of this stuff Insel dreams of has felt like he’s trying to reprogram a computer with a screw·driver and a soldering iron. I’ve focused more on the programming languages.

Pushing that simple analogy, many critics would go further and say that it’s all software [as in the BPS Report Understanding Psychosis and Schizophrenia] or Schizophrenia: a critical psychiatry perspective] taking the psycho·social·perspective to extremes, saying that mainstream psychiatry is totally at sea in its hardware bio·perspective. But as much as I enjoy reading about the neuroscience, my take on Insel’s NIMH 2015 Strategic Plan is that it’s wildly speculative, making fantasmagoric extrapolations that move way, way beyond the frontiers of anything we know [but then again, I felt something similar in the other direction about the those psycho·social articles].

Back to Insel, I first started thinking about his rhetorical On the other hand… trick back when I read this blog of his a few years ago:
NIMH: Director’s Blog
by Thomas Insel
January 26, 2012

NIMH, like all Institutes at NIH, has an advisory council that meets three times each year. The National Advisory Mental Health Council [NAMHC] is a distinguished group of scientists, advocates, clinicians, and policy experts. Each of our meetings includes a closed session to review individual grants considered for funding and a session open to the public that engages this diverse group in discussions about the larger issues that guide NIMH funding.

At last week’s session, we heard a recurrent tension around one such larger issue. Some members of Council bear witness to the poor quality of care, the unmet medical need, and the diminishing investments by states on behalf of people with mental disorders. They reasonably ask, “How are we ensuring that the science that NIMH has produced is implemented where the need is greatest?” They also question on the pay-off of genetics research. After all, two decades after the gene for Huntington’s disease was identified, we still have no effective treatments, and Huntington’s disease is genetically far simpler than schizophrenia or bipolar disorder. In contrast to so many neurological diseases, we have effective treatments for schizophrenia and bipolar disorder. NIMH should be investing to ensure these are available.

The opposing argument runs something like this. There has been no major innovation in therapeutics for most mental disorders since 1960. Current treatments are not good enough for too many. Rather than investing scarce dollars for incremental improvements or increased dissemination of mediocre interventions, we need invest in the fundamental science of brain and behavior so that we can understand how to develop better treatments…
And in that blog, at the end, he pulled out the polio miracle to bolster his case.
Sixty years ago, the nation faced a similar short-term vs. long-term debate about polio. The needs were growing and the causes were unknown. Some wanted funds invested only in better services, including improved iron lungs. Others argued for investing in a vaccine with a long-term goal of eradication. As David Oshinsky explains in his outstanding retelling of this debate, the government went with the services approach, leaving advocates and families to raise funds for vaccine development. Let us hope we don’t short-change our grandchildren, sixty years from today, by failing to invest in the long-term promise of more effective diagnostics and therapeutics for mental disorders.
I’m convinced that so long as it’s Insel’s show, the only alternatives are to send him on a prolonged [permanent] sabbatical or rename the NIMH the National Institute of Neuroscience. I mean that without tongue in cheek. He’s so far into his on-the-other-hand-land basic neuroscience that there’s little hope that he will ever take a balanced look at Mental Health. Even when they fund a study like RAISE-ETP in First Episode Schizophrenic patients, the psychosocial component is heavily weighted towards being a chemical imbalance and take your meds manual. And as for his ability to predict the future, how about this 2005 effort from his psychiatry as clinical neuroscience days?

And I think I would insist that his successor, if we ever get one, be required to spend at least a half-day a week seeing patients in a local mental health clinic – something Dr. Insel has never done since his residency training.
Mickey @ 6:50 AM

