and guild wars…

Posted on Friday 17 July 2015

In case you’re behind on the APA/Torture story, here are a few catch-up links. Also see Rob Purssey’s comment to the last post [UPDATE: There’s a more readable version here]:
I spent a lot of time in the period between 2005 and 2008 blogging about the misadventures of the Bush Administration and learned more than I ever wanted to know about the CIA/DoD Torture Program. Last night, I looked over some of those posts and felt the same fire in the belly I felt when I wrote them. I reread about the American Enterprise Institute, the Project for the New American Century, the Federalist Society, the Niger Forgeries, Valerie Plame, The Torture Memos, American Dominion, the Unitary Executive, etc. They wanted us to opportunize on the fall of the Communist Bloc and take over as the sole super-power. And they used the tragedy of 911 to jump·start their New American Century by invading Iraq. It was painful to read all of that again and I  stopped when I began to feel nauseated.

But there was one piece in all of what I had forgotten about those crazy times that relates to the present point. Remember that the Bybee/Yoo Torture Memos appeared quickly after 911, and the torture program at GITMO started early, almost as soon as the detainees captured in Afghanistan started arriving. In 2008, the Senate Investigation [The Treatment of Detainees in U.S. Custody] told us why [see the the why of torture…]:
When Psychiatrist Major Paul Burney arrived at Guantanamo Bay in June 2002, he was unaware that he would be assigned to BSCT [Behavioral Science Consultation Team] to support interrogations.
    [1] Three of us; [the enlisted psychiatric technician], and I, were hijacked and immediately in processed into Joint Task Force 170, the military intelligence command on the island. It turns out we were assigned to the interrogation element because Joint Task Force 170 had authorizations for a psychiatrist, a psychologist, and a psychiatric technician on its duty roster but nobody had been deployed to fill these positions. Nobody really knew what we were supposed to do for the unit, but at least the duty roster had its positions filled.

    They knew nothing of interrogation, so the psychologist contacted a psychologist he had met, LTC Banks, who was [unknown to the contacting psychologist] working with SERE. Banks set out to arrange training. BSCT thought they were going there just to learn about interrogation, but their CO wanted them to bring back SERE techniques to try.

    [2] At the time, there was a view by some at GTMO that interrogation operations had not yielded the anticipated intelligence, MAJ Burney testified to the Army IG regarding interrogations: "This is my opinion, even though they were giving information and some of it was useful, while we were there a large part of the time we were focused on trying to establish a link between al Qaeda and Iraq and we were not being successful in establishing a link between al Qaeda and Iraq. The more frustrated people got in not being able to establish this link, there was more and more pressure to resort to measures that might produce more immediate results."
They actually tortured one detainee into saying that there was an al Qaeda·Iraq connection, but he recanted as soon as they stopped drowning him every day [no big surprise]. And in case you didn’t catch it, the "LTC Banks" mentioned by Major Burney is the same "Banks" that ended up orchestrating the APA PENS Task Force in consort with Stephen Behnke, the APA Ethics Director.

The point is simply that besides being an indelible blot on the moral integrity of our country and failing to yield anything of any worth to us, the Torture Program was actually used as a tool to take advantage of our wounded and frightened state to trump up a reason to invade a sovereign country that had nothing to do with 911 by trying to link al Qaeda and Iraq, probably partly motivated to gain access to Iraq’s oil reserves and partly as a showpiece for their Project for the New American Century – AKA American Dominion on the world stage. So why did the APA Ethics Director, Stephen Behnke, and his cohort in the APA leadership do it? Was he part of the Bush Administration megalomania. No, it was something much simpler…

…to repeat «from the Hoffman Report, page 14»
APA’s motive to please DoD

The very substantial benefits APA obtained from DoD help explain APA’s motive to please DoD. and show that APA likely had an organizational conflict of interest, which it needed to take steps to guard against. DoD is one of the largest employers of psychologists and provides many millions of dollars in grants or contracts for psychologists around the country. The history of DoD providing critical assistance to the advancement and growth of psychology as a profession is well documented, and includes DoD’s creation of a prescription-privileges "demonstration project" in which psychologists were certified to prescribe psychiatric drugs within DoD after going through a two-year training course… And by the time of the PENS Task Force, contemporaneous internal discussions show that improving APA’s already strong relationship with DoD was a clear priority for officials working on the PENS Task Force.

In addition, at the time of the task force’s creation, DoD was in the midst of developing policy about how psychologists and psychiatrists could participate in interrogations and other intelligence-collection activities. APA wanted to positively influence DoD regarding this policy so that psychologists would be included to the maximum degree possible, and psychologists would not lose the lead role to psychiatrists. APA used the pro-DoD task force composition and report to show its strong support to DoD, with the hope or expectation that APA would be rewarded with a very prominent role for psychologists in this new policy. And in fact, the policy did provide a very prominent role for psychologists, a fact celebrated by the APA officials who had worked most closely on the task force…
And in response to allegations that psychologists had behaved unethically and actively participated in Torture:

«from the Hoffman Report, page 63»
Behnke failed to proceed with and actively resisted proceeding with these complaints. The evidence shows that Behnke knew that the adjudications process was not equipped to address ethical complaints regarding psychologists’ participation in interrogations — and that it would not lead to any sort of meaningful or thorough investigation.

