under fire III…

Posted on Monday 13 April 2015

The head of the U’s psychiatry department is leaving his role amid a swarm of criticisms.
The Minnesota Daily
By Christopher Aadland
April 13, 2015

With the controversies around the department, especially the two recent investigations, I felt it was most constructive for me to step down as the chair of the Department of Psychiatry,” Schulz said. Since he came to the University to lead the department in 1999, Schulz has spent his career working with patients, like Markingson, who have schizophrenia or borderline personality disorder. While Schulz said the department has made many accomplishments under his leadership, he said he regrets dismissing some of the concerns that surfaced after Markingson’s death. He said he wishes he would have met with Markingson’s mother, Mary Weiss, to discuss the concerns she raised during and after Markingson’s death. “You can imagine, for years now, that’s been on my mind,” Schulz said…
In under fire I…, I was talking about the evolution of Clinical Trial methodology in the area of psychoactive medications, and how the traditional tool of psychiatry [the clinical interview] was too subjective for the realm of drug trials. Not only was it a subjective opinion about a subjective illness [mental illness], it wasn’t very sensitive nor was it easy to quantify. The procedures, randomization, placebo control, double blinds, rating scales, techniques for dealing with inclusion and attrition, and the statistical analytic techniques all were oriented towards objectifying and quantifying the effects of these new medications on the subjectivity of the patients. Over time, these objectified parameters became the proxies for psychiatric ill·ness. The same thing happened in the realm of psychiatric diagnosis. The former narrative and subjective assessments were replaced, at least in the research realm, with structured interviews and rating scales. So things like the SCID, the K-SADS-L, the HAM-D, the MADRS, the CGI, the BPRS, the PANSS, etc. became the psychiatric equivalents of the white cell count, the TSH level, the blood chemistries – objective markers that could be quantified. And in  Clinical Trials, they were more sensitive – able to detect smaller differences between groups that might not be apparent to the traditional psychiatric interviewer.

These proxies were a step forward in that they offered a way to attach an objective value to the symptoms of mental illness. But they also brought a bag-full of new potential errors into the mix. Because they seemed to objectify the subjective, they gave the illusion that mental illnesses were, indeed, objective in the same way physical illnesses are. That may or may not be true in any given instance, but that still needs to be proved rather than just assumed because something can be measured. So many think, or at least talk like they think, that all mental illnesses are physical – caused by some identifiable pathogen. But there are other pitfalls. A Clinician-Rated PANSS Form is obviously not on the same level as a centrifuged blood sample measuring the % of the blood volume taken up by red cells [Hematocrit]. Just look at the PANSS Forms for Dan Markingson. I don’t know who did the rating, but at a time when we know from his mother’s reports, his own personal journal, and the comments from people around him that he was still lost in a psychotic fog – those objective measures [the PANSS ratings] said he was doing fine. That was not true, and those PANSS results were anything but a psychic hematocrit. The rating scales were never intended to be used for diagnosis. They’re for registering changes. And the reason they’re clinician-rated is to have an actual clinician in the mix to recognize when a subject is just telling the raters what he thinks they need to hear get them out of his face – which is likely what happened with Dan.

I’m not questioning the rightness of the many things already declared wrong in the story of what happened to Dan Markingson [and his mother]. CAFE was, as many have said, an un-necessary Clinical Trial – what Dr. Bernard Carroll dubbed an experimercial, the Clinical Trials undertaken to advance the sales of a medication rather than to refine our scientific understanding of the drug. I don’t question that the design of the study was flawed [for example, leaving out criteria to determine a non-response to the assigned study drug]. I was as appalled by the way Dan was recruited into and retained in the study as anyone else. And I agree with the recent investigations that shut down the whole clinical research enterprise pending a lot of needed reform.

But I want to add something else to the list. The notion of objectifying and quantifying mental illness is a laudable goal. I’m as much of a numbers/graphs guy as anybody around. But mental illness, particularly severe mental illness, is a subjective experience – and the subjectivity of the person doing the evaluation is an important part of assessment. You can’t see a case in the proxies – you have to see the case. And the objective measures used in clinical trials like a PANSS score are soft proxies as opposed to the Hematocrit or blood chemistries. The people who saw Dan at the Theo House, at OT, at the Day Hospital, his mother – all knew that Dan was very ill all along, but the people in charge didn’t. The biggest ethical breach in this whole story was that his doctor, Stephen Olson, didn’t respond to the loud noises screaming "somethings wrong!" by stopping by the Theo House on the way home and spending some serious time evaluating Dan Markingson in depth, in person. In the article above, Dr. Schulz, the co-principle investigator, regrets that he hadn’t "met with Markingson’s mother, Mary Weiss, to discuss the concerns she raised during and after Markingson’s death." Instead, I want Dr. Schulz to regret that he didn’t drive over to the Theo House and interview Dan Markingson himself, in depth, in person, to have the kind of direct clinical knowledge he would’ve needed to have to have met with and responded to Mary Weiss [maybe he could’ve met her there].

There’s a story of a Zen Master who comes upon a scholar pointing at the moon and lecturing on and on to his students. The Master comments, "that fellow is confusing his finger with the moon." In this case, I’m suggesting that the KOL brand psychiatrists have confused their soft proxies [clinical trials and rating scales] for the actual patients in many instances. In this case, I’m suspicious that they paid attention to the rating scales and not the patient. In other places, they’ve claimed that minor differences have clinical meaning when they don’t. But we often think that all examples portend bad motives, and in some cases they do. But this is an error one can make even without bad motives – by overvaluing secondary information without investigating further.

There were more than enough warning signs to warrant re-evaluating Dan Markingson’s case in depth, in person, long before things went so very sour…
Mickey @ 10:56 PM

under fire II…

Posted on Monday 13 April 2015

I guess I ought to start this post by saying what it’s all about, because I doubt I’ll get to the end even in this second post. It’s based on some observations. First, although the direct information on Dan Markingson’s clinical state during his time in the CAFE Trial is spotty, I haven’t read anything that sounds like "better" along the way. His mother was sure he wasn’t improving throughout the whole study. In the month before his suicide, she wrote to Dr. Schulz:
On March 15. 2004 I sent via certified mail a letter addressing my concerns regarding the treatment my son, Dan Markingson, is receiving through the CAFE program. I have not had the courtesy of a reply. I have again left messages for Dr. Olson asking him to point out how he feels Dan is doing better than when hospitalized. I have not received a reply. Actually. I believe the most lucidity I’ve seen Dan in the last six months was when he was first hospitalized, and was on an anti-anxiety medication. He said to me, "Mom. Through all of this you never told me everything would be okay" [I. of course, assured him it would, and it will!]. That was also the only time he indicated any awareness of a problem!…
Weiss letter to Schulz April 26, 2004
It sounds to me like he was in the throes of his psychosis the whole time. Second, the Protocol is clear that the foremost criteria for discontinuing a subject from the study was lack of improvement on the study drug, and that was a decision to be made by the clinician [see Protocol p.9]. Third, In his deposition, Dr. Stephen Olson seems absolutely convinced that Dan was not psychotic or deteriorating:
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.
I’m not aware that there are substantial data – you’re implying from rating scales that we’re performing, no, I’m not aware that there is evidence of substantial deterioration.
These three things just don’t go together. There’s a disconnect… 