jettison schizophrenia? no thanks…

Posted on Friday 27 March 2015

Picking up where I left off in jettison schizophrenia?…, I’m talking about my objections to getting rid of the diagnostic category called Schizophrenia for the last century. First, some case examples:
  1. Recently, I mentioned the first case assigned to me as a psychiatry resident, a woman I called Gloria [back to the drawing board…] who was hospitalized awaiting a transfer to a long term facility as a NGRI [Not Guilty by Reason of Insanity] case after drowning her son during a psychotic episode. I came to my residency after a tour of duty in an overseas Air Force hospital where I was an Internist. When I decided to change specialties, while still there, I read everything I could get my hands on about psychiatry. There was a copy of Eugen Bleuler’s 1911 Dementia Praecox or the Group of Schizophrenias in the hospital library, and I read it from cover to cover. Why it was in the small library of our small hospital in rural England is unknown to me. But I was taken with his description of the premorbid personality of patients who went on to develop Schizophrenic illnesses, and what he called the Primary Symptoms [the four As: loosened Association of thought, inappropriate Affect, global Ambivalence, and Autism – private logic]. I also read the Psychiatry Textbook of the day, Friedman and Kaplan, that had a detailed discussion of the "psychotic break" in the Schizophrenic patient. In back to the drawing board…, I mentioned a conversation with Gloria’s mother, but that was only one of several. Her mother came at every visiting time, and would often catch me and talk about her daughter. It seemed to help her tell the story, and I was more than happy to listen. She described her daughter exactly as Bleuler and the text I had read – schizoid features in her persona, periodic temper outbursts, a long period of seeming confusion prior to "the break." I was amazed at the concordance of her description and Bleuler’s century-old writings.
  2. A few years ago, I described a case I saw not long after finishing my residency [see 1. from n equals one, 2. from n equals one, etc]. She was hospitalized after she had been stopped from jumping from the 14th floor of the atrium in a downtown hotel. I was the fourth psychiatrist to see her and none of us quite knew what was going on. From my previous post:
    She was confused. My friend was confused. So was I. She didn’t seem depressed and had no explanation for her behavior. At the time I saw her, she was completely focused on getting out of the hospital because she didn’t want to be a financial burden on her parents. It was over thirty years ago, but I recall  the interview clearly. She was coherent with no signs of psychosis. She was ill-suited and untrained for her job, but mainly felt she’d failed her parents who had been instrumental in getting it through a friend at the bank. She had no explanation for her behavior. What I mainly recall from the interview was that she tried very hard to answer every question I asked her, but looked at me oddly, as if to say, "Why are you asking that?" I saw her several times, still feeling somewhat lost. By this time, the pressure to leave the hospital had escalated and they set up a plan. She would go home to her parents house, take a leave from her job, and see both my friend and I as an outpatient. Once home, she refused both options, or to take any medicine, or to see anyone else. She told her parents that she would see me in the future, when she’d "sorted things out."
    I had a hunch that this was the prodrome to a schizophrenic break based on her history, presentation [and reading Bleuler]. She had already been tried on an antipsychotic with no effect. I saw her parents as something as an advisor while she lived at home, obviously uncomfortable but steadfast in her resolve to sort things out by herself. Then one day, she asked to see me, appearing in my waiting room that afternoon in a psychotic state and was admitted for the first of several hospitalizations. I followed her at varying intervals until I retired some  twenty plus years later.
  3. In the recent weeks, we’ve finally seen the case of Dan Markingson being definitively dealt with [from Minnesota: Dan Markingson revealed…, ethics…, making sense…]. In making sense…, I was discussing the last several moths of his life. He was apparently not overtly psychotic. There’s no mention of hallucinations or the bizarre delusions that had been apparent in the earlier period of his illness. But he was not doing well at all. There are indicators from most of the venues where he was seen and his own journal that he was decompensating without the psychotic symptoms he’d had on admission – instead he had the "Primary Symptoms" as described by Bleuler.
So when Moncrieff and Middleton say [see jettison schizophrenia?…]…
    Schizophrenia is a label that implies the presence of a biological disease, but no specific bodily disorder has been demonstrated, and the language of ‘illness’ and ‘disease’ is ill-suited to the complexities of mental health problems. «Neither does the concept of schizophrenia delineate a group of people with similar patterns of behaviour and outcome trajectories»
… I wonder if they’ve seen the same kind of patients I’ve seen over the course of my career. I share their outrage with those in this generation of psychiatrists who have made such a mess of things by allying themselves with the pharmaceutical industry, or who have steadfastly stuck with the silly notion that all mental illness has some biological basis, or who think that the solution to mental illness will come in a pill bottle or a long acting injection. But I can’t imagine seriously suggesting that Schizophrenia is on a continuum with normality as we heard about in the BPS Report [Understanding Psychosis and Schizophrenia], or not even really a distinct syndrome as suggested here – merely psychosis or madness. We know a whole lot about Schizophrenia, and a lot about being Schizophrenic, and a lot about the difficulties that can come as a consequence. Rather than jettison the diagnosis, we would be better placed to jettison the mistakes of the past that may have lead to a generic and simplistic approach to this prevalent and sometimes devastating illness.

In case 2. above, if I hadn’t suspected that this patient was in the throes of an incipient Schizophrenic break, I wouldn’t have been able to work with her parents to put here in an environment that could catch her the minute she fell through the ice instead of making another forray to a 14th floor balcony and plunging to her death. I wish we knew how to short circuit the breakdown, but we don’t [at least I don’t]. In case 3., if Dan Markingson’s caretakers had been more knowledgeable about this illness and more attentive to Dan in those latter months, they might have recognized that he was decompensating in front of their very eyes, even in the absence of the psychosis and delusions that he’d shown them earlier. If they had, they would’ve removed him from the study and gotten him the treatment he clearly needed [which in this case would’ve likely involved more and/or different medication, for one thing]. And Gloria and her mother [1.] will be haunted for all times by what she did in the midst of a psychotic decompensation. If only she’d been seen by someone who knew what was happening. That’s what her mother wanted to talk to me about in those evening chats, "Why didn’t I know what I was seeing?" Throwing out the baby with the bathwater just isn’t the right way to go about things.
Mickey @ 7:00 PM