The end result of the limited nature of the ethics investigations and the Ethics Office’s purposeful unwillingness to thoroughly investigate allegations of unethical conduct by psychologists who participated in interrogations was that the Ethics Office prioritized the protection of psychologists — even those who might have engaged in unethical behavior — above the protection of the public.

Mickey @ 2:03 PM

guild interests…

Posted on Thursday 16 July 2015

Much of what I write about here has to do with the corruption of the medical record by industry funded clinical trials that have distorted both the efficacy and the safety of our treatments – specifically in psychiatry. But the topic has really been the erosion of the medical ethic of the authors and editors that have allowed [and placed] these studies in our literature. We’re fortunate to be in a time when there’s a palpable movement afoot to do something about it. This post is also about ethics, but in a related professional arena – organized psychology.

After 911, the country was united in a surge of patriotic zeal that the Bush Administration used to take us into a war with Iraq that we would have declined in other circumstances. The prisoner abuse at Abu Ghraib prison and torture at Guantanamo Bay were among the many disillusioning revelations that came out of that war. We learned that two DoD contract psychologists, Jim Mitchell and Bruce Jessen, had a central role in the development and implementation of the enhanced interrogation techniques [AKA Torture]. Less widely known, the APA [American Psychological Association] also had a part in this story – specifically addressing the ethical obligations of the psychologists involved in the interrogation process.

Last Friday, the APA released an independently commissioned report focusing on the details – specifically the actions of the APA’s Presidential Task Force on Psychological Ethics and National Security [PENS] in 2005 and the years that followed. Here are a few snippets from the Press Release and 500+ page report. It’s not pretty:
American Psychological Association
June 10, 2015

… The Hoffman report contains deeply disturbing findings that reveal previously unknown and troubling instances of collusion,” said Dr. Susan McDaniel, a member of the Independent Review’s Special Committee. “The process by which the Presidential Task Force on Psychological Ethics and National Security [PENS] was created, the composition of the membership, the content of the PENS report and the subsequent activities related to the report were influenced by collusion between a small group of APA representatives and government officials.

The Hoffman report states that the intent of the individuals who participated in the collusion was to “curry favor” with the Defense Department, and that may have enabled the government’s use of abusive interrogation techniques. As a result, the 2005 PENS report became a document based at least as much on the desires of the DoD as on the needs of the psychology profession and the APA’s commitment to human rights…
Sidley Austin law firm
by Douglas Hoffman
Commisioned by the American Psychological Association
June 2015

«from the Hoffman Report, page 14»

APA’s motive to please DoD

The very substantial benefits APA obtained from DoD help explain APA’s motive to please DoD. and show that APA likely had an organizational conflict of interest, which it needed to take steps to guard against. DoD is one of the largest employers of psychologists and provides many millions of dollars in grants or contracts for psychologists around the country. The history of DoD providing critical assistance to the advancement and growth of psychology as a profession is well documented, and includes DoD’s creation of a prescription-privileges "demonstration project" in which psychologists were certified to prescribe psychiatric drugs within DoD after going through a two-year training course. While APA took one significant step in 1991 that disappointed many military psychologists — refusing to allow DoD ads in APA’s publications because of DoD’s discriminatory position regarding gays and lesbians in the military — APA had lifted its advertising ban in 2004. And by the time of the PENS Task Force, contemporaneous internal discussions show that improving APA’s already strong relationship with DoD was a clear priority for officials working on the PENS Task Force.

In addition, at the time of the task force’s creation, DoD was in the midst of developing policy about how psychologists and psychiatrists could participate in interrogations and other intelligence-collection activities. APA wanted to positively influence DoD regarding this policy so that psychologists would be included to the maximum degree possible, and psychologists would not lose the lead role to psychiatrists. APA used the pro-DoD task force composition and report to show its strong support to DoD, with the hope or expectation that APA would be rewarded with a very prominent role for psychologists in this new policy. And in fact, the policy did provide a very prominent role for psychologists, a fact celebrated by the APA officials who had worked most closely on the task force…

«from the Hoffman Report, page 9»


Our principal findings relate to the 2005 task force, which was formally empaneled by the APA President and was called the Presidential Task Force on Ethics and National Security, or "PENS." The task force finalized a report on June 26, 2005 containing 12 ethical guidelines that were adopted as official APA ethics policy by the APA Board on an emergency basis less than one week later.

Our investigation determined that key APA officials, principally the APA Ethics Director joined and supported at times by other APA officials, colluded with important DoD officials to haw APA issue loose, high-level ethical guidelines that did not constrain DoD in any greater fashion than existing DoD interrogation guidelines. We concluded that APA’s principal motive in doing so was to align APA and curry favor with DoD. There were two other important motives: to create a good public-relations response, and to keep the growth of psychology unrestrained in this area.