In a tweet about Schulz stepping down, Carl Elliot mentioned a 2011 article that he suggested reviewing in the Minneapolis City Pages. I think he made that recommendation because it has a section on Schulz’s history, and his relationship with AstraZeneca, maker of Seroquel® and sponsor of the CAFE study. But I didn’t make it that far down the page, because it began with some things about the case of Dan Markingson that tapped these still open questions for me. In the first thing I ever read about this case [The Deadly Corruption of Clinical Trials], there are a number of vignettes and several emails that document the intensity of Dan’s psychosis. This article mentioned by Carl Elliot adds more to the story that I didn’t know:
Is U of M department of psychiatry chair in the pocket of AstraZeneca?
Minneapolis City Pages
By Andy Mannix
Feb 2, 2011

Mary Weiss knew something wasn’t right with her son. Only a year before, Dan Markingson had seemed perfectly normal. But his latest letter from Los Angeles suggested a troubled mind. He claimed he was about to become famous. He was at a crossroads in his life, and would soon have more free time. He even had a big movie premiere in the works. "I knew then that something was wrong," says Weiss. "I knew that there wasn’t a premiere, and when he said he was going to have a lot more free time, I thought he was quitting his job."

Weiss immediately jumped in her car and drove to California. When she arrived, she found her son far worse off than she’d feared. He was talking nonsense and couldn’t be reasoned with. Weiss tried to convince Markingson to come back to Minnesota, where she could look after him. But he had a stipulation: He would only return home if his dead grandmother Daisy told him to. Weiss went to an internet cafe down the street and created an email account under the name "GuardianAngelDaisy." Pretending to be her own deceased mother, she urged Markingson to return to Minnesota. Eventually, he agreed.

He was home for only 10 days before he decided to return to California. Weiss pleaded with him to stay, but he refused. She could either drive him to the airport, or never see him again. Weiss followed him to Los Angeles, where she again tried to urge her son to go back to Minnesota. But this time, his grandmother’s emails weren’t enough. Markingson wanted to talk to a higher authority: Michael the Archangel.

Weiss created another fake email account as Archangel Michael. The two exchanged emails for more than a week before Markingson finally agreed to fly home. Once he was back, Weiss called the South St. Paul police. An officer came to her home to evaluate her son. During the interview, Markingson casually mentioned he would soon be attending a devil-worshipping event in Duluth, and might be ordered to kill people.

That triggered a trip to Fairview University Medical Center, where Markingson was diagnosed with psychosis and placed on a 72-hour hold…

In forty years of practice, I’ve never heard a story like that – the part about the emails to his dead grandmother and the Archangel Michael. I can’t think of any way to read that except as an indicator of how real and how all consuming his psychotic experiences were [and how clever his mother was]. Next came the well known circumstances of his ending up in the CAFE study:
In order to be released, Markingson agreed to a stay of commitment, which would allow him to leave the hospital as long as he followed a treatment plan. The plan involved Markingson enrolling in a study called Comparison of Atypicals in First Episode, or CAFE. The research was sponsored by AstraZeneca, maker of Seroquel, one of the anti-psychotic drugs being investigated. When Weiss found out her son was a human guinea pig, she was furious. She called the hospital and tried to pull her son out of the treatment plan, to no avail. Although Markingson was mentally unfit, he was somehow able to consent to the drug trial.
That Dan was able to keep his psychotic experiences to himself was already well known. He had fooled the police in California on his mother’s first trip. And was apparently on the same path in Minnesota with the police until he "casually" mentioned the devil worshiper thing:
Over the next few months, Markingson’s condition only worsened, Weiss says. His doctor wouldn’t return her calls, so she tried writing a letter to the head of the department, Dr. Charles Schulz. He didn’t reply.

It wasn’t until April 28, after Weiss’s third letter, that she received a cursory response, in which Schulz wrote, "it was not clear to me how you thought the treatment team should deal with this issue." Ten days later, on May 8, Markingson sat in the bathtub of the halfway house where he was staying and stabbed himself to death with a box cutter. "I left this experience smiling!" read the suicide note.
I’ve spent more time than I’d like to admit looking for evidence that Dan improved in the time from his first psychotic communications to his mother until his suicide, and I haven’t found anything. I put what I found in making sense… and I’ve written people who have seen Dan’s whole journal and say that it’s just more of the same confused psychotic "gibberish." His mother was consistent throughout in saying that what he said while he was in the halfway house didn’t make any sense. Same for the Occupational Therapy and Day Hospital people. I can only conclude that my clinical impression is that he was lost in the throes of his psychosis throughout much of the whole six month period he was in the CAFE study. I can confirm what his mother said [above] in that in his STRUCTURED CLINICAL INTERVIEW FOR DSM-IV AXIS I DISORDERS he described delusional thoughts, but seemed to have some insight. At that time, he had been on Risperidone 3mg/day for 1½ weeks. In the archives on the Fear and Loathing site, there’s a collection of Study Documents which has the SCID on Intake and the PANSS Scale forms [clinician rated] at approximately monthly intervals. They record no psychotic symptoms. The only comment box filled out is on the last form [04/28/2004 – 10 days before his suicide]:
So in the first post of this series [under fire I…], I reviewed the evolution of the methodology used in clinical trials of psychoactive drugs from the early days when the outcome came from the subjective reports of clinicians and the trial subjects, to today’s sophisticated rating scales analyzed with supercharged statistics – a move from the subjective to the objective, to evidence-based medicine. In this post, I’ve discussed a case well known to us, a patient in a study for the treatment of a First Episode of a Schizophrenic illness. He was randomized to be treated with Seroquel, and from any perspective I can find here eleven years after the fact, he never responded to that drug even though that wasn’t apparent to his treating physician or in the Clinician rated metrics available to us. His lack of response was certainly apparent to his mother:
I gave Dr Olson examples of Dan’s behavior that lead mc to believe the drug he is on is not beneficial: He still believes he is "bulletproof’ [Dan had told my on several occasions in Los Angeles that he is "bulletproof’, and that I was also when I was with him]. He still believes both that he is an actor [not true], and that he will make a living by giving walking tours of Hollywood. He believes his finances are fine [he owes more than $6,000]. He takes no interest in his appearance [he has been wearing the same pair of khaki pants and cutoff sweatshirt since last November]. Does this sound to you like someone who is getting well?
Weiss letter to Schulz April 26, 2004
It is inconceivable to me that any competent clinician could have spent time with Dan and missed the fact that he was quite ill, and that his internal experience was a jumble of disorganized psychotic thinking like the things he wrote in his 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]
I would expect that to be apparent to a first year psychiatry resident, medical student, or psychology intern after a month or two on the wards. I can only conclude that whoever filled out those clinician-rated PANSS forms was not such a clinician. Not even close. And when Dr. Olson is answering questions in his 2007 deposition, he’s not basing what he says on any meaningful one-to-one engagement, but rather from looking at the PANSS scores or some very superficial contact:
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…
I’m not aware that there are substantial data – you’re implying from rating scales that we’re performing, no, I’m not aware that there is evidence of substantial deterioration.
So in the next post, I’ll try to stitch together why I think that the evolution of modern Clinical Trial methodology [under fire I…] and the tragedy of the Dan Markingson case [this post] are linked together. And we might as well throw in the fact that the prime protocol-defined reason for discontinuing the study was non-response to the study medication. Yet in his six months in the Clinical Trial with no evidence of improvement, he was not removed – even under the escalating pressure on this very point from Dan’s mother, communicated repeatedly to the Study Coordinator [Jeanne Kenney], Dan’s psychiatrist [Stephen Olson], and the Chairman of Psychiatry [Charles Schultz]…
Mickey @ 7:08 PM