jettison schizophrenia?…

Posted on Thursday 26 March 2015

Current Opinion – Review
by Joanna Moncrieff and Hugh Middleton
2015

Purpose of review The term ‘schizophrenia’ has been hotly contested over recent years. The current review explores the meanings of the term, whether it is valid and helpful and how alternative conceptions of severe mental disturbance would shape clinical practice.
Recent findings Schizophrenia is a label that implies the presence of a biological disease, but no specific bodily disorder has been demonstrated, and the language of ‘illness’ and ‘disease’ is ill-suited to the complexities of mental health problems. Neither does the concept of schizophrenia delineate a group of people with similar patterns of behaviour and outcome trajectories. This is not to deny that some people show disordered speech and behaviour and associated mental suffering, but more generic terms, such as ‘psychosis’ or just ‘madness’, would be preferable because they are less strongly associated with the disease model, and enable the uniqueness of each individual’s situation to be recognized.
Summary The disease model implicit in current conceptions of schizophrenia obscures the underlying functions of the mental health system: the care and containment of people who behave in distressing and disturbing ways. A new social framework is required that makes mental health services transparent, fair and open to democratic scrutiny.
It would be foolish to argue with Drs. Moncrieff’s and Middleton’s point that diagnostic labels can and have been used to imply a biologic causes, particularly when the Director of our National Institute of Mental Health proposes we look at Psychiatry as a Clinical Neuroscience Discipline, or when commentary like this …
    Major depression is now recognized as a highly prevalent, chronic, recurrent, and disabling biological disorder with high rates of morbidity and mortality. Indeed, major depression, which is projected to be the second leading cause of disability worldwide by the year 2020, is associated with high rates of mortality secondary to suicide and to the now well-established increased risk of death due to comorbid medical disorders, such as myocardial infarction and stroke…
    by Sally Laden for Nemeroff et al
… abounds in the contemporary psychiatric literature and dialog. The bio-psychiatry that Moncrieff and Middleton are arguing against is actually quite a leap from Dr. Spitzer’s introduction to the DSM-III in 1980:
    For most of the DSM-III disorders, however, the etiology is unknown. A variety of theories have been advanced, buttressed  by evidence – not always convincing – to explain how these disorders came about. The approach taken in DSM-III is atheoretical with regard to etiology or pathophysiological process except for those disorders for which this is well established and therefore included in the definition of the disorder. Undoubtedly, with time, some of the disorders of unknown etiology will be found to have specific biological etiologies, others to have specific psychological causes, and still others to result mainly from a particular interplay of psychological, social, and biological factors…
    Robert Spitzer, in the DSM-III, p 6.
It’s now well known that one agenda of that DSM-III effort was to remove the influence of psychoanalysis from American psychiatry, an effort that was largely successful. And it’s also clear that the biological agenda of the neoKraepelinians was a powerful force in shaping the form of that revision. In fact, one of the enduring flaws in the DSM-III system – the lumping of the Major Depressive syndromes with the much more common reactive depressions – was driven by the zeal to remove depressive neurosis from the diagnostic system [see a mistake…]. The net result was to shut down productive research on those major syndromes [by dilution] and to open the door [by inclusion] to industry and their minions [like Dr. Nemeroff and ghost·writer Sally Laden above] for a decades·long antidepressant marketing spree. We were not led from «atheoretical with regard to etiology» to «a highly prevalent, chronic, recurrent, and disabling biological disorder» by scientific discovery – it was by rhetoric, extrapolation, and the persistent vilification of defeated enemies.
    «Schizophrenia is a label that implies the presence of a biological disease, but no specific bodily disorder has been demonstrated, and the language of ‘illness’ and ‘disease’ is ill-suited to the complexities of mental health problems»
Again, I’m not arguing with their assertion that diagnostic labels in psychiatry have come to imply the presence of a biologic disease in many circles. That bothers me as much as it seems to bother them. But it doesn’t take an Etymologist to see that the "language of ‘illness’ and ‘disease’" doesn’t come from biological causation. Both ‘ill-ness’ and ‘dis-ease’ describe how a patient feels, not what is causing the discomfort. They are symptom words. And that’s no minor point – one that describes Medicine from the dawn of time. In fact, the word diagnosis itself [Greek diagnôsis, discernment, from diagignôskein, to distinguish : dia-, apart] has nothing to do with cause. It literally means to know apart.

I came to psychiatry from a career in Internal Medicine [formerly known as Diagnosticians]. And my first encounter [in my life] with the phrase medical model of disease or the idea that a diagnosis implied biological causation came from a fellow first year psychiatry resident [whose copy of Szasz’s The Myth of Mental Illness was always within arms reach – see Szasz by proxy…]. The idea that disease was certified by objective biosignatures was foreign to me. So I read Szasz’s books and I think I gained some things by pondering the questions he raised, but his were forced arguments to me. Diagnosis didn’t lead to cause for me in either career – it lead to action, to treatment. If I were a surgeon at the Battle of Gettysburg and you were brought to me with a gunshot wound to the leg, I sawed your leg off. It wasn’t because I knew anything about infection. During our Civil War, Louis Pasteur was still studying wine-making [it was well after Appomattox when he came up with his germ theory of disease]. I sawed off your leg because I knew you’d die if I didn’t.

And as a Rheumatologist in that former life, there were only a few lab tests that helped at times, but the main guideposts for treatment and prognosis came from careful clinical diagnosis. So although like Moncrieff and Middleton, I can see that psychiatric diagnosis has been jury-rigged to imply biological causality by too many people in high places, I see that as a perversion of the meaning of medical diagnosis – something that needs to be fixed and clarified.

And agreeing with the problem they describe doesn’t lead me to necessarily agree with their solution. If they were talking about the DSM-III-IV-5 category Major Depressive Disorder, I’d jump on the train in a blue second. But I’m balking at following along with Schizophrenia. One reason for my hesitation is that their reason to jettison the diagnosis relies heavily on their aversion to the implications of the diagnosis – implications imputed there without solid scientific back-up, as perversions of the traditional meanings and uses of medical diagnosis. It’s a reaction against something. I felt the same way about the BPS Report [Understanding Psychosis and Schizophrenia] which was also driven by a reaction against that same something [see <to be continued>…, back to the drawing board…]. That’s what Dr. Spitzer’s DSM-III did, reacted so strongly against something that the result was the creation of some big problems [this one included] that we still deal with some thirty-five years later. Likewise, Moncrieff and Middleton clearly have some «alternative conceptions of severe mental disturbance» that remain as speculative as those of their biologically inclined counterparts.

