1 Boring Old Man

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…

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.

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.

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]

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]

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]

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 Seroquel®. 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 Seroquel® 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.

• 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?"]

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

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

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.

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

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 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.

Compliance with results reporting at ClinicalTrials.gov

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.

[full text on-line]

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.]

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:

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:

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…

I’m old enough to have been in training when the classic version of Manic Depressive Illness was still the predominant view – a familial Illness characterized by recurrent episodes of either Mania or Severe Depression that began in adulthood. After the coming of the DSM-III, the domain of that diagnosis expanded in multiple dimensions, and at the turn of the century had been extended into the childhood, primarily by Dr. Joseph Biederman and his group at Harvard. The syndrome they described in children didn’t fit the classic intermittent pattern and had as the main symptom "super angry/grouchy/cranky irritability." The notion of the "Bipolar Child" swept through the ranks of Child Psychiatry like wildfire with much fanfare and a forty fold increase in diagnosis in a short period of time.

The topic of the "Bipolar Child" and the use of Atypical Antipsychotics in children were intimately intertwined from the outset. J&J had initially hoped to obtain an indication for its first ever Atypical Antipsychotic, Risperdal®, for behavior control in intellectually impaired children, completing a Clinical Trial in 1998 [Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence]. But the FDA turned them down. After Biederman’s 2000 paper, Pediatric mania: a developmental subtype of bipolar disorder?, there was an explosion of interest and the Harvard group published series of clinical trials of various Atypical Antipsychotics in Bipolar children [see bipolar kids: biedermania and super angry/grouchy/cranky irritability…], including a ghost-written rewrite of that earlier disruptive behaviors paper, this time pitched towards affective symptoms [see trial 93: a bad penny…, trial 93: a very bad penny…, trial 93: a very very bad penny…]. The "Bipolar Child" epidemic seemed to take a dive when Senator Grassley’s investigations of unreported pharmaceutical income in 2008 included Dr. Biederman, and he was censured by Harvard [bipolar kids: harvard acts…][see also The False Epidemic of Childhood Bipolar Disorder].

Examination of prior authorization policies for antipsychotic prescribing to children

JAMA – Journal of the American Medical Association

March 3, 2015

Summary:
With a concern about inappropriate prescribing of antipsychotic medications to children, 31 states in the U.S. have implemented prior authorization policies for atypical antipsychotic prescribing, mostly within the past 5 years, and with most states applying their policies to children younger than 7 years of age, according to a study.

Over the past two decades, antipsychotic prescribing to youth, almost exclusively comprising atypical antipsychotic medications, was estimated to have increased from 0.16 percent in 1993-1998 to 1.07 percent in 2005-2009 in office-based physician visits. Antipsychotic use is also 5-fold greater in Medicaid-insured youth than in privately insured youth, and occurs mostly for indications not approved by the U.S. Food and Drug Administration [FDA]. In light of antipsychotic treatment-emergent cardiometabolic adverse events, several government reports called for efforts to improve pediatric psychotropic medication oversight in state Medicaid agencies. Such efforts have included age ­restricted prior authorization policies, which require clinicians to obtain preapproval from Medicaid agencies to prescribe atypical antipsychotics to children younger than a certain age as a condition for coverage, according to background information in the article…

And related articles are becoming increasingly common in a variety of venues [Antipsychotics For Poor Kids Are Booming, It’s Time To Look At Prescriber Decision-Making referring to Antipsychotic Medication Prescribing in Children Enrolled in Medicaid]. In the antipsychiatry writings, it’s seen as a paradigm of medical-model thinking [The Drugging of Children in Foster Care]. Meanwhile, Dr. Biederman is still chasing the Bipolar Child disease entity [Further evidence for robust familiality of pediatric bipolar I disorder: results from a very large controlled family study of pediatric bipolar I disorder and a meta-analysis]. So with that as a background, we read this Friday in the PsychiatricNews:

FDA Approves Antipsychotic for Treatment of Pediatric Bipolar Disorder

PsychiatricNews

March 13, 2015

The Food and Drug Administration [FDA] has approved Saphris [asenapine] as a therapy for the acute treatment of manic or mixed episodes associated with bipolar I disorder in pediatric patients. Saphris becomes the first atypical antipsychotic to be approved for children with bipolar I disorder in the last five years. The medication was initially approved in 2009 for the acute treatment of bipolar I disorder and acute/maintenance treatment of schizophrenia in adults.