under fire I…

Posted on Monday 13 April 2015

"The development of psychopharmacologic agents over the past 6 decades has been characterized by a paradoxical relationship between medication discovery and clinical trial methodology. The methodology during the most productive decade, 1949–1958, was primitive. Since then, there have been tremendous advances in clinical trial design, assessment, and statistical analyses. Yet, despite numerous innovations in methodology, the discovery of new mechanisms of action and blockbuster interventions seems to have slowed—especially during the past decade. In an effort to understand this phenomenon, the evolution of trial design and analysis during the lifespan of psychopharmacology is examined here…"

So goes the introduction to the article below, introducing a topic that has dominated the field of psychiatry since the 1950s, the coming of psychopharmacology. In those early days, drug testing was little different from routine office visits to the family doctor. Now, it’s a complex scientific process with protocols and procedures. It’s also the focus of much attention and many questions. This article is a review of how clinical trials evolved and may help understand something about what happened along the way – How did we get from that era of hope to today, when the chairman of a major department of psychiatry is resigning in disgrace over something that happened in a clinical drug trial eleven years ago [Under fire, Schulz stepping down]?
by Andrew C. Leon, PhD
Journal of Clinical Psychiatry 2011 72[3]:331–340.

Objective: The evolution of trial design and analysis during the lifespan of psychopharmacology is examined.
Background: The clinical trial methodology used to evaluate psychopharmacologic agents has evolved considerably over the past 6 decades. The first and most productive decade was characterized by case series, each with a small number of patients. These trials used nonstandardized clinical observation as outcomes and seldom had a comparison group. The crossover design became widely used to examine acute psychiatric treatments in the 1950s and 1960s. Although this strategy provided comparison data, it introduced problems in study implementation and interpretation. In 1962, the US Food and Drug Administration began to require “substantial evidence of effectiveness from adequate and well-controlled studies.” Subsequent decades saw remarkable advances in clinical trial design, assessment, and statistical analyses. Standardized instruments were developed and parallel groups, double-blinding, and placebo controls became the benchmark. Sample sizes increased and data analytic procedures were developed that could accommodate the problems of attrition. Randomized withdrawal designs were introduced in the 1970s to examine maintenance therapies. Ethical principles for research became codified in the United States at that time. A wave of regulatory approvals of novel antipsychotics, antidepressants, and anticonvulsants came in the 1980s and 1990s, each based on data from randomized double-blind, parallel-group, placebo-controlled clinical trials. These trial designs often involved fixed-dose comparisons based, in part, on a greater appreciation that much of the benefit and harm in psychopharmacology was dose related.
Conclusions: Despite the progress in randomized controlled trial [RCT] design, the discovery of new mechanisms of action and blockbuster interventions has slowed during the past decade.
Most likely know this first part. In the golden age of psychopharmacology, a clinical trial was simple. Gather a few patients and give them the medication you want to test – then interview them about what happened. No control group. No randomization. No blinding. No rating scales. No statistics. As I said, it was very much like the natural world of a medical practice – prescribe, then ask how it went:
The initial trials in psychopharmacology involved case series, each with a small number of patients. Cade reported the antimanic properties of lithium based on a series of 10 cases in Australia in 1949. In 1952, the initial psychiatric study of chlorpromazine, which was previously used for nausea in surgical patients, involved 20 patients with psychosis and reported symptomatic improvement. Chlorpromazine was approved by the FDA in 1954 for psychosis. Imipramine has a molecular structure similar to that of chlorpromazine and for that reason was initially tested as an antipsychotic in 1957 with several hundred cases. Although that effort did not demonstrate effectiveness for psychosis, observation of about 12 of the cases with depression revealed the antidepressant property of imipramine. Iproniazid, a monoamine oxidase inhibitor (MAOI), was used for tuberculosis and clinical observation on the tuberculosis wards reported that patients expressed joy and optimism, despite their prognosis. In 1957, a case series of patients with depression showed beneficial effects of iproniazid. The decade from 1949 to 1958 is unparalleled in the history of psychopharmacology, with the discovery of the first mood stabilizer, the first antipsychotic, and 2 antidepressants, a tricyclic and an MAOI. Yet, none of these case series involved a control.
First, with the acknowledgement of the placebo effect, several things were added to the Clinical Trial routine – [placebo] controlled, [double] blinded:
In 1955, Beecher described placebo response rates across a wide range of indications including anesthesia for surgery, highlighting the need for trials to include a comparator.8 He stated, “Many a drug has been extolled on the basis of clinical impression when the only power it had was that of a placebo.”
Then gradually, the criteria for inclusion became more precise [the DSM-III] and drug studies and approvals were more tightly tied to diagnosis:
The inclusion criteria in the early studies were often rather broad perhaps, in part, because the diagnostic nosology of the era, DSM-I [1952] and DSM-II [1968], were narrative based. It was not until Feighner criteria in 1972, Research Diagnostic Criteria in 1978, and DSM-III in 1980 that nosology became criterion based.
Obviously, the next step was to be the rating scales, and with their increased precision came the statistics:
Standards for the study design and analysis continued to evolve. Max Hamilton, MD, a psychiatrist and namesake of a rating scale for depression, published a text that comprised 12 of his lectures covering a range of areas in clinical research design and analysis including stages of experimentation, design of experiments, measurement of variability, tests of statistical significance, t test, χ2, ANOVA, correlation, selecting cases and treatment, and problems in design and analysis.
For all these bells and whistles, we should back up. The 1950’s was an exciting decade for psychopharmacology, and in 1959, Jonathon Cole was appointed head of the new Psychopharmacologic Research Branch [PRB] at the NIMH where many of the rating instruments and Clinical Trial procedures were subsequently developed and tested. By 1967, the Early Clinical Drug Evaluation Unit [ECDEU] offered a centralized service for Clinical Trials to NIMH grantholders. This is from a 1976 ECDEU Manual:
As originally conceived, the ECDEU program consisted primarily of grant- supported clinical investigators working in tine common area of psychotropic drug evaluation [both new and established compounds]. One of the problems they encountered, and task they accomplished, was the development of a uniform battery of clinical assessment instruments known as the ECDEU Standard Reporting System, first introduced for utilization in 1967. The rationale behind this effort was twofold. First, it was felt that such a system would enhance both the quality of early clinical drug research and allow greater generalizability of results across studies and investigating units. Second, data collected on common forms could be stored in a data bank for future study and research. Since the implementation of this Standard Reporting System and the Biometric Laboratory Information Processing System [BLIPS], the ECDEU program has evolved into more than an extramural grant support program for psychotropic drug research teams. In collaboration with The George Washington University Biometric Laboratory, the ECDEU Standard Reporting System has been made available to any investigator interested in conducting clinical trials, whether federally grant supported or not. To utilize these services, the investigator is requested to:
    1. Submit a Research Plan Report and agree to send the study data to the Biometric Laboratory.
    2. Collect sufficient information about the subjects in his study so that the data can be entered into the ECDEU data bank. This means, essentially, that a core of data must be collected for each patient…
In return, he receives a sufficient number of assessment scales to conduct his research. Once the trial is completed, the forms are returned to the Biometric Laboratory for processing and data analyses, the results of which are sent to the investigator in the form of a standard data package. The rating scales and data processing services are provided at no charge – our sole "remuneration" being the opportunity to add the investigator’s data to the data bank. It should be stressed that an investigator’s data and/or results are never published or disseminated to others without his permission.
I find it telling that the NIMH program [ECDEU] had been set up to have a central data registry and to have the NIMH actually doing the data analyses. It sounds like data-sharing and data transparency were part of the original plan! And all of this was going on at the NIMH in the 1970s, at the same time that Robert Spitzer was also working with the Feighner Criteria, developiing the Research Diagnostic Criteria [RDC] on an NIMH grant, and aiming towards producing the 1980 DSM-III. We all know that there were some major changes in the 1980s and 1990s. Instead of the NIMH, the trials were being done by pharmaceutical companies themselves using the Clinical Research Industry to manage them. The companies analyzed their own data [which they held onto as if it were a carefully guarded state secret]. I haven’t found any resources that talks about how that happened, but we all know by now that the Clinical trials of CNS drugs became a playground for a lot of dodgy science in the process. And to return to the original point, after the flurry of discovery in the 1950s, there have been precious few advances in the area of CNS drug development in spite of all the changes. And what does all of this have to do with the eleven year old Dan Markingson case? or Dr. Charles Schulz’s resignation as Chairman of the Psychiatry Department at the University of Minnesota? Or the down-side of evidence based medicine? Stay tuned…
Mickey @ 5:40 PM