But neither of those things get at my main objection to their recommendation to jettison the diagnosis of Schizophrenia. I still find that diagnosis clinically useful, much more useful than «‘psychosis’ or just ‘madness’» would be. I’ll try to flesh out why I say that in the next post…
Mickey @ 6:00 PM

making sense…

Posted on Monday 23 March 2015

The Board of Regents has closely followed the work of the external review panel and is aware of OLA’s findings. Chair Beeson and Regent Simmons have already created a plan for the Board to take an active role in shaping the University’s action plan. The Board will provide ongoing implementation oversight through its Audit Committee to ensure transparency and accountability. I look forward to demonstrating to the Regents our commitment to improve. To that end we are taking immediate actions:
  • Suspending enrollment in all Department of Psychiatry interventional drug studies currently active or awaiting approval…
  • Using an independent IRB and the University’s post approval monitoring process, we will sample additional interventional clinical studies targeting vulnerable populations…
  • Appointing a Community Oversight Board, comprised of external experts in human subjects research and research ethics…
  • Visiting leading institutions to learn the best practices followed by their IRBs.
  • Implementing new IRB software…
With this letter from the University of Minnesota, President Eric Kaler and the Board of Regents suspended enrollment in all present and future Clinical Trials in the Department of Psychiatry pending review. They were responding to the Report by the Office of the Legislative Auditor released last Thursday. To those of us who have followed this case, this is welcomed news. From first reading, this case has been troubling, and as time passed, every new data point confirmed the need for thorough investigation. But what kind of case is it? Is it a legal case? Is it a research case that relates to the clinical research program at the University of Minnesota? Is it a psychiatric case study of Schizophrenia? Is this a case of the human tragedy of a suicide? Or is this a case that’s an inkblot to contain our various biases and projections? There’s one thing for sure – it was not a case that had been thoroughly investigated!

Over time, Carl Elliot and his colleagues have collected a number of documents [subpoenaed, FOIA, etc] that are collected «here» as Scribe documents. I had looked at some of them, but wanted to look at a few others to see if I could clear up questions I had in my own mind. Let me first admit that although I spend a lot of time on this blog looking at Clinical Trials [groups], by interest and inclination, I am an n=1 type – most at home with case studies, and this is certainly one of those.

For reasons now obvious to us all, I thought from the start that Dan shouldn’t have been allowed into the C.A.F.E. study to begin with. But I had a lingering curiosity about how that happened, and there were comments in various reports that he had responded to the Risperdal® started on his initial admission and that had something to do with it. Where did that information come from? He was admitted to the hospital involuntarily on Nov 12th, 2003 and soon started on Risperdal® 3mg at bedtime. He was committed on November 17th; was approached about CAFE on Nov 19th; was granted a stay of commitment on Nov 20th if he agreed to cooperate with treatment; and he signed up for CAFE on Nov 21st. On Nov 24th, he had a SCID Structured Interview [see Study Visits p. 4] in which his communications were lucid. He said his difficulties began in late July with "inaccurate ideas". He quit his job in early August and "did some traveling." In late September, he wrote the delusional emails that disturbed his mother [see Elliot’s The Deadly Corruption of Clinical Trials p.1]. In the SCID Interview on Nov 24th [CAFE Intake], he said his conditioned worsened two weeks earlier: "episodes of extreme confusion, sleep deprived, tense living situation – two weeks ago, no sleep, inaccurate beliefs" and "gradually beliefs more firmly planted, 12 days ago – things were alarming" [see Study Visits p. 5]. He attributed these symptoms to "lots of work, little sleep. thinks it made him vulnerable to those thoughts. no other problems." My point is that he did respond to the Risperdal®. He may not have ascribed it to an illness, but he was talking about it from a place in our shared reality. Of course he shouldn’t have been accepted into CAFE, but his response to Risperdal® makes the story make more sense.