The FDA approval of Saphris is based on the positive results of a clinical trial of 403 children [aged 10 to 17] examining the effects of twice daily doses of 2.5 mg, 5 mg, or 10 mg of the drug. All three dose levels were associated with improvements in both mania and overall disease severity compared with placebo. Side effects included sleepiness, dizziness, strange taste sensations, numbness of the mouth, nausea, tiredness, increased appetite, and weight gain…

To read more about the treatment of pediatric bipolar disorder, see the FOCUS article "Management of Bipolar Disorder in Children and Adolescents."

The results are posted on clinicaltrials.gov [NCT01244815], though I don’t think there’s a published paper, and the only thing on Drugs@FDA is the Approval letter:

There was an Extension Study [NCT01349907] of maintenance therapy for up to 50 weeks with two groups, the Placebo group and those treated with Asenapine in the Acute 3 week study. Both groups were treated with maintenance Asenapine for up tp 50 Weeks. The primary outcome measure was the number without any adverse event:

While I think that table is right, the results database and numbering on clinicaltrials.gov was obscure to me. Assuming I got it right, the Maintenance phase study was a bust. The Atypical Antipsychotics have generally been approved by the FDA for adolescents like this approval for Saphris®, but not for children where they have been prescribed "off-label."

And finally, here are three guides for Pediatric Bipolar Disorder for Parents and Families from the National Institute of Mental Health, the American Academy of Child and Adolescent Psychiatry, and the Balanced Mind Parents Network respectively:

^{[click on an image to link to the guide’s content]}

If this post has seemed to wander aimlessly from topic to topic without any organizing outline, that was my intent rather than a lack of direction or purpose. That’s exactly how this whole story of the Pediatric Bipolar Disorder feels to me – a confusing collage of disjointed trends that can’t seem to land on any organizing principle. It’s as if the Diagnosis actually grew to meet the arrival of a new Treatment, rather than the other way around.

Not long after the Atypical Antipsychotics came on the scene, Dr. Biederman’s group [who had been primarily focused on kids with ADHD/ADD] proposed that a subgroup of their ADHD kids [a subgroup that were prone to temper outbursts and agitation] were in fact children with Bipolar Disorder. These were "super angry/grouchy/cranky irritable" kids who did not seem to have periodic illness as the classic adult Bipolar Disorder patients – nonetheless, the hypothesis was that this is the childhood equivalent of Mania. The newly introduced Risperdal had been shown to be effective in disruptive intellectually impaired children, and in a series of studies, the Atypical Antipsychotics were found effective in the kids described by Dr. Biederman’s newly minted Bipolar Disorder. As mentioned, this Diagnosis caught on like a new cell-phone technology and there was an epidemic of Pediatric Bipolar Disorder. At the same time, there was an epidemic of the rampant use of Atypical Antipsychotics in children in Foster Care. While many were diagnosed as "Bipolar," the clear implication was that the medication was being used for behavior control.

Dr. Biederman’s fall from grace in the Grassley Investigation also threw his new version of Bipolar Illness into question. The APA even actively created a new disorder in the DSM-5, Disruptive Mood Dysregulation Disorder, designed to divert people from making the diagnosis of pediatric Bipolar Disorder. A distinguishing feature of this new category was that it was non-episodic. But pediatric Bipolar Disorder didn’t retreat back into its preBiederman infrequency. It has stayed very much on the front burner. And the makers of the Atypical Antipsychotics have applied for and been granted FDA indication approval as the drugs have come onto the market [allowing them to advertise]. In the family guides above, there’s reference to the original Biederman version [super angry/grouchy/cranky irritable kids] – a negative reference [see here]. The version described in the guides is similar to the more usual adult form of the illness. In the four or five years I volunteered in a Child and Adolescent clinic that saw primarily Medicaid kids, I never saw a case that would fit the patients mentioned in those guides, though I saw a number with that diagnosis who had been put on an Atypical Antipsychotic. I did see a lot of the Biederman version, out of control disruptive kids who were among the ranks of those who had grown up pillar to post, in and out of foster care.