still not…

Posted on Sunday 12 April 2015

A call from the former Governor for University of Minnesota’s President, Eric Kaler, and involved members of the Board of Regents to step down or be removed in the wake of the recent reports on the handling of the Dan Markingson case:
Years of stonewalling have done too much damage.
Minnestota Star Tribune Commentaries
by ARNE H. CARLSON [Governor of Minnesota 1991-1999]
April 10, 2015

“The University constructed a defense to deny liability by claiming immunity. I think that defense evolved or you might say devolved into a strategy to simply avoid any accountability or responsibility and to deny that there were any serious ethical issues. And we found that serious ethical issues and conflicts of interest just permeated this case.”
James Nobles, legislative auditor, March 20, 2015

The University of Minnesota, like many other universities, has a sizable clinical research program that tests experimental drugs for safety and efficacy. The understanding between the companies that develop these drugs and the consuming public is that such drugs are carefully tested on humans and that these clinical trials must comply with strict ethical, scientific and regulatory standards. These research protections were developed after a series of research scandals that involved abusive treatment of vulnerable populations such as economically disadvantaged communities, prisoners, children, and individuals suffering from mental illness.

Ever since the violent suicide of Dan Markingson in 2004, the administration of the University of Minnesota has received repeated calls for the release of more details about the care and protection afforded the victim. These calls have come from faculty members at the university, from local community members and from researchers from around the world. But instead of being transparent and forthright, the administration created a standard response similar to that expressed by the university’s former general counsel, Mark Rotenberg: “As we’ve stated previously, the Markingson case has been exhaustively reviewed by Federal, State and academic bodies since 2004. The FDA, the Hennepin County District Court, the Minnesota Board of Medical Practice, the Minnesota Attorney General’s office and the University’s Institutional Review Board have all reviewed the case. None found fault with any of our faculty.”

If correct, that would be a most understandable and appropriate response. However, it falls far short of the truth. Consider this:
Here former Governor Carlson lists the sham investigations that we all know about…
During his first year at the university, Kaler had to make a major decision. Prudent management would have involved meeting with Elliott, learning about the specific ethical issues related to Markingson and broader concerns about psychiatric clinical research, and dealing with the growing scandal. But Kaler chose instead to perpetuate the prevailing coverup. He opposed any independent review, never responded to the charges made in the media, ignored or dismissed critics, and stood firm in his belief that it would all blow over.

In so doing, President Kaler tarnished his office and abandoned the principles of truthfulness, openness and integrity. He also frittered away the moral authority that is so essential to governance. His failure to provide ethical leadership permitted the scandal to grow. The result was more stonewalling of requests for information from faculty and media and increased attempts by administration officials to demonize critics, including referring to some scientists as “wackos.” Perhaps most troubling is the culture of intimidation associated with the Department of Psychiatry. The university’s own external review refers to this culture as a “climate of fear.” Extending from that department to the university’s senior management team, the apparent goal was to make certain no one questioned authority.

On June 16, 2014, I met with Kaler and Board of Regents Chairman Richard Beeson, and went over all the materials covering conflicts of interest, the falseness of their claims of endless investigations, as well as the damage being done by news articles highly critical of the university’s handling of the Markingson scandal. Kaler was quiet and rarely asked a question. As a result, I focused more attention on the lack of oversight and leadership provided by the Board of Regents and its failure to examine the circumstances of Markingson’s death. Given the deeply troubled history of research in the Department of Psychiatry over the past 25 years, a history that includes six suicide deaths, untold injuries, the conviction and imprisonment of one professor, the barring of two researchers by the FDA, and a barrage of poor publicity, I was stunned by Beeson’s response that this matter “has not risen to the level of our concern.”