And speaking of not making sense, this portion of the narrative in the OLA Report doesn’t either [see OLA Report p. 13]:
Mary Weiss and Markingson’s treatment team sharply disagreed over the state of Markingson’s mental health. Mary Weiss frequently reported to Dr. Olson, Kenney, and Pettit that her son was deteriorating and needed help. Generally, Pettit, the medical team, and group home staff reported Markingson was doing well, at least for the first few months after he came to the group home. In the month before Markingson died, however, more observers reported some decline in his condition. One report found that Markingson appeared very inattentive in his group therapy; he sat smiling to himself. Two days later, Markingson said he had never heard of the Easter holiday even though he said he was raised Catholic. Other observers noted that he looked more disheveled and had a mildly “wilder” look in his eyes but still in contact with reality.
In a later deposition where Dr. Olson was being grilled about those latter months of Dan’s life, the lawyer produced Dan’s Journal [hitherto unknown by Dr. Olson]:
Mar 9, 2004: "You’ve been given observation on truth today, Dan. If someone makes an assumption in asking for a confirmation, such as you’ve seen Friday right? You may recast the question by saying, Have I seen Friday or more generously, if you think the assumption might possibly be all right to make concerning the average person, like you’ve seen Star Wars, right. You may answer the question, then say is it good enough to assume that somebody’s seen it." [Olson 2007 p. 465]
Mar 23, 2004: "world walking, you were at a farm house and we’re getting presents from dogs who had presents fastened in plastic bags to their snouts… in the gloaming and breening, you were thinking of naming it gloaming and greening or gloam-green. That was someone brings a snowslide in summer or midsummer. It has been left behind…" [Olson 2007 p. 467]
Mar 25, 2004: Lawyer, "he says he’s leaving for California as soon as court order expires…" [Olson 2007 p. 471]
In that same Deposition, there were notes from occupational therapy…
Lawyer: "Had you seen any notes in the occupational therapy records that in April of 2004 that said that over time client has become more isolated. He seems to have no interest in interacting with his peers. Personal appearance, disheveled, isolated and withdrawn, poor insight and self awareness. Plan to become an actor in California continues. Delusions seems fixed." [Olson 2007 p. 489]
and the counseling center…
Lawyer: "During the time you were treating Dan, did you see the Eagan Counseling Clinic notes of March 29th, 2004 stating that he is showing slightly more disorganization and thought and stream of speech and risk to self low with plan." [Olson 2007 p. 485]
And this was the time period during which Mary Weiss was raising holy hell about her son’s condition deteriorating. So there’s an even bigger question, "Why was he allowed to stay in the CAFE Study?" The Protocol is quite clear about the criteria for withdrawing subjects from the study [see Protocol p.9]…
3.3.4.1. Criteria for Discontinuation
Patients may be withdrawn from the trial for any of the following reasons:
  1. Inadequate therapeutic effect [requiring alternative treatment]. [Note: subjects shall not be withdrawn due to lack of efficacy if the maximum dose has not been achieved; except if the patient is not having adequate response but higher doses are not tolerated, then this can be considered as a discontinuation for lack of efficacy.]
  2. Unacceptable side effects
  3. Patient decision [examples include but are not limited to]:
    • Withdrawal of informed consent.
    • Subject lost to follow-up [dropouts].
  4. Administrative [examples include but are not limited to]:
    • Site protocol noncompliance [protocol violations or deviations].
    • Other independent external events that preclude further participation in the protocol for a subject who would otherwise continue [e.g. moving, accidental death, pregnancy].
The primary outcome measure was the proportion of patients who withdrew from the study prior to 52 weeks of treatment [“all- cause pharmacological treatment discontinuation”]. The reason for discontinuation was recorded according to a predetermined algorithm: [1] administrative discontinuation due to an independent external event [e.g., moving with family to another state]; [2] a clinician decision to discontinue treatment because of inadequate therapeutic effect or intolerable side effects whether or not the patient wanted to discontinue; or [3] a patient decision to discontinue although the clinician believed the treatment to be adequately efficacious, tolerable, and safe.

The responsibility for withdrawing a subject from the study for inadequate therapeutic effect [efficacy] rested with the clinician, not the patient. Because of the bind Dan was in, he was unlikely to withdraw himself for fear of being sent to the State Hospital under the terms of his Stay of Commitment agreement. As I now read the timeline, he was involuntarily admitted to the hospital with a flagrant psychosis and lethal thoughts. He responded to his initial treatment with Risperdal® [above], and was accepted into the CAFE Trial, randomized to Seroque. He apparently did reasonably well at first – living in a group home, attending Day Treatment, seeing a Counselor. He was driven to these various places by his mother, Mary Weiss, and her friend, Mike Howard. But over the last two months of his Stay of Commitment [and life], he showed signs of progressive deterioration reported from all venues. He was not talking about the delusions as he did on admission, but he instead had primary symptoms [Bleuler]. And he certainly qualified as having an "inadequate therapeutic effect." It wasn’t subtle, and was noted generally. There was some question as to whether he had stopped taking the study medication or not. But whether he had stopped or the Seroque just wasn’t up to the task doesn’t matter. By Protocol, he should’ve been withdrawn by the clinician in charge of the study. He wasn’t just having an "inadequate therapeutic effect." He was decompensating.

The Deposition I have been quoting [Olson 2007] is hard to read because it is so contentious, but when the Lawyer begins to imply that Dan was getting sicker, Dr. Olson seemed shocked:
"To the best of my knowledge, we thought Dan was taking his medication and it was being monitored after January and February by the staff at Theo House. And in terms of the deterioration, there was no evidence that came to light either before his suicide or after that he was suffering a psychotic decompensation. The only deterioration that we noted was some deterioration in his grooming and other negative symptoms which are  manifestations of schizophrenia that do tend to  increase over time, but they’re not amenable to treatment with antipsychotic medications, and there was no indication that he had any return of the behavior being influenced by his delusional thinking. [see Olson 2007  p.451]."
More than 100 years ago, Eugen Bleuler made the distinction between primary symptoms:
  • loosened associations of thought
    ["in the gloaming and breening, you were thinking of naming it gloaming and greening or gloam-green"]
  • inappropriate or flattened affect
    [
    "he sat smiling to himself"]
  • autistic thinking – as in a private logic
    ["You’ve been given observation on truth today, Dan. If someone makes an assumption in asking for a confirmation, such as you’ve seen Friday right?…"]
  • and ambivalence
    ["Are you asking me or telling me?"]
and secondary symptoms like delusions and hallucinations. When the DSM-III came along, the criteria were organized differently, but all of those things are among them. Dan was decompensating with all of the primary symptoms – often referred to as becoming disorganized
Mickey @ 9:28 AM