This clinical trial with Saphris is typical of the Antipsychotics. One can sedate any kind of out-of-control-ness with the Atypicals [just like with the First Generation Neurpleptics], so there’s no surprise that they worked acutely. However, it’s rarely true that these drugs can be taken long-term without adverse side effects of one kind or another as seen in this trial.

The Future of Psychiatry as Clinical Neuroscience: Why Not Now?

JAMA: Psychiatry

Viewpoint

by David A. Ross, MD, PhD; Michael J. Travis, MD; and Melissa R. Arbuckle, MD, PhD

Published online March 11, 2015.

In 2012, Thomas Insel, director of the National Institute of Mental Health, wrote an essay entitled The Future of Psychiatry ( = Clinical Neuroscience), echoing a familiar trope in our field. The themes he described then are even more relevant today. Technologic advances have enhanced our ability to study the brain, and new findings have reshaped the fundamental way in which we understand psychiatric illness. For example, although depression was once characterized as simply a monoaminergic deficit, new research is expanding our understanding of depression across multiple levels of analysis—from circuits, to neurotransmitters, to synaptic plasticity, to second messenger systems, to epigenetic and genetic differences.

To date, however, these advances seem largely limited to the pages of our leading research journals. We have not yet experienced a paradigm shift in the way most physicians approach patient care or in the way we communicate about our field with each other and with the lay public. Given how much progress has already been made, why does this transition remain a thing of the future? What barriers prevent our field from embracing a new identity today?…

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Funding/Support: This study was supported by grant 3R25MH101076-02S1 [PI: Jane Eissen MD] from the National Institute of Mental Health to develop the National Neuroscience Curriculum Initiative [Drs. David A. Ross, Michael J. Travis, and Melissa R. Arbuckle].

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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.

CHANGING PSYCHIATRY, TODAY

The diseases that we treat are diseases of the brain. The question that we need to address is not whether we integrate neuroscience alongside our other rich traditions but how we work as a field to overcome the barriers that currently limit us. Ultimately, the most powerful force will be the improved translation of research into more refined explanatory models of psychiatric pathology and into novel therapeutics. To ensure that our field is ready to embrace new findings as they emerge, we need to begin the process of culture change today by enhancing communication and collaboration between researchers and practitioners.

In this regard, the struggle of residency programs to implement robust neuroscience curricula may be seen as emblematic: if we cannot succeed in changing the conversation within the confines of our most distilled educational setting, how can we effect change more broadly? One lesson may be that it is not possible to address this challenge at an individual [or program] level. Just as cutting-edge research requires a team-based, collaborative approach, so too does cutting-edge education.

We need to begin by facilitating partnerships between the distinct communities of scientists and educators. The more sophisticated and nuanced our science becomes, the more critical it is to have individuals who can translate this work to make it accessible to students at all levels. It is imperative to have skilled educators who can craft classroom experiences that are consistent with the extensive literature on how adults learn. In addition to core content, learning objectives should explicitly address both attitudes toward neuroscience and behavioral skills, such as the ability to incorporate neuroscience data into patient formulations and the ability to communicate effectively with a lay audience…

"To ensure that our field is ready to embrace new findings as they emerge, we need to begin the process of culture change today by enhancing communication and collaboration between researchers and practitioners" strikes me as old news. It has been the Mantra from on high for a long time. I would suggest an alternative more based in the reality of our recent past. The neuroscience of today isn’t likely to be the neuroscience of next year. One need only read the various iterations of Dr. Insel’s versions of this paper to see that. The problem has been that psychiatrists have not been skilled in evaluating the information presented to them. One example is Clinical Trial articles. They poured into our literature for 15 or 20 years and had an enormous impact on clinical practice, and the average psychiatrists had no ability to read them critically – and they really needed to be read critically. A course on clinical trial methodology and analysis including a close reading of examples would be a stellar idea. We’ve been inundated with neuroimaging papers, but few psychiatrists not involved in that kind of research understand the fMRIs, the measurements, or the anatomy being presented. Genomic studies abound, but their techniques and complexities aren’t slightly transparent. 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. We were carried down some dark roads by embracing new findings somewhat blindly, and the results have not done us proud at all. In my Internal Medicine Residency, that’s the kind of exposure to basic techniques we received in the advanced subspecialty rotations. It should be the same in psychiatry.