We also found that in the three years following the adoption of the 2005 PENS Task Force report as APA policy, APA officials engaged in a pattern of secret collaboration with DoD officials to defeat efforts by the APA Council of Representatives to introduce and pass resolutions that would haw definitively prohibited psychologists from participating in interrogations at Guantanamo Bay and other U.S. detention centers abroad. The principal APA official involved in these efforts was once again the APA Ethics Director, who effectively formed an undisclosed joint venture with a small number of DoD officials to ensure that APA’s statements and actions fell squarely in line with DoD’s goals and preferences. In numerous confidential email exchanges and conversations, the APA Ethics Director regularly sought and received pre-clearance from an influential, senior psychology leader in the U.S. Army Special Operations Command before determining what APA’s position should be. what its public statements should say. and what strategy to pursue on this issue…
I’ve only read the 73 page Executive Summary, but the facts are pretty clear. In response to the revelations of the involvement of psychologists in the torture of prisoners, the APA quickly gathered a Task Force to clarify the APA’s ethical guidelines. The Ethics Director assembled a Task Force heavily weighted with DoD psychologists and created guidelines with vague generalities that essentially allowed the DoD to continue doing what they were doing. The dissenting non-DoD psychologists on the Task Force were lied to about some future specific limits on the interrogations. All of this was done in close [private] consultation with the DoD itself, a collusion that continued for the duration of the Bush Administration. It was a sham, motivated by currying favor with the DoD in a guild competition with psychiatry; an attempt at mitigating against bad PR; but it had nothing to do with the manifest topic – the ethics of the torture program. Input from the representative body or general membership of the APA was carefully avoided.

This report documents how guild interests can corrupt the basic values of the guild itself. In spite of the dark side revealed here, the APA deserves praise for commissioning this report and revising ethical guidelines based on the findings. Psychiatry could learn a thing or two from this example. A similar investigation into the widespread participation of academic psychiatrists in the authorship of jury-rigged industry-funded clinical trials and other drug marketing collusions is long overdue…

see also:
Mickey @ 1:34 PM


Posted on Wednesday 15 July 2015

Another lightning strike! Awaiting Internet repair…

Mickey @ 1:23 PM

probably approximates zero…

Posted on Tuesday 14 July 2015

When Risperdal® [Risperidone] came along in 1994, it was widely hoped [and hyped] that it would release patients from the heavy and sometimes dangerous side effect burden of the earlier neuroleptic medications. One of Janssen’s targeted indications was in to control disruptive behaviors in intellectually impaired children. This RCT was completed in 1998, and used in a submission to the FDA…
by Michael G. Aman, Ph.D., Goedele De Smedt, M.D., Albert Derivan, M.D., Ben Lyons, Ph.D., Robert L. Findling, M.D., and the Risperidone Disruptive Behavior Study Group
American Journal of Psychiatry 2002 159:1337-1346.
[ Identifier: NCT00266552]

Objective: The short-term efficacy and safety of risperidone in the treatment of disruptive behaviors was examined in a well-characterized cohort of children with subaverage intelligence.
Method: In this 6-week, multicenter, double-blind, parallel-group study of 118 children [aged 5-12 years] with severely disruptive behaviors and subaverage in- telligence [IQ between 36 and 84, inclusive], the subjects received 0.02-0.06 mg/kg per day of risperidone oral solution or placebo. The a priori primary efficacy measure was the change in score from baseline to endpoint on the conduct problem subscalc of the Nisonger Child Behavior Rating Form.
Results: The risperidone group showed significantly greater improvement than did the placebo group on the conduct problem subscale of the Nisonger Child Behavior Rating Form from week 1 through endpoint [change in score of -15.2 and -6.2, respectively]. Risperidone was also associated with significantly greater improvement than placebo on all other Nisonger Child Behavior Rating Form subscales at endpoinl. as well as on the Aberrant Behavior Checklist subscales for irritability, lethargy-social withdrawal, and hyperactivity; the Behavior Problems Inventory aggressive -destructive behavior subscale; a visual analogue scale of the most troublesome symptom; and the Clinical Global Impression change score. The most common adverse effects reported during risperidone treatment were headache and somnolence. The extrapyramidal symptom profile of risperidone was comparable to that of placebo. Mean weight increases of 2.2 kg. and 0.9 kg occurred in the risperidone and placebo groups, respectively.
Conclusions: Risperidone was effective and well tolerated for the treatment of severely disruptive behaviors in children with subaverage IQ.

… that was denied, not because of lack of efficacy, but because the FDA felt the indication was too broad and might lead to the overmedication of kids. This Janssen study was repurposed, rewritten [ghost written], and republished under Dr. Joseph Biederman’s name in 2006 as part of his series on the treatment of the Bipolar Child [bipolar kids: biedermania and super angry/grouchy/cranky irritability…]. Janssen was later fined for off-label promotion and other forbidden marketing practices.