ethics…

Posted on Friday 20 March 2015

    par·a·digm  (pr-dm)
    noun
    noun: paradigm; plural noun: paradigms
    1. [technical] a typical example or pattern of something; a model.
The case of Dan Markingson is a paradigm representing something terrible, a period in our medical history when the scientific processes designed to evaluate medications for use in the treatment of illness were perverted and used for commercial purposes. Surely, with the addition of such strong testimony as that of Nikki Gjere, the long avoided investigation of this case will finally become a reality. There are others: Paxil® Study 329, a trial that fallaciously reported that a medication was effective and safe in childhood depression; Seroquel® Study 15, a trial that was definitive but unpublished because the sponsor didn’t like the outcome…
from  a paradigm…  11/30/2014
Well, it seems the investigation[s] were already in the works. First there was the surprise when the external panel appointed by the Association for the Accreditation of Human Research Protection Programs presented their findings about the research program to the faculty senate at the UMN last week [An External Review of the Protection of Human Research Participants at the University of Minnesota with Special Attention to Research with Adults Who May Lack Decision – Making Capacity]. It was more an Indictment than Report [see done nothing wrong… and not trivial stuff!…]. But this week’s report is the bombshell [A Clinical Drug Study at the University of Minnesota Department of Psychiatry: The Dan Markingson Case] from the Office of the Legislature Auditor [OLA]. It goes through the case documenting the form-without-substance way in which the University, the Department of Psychiatry, and the Principals responded to the many calls to action from a variety of sources.
At first, it seems an odd candidate as a symbol for problems with the current clinical trial culture. It’s a trial at an academic center rather than one run at some commercial clinical trial center. The Principle Investigator is the Chairman of Psychiatry at Columbia, the P.I. of the widely quoted NIMH C.A.T.I.E. trial, and the immediate past president of the APA. The C.A.F.E. Trial that Dan Markingson participated in was, in fact, modeled on C.A.T.I.E. – the differences being that it was industry financed and that it focused on acute psychosis rather than chronic cases. Even more unusual for the cause of much other protest, Dan Markingson may well have been under- rather than over-medicated. But there were a few very unusual features that make it stand out:
  1. Suicidal patients were excluded from the C.A.F.E. study. Dan was admitted with expressed homicidality. In psychiatry, there is no distinction between suicidality or homicidality that I’ve ever heard. Commitment laws invariably say "dangerous to self or others" in one breath. The lectures have titles like "The Lethal Patient." The claim that he was eligible because he was only homicidal is clinically absurd.
  2. Dan was declared incompetent and involuntarily committed, but within days allowed to enter a voluntary drug study in lieu of going to the State Hospital. Another absurdity.
  3. The outcome parameter for C.A.F.E. was voluntarily continuing the medication, yet Dan’s conditions for avoiding institutionalization were that he stay on the medication. That invalidates any reason for him to be in the study – need I say absurd once again?
  4. In the treatment center where he was staying, the staff saw little to suggest any improvement. Dan’s mother increasingly worried about Dan’s clinical state and yet was told he was doing fine. Then at six months, his involuntary commitment was extended for another six months, the duration of the clinical trial. Further absurdity.
Even the most radical of antipsychiaty activists would’ve likely agreed that Dan should be tried on another drug regimen to control his ongoing and dangerous delusional state. On the face of things, it’s hard to come up with anything that would explain any of the four absurdities listed above. And the most absurd thing of all – up until the day he killed himself, he would’ve been tallied as a treatment success because he was still taking his medications…
from  a mockery…  05/21/2014
People don’t always like it much when I start talking in the psychodynamic way I discovered half my life ago [and never got over], but I don’t know any other way to say what’s on my mind now that this case has finally had a day in court. Back in the 1970s when I came to a psychiatric residency, it was a time like this. We had lots of interdisciplinary meetings and conferences where fur regularly flew around like tumble-weed. We had analysts, biologists, Szaszians, experiential therapists, hippies, suits, etc. and the fights were often anything but civil. I knew almost everybody in the room, and often worked with them in the Grady Hospital Crisis Center – the Emergency Receiving Facility for downtown Atlanta. In that Emergency Room where we all worked, none of the bitter divisions that characterized the conference atmosphere ever came up. It was just the team du jour dealing with difficult cases, and the ideological what·evers disappeared. But at the next gathering, we turned back into cardboard icons representing various blind men describing our favorite part of the elephant. We simplified each other, turned others into Straw Men in our zeal to make a  point.

Years later, I had the hobby of translating the jargonized way psych·types sometime talk into everyday language. The residents could say projective identification and splitting, but they really didn’t know what the terms meant. But if I said, "Borderline patients simplify other people", they knew exactly what I was talking about. And I used the difference between how people acted in conferences contrasted with how they worked together in the ER. Then I’d say, "Borderline and Paranoid patients  simplify other people all the time." They got it, [and more importantly] remembered it. When I first read about Dan Markingson in Carl Elliot’s, The Deadly Corruption of Clinical Trials, in Mother Jones back in 2010, I thought about those days long ago. No matter what their favorite part of the elephant, nobody was going to read this case and not know that something was dreadfully wrong in the place where it happened. Nobody. That’s why I call it a paradigm, or a symbol, or a mockery. No matter where you’re positioned in the arguments that fly in conferences, or on blogs, or in the comments here, no matter how much we simplify each other, the something-wrongness with this case is absolute, and that was true from the start.

First off, it was an experimercial rather than a scientific study. AstraZenica was looking for a selling point. It was a poor design, First Episode Psychotic Illness is no place for a blinded study with no initial stabilization. And Dan Markingson was not exactly a typical First Episode case. He’d been ill for a while, and had many characteristics of a chronic case with complex and lethal delusions. And then there were all those absurdities listed above, and in the findings of the OLA [from Minnesota: Dan Markingson revealed…]. And the way this case and Dan’s survivors have been dealt with from the highest level of the University of Minnesota down to Dan’s day-to-day management were insensitive, dismissive, and at times, devious. Until nurse Nikki Gjere [INVESTIGATORS: Nurse questions integrity of U of M drug researchers] finally came forward, there was no break in the clouds. Apparently, the staff was up in arms about this case all along, but the climate of things kept that off the radar. Also, the OLA Report makes it clear that he never improved on treatment, in fact, becoming visibly worse towards the end of the study [and his life]. So, nobody, no matter their discipline, has ever defended how he was treated in any comments, or engaged this story except to decry the deadly corruption of clinical trials – this trial in particular.