Farewell to “Molecules to Medicine” on SciAm

Scientific American

By Judy Stone

December 15, 2014

… Thanks, too, to the SciAm editors for having allowed me to post on topics that I was passionate about, including the problems of rural hospitals and research ethics and, in particular, having supported my series on the ethical lapses in psychiatric trials at the University of Minnesota, aka the Markingson case…

UMN’s Clinical Research Practices: Far From ‘Beyond Reproach’

Forbes

by Judy Stone

3/10/2015

It is unfortunate that, in presenting their report to the UMN Faculty senate, the AAHRPP consultants refused to make any statements critical to the UMN, undermining faculty demands for real reform.  In Part 2 on the UMN review, tomorrow, I address what the AAHRPP reviewers missed – or ignored – in their reporting.

What A Scathing External Report On Protections In Research Missed — Or Ignored

Forbes

by Judy Stone

3/11/2015

"The five most critical unreported items, although the AAHRPP was informed of them, follow:

1. "First, nurses on the psych unit did not even know if a patient was participating in a clinical trial. Thus, they wouldn’t know if a change in the patient might be due to an adverse reaction to a med… Yet Niki Gjere, a clinical nurse specialist on that unit, said she was unaware of any clinical trials being conducted then. This incident spurred her to speak out about breaches in standard clinical trial conduct"… [see a paradigm…].
2. "Shockingly, experimental medicines were not documented on the MAR (med administration record) or inpatient chart. One staff nurse suspects that either the physicians administered the investigational meds when they rounded or the patients received the investigational meds when they were taken to an adjacent ambulatory center. This is unheard of in any trial I did, where drug accountability for investigational meds was akin to tracking narcotics"…
3. "Possible HIPAA violations reportedly occurred—intake people at Fairview Hospital gave the psychiatry department information about admitting diagnoses without the patients’ consent, allowing coordinators to then approach the patient about clinical trials. This is a serious breach of patient confidentiality"…
4. "While some recusals from IRB review did occur [p. 25], leaving the IRB without a subject matter expert, certainly there were egregious conflicts of interest on the IRB. For example, Dr. David Adson was Chair of the IRB panel that reviewed Markingson’s death on the CAFÉ trial. Adson was a colleague to Dr. Olson, the Principal Investigator on that trial, and reported to Charles Schulz, Chair of his department and coinvestigator on the CAFÉ trial. It gets better. Adson chaired the IRB that approved the CAFÉ study, and then chaired the panel that “examined” the report of Markingson’s death…nothing to see here; move along… Adson had large financial conflicts of interest as well with AstraZeneca, sponsor of the CAFÉ trial, detailed in this Hastings Center report"…
5. "Finally, the consultant AAHRP reviewers were told by faculty about seemingly fraudulent appearing forms assessing the patient’s capability to consent. While they may claim that this was not part of the charge they received from President Kaler, did they not have a moral and ethical obligation to include an apparent illegal activity in their report?"… [see living history… and intrinsically flawed, and dangerous…]

One of the most troublesome things is the response of the UMN leadership to these findings. President Kaler cheered the AAHRPP report, exclaiming, “I am particularly gratified—but not surprised—that the panel found no legal or compliance violations, affirming numerous previous reviews and accreditations of our program.” He seems oblivious to how the UMN was skewered in a report that was, in some circles, anticipated to be another whitewash. The AAHRPP slammed the IRB for failure to engage “in a meaningful process of evaluating research risk” [p. 78], for lacking “scientific expertise necessary to review studies [p. 26] and for lacking adequate protections for vulnerable patients. They scathingly note, ““Most striking was the commonly conveyed sense of doubt in leadership’s commitment to human subjects protection,” yet Kaler is proud of the UMN’s program…