In the intervening decades, the Atypical Antipsychotics haven’t lived up to those early expectations, at least in a medical sense. But they became blockbusters at the marketplace – one or another of them dominating the sales charts for years. While the side effect profiles differ from those of  the first generation drugs, they are hardly benign. And the feared overmedication of children moved out of the domain of future worry into our current reality. This next article by Olfson et al is a new population survey of antipsychotic medication use in youth that aims to flesh out that current reality [the reason I started with Aman et al’s early trial  will become obvious]:
by Mark Olfson, MD, MPH; Marissa King, PhD; Michael Schoenbaum, PhD
JAMA Psychiatry. online July 01, 2015. doi:10.1001/jamapsychiatry.2015.0500.

Importance Despite concerns about rising treatment of young people with antipsychotic medications, little is known about trends and patterns of their use in the United States.
Objective To describe antipsychotic prescription patterns among young people in the United States, focusing on age and sex.
Design, Setting, and Participants A retrospective descriptive analysis of antipsychotic prescriptions among patients aged 1 to 24 years was performed with data from calendar years 2006 [n = 765,829], 2008 [n = 858,216], and 2010 [n = 851,874], including a subset from calendar year 2009 with service claims data [n = 53,896]. Data were retrieved from the IMS LifeLink LRx Longitudinal Prescription database, which includes approximately 60% of all retail pharmacies in the United States. Denominators were adjusted to generalize estimates to the US population.
Main Outcomes and Measures The percentage of young people filling 1 or more antipsychotic prescriptions during the study year by sex and age group [younger children, 1-6 years; older children, 7-12 years; adolescents, 13-18 years; and young adults, 19-24 years] was calculated. Among young people with antipsychotic use, percentages with specific clinical psychiatric diagnoses and 1 or more antipsychotic prescriptions from a psychiatrist and from a child and adolescent psychiatrist were also determined.
Results The percentages of young people using antipsychotics in 2006 and 2010, respectively, were 0.14% and 0.11% for younger children, 0.85% and 0.80% for older children, 1.10% and 1.19% for adolescents, and 0.69% and 0.84% for young adults. In 2010, males were more likely than females to use antipsychotics, especially during childhood and adolescence: 0.16% vs 0.06% for younger children, 1.20% vs 0.44% for older children, 1.42% vs 0.95% for adolescents, and 0.88% vs 0.81% for young adults. Among young people treated with antipsychotics in 2010, receiving a prescription from a psychiatrist was less common among younger children [57.9%] than among other age groups [range, 70.4%-77.9%]. Approximately 29.3% of younger children treated with antipsychotics in 2010 received 1 or more antipsychotic prescriptions from a child and adolescent psychiatrist. Among young people with claims for mental disorders in 2009 who were treated with antipsychotics, the most common diagnoses were attention-deficit/hyperactivity disorder in younger children [52.5%], older children [60.1%], and adolescents [34.9%] and depression in young adults [34.5%].
Conclusions and Relevance Antipsychotic use increased from 2006 to 2010 for adolescents and young adults but not for children aged 12 years or younger. Peak antipsychotic use in adolescence, especially among boys, and clinical diagnosis patterns are consistent with management of developmentally limited impulsive and aggressive behaviors rather than psychotic symptoms.

I’ve spent a couple of days reading over this article and its companion editorial. I suppose I wanted to find something profound to say about it, or maybe decry what it has to say in some new way, or even find some new target to blame. But I can’t beat the authors’ conclusion:
Peak antipsychotic use in adolescence, especially among boys, and clinical diagnosis patterns are consistent with management of developmentally limited impulsive and aggressive behaviors rather than psychotic symptoms.
In the text they go on to make recommendations:
Clinical policy makers have opportunities to promote improved quality and safety of antipsychotic medication use in young people through expanded use of quality measures, physician education, telephone- and Internet-based child and adolescent psychiatry consultation models, and improved access to alternative, evidence-based psychosocial treatments.
This paper documents a simple fact – what used to be called antipsychotic medication is being used as a behavior control aid in children and adolescents, much like Aman et al discussed using it in the earliest of days. The likelihood that these latter suggestions will be implemented or that they would make much difference if they were probably approximates zero without a palpable change in the current climate of child and adolescent psychiatry and its professional organizations…
Mickey @ 2:30 PM

after the fact…

Posted on Saturday 11 July 2015

The place of antipsychotics in the treatment of Psychosis remains clouded in controversy in spite of more than a half century of study, experience, and debate. Neither Kraepelin’s Dementia Praecox, a progressive deteriorating illness leading to an early death, nor Bleuler’s Schizophrenia, a defined syndrome with multiple types, survives as the dominant model for predicting the course of illness. We now tend to see episodes of psychosis punctuating a variable level of functional impairment over time. While traditional guidelines call for maintenance medication based on relapse prevention, long term studies document that many patients regularly discontinue the treatment. And others feel strongly that maintenance medication itself interferes with recovery. Both of these opposing recommendations are backed by studies, anecdotal case reports, passionate ideologies, and interpretations of the bias of the opposing view. Since these medication have now been around now for a lifespan we’re seeing large population surveys that bear on this controversy. This one’s from Scandanavia, a traditional resource for this big population studies:

by Torniainen M, Mittendorfer-Rutz E, Tanskanen A, Björkenstam C, Suvisaari J, Alexanderson K, and Tiihonen J.
Schizophrenia Bulletin. 2015 41[3]:656-663.