Last week, the university announced that Charles Schulz has decided to resign as chairman of the Department of Psychiatry. He will retain his position as executive medical director, and his faculty appointment. The news release announcing his departure made no mention of the department’s troubled record, or the research controversies in which Schulz has been personally involved. Rather than removing him as department chairman and taking additional disciplinary action, the university has provided Schulz with a soft landing. The very administrators and regents responsible for the current debacle now promote themselves as trustworthy agents of change. We will not see meaningful reform of research on human subjects, nor the restoration of prestige at the university, so long as Kaler, Beeson and other leaders responsible for years of denials and stonewalling remain in charge.
It’s hard to imagine that President Kaler can survive this scandal. His obstructionism has been too consistent and too public to be spun into any other narrative than the one presented here. There’s something of a paradox in that response of the Chairman of the Board of Regents to Arne Carson. President Kaler and the Regents have been the public face of the resistance to the calls for the investigation of this case rather than the Medical School or the Department of Psychiatry. To say that "this matter ‘has not risen to the level of our concern’" seems almost comical. The irony of all of this to me is that the Case of Dan Markingson itself has still not been investigated…
Mickey @ 7:00 AM

Schulz out in Minnesota…

Posted on Thursday 9 April 2015

Star Tribune
April 9, 2015

The University of Minnesota is replacing its Psychiatry Department chairman following an external review that identified subpar safety protocols in research involving human subjects and a legislative audit that chastised the department for its recruitment of a troubled man who later died by suicide in a schizophrenia drug trial. While Dr. Charles Schulz will continue clinical care and research in the department he has led since 1999, Thursday’s announcement that he is stepping down reflects a metamorphasis for a university that even a month ago was adamantly defending his department against claims of coercive recruiting of vulnerable patients into research.

“Changing one person — it’s not like switching a light switch” and problems will be fixed, said Leigh Turner, a U bioethicist who has demanded changes in administration due to problems with psychiatric research. “But there is a symbolic dimension to it. A chair is a symbolic face of a department. And this is a department that has been through a long period of controversy and questions about the conduct of its clinical trials.”

Much of the criticism has centered around the recruitment of Dan Markingson, who died by suicide in 2004 while enrolled in the university’s arm of a national study that compared the effectiveness of three antipsychotic drugs. Markingson was recruited at the time by Dr. Stephen Olson, a psychiatrist who was treating him, and running the study, and advising a judge on whether Markingson should be committed to a locked inpatient facility. Legislation following media coverage of this case in 2008 made this type of potentially coercive recruiting situation illegal…

Schulz brought prestige and a track record for amassing research grants and studying the origins of schizophrenia when he took over the department 15 years ago. He had previously been psychiatry chairman at Case Western Reserve University in Cleveland, and chief of the schizophrenia research branch for the U.S. National Institute of Mental Health…

Schulz has, like other doctors in recent years, been scrutinized for the thousands of dollars he has received from drug companies such as AstraZeneca, the sponsor of the study in which Markingson was enrolled. Schulz’ name surfaced in documents submitted in a lawsuit against AstraZeneca, indicating that back in 2000 he made statements about the superiority of the company’s new antipsychotic drug, Seroquel, that were more favorable than research indicated…
Schulz’s resignation is hardly a surprise, given the recent reports. I can’t find anything mentioning Stephen Olson who was actually in charge of the Study that Dan Markingson was enrolled in – CAFE. But I doubt he has much job security right now. President Eric Kaler is still leading the University as President, but his obstructionism over the last several years isn’t going to hold up well if there is anything like a reasonable re-organization.

What’s happening at this point is anticlimactic. The powers that be felt like they could just wait things out, and the Dan Markingson case would simply fade away. Throughout the whole eleven years, they treated it as a nuisance. Carl Elliot has Schulz’s only public comments on it here [back in 2010] on his blog. And looking back, this piece gives a lot of information about the case and Schulz I haven’t seen before.

It’s reminiscent of 2008 when Senator Grassley and Paul Thacker exposed the unreported PHARMA incomes. Drs. Nemeroff at Emory, Schhatzberg at Stanford, and Keller at Brown stepped down as chairmen [or were stepped down], but stayed on in their departments. Apparently, Schulz will remain as executive medical director [whatever that is]. Such things end like this – "not with a bang, but a whimper…"
Mickey @ 11:38 PM

without firm action…

Posted on Thursday 9 April 2015

"There were approximately 600 clinical trials mentioned in the documents we gathered; owing to redactions, most of these trials could not be identified. However, in some cases, key information was not redacted from the documents, allowing us to identify 101 trials in which at least one clinical trial site received an OAI grade on an inspection."
OAI = Official Action Indicated

A few years back when I started looking into the Clinical Trials literature, I developed a solid case of Cognitive Dissonance. I couldn’t get my mind around how much research misconduct and deceitful science I found in plain view, and how much more people who knew a lot more about these things than I did were able to show me. After a few years, I got kind of jaded, used to reading articles looking for the various ways that things were being distorted. I acclimated to my disillusionment and expected the worst. When I first read this article below, I saw it as just more of the same. But then something told me to read it again. It is of much greater import than I saw the first time around:
Out of Sight, Out of Mind, Out of the Peer-Reviewed Literature
by Charles Seife, MS
JAMA Internal Medicine. 2015 175[4]:567-577.

IMPORTANCE Every year, the US Food and Drug Administration [FDA] inspects several hundred clinical sites performing biomedical research on human participants and occasionally finds evidence of substantial departures from good clinical practice and research misconduct. However, the FDA has no systematic method of communicating these findings to the scientific community, leaving open the possibility that research misconduct detected by a government agency goes unremarked in the peer-reviewed literature.
OBJECTIVES To identify published clinical trials in which an FDA inspection found significant evidence of objectionable conditions or practices, to describe violations, and to determine whether the violations are mentioned in the peer-reviewed literature.
DESIGN AND SETTING Cross-sectional analysis of publicly available documents, dated from January 1, 1998, to September 30, 2013, describing FDA inspections of clinical trial sites in which significant evidence of objectionable conditions or practices was found.
MAIN OUTCOMES AND MEASURES For each inspection document that could be linked to a specific published clinical trial, the main measure was a yes/no determination of whether there was mention in the peer-reviewed literature of problems the FDA had identified.
RESULTS Fifty-seven published clinical trials were identified for which an FDA inspection of a trial site had found significant evidence of 1 or more of the following problems: falsification or submission of false information, 22 trials [39%]; problems with adverse events reporting, 14 trials [25%]; protocol violations, 42 trials [74%]; inadequate or inaccurate recordkeeping, 35 trials [61%]; failure to protect the safety of patients and/or issues with oversight or informed consent, 30 trials [53%]; and violations not otherwise categorized, 20 trials [35%]. Only 3 of the 78 publications [4%] that resulted from trials in which the FDA found significant violations mentioned the objectionable conditions or practices found during the inspection. No corrections, retractions, expressions of concern, or other comments acknowledging the key issues identified by the inspection were subsequently published.
CONCLUSIONS AND RELEVANCE When the FDA finds significant departures from good clinical practice, those findings are seldom reflected in the peer-reviewed literature, even when there is evidence of data fabrication or other forms of research misconduct.
hat·tip to Elia…  
This report required a lot of dedicated sleuthing. They were looking for Clinical Trial Site inspections that received an OAI rating [official action indicated] which means there was a serious problem. So, first off, "Who are they?" The author is Charles Seife is a journalism professor at New York University. And "they" are Professor Seife and his journalism students. The full text of the medical article isn’t on-line, but there’s a fine version in Slate:
FDA buries evidence of fraud in medical trials. My students and I dug it up.
by Charles Seife
Feb 9, 2015