While there is no explicit requirement for ethics education for investigators imposed by the federal research regulations, such education is a requirement of NIH and NSF supported research and is widely considered to be a valuable element of a research protection program. The external review team noted the University’s recent introduction of policy changes that mandate additional training of IRB members. However, the broader educational policies and practices at the University fulfill minimal standards but represent a missed opportunity for a richer and more sophisticated institution ? wide approach to investigator training.
In my mind, ethics are the common threads that bind people of diverse opinion and temperament together in the face of real situations. I said it this way recently:
Surely ethics refers to more than a code of conduct, or the rules of right and wrong, or even the letter of the law. It comes from the word ethos, the culture of a place, and should offer a compass for navigating situations where there are no standing rules or precedents – something more felt than transcribed, something conveyed by example rather than memoranda or training manual…

In a Clinical Trial of a new medication, it’s incumbent on the trialist to be vigilant that the subject’s health and medical care is not compromised by participation…

Carl Elliot, Leigh Turner, Mike Howard, and Dan’s mother, Mary Weis, have done something remarkable. They’ve moved rhetorical deliberations about medical ethics out if the ivory towers of academia; breathed a new life into them with this paradigmatic real world case; and taken their campaign to the streets.
from  done nothing wrong…  03/10/2015
I made that up, but what I was getting at was that I’m not sure you can really teach ethics. You can discuss ethics in a seminar, refine the concepts, model ethical behavior, but I guess I see it as more a part of a person than something one chooses or teaches or learns. And in a system, it comes from the top down into the ethos. It’s sadly missing in this story where we hear and see adherence to the letter of the law if necessary, but don’t find an ethical soul. Carl Elliot and Leigh Turner are Bioethicists, but they’re also obviously ethical people. And while I’m aware that this is the worst thing I can possibly say, it’s missing in the people at the upper levels at "the U" in this story, including the Institutional Review Board [IRB]. And I kind of doubt that will change unless somebody’s looking. The Board of Regents put all kind of external supports in place [external ethical oversight], suggesting they have the same concerns. I wonder about a place where it takes eleven years, a group of dedicated campaigners, a faculty Senate revolt, an ex-Governor’s intervention, and international outrage to finally get the ball rolling. So some are already calling for a change of administration and I would anticipate that cry will become louder.

Does this case generalize to industry funded, commerce driven, CRO managed, KOL created clinical trials? I think it’s a fair assumption to postulate that a trial conceived for commercial purposes, run by a CRO-in-a-hurry, that partitions it out to sites all over the place globe, and who is into cost-accounting, sure would be prone to simplifying the patients into cardboard subjects or fudging during recruitment to meet a quota, or any number of other things. And I would really worry about Institutional Review Boards becoming rubber stamp approval machines. That same lassitude might be true at any level in the process of conducting a trial.

This case will be in books and textbooks where it belongs long after most of us are no longer around to read them. That was never guaranteed, and getting it there is quite an accomplishment…
Mickey @ 12:31 PM

from Minnesota: Dan Markingson revealed…

Posted on Thursday 19 March 2015

This report was released at 2:00 PM today from the Minnesota OFFICE OF THE LEGISLATIVE AUDITOR:*

This is the one released last week by group of six experts appointed by the Association for the Accreditation of Human Research Protection Programs:


  • Finding 1. Dan Markingson was extraordinarily vulnerable when Dr. Olson recruited him into a drug study; Markingson was mentally ill and faced commitment to a state psychiatric hospital if he did not cooperate with the Fairview University Medical Center treatment plan and his treatment team’s aftercare recommendations following discharge. In 2009, the Legislature pass ed a law restricting the enrollment into drug trials of persons under a stay of commitment.
  • Finding 2. AstraZeneca, the financial sponsor of the CAFÉ drug study, prorated its payments to the University based on the number of subjects Dr. Olson enrolled in the study and the number of follow -up meetings the subjects completed. Dr. Olson’s goal was to enroll 30 people, and he had difficulty meeting that goal. This created an incentive to enroll and keep Dan Markingson in the CAFÉ drug study in November 2003.
  • Finding 3. Markingson’s mother, Mary Weiss, expressed strong concerns about her son ’s participation in the drug study and continually warned that he was not improving. There is little evidence that the study team adequately followed up with her about her concern.
  • Finding 4. Dr. Olson told the University’s Institutional Review Board (IRB) that drug study participants would each have an advocate, but Markingson did not have an advocate with him at the time he signed the informed consent to participate in the CAFÉ drug study.
  • Finding 5. The University of Minnesota’s Institutional Review Board (IRB) conducted a superficial review of Dan Markingson’s suicide. The IRB did not review medical records, did not seek information from anyone other than Dr. Olson, and did not review information about Markingson’s suicide.
  • Finding 6. The Minnesota Board of Social Work investigated CAFÉ study coordinator Jean Kenney, a licensed independent clinical social worker . 61 The Board found that she performed tasks beyond her competency and made significant errors. As a result, the Board entered into an Agreement for Corrective Action with Kenney. Although the Board only had jurisdiction over Kenney, we believe its findings suggest that Dr. Olson inappropriately delegated tasks to Kenney and failed to provide her with adequate supervision.
  • Finding 7. The Minnesota Board of Medical Practice’s review of Dr. Stephen Olson was compromised because the expert consultant the Board hired to analyze the case had numerous conflicts of interests.
  • Finding 8. University leaders — both administrators and regents — have responded to the Markingson case by dismissing the need for further review and ignoring serious ethical issues.
  • Finding 9. An external panel of experts that recently reviewed the University’s current human subjects protection program found significant and troubling problems.
Mickey @ 2:31 PM