BACKGROUND: It is generally believed that long-term use of antipsychotics increases mortality and, especially, the risk of cardiovascular death. However, there are no solid data to substantiate this view.
METHODS: We identified all individuals in Sweden with schizophrenia diagnoses before year 2006 [N = 21 492], aged 17-65 years, and persons with first-episode schizophrenia during the follow-up 2006-2010 [N = 1230]. Patient information was prospectively collected through nationwide registers. Total and cause-specific mortalities were calculated as a function of cumulative antipsychotic exposure from January 2006 to December 2010.
RESULTS: Compared with age- and gender-matched controls from the general population [N = 214920], the highest overall mortality was observed among patients with no antipsychotic exposure [hazard ratio [HR] = 6.3, 95% CI: 5.5-7.3], ie, 0.0 defined daily dose [DDD]/day, followed by high exposure [>1.5 DDD/day] group [HR = 5.7, 5.2-6.2], low exposure [<0.5 DDD/day] group [HR = 4.1, 3.6-4.6], and moderate exposure [0.5-1.5 DDD/day] group [HR = 4.0, 3.7-4.4]. High exposure [HR = 8.5, 7.3-9.8] and no exposure [HR = 7.6, 5.8-9.9] were associated with higher cardiovascular mortality than either low exposure [HR = 4.7, 3.7-6.0] or moderate exposure [HR = 5.6, 4.8-6.6]. The highest excess overall mortality was observed among first-episode patients with no antipsychotic use [HR = 9.9, 5.9-16.6].
CONCLUSIONS: Among patients with schizophrenia, the cumulative antipsychotic exposure displays a U-shaped curve for overall mortality, revealing the highest risk of death among those patients with no antipsychotic use. These results indicate that both excess overall and cardiovascular mortality in schizophrenia is attributable to other factors than antipsychotic treatment when used in adequate dosages.
The conclusions are relatively straight-forward. In this large cohort study, there was shortened lifespan associated with Schizophrenia, no matter how it was treated. Antipsychotic medication decreased that effect in any dose, but more·so in the low·to·moderate dose ranges [the data-set they had couldn’t address the possibility that the high dose patients had more severe illness than the others].

While the implications of this study may seem to conflict with other oft·quoted papers [eg Wunderink, Harrow, etc] the outcome parameters are different – functional improvement there vs overall mortality here. Further, all of these reports can’t possibly factor in the most confounding variable of all – the unique clinical field that the patient, the clinician, and the family face at any given moment in time. So reading the blogs, the individual case reports, and the various commentaries on this topic can be confusing as they often discuss these decisons as if they fall into the domain of morality – using maintenance medication is good as opposed to using maintenance medication is bad.

Like so many decisions in clinical medicine, there really isn’t yet an over-riding guiding principle here that I can see – no solid one-size fits all. The best advice in these circumstances is to be as informed as possible, to live with the intrinsic ambiguities, to take your best shot given the particulars of the given case,  and then be careful to follow up on the impact of the intervention. Frequently, if there is to be clarity, it will become apparent after the fact. That’s just how clinical medicine works…
Mickey @ 1:25 PM

come a time…

Posted on Thursday 9 July 2015

Washington Post
By Elahe Izadi and Abby Phillip
July 9, 2015

South Carolina Gov. Nikki Haley is set to sign a bill that will bring down the Confederate flag on the statehouse grounds, less than a day after lawmakers in the state House of Representatives voted to remove it. Haley, a Republican, called for the flag’s removal last month in the wake of the shooting massacre inside a Charleston church. The bill cleared its final legislative hurdle early Thursday morning when the House voted 94 to 20 in favor of the proposal.

After more than 13 hours of debate — which became increasingly contentious as the night wore on — House Republicans and Democrats agreed not to amend the legislation with a proposal that threatened to make final passage more difficult. Just before 1 a.m., the lawmakers voted 93 to 27 to move it forward in a critical second-reading vote. Minutes later, the bill easily cleared the two-thirds threshold needed for it to officially pass the chamber, a hurdle the state Senate cleared earlier this week.
If you didn’t grow up in the South in the 1940s and 1950s, you couldn’t possible imagine how big this is. That license plate on the right was on the front of many cars [in some places "most cars"] and "The South shall rise again!" was a stock phrase. Even those of us who were dedicated to racial equality and were marching in the streets saw that flag and those slogans, as having some misty-eyed meaning. That was wrong. And many of us figured that out along the way. But for the Legislature of the State of South Carolina to actually do something about it is truly a something I thought I’d never see. There will come a time when this something will be the history that South Carolinians are proud of…
Mickey @ 8:43 PM

still happening…

Posted on Sunday 5 July 2015

[click image for the full version]