Worse, the response of the UMN Administration has been to deal with criticism with a fly-swatter, as if the critics are gnats, dedicated trouble-makers, rather than principled experts bringing up legitimate concerns obvious to any other principled experts who take a serious look. This external review commissioned with its limited scope found devastating evidence – even while leaving out the damning pieces noted by Dr. Stone. The president’s comment, "the panel found no legal or compliance violations," fits with the refrain from the last post, "we did nothing wrong." Again he’s happy to report that they aren’t criminally liable – hardly a remotely appropriate standard for a medical research enterprise. It’s form over substance at its worst, and an attitude that has no place in medical research, or for that matter, medical anything. The morality of academia is then no different from the morality of the streets.

Human subjects protections under fire at the University of Minnesota

SCIENCEINSIDER

by Jennifer Couzin-Frankel

March 2015

A damning report on how the University of Minnesota [UM] protects volunteers in its clinical trials concludes that researchers inadequately reviewed research studies across the university and need more training to better protect the most vulnerable subjects. It also found that a “climate of fear” existed in the Department of Psychiatry, where concerns about clinical trials first surfaced.

The 97-page report, released 27 February, was prepared by a group of six experts appointed by the Association for the Accreditation of Human Research Protection Programs. It comes after years of complaints by some UM faculty members, led by bioethicist Carl Elliott. They charged that the school and its doctors failed to protect 27-year-old Dan Markingson, who died by suicide while enrolled in a psychiatric drug trial in 2004. They also expressed grave concerns about how Markingson’s death was investigated. [More on that case is here and here.[

Recently, Elliott’s crusade began having an impact. In December 2013, the UM Faculty Senate called for an independent review of current practices in clinical trials. The administration agreed to open its records to outsiders. Although the review did not look back at history, it nonetheless had plenty to say about how the university handles trials, which bring in millions of dollars from drug companies along with much prestige.

“[T]he external review team believes the University has not taken an appropriately aggressive and informed approach to protecting subjects and regaining lost trust,” the authors write. They examined protocols from 20 active trials as well as minutes from meetings of the institutional review board [IRB]. Many IRB members, the panel noted, did not regularly attend meetings from January to July 2014. “[T]here were no individuals on the IRB during this time period with expertise in adult hematology, oncology and transplant, cardiology, surgery, or neurology, although those fields taken together represented over 300 protocols. There was only one psychiatrist on the IRB, despite the fact that the Psychiatry Department submitted 85 protocols for review during the time period examined.” That doctor attended only four of the 26 medical IRB meetings at which new protocols were reviewed. “This departure not only contravenes the University’s own policy of having at least one member with ‘primary professional expertise in a scientific field relevant to the type of research reviewed by that panel,’ but also prompts concern about the quality of review.”

Fueling those concerns, the authors noted that the IRB spent an average of 3 to 5 minutes discussing each protocol, and there was “little discussion of the risks and benefits to subjects.” Most of the protocol changes the IRB asked researchers to make addressed administrative issues such as misspellings or adding standard language to a consent form. Requests by researchers running trials to modify who was eligible for a study—“changes that may increase or decrease risks to subjects—were almost always approved without any documentation of related discussion,” the authors write. “The review process, as documented in the minutes, does not reflect a meaningful discussion of the risks and benefits of research protocols and the necessary steps taken to protect human subjects in the face of scientific or ethical concerns”…

In interviews, some University personnel described considerable “fatigue” related to what they considered unrelenting and unjustified criticism of the University’s human subjects protection program. In contrast, others expressed bewilderment and frustration that, in their view, the University has failed to understand and remedy problems stemming from and related to “Markingson.” Most striking was the commonly conveyed sense of doubt in leadership’s commitment to human subjects protection. The widespread characterization of a few researchers in the Department of Psychiatry as “untrustworthy” and as creating a “culture of fear” in relation to efforts to enhance the protection of research subjects was of major concern to the external review team.