… Much of my research has to do with follies, foibles, and fraud in science, and I knew that the FDA wasn’t exactly bending over backward to correct the scientific record when its inspectors found problems during clinical trials. So as part of my investigative reporting class at New York University, my students and I set out to find out just how bad the problem was — and how much important information the FDA was keeping under wraps. We didn’t have to search very hard to find FDA burying evidence of research misconduct. Just look at any document related to an FDA inspection. As part of the new drug application process, or, more rarely, when the agency gets a tipoff of wrongdoing, the FDA sends a bunch of inspectors out to clinical sites to make sure that everything is done by the book. When there are problems, the FDA generates a lot of paperwork — what are called form 483s, Establishment Inspection Reports, and in the worst cases, what are known as Warning Letters. If you manage to get your hands on these documents, you’ll see that, most of the time, key portions are redacted: information that describes what drug the researcher was studying, the name of the study, and precisely how the misconduct affected the quality of the data are all blacked out. These redactions make it all but impossible to figure out which study is tainted. My students and I looked at FDA documents relating to roughly 600 clinical trials in which one of the researchers running the trial failed an FDA inspection. In only roughly 100 cases were we able to figure out which study, which drug, and which pharmaceutical company were involved. [We cracked a bunch of the redactions by cross-referencing the documents with clinical trials data, checking various other databases, and using carefully crafted Google searches.] For the other 500, the FDA was successfully able to shield the drugmaker [and the study sponsor] from public exposure…

And these weren’t minor infractions. They were fraud, big time fraud [from the JAMA]:
Case 3
A researcher was caught falsifying documents in a number of trials, in part because those falsifications led to the death of a patient undergoing treatment in a clinical trial comparing 2 chemotherapy regimens. The researcher had falsified laboratory test results to hide the patient’s impaired kidney and liver function, and the first dose of the treatment proved to be fatal.The researcher pleaded guilty to fraud and criminally negligent homicide and was sentenced to 71 months in prison. Although this episode is described in detail in FDA documents as well as court documents, none of the publications in the peer-reviewed literature associated with the chemotherapy study in which the patient died have any mention of the falsification, fraud, or homicide. The publications associated with 2 of the 3 other studies for which the researcher falsified documents also do not report on the violations.
And here’s the bottom line question. Why does the FDA keep stories like this secret? [from the JAMA]:
The FDA does not typically notify journals when a site participating in a published clinical trial receives an OAI inspection, nor does it generally make any announcement intended to alert the public about the research misconduct that it finds. The documents the agency discloses tend to be heavily redacted. As a result, it is usually very difficult, or even impossible, to determine which published clinical trials are implicated by the FDA’s allegations of research misconduct. The FDA has legal as well as ethical responsibilities regarding the scientific misconduct it finds during its inspections. When the agency withholds the identity of a clinical trial affected by scientific misconduct, it does so because it considers the identity to be confidential commercial information, which it feels bound to protect. However, failing to notify the medical or scientific communities about allegations of serious research misconduct in clinical trials is incompatible with the FDA’s mission to protect the public health…
First off, we are in Professor Seite’s and his investigative journalism students’ debt. I’m not sure that any of us bloggers could have pulled this off. They pored over the data sources with a fine tooth comb to match the reports of failed FDA Inspections with the published Clinical Trials, against a gradient of FDA attempts to hide the connection by redaction. So we know that’s just the tip of an iceberg. These are not just the kinds of research misconduct we’ve found all over the place – subtle methods to accentuate the positive and eliminate the negative. These are examples of outright fraud being actively kept out of the public eye by the FDA under the guise of protecting CCI [Confidential Commercial Information]. CCI my ass! This is simply criminal behavior that probably ought to disqualify the trials altogether. Data Transparency won’t do anything about this. So in its zeal to protect this precious [and largely mythical] CCI, the FDA, a public agency whose existence rests on protecting the public, becomes an active co-conspirator in criminal fraud. Back when I tried to look at the origins of this notion of proprietary ownership of data and Confidential Commercial Information, I was surprised that it was not based on any laws. It rested on interpretations of Trade Agreements [a crushing setback…, except where necessary to protect the public…].  But as this article makes very clear, it has been used to keep all kinds of unsavory behavior from the medical community and the public at large [from the Slate article]:
The sworn purpose of the FDA is to protect the public health, to assure us that all the drugs on the market are proven safe and effective by reputable scientific trials. Yet, over and over again, the agency has proven itself willing to keep scientists, doctors, and the public in the dark about incidents when those scientific trials turn out to be less than reputable. It does so not only by passive silence, but by active deception. And despite being called out numerous times over the years for its bad behavior, including from some very pissed-off members of Congress, the agency is stubbornly resistant to change. It’s a sign that the FDA is deeply captured, drawn firmly into the orbit of the pharmaceutical industry that it’s supposed to regulate. We can no longer hope that the situation will get better without firm action from the legislature. The FDA wants you to take it on faith that its officials have the public’s best interest at heart. Justification through faith alone might be just fine as a religious doctrine, but it’s not a good foundation for ensuring the safety and effectiveness of our drugs. After all, the whole point of science-based medicine is to keep us from having to make a leap of faith every time we swallow a pill.
Mickey @ 7:00 AM

the other side of the story…

Posted on Wednesday 8 April 2015

This presentation by Anthony Morrison is from the BPS DCP Conference, 2012 – after the publication of the Exploratory Study below, but before the publication of the Pilot Study results [see a pilot…, slim pickings…, and above the din…]
Mickey @ 10:01 AM

above the din……

Posted on Tuesday 7 April 2015

Back in ancient history when CBT first came along, we used to joke that if you needed a publication for tenure, you could always do a study with four groups: Placebo, CBT, Antidepressant, CBT+Antidepressant. It seemed like that was the most repeated study in history and they always seemed to come out the same. CBT and Antidepressant always came out as effective, but the combo Rx was the most effective. Back then, I think most of us incorporated some aspect of CBT. For me, it was identifying and commenting on maladaptive thinking, though I was never trained in or did CBT proper. Over the years, I’ve worked with lots of therapists, and most define themselves as having a CBT orientation these days, but in practice, most of us actually do the same things. My fantasy is that all those studies defined CBT as "evidence-based therapy," and that’s a claimable moniker in a modern world, certifiable EBM. These clinical trials, however, are CBT of the formal kind. I thought this one was a creative idea – treat the Worry in delusional patients and see if it helps with secondary symptoms [delusions]:
An explanatory randomised controlled trial testing the effects of targeting worry in patients with persistent persecutory delusions: the Worry Intervention Trial [WIT].
Editors: Freeman D, Dunn G, Startup H, and Kingdon D
Lancet. 2015 2[4]:305-313.
NCBI Bookshelf: Queen’s Printer and Controller of HMSO 2015.