In the 2000 US Census, they asked people to describe their ancestry. The map showing the dominant answer by County had an interesting spot. Instead of some comment about a foreign lineage, they just wrote "American." It’s in yellow and we call it Appalachia for obvious reasons. Outside the cities, it’s a culturally distinct place, generally poor, and filled with independent people descended from the independent people who gravitated to these mountains from who-knows-where. I live there, and one thing you keep up with in this part of the world is "drugs." This has been the moonshiner territory since the Civil War, and it remains a center for drug use – both legit [better than a sudoku…] and street drugs. If you practice medicine here, you definitely hear about drugs. But that’s just a little epidemiological side trip. Here’s the main storyline.

Some time back, I began to hear a new term – "New Vigil." I thought it was a street drug – slang – because the people where I live were traveling some 50 miles away during the recession to work in the numerous chicken processing plants there [shift work]. So I thought "New Vigil" was a nickname for some new version pep pill they were taking to stay up all night plucking chickens.

That was sort of right, in spirit, but it was the prescription medication – Nuvigil® they were seeking. It’s advertised for excessive daytime sleepiness, but was being used for excessive nightime sleepiness on the graveyard shifts at the chicken plants – much in demand. The manufacturer, Teva, has cast a wide net looking for other indications [see]. Here’s one of their studies in Bipolar Depression:
by Ketter TA, Yang R, and Frye MA.
Journal of Affective Disorders. 2015 181:87-91.

BACKGROUND: In a previous study, adjunctive armodafinil 150mg/day significantly improved depressive symptoms associated with bipolar I disorder.
METHODS: Multicenter, double-blind study of patients with a major depressive episode despite bipolar I disorder maintenance therapy randomized to adjunctive placebo or adjunctive armodafinil 150 or 200mg/day for 8 weeks; for logistical reasons, assignment to armodafinil 200mg/day was discontinued early. Primary efficacy was measured by change from baseline to week 8 in 30-Item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) total score.
RESULTS: Patients were randomized to adjunctive placebo (n=230), adjunctive armodafinil 150mg/day (n=232), or adjunctive armodafinil 200mg/day (n=30; analyzed for safety only). Least-square mean change in IDS-C30 total score was numerically superior for adjunctive armodafinil 150mg/day vs adjunctive placebo, but was not statistically significant (p=0.13). Armodafinil was well-tolerated. Adverse events (AEs) observed in >5% with adjunctive armodafinil 150mg/day and more frequently than with adjunctive placebo were headache (16% [38/231] vs 13% [30/229]) and nausea (7% [17/231] vs 2% [5/229]). The most common AEs with adjunctive armodafinil 200mg/day were diarrhea and dry mouth (17% [5/30] each vs 6% [13/229] and 1% [3/229], respectively, with adjunctive placebo).
LIMITATIONS: Early study discontinuation for logistical reasons by the sponsor limited adjunctive armodafinil 200-mg/day assessment.
CONCLUSIONS: FDA-approved bipolar I depression treatments are limited. Adjunctive armodafinil 150mg/day reduced depressive symptoms associated with bipolar I disorder to a greater extent than adjunctive placebo, although the difference failed to reach statistical significance. Safety data indicate treatment with adjunctive armodafinil was well-tolerated.
If you actually read that abstract, you already know it was a very fishy write-up [in fact, it was outrageous]. Neuroskeptic spells it out for us:
Discover Magazine Blogs
By Neuroskeptic
June 28, 2015

A misleading piece of statistical rhetoric has appeared in a paper about an experimental antidepressant treatment. The study is published in the Journal of Affective Disorders. JAD is a respectable mid-ranked psychiatry journal – yet on this occasion they seem to have dropped the ball badly. The study examined whether the drug armodafinil [Nuvigil] improved mood in people with bipolar disorder who were in a depressive episode. In a double-blind trial, 462 patients were randomized to treatment with either armodafinil 150 mg/day, or placebo, in addition to their regular medication, for 8 weeks.

The results showed no statistically significant difference between the two groups in change on the depression rating scale, the IDS-C30. [p = 0.24 LOCF, p = 0.13 at week 8]. So this means that there was no evidence that armodafinil helped treat depression. Oh dear. It’s a textbook example of a negative, or null, result. Despite this, however, the paper’s abstract concludes on a remarkably upbeat note…
    FDA-approved bipolar I depression treatments are limited. Adjunctive armodafinil 150mg/day reduced depressive symptoms associated with bipolar I disorder to a greater extent than adjunctive placebo, although the difference failed to reach statistical significance.
The second sentence is quite misleading. The mean reduction in symptoms was indeed slightly higher in the armodafinil group than in the placebo group, but in the absence of statistical significance, the difference of means is meaningless [no pun intended]. Even assuming that the drug has no effect, there would be a 50% chance of the drug group having the greater improvement – and a 50% chance of the placebo being greater. One of the values has to be greater, after all. There will always be some mean difference. Which is why we need statistical significance testing.