“We’re acting as though this report is news, but in fact there’s been several years where concerns have been brought forward in very detailed, concrete ways,” he said at the meeting. Turner said University leadership hasn’t adequately responded to problems he says have been happening within the program for years, and he questioned University President Eric Kaler’s commitment to repair the program’s current state.

"We did nothing wrong" is a legal standard – the standard by which we define criminal behavior in a free society based on the rule of law. An ethical standard is different. For one thing, in medicine, it is impossible to do "nothing wrong." But beyond that, an ethical standard has to do with maintaining an ethos, a culture. 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.

• the design and purpose of the C.A.F.E. study
• the oversight function of the Institutional Review Board
• the recruitment and inclusion of Dan Markingson
• his ongoing psychiatric care
• the subsequent responses of Institution

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. Likewise, the external reviewers appointed by the the Association for the Accreditation of Human Research Protection Programs who were given only a restricted scope of inquiry [too deep to ignore…, almost inevitable…, a paradigm…] were still able to identify fundamental deficiencies in the Clinical Trial Program at the University of Minnesota, even after a decade of opportunity to make needed changes since Markingson’s death. Elliot’s team and these reviewers have obviously "done something right."

Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study.

by Fleischhacker WW, Sanchez R, Perry PP, Jin N, Peters-Strickland T, Johnson BR, Baker RA, Eramo A, McQuade RD, Carson WH, Walling D, and Kane JM.

British Journal of Psychiatry. 2014 205[2]:135-44.

[clinicaltrials.gov: NCT00706654][with results]

[full text on-line]

The authors in red are either heavily industry-funded by or employees of Otsuka, The Study Director was Otsuka employee, Raymond Sanchez. There were 98 clinical trial sites, and an army of editorial assistants and consultants suggesting that it was ghost-written and ghost-analyzed. The senior listed author, John Kane, is in charge of the influential ACA funded NIMH RAISE study of the treatment of First Episode Schizophrenia. This study analysis seemed legit to me.

Except for the fact that the industry credits scrolled by like at the end of a Hollywood Blockbuster, and I kind of wonder why the industries were mostly for-hire or why they even bother to list academic authors as anything other than ticket holders for admission to an academic journal, my point really isn’t about Abilify Maintena® or even Long Acting Injectable antipsychotics. It’s about advertisement and conflicts of interest. Continuing Medical Education was made a requirement for licensure in my medical lifetime. The intent was to insure that as doctors age, they are kept abreast of the rapidly changing medical/scientific landscape. And our peer reviewed medical journals perform the same function. Traditionally, individual physicians paid for both – CME presentations and our Journals. But sometimes they are free…

So last time, we had an LAI paper from an author at the Rand Corporation on the Janssen payroll [impossibility…]. Now comes a Free CME that was "supported by an independent educational grant from Otsuka America Pharmaceuticals, Inc", who happen to have a new LAI on the market [Abilify Maintena®], approved by the FDA based on an industry study with senior author John Kane, who happens to be funded himself by Otsuka, who happens to direct an NIMH Project treating Schizophrenia being picked up already by SAMHSA’s Block Grant program, who happens to write about the drugs used to treat Schizophrenia, and who was skeptical about Tardive Dyskinesia as far back as 1982.

• Christoph U. Correll, MD
  Professor of Psychiatry and Molecular Medicine
  Hofstra North Shore – LIJ School of Medicine
  Medical Director of Recognition and Prevention (RAP) Program
  The Zucker Hillside Hospital
  Glen Oaks, NY
• John M. Kane, MD
  Professor of Psychiatry
  Hofstra North Shore – LIJ Health System School of Medicine
  Vice President
  Behavioral Health Services of the North Shore – LIJ Health System
  Chairman of Department of Psychiatry and Chief of Staff
  The Zucker Hillside Hospital
  Glen Oaks, New York
• John Lauriello, MD
  Chancellor’s Chair of Excellence in Psychiatry
  Executive Medical Director of the Missouri Psychiatric Center
  School of Medicine, University of Missouri Health System
  Columbia, MO

Take a look at the Learning Objective and guess what you’re going to learn – for free. Oh by the way, John Lauriello, MD is the senior author of a glowing handout review of Abilify Maintena®.