put a cork in it…

Posted on Thursday 19 March 2015

In November [2014], the NIH announced  that it was going to put some teeth into the ignored requirement that completed Clinical Trials post their results in the Results Database of ClinicalTrials.gov [see speaking of about time!…, Honoring Our Promise: Clinical Trial Data Sharing and promises, promises…]. I had looked at the ClinicalTrials.gov Results Database several years ago and  decided it was an improvement over just having the published paper because of its structure, but was far short of having the raw data itself  [see eyes wide shut open I…, eyes wide shut open II…, eyes wide shut open III…, and eyes wide shut open IV…]. This report from last week documents the extent of the problem [medicine-wide]:
by Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, and Califf RM
The New England Journal of Medicine. 2015 372[11]:1031-1039.

BACKGROUND: The Food and Drug Administration Amendments Act [FDAAA] mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results.
METHODS:Using an algorithm based on input from the National Library of Medicine, we identified trials that were likely to be subject to FDAAA provisions [highly likely applicable clinical trials, or HLACTs] from 2008 through 2013. We determined the proportion of HLACTs that reported results within the 12-month interval mandated by the FDAAA or at any time during the 5-year study period. We used regression models to examine characteristics associated with reporting at 12 months and throughout the 5-year study period.
RESULTS: From all the trials at ClinicalTrials.gov, we identified 13,327 HLACTs that were terminated or completed from January 1, 2008, through August 31, 2012. Of these trials, 77.4% were classified as drug trials. A total of 36.9% of the trials were phase 2 studies, and 23.4% were phase 3 studies; 65.6% were funded by industry. Only 13.4% of trials reported summary results within 12 months after trial completion, whereas 38.3% reported results at any time up to September 27, 2013. Timely reporting was independently associated with factors such as FDA oversight, a later trial phase, and industry funding. A sample review suggested that 45% of industry-funded trials were not required to report results, as compared with 6% of trials funded by the National Institutes of Health [NIH] and 9% of trials that were funded by other government or academic institutions.
CONCLUSIONS: Despite ethical and legal obligations to disclose findings promptly, most HLACTs did not report results to ClinicalTrials.gov in a timely fashion during the study period. Industry-funded trials adhered to legal obligations more often than did trials funded by the NIH or other government or academic institutions.
[Funded by the Clinical Trials Transformation Initiative and the NIH.]
I’m not even going to bother with the excuses people make for not filling it out. Those are speculations. It’s totally simple to do, compared to other hoops people are asked to jump through. So my working hypothesis is that it’s straighforward and doesn’t have all the play one has in a published article to make things look better than [or not as bad as] they are. Whatever the reason, the compliance record is pitiful!

Just this week, I had an example of how useful the Results Database of ClinicalTrials.gov can be [see inertia…]. I was looking at the Clinical Trials for Saphris® [Asenapine] that was submitted for its FDA Approval [NCT01244815 and NCT01349907]. There’s no published paper, but I happened to notice that the Results of these Clinical Trials were already posted – a miracle all on its own!  And they had something of an answer to an open question. In the first trial, they gave Saphris® for three weeks to kids diagnosed with a Manic episode:

Acute: Measured Values after 3 Weeks


  Placebo Asenapine
2.5 mg BID
Asenapine
5.0 mg BID
Asenapine
10.0 mg BID
Participants 79 88 87 81
Change in Y-MRS
Mean ± SD
-9.6 ± 7.8 -12.3 ± 9.0 -15.1 ± 9.5 -15.9 ± 9.1
P Value   =0.008 <0.001 <0.001

There’s no surprise here – that one can knock down an agitated state with an antipsychotic. But these drugs have been used long term in these patients. What about that? In the extension study, things didn’t look so rosy:

Maintenance: After 50 Weeks of Asenapine


Acute Asenapine/Asenapine Placebo/Asenapine
Participants 241 80
With Adverse Event 197 74
Completed Study 102 38

I guess they were looking for a maintenance selling point in the extension phase of the study, but they sure didn’t find it – quite the opposite. One way to not deal with that finding would be to not publish it [publication bias]. Requiring a completed Results Database in ClinicalTrials.gov blocks that solution deception – instead it adds yet another piece of evidence that maintenance Atypical Antipsychotics are fraught with problems.

The Results Database in ClinicalTrials.gov may be only Data Transparency lite, but given the recent past, it’s going in the right direction. ClinicalTrials.gov, indeed the whole idea of requiring Clinical Trials themselves, was a reform move intended to give me access to the best evidence for the efficacy and safety for the drugs I prescribe. But the pharmaceutical industry has systematically used them as ways to deceive me [us] – engaging physicians in high places to collude with them in the process. This may be only one of the holes in the system that keeps me up to date on medications, but it’s time to put a cork in it and move on to the next leaky spot in the dyke…
Mickey @ 10:52 AM