So we simply can’t say that the drug “reduced depressive symptoms to a greater extent”, not even if we qualify this with the caveat that the effect was not statistically significant. The caveat is so big that it negates the entire statement. Other statements about how the drug group showed “numerically greater” improvement appear in the main text…
When I first read this, I laughed it off – thinking they were responding to the new injunction to publish negative studies because of the ubiquitous "publication bias," but unable to just say, "negative study." But somebody pointed out to me that this was not a benign act. Some journal editor let these bizarre conclusions through and that’s cancer.

There’s some other weirdness – like "Received  30 March 2015, Accepted  2 April 2015."  When did they even do peer review? And there’s something else worthy of note. There are four studies of in Bipolar Depression, and three of them share something peculiar:

Clinical Trials of Nuvigil®
subjects sites mean

499 92 5.4
257 55 4.6
399 130 3.0
897 33 27.2

The CROs spread their studies over multiple sites to make recruitment easier and and speed up the trial. But I’ve never seen anything that approximated this number of sites. There’s a statistical method to partition variance to separate out the effect of the sites from the effect of the drug, and testing the drug x site interaction checks for particular sites skewing the results [though I couldn’t see that they availed themselves of that test]. But even if they had, this pushes the practice of using multiple sites well beyond any credibility.

It’s tedious, but I’m thinking that the vigilance about industry-funded trials is not yet over. It’s still happening…
Mickey @ 9:24 AM

further study…

Posted on Saturday 4 July 2015

Here’s a study that’s likely to engender a brisk discussion:
by Sharifi V, Eaton WW, Wu LT, Roth KB, Burchett BM, and Mojtabai R.
British Journal of Psychiatry. 2015 May 7 [Epub ahead of print].
[First received 10 Dec 2013, final revision 24 Nov 2014, accepted 24 Nov 2014, Published online 1 July 2015.]

Background: Psychotic experiences are common in the general population and are associated with adverse psychiatric and social outcomes, even in the absence of a psychotic disorder.
Aims: To examine the association between psychotic experiences and mortality over a 24-27 year period.
Method: We used data on 15,049 adult participants from four sites of the Epidemiologic Catchment Area baseline survey in the USA in the early 1980s, linked to the National Death Index and other sources of vital status up until 2007. Psychotic experiences were assessed by the Diagnostic Interview Schedule.
Results: Lifetime psychotic experiences at baseline [n = 855; weighted prevalence, 5.5%] were significantly associated with all-cause mortality at follow-up after adjustment for sociodemographic characteristics and psychiatric diagnoses, including schizophrenia spectrum disorders [P<0.05]. Baseline psychotic experiences were associated with over 5 years’ shorter median survival time. Among the underlying causes of death, suicide had a particularly high hazard ratio [9.16, 95% CI 3.19-26.29].
Conclusions: Future research needs to explore the association of psychotic experiences with physical health and lifestyle factors that may mediate the relationship of psychotic experiences with mortality.
[note that it was accepted November 24, 2014 and that the BPS final draft for Understanding Psychosis and Schizophrenia is dated 19 November 2014 suggesting to me that they were generated independently from and blind to one another].

Earlier this year when the British Psychological Society released their Understanding Psychosis and Schizophrenia, Dr. Jeffrey Lieberman unleashed an ad hominem attack that a lot of us felt was way out of bounds [even for him] [see which side of the street?…] similar to another a bit later against Robert Whitaker [just stop…]. But calling out Dr. Lieberman for conduct unbecoming didn’t necessarily signal support for the BPS Report. It really was a hard report to even discuss because it was presented more as an emotional polemic than a scientific report. If you haven’t read it, please do. It isn’t something that can be easily summarized. But there are only two possible responses: Psychiatry pathologizes normality or The BPS normalizes pathology. Here were some of my reactions at the time it came out : <to be continued>…, back to the drawing board…, impossibility…, jettison schizophrenia?…, and jettison schizophrenia? no thanks…. In this study, beside the loss of 6+ years from the lifespan [survival curve above], the other data of note in this paper is in Table 2 [abbreviated below]:

[truncated for simplicity]

In both the Cox and the Generalized Gamma Models, the shortened lifespan was significant for the overall group reporting psychotic experiences [p<0.001]. And when the analysis was repeated with the covariates separated out [formal psychotic disorders like Schizophrenia, Bipolar Disorder, etc], the significance remained [p<0.05]. In the overall group with psychotic experiences, suicide was a particularly prominent cause of death [Cox Model 9.16(3.19–26.29) p<0.001], but not in the psychotic experience without psychotic disorder group [Cox Model 2.28 (0.36–14.41) p>0.05].

This was a population study with information limited to the recorded parameters without specific subject narratives. But the difference, over a six year shortening of lifespan, is impressive. The contrast between the pictures painted by the British Psychological Society’s Understanding Psychosis and Schizophrenia and an article like this one is dramatic. The BPS Report would characterize the psychotic experience without psychotic disorder group as a benign variant of normal, not something that would be expected to be associated with morbidity or shortened life.