BACKGROUND: Persecutory delusions are a key experience in psychosis, at the severe end of a paranoia continuum in the population. Treatments require significant improvement. Our approach is to translate recent advances in understanding delusions into efficacious treatment. In our research we have found to be an important factor in the occurrence of persecutory delusions. Worry brings implausible ideas to mind, keeps them there and makes the experience distressing. Reducing worry should lead to reductions in persecutory delusions.
OBJECTIVE: The objective was to test the clinical efficacy of a brief cognitive–behavioural intervention for worry for patients with persistent persecutory delusions and determine how the treatment might reduce delusions. Embedded within the trial were theoretical studies to improve the understanding of worry in psychosis…
MAIN OUTCOME MEASURES: The main outcomes measures were of worry [Penn State Worry Questionnaire; PSWQ] and persecutory delusions [Psychotic Symptom Rating Scales; PSYRATS]. Secondary outcome measures were paranoia, overall psychiatric symptoms, psychological well-being, rumination and a patient-chosen outcome.
RESULTS: In total, 95% of the patients provided primary outcome follow-up data. For the primary outcomes, in an intention-to-treat analysis, when compared with treatment as usual, the therapy led to highly significant reductions in both worry [PSWQ: 6.35, 95% confidence interval [CI] 3.30 to 9.40; p < 0.001] and the persecutory delusions [PSYRATS: 2.08, 95% CI 0.64 to 3.51; p  = 0.005]. The intervention also led to significant improvements in all of the secondary outcomes. All gains were maintained. A planned mediation analysis indicated that change in worry explained 66% of the change in the delusions. We also found that patients without intervention report a passive relationship with worry, feeling unable to do anything about it; worry brings on depersonalisation experiences; and the patient group has very low levels of psychological well-being.
CONCLUSIONS: This was the first large randomised controlled trial specifically focused on the treatment of persecutory delusions. Long-standing delusions were significantly reduced by a brief CBT intervention targeted at worry. The intervention also improved well-being and overall levels of psychiatric problems. An evaluation of the intervention in routine clinical setting is now indicated. We envisage developing the intervention booklets for online and app delivery so that the intervention, with health professional support, has the possibility for greater self-management.
The graph shows the result of a six week course of their focused CBT on Worry as measured by the PSWQ instrument, and the improvement was matched by a similar fall in the PSYRATSdelusion Score. While the effects weren’t massive, they were significant [shown with full 95% Confidence Interval].

But that’s not why the study is here. I was reading the Lancet COMMENT that accompanied it, and I ran across this [note the careful wording - safe and acceptable]:
Daniel Freeman and colleagues report the results from thei r trial that investigated the clinical effects of an intervention targeting worry in patients with non-affective psychosis. The authors accurately write in their Introduction that treatments for psychotic conditions, such as schizophrenia, need substantial improvement. The first-line treatment of schizophrenia—ie, antipsychotics—can suppress delusions and hallucinations, but patients still suffer from other symptoms such as negative symptoms, and often report adverse side-effects from the medication [eg, apathy, neurological side-effects, serious weight gain, and sexual dysfunction]. The percentage of non-compliance with medication in patients with schizophrenia is as high as 40–50%, and 74% of patients discontinue their medication within 18 months. Furthermore, Wunderink and colleagues report that dose reduction or discontinuation of antipsychotics during the early stages of remitted first-episode psychosis is associated with superior long-term [7 years] recovery rates [40·4%] compared with the rates achieved with antipsychotic maintenance treatment [17·6%]. Additionally, Morrison and colleagues reported that cognitive therapy significantly reduced psychiatric symptoms and seems to be a safe and acceptable alternative for people with schizophrenia and related disorders who have chosen not to take antipsychotic medication. In consideration of low patient compliance with antipsychotics, evidence for improved long-term functional recovery with dose reduction or discontinuation of antipsychotic medication,  and the promising results from trials of psychological treatments, intervention options for patients with a psychotic disorder are clearly needed that are effective, have fewer side-effects, and are more acceptable to some patients than antipsychotics.
11.1.1 Effectiveness of cognitive behaviour therapy There is a consistent evidence base suggesting that many people find CBTp helpful. Other forms of therapy can also be helpful, but so far it is CBTp that has been most intensively researched. There have now been several meta-analyses [studies using a statistical technique that allows findings from various trials to be averaged out] looking at its effectiveness. Although they each yield slightly different estimates, there is general consensus that on average, people gain around as much benefit from CBT as they do from taking psychiatric medication

The National Institute for Health and Care Excellence [NICE] considers the evidence strong enough to recommend that everyone with a diagnosis of schizophrenia should be offered CBT. NICE recommends that people should be offered at least 16 one-to-one sessions over a minimum of six months. However, this is far from being the case everywhere: indeed the Schizophrenia Commission found that only one in ten people who could benefit from it have access to good CBTp. We view this with grave concern – indeed, it has been described as scandalous

11.10 Conclusions There is now overwhelming evidence that psychological approaches can be very helpful for people who experience psychosis. However, there remains a wide variation in what is available in different places. Even the most successful approaches, such as early intervention and family work, are often not available, and nine out of ten of those who could benefit have no access to CBT. There is a pressing need for all services to come up to the standard of the best and to offer people genuine choices. Perhaps most importantly, we need a culture change in services such that the psychological understanding described in this report informs every conversation and every decision…
And this from Noel Hunter’s Report on the ISPS 2015 meeting:
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.
I expect that where I’m headed with all of this is obvious. I spent more than a few days with Cognitive therapy for people with a schizophrenia spectrum diagnosis not taking antipsychotic medication: an exploratory trial and Understanding Psychosis and Schizophrenia and I didn’t find Morrison et al deserving of those accolades – nor did others [see a pilot…, slim pickings…, and the comments]. Here’s the graph again:
I’ve given only a few examples, but there are plenty of others strewn about – enough for me to think that this is a campaign extraordinaire. After all the campaigns of PHARMA, Managed Care, the Psychiatric KOLs, the misreported RCTs of the psychiatric drugs, and the DSM-5 debacle, it’s hardly surprising. But, two wrongs don’t make a right. Right now, the important agenda is Data Transparency – not more Irrational Exuberance. And these CBT results in psychosis are being way over-sold. When in a period like this one where the dominant paradigm has reached [or perhaps exceeded] its limits and explanatory powers [paradigm exhaustion], lot’s of things can happen – not necessarily good things. Looking back on the time this kind of foment was in the wind – the 1980 Psychiatry revolution – it’s hard not to notice that things can go badly and the seeds of the next major catastrophes can be planted everywhere. This is again such a time. No one who is alert and paying attention could miss that fact. It’s all around us. So we don’t need to step off on a new path with exaggeration and rhetoric like we did 35 years ago. What we need is a time of reflection, a voice of restraint, and I’m not sure I can yet hear either above the din…
Mickey @ 3:41 PM

the price of admission…

Posted on Monday 6 April 2015

A few weeks ago, I was commenting on an article in JAMA:Psychiatry by three Residency Training Directors [yellow brick roads…] who were advocating a curriculum for psychiatry residents in neuroscience [The Future of Psychiatry as Clinical Neuroscience: Why Not Now?]. The gist of the article had to do with preparing future psychiatrists for the expected breakthroughs coming in neuroscience. Going so far as to say…

The overarching goal is that residents will incorporate a modern neuroscience perspective as a core component of every formulation and treatment plan and bring the bench to the bedside.
…which I thought sounded like something the USSR of old might have come up with back in the days before the walls fell down. I recalled a graphic I came up with four years ago about Tom Insel’s campaign for clinical neuroscience. I made it from an old Red Army poster from the days of the Russian Revolution, so I guess that I’ve thought of that analogy before. The constant hype about Neuroscience has been like the seven decades of Russian Communism, hope was always in the future [a future that ever came]. Note also the allusion to the Translational Medicine metaphor – another NIMH favorite [moving research findings rapidly from "the bench to the bedside"]. Best I can tell, we’ve established a network of Translational Centers all decked out for service, but there’s been nothing of note to translate.