I find the controversies that swirl around these differences difficult. In their recent book, Psychiatry Under the Influence, Whitaker and Cosgrove make much of the guild interests that have driven a lot of the psychiatric literature in the recent decades, and they are justified – as am I when I make similar complaints. But I can’t read that BPS Report or many of the like-minded blog posts without seeing the guild interests of those authors front and center as an equally prominent force. I expect there will come a time when all of this is will be clear, but I’m not sure this is it. It feels like it’s a yes/no argument that needs a large [non-binary] study that reframes the issue into one with many answers done by impartial people, and there aren’t many in sight. Guild wars appear to be the currency of the day.

I know that as a clinician, the non-psychotic disorder people with reported psychotic experiences are much more common than I knew. I’ve seen patients who would go in either category, and plenty where I had no clue. Personally, I’ve come to see their reports as in need of exploring, but not de novo evidence of problems. That determination is on other grounds – usually patient defined, based on something they say, not something I think. And at least in my experience, these patients aren’t particularly guarded in talking about their experiences, something of a surprise. While it’s a line in every paper these days, these findings are suggestive, but deserve further study [as does that BPS Report!]…
Mickey @ 6:06 PM


Posted on Friday 3 July 2015

Internet hit by lightning.

see you next week…


Mickey @ 4:26 PM

how to play the system…

Posted on Thursday 2 July 2015

I suppose that if a pharmaceutical company is selling a treatment with a recommended 90 day course at $1,000.00 per pill, we shouldn’t be surprised that the CEO’s yearly salary is beyond obscene…

… and even though it’s not a psychiatric drug, I can’t seem to pass up an opportunity to talk about Gilead’s Solvadi® when it’s in the news. But first, where did Solvadi® come from? How did Gilead, a maker of AIDS drugs, discover Solvadi®?
By Bill Berkrot
November 22, 2011

Investors in Gilead Sciences may believe the company is paying too much to buy Pharmasset Inc VRUS.O at $11 billion. Emory University researcher Raymond Schinazi, who founded Pharmasset, knows by just how much. "They could have had the company for $300 million or less in 2004. Somebody made a huge mistake," Schinazi said in a telephone interview a day after the big deal was announced.

Schinazi, 61, is the largest individual shareholder of Pharmasset and saw the value of his own 4 percent stake leap to more than $440 million. The biotech is developing a hepatitis C treatment considered so promising that Gilead agreed to an 89 percent premium over Pharmasset’s already soaring stock price. Schinazi said he was surprised that Gilead, the world’s largest maker of HIV drugs and a company well-versed in antiviral treatments, did not recognize what Pharmasset was offering when it solicited offers back in 2004. "Now they paid the premium. Of course, now the risk has been reduced significantly," he said of the drug that has demonstrated impressive results in clinical trials…

Something of a one-man bridge between the worlds of academic and commercial science, Schinazi is director of the Emory University Center for AIDS Research and a star in the world of HIV research and treatment. He has also founded five companies developing treatments for viral diseases such as AIDS, hepatitis and herpes…

He has not been involved in running Pharmasset since 2006 and had no part in the Gilead deal announced on Monday. But he was chairman of the board and led its chemistry group when the molecule that led to the hepatitis treatment was discovered…
Well, Gilead didn’t discover Solvadi® after all. They bought it for $11 B [ultimately passing their acquisition costs on to the patients]. As I have mentioned before [the business of doing business…], we give drug companies a sweetheart patent deal to pay them back for their hard work in R&D developing our pharmaceuticals – beyond generous patent protection. Only, in this case, Gilead didn’t do the hard work of developing Solvadi®. They bought it after it had shown promise in Clinical Trials. And speaking of sweetheart deals, the FDA put Solvadi® on a fast track ["known as a breakthrough designation"] to rush it to market. It’s special handling from the get-go…
Pharmalot: WSJ
by Ed Silverman

A pair of public health advocacy organizations has filed a lawsuit against the FDA, claiming the agency failed to release clinical trial data for Gilead Sciences  hepatitis C treatments on a timely basis. And the move is only the latest installment in an ongoing drama in which researchers and patient advocates have tussled with drug makers and regulators over access to such information.

Here’s what happened: Late last year, Treatment Action Group and the Global Health Justice Partnership asked Gilead for patient-level trial data for the Sovaldi and Harvoni drugs. They sought the data because the drugs are widely prescribed, thanks to very high cure rates, and because the FDA approved the drugs as part of a regulatory process known as a breakthrough designation, which accelerated review…

In their lawsuit, the groups maintain doctors “lack the benefit of any independent assessment of the data.” And given the high cost of the drugs, the groups argue in their lawsuit that it is “crucial that policymakers be able to evaluate the cost-effectiveness… based on the underlying clinical data…” Sovaldi and Harvoni cost $84,000 and $94,500, respectively