I suggested that a neuroscience track ought to aim at arming the residents with the tools to evaluate emerging technologies:
Rather than being "ready to embrace new findings as they emerge", tomorrow’s psychiatrist needs to know how to critically evaluate new findings as they emerge.
Psycritic has a new post up on this topic that takes a somewhat different tack than mine [Psychiatry as a Clinical Neuroscience, Why Not?] – a deeper look on the place of neuroscience in psychiatry in general though equally cautious. He mentions this example…
I remember being taught as a resident about Broadmann Area 25 being critical in the pathogenesis of depression, based on exciting initial deep brain stimulation results from Dr. Helen Mayberg. This was almost treated as an established fact, despite the very preliminary nature of the research. Well, what happened when they tried to do a larger clinical trial? Neurocritic reported that the trial was halted before its planned endpoint in December 2013, and last month it was revealed that the medical device company conducting the trial [St. Jude] stopped it due to perceived study futility.
…and that’s what bothers me about the constant focus on the brain studies – as if they are the harbingers of something just around around the corner. Tentative signals get treated as "known facts," and it feels as if there’s a real pressure to put them into action [like for example the injunction to "incorporate a modern neuroscience perspective as a core component of every formulation and treatment plan"]. I can’t imagine how one might do that. It is, in fact, the very point that our critics legitimately hammer on – psychiatry forcing everything into an biomedical framework where much of it doesn’t fit. Psycritic goes on to reflect on his college Neuroscience Professor who gave the students a broad view of brain function:
"All of the neurons together in one brain form more connections with each other than there are stars and planets in the galaxy." The professor ended his lecture by giving us some practical tips based on his knowledge of neuroscience. Time and repetition, he told us, is what will help us succeed in the class, because that is how neuronal circuits are programmed and how processes in the brain ranging from retrieving facts from memory to riding a bicycle become automatic. I use the same advice almost daily with my patients when I emphasize to them the importance of practicing new behaviors or ways of dealing with difficult thoughts and emotions. Similarly, based on my reading of research on the effects of sleep, exercise, and social interactions on the brain, I share with my patients the importance of getting enough of each.
… as opposed to the narrow view:
… the narrow view tends to emphasize things like genetics, neurotransmitters, biomarkers, and circuits.
[Being an old man, I still have permission to call that broad view "the mind" if I want to]. I’ll leave it for Psycritic to relate his Professor’s story about Hemingway’s shortest story – one worth way more than the price of admission…

Also: I would recommend reading Philosophy Professor Anderson Brown’s blog on the "Mereological Fallacy"…
Mickey @ 4:00 PM

slim pickings…

Posted on Saturday 4 April 2015

When I wrote the last post [a pilot…], I was aware that there had been letters in the Lancet about the Morrison et al article, that I couldn’t access. They’re by statistically much more sophisticated critics than I, but have similar reservations and more. But I wanted to mention the opening to the authors’ reply to the critics:
Authors’ reply
Our trial was not designed to change clinical practice. It was a preliminary trial, which needs to be followed up by a larger, pragmatic multicentre study. It is important not to over·interpret our data, and we explicitly advised against discontinuation of medication. We claimed the trial showed that cognitive therapy was safe and acceptable, not safe and effective
And that’s true – that is exactly what they said at the end of the abstract…
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.
…but I didn’t notice that subtle bit of wording the first time around [did you?]. There are some really fine comments to my last post – all worth taking a look at and adding lots of things I hadn’t really thought of. I’m not going to summarize them, but rather suggest you take a look. There’s also an excellent collection of articles on the topic at the Mental Elf – CBTp. I went back and took a look at the prequel, Morrison et al’s exploratory trial prior to this pilot trial:
by A. P. Morrison, P. Hutton, M. Wardle, H. Spencer, S. Barratt A. Brabban, P. Callcott, T. Christodoulides, R. Dudley, P. French, V. Lumley, S. J. Tai and D. Turkington
Psychological Medicine. 2012 42[05]:1049-1056.

Background Although antipsychotic medication is the first line of treatment for schizophrenia, many service users choose to refuse or discontinue their pharmacological treatment. Cognitive therapy (CT) has been shown to be effective when delivered in combination with antipsychotic medication, but has yet to be formally evaluated in its absence. This study evaluates CT for people with psychotic disorders who have not been taking antipsychotic medication for at least 6 months.
Method Twenty participants with schizophrenia spectrum disorders received CT in an open trial. Our primary outcome was psychiatric symptoms measured using the Positive and Negative Syndromes Scale [PANSS], which was administered at baseline, 9 months [end of treatment] and 15 months [follow-up]. Secondary outcomes were dimensions of hallucinations and delusions, self-rated recovery and social functioning.
Results T tests and Wilcoxon’s signed ranks tests revealed significant beneficial effects on all primary and secondary outcomes at end of treatment and follow-up, with the exception of self-rated recovery at end of treatment. Cohen’s d effect sizes were moderate to large [for PANSS total, d=0.85, 95% CI 0.32–1.35 at end of treatment; d=1.26, 95% CI 0.66–1.84 at follow-up]. A response rate analysis found that 35% and 50% of participants achieved at least a 50% reduction in PANSS total scores by end of therapy and follow-up respectively. No patients deteriorated significantly.
Conclusions This study provides preliminary evidence that CT is an acceptable and effective treatment for people with psychosis who choose not to take antipsychotic medication. An adequately powered randomized controlled trial is warranted.
Again, I had trouble reproducing their analyses [and again, access to the raw dataset would’ve been useful to figure out why]. Notice the wording:
Conclusions This study provides preliminary evidence that CT is an acceptable and effective treatment for people with psychosis who choose not to take antipsychotic medication. An adequately powered randomized controlled trial is warranted.
Here is the Primary Outcome variable [PANSStotal] for the two studies [with 95% CI]:
It looks a lot like any number of the Clinical Drug Trials I’ve vetted before. Slim pickings [slim to none]…
Mickey @ 3:32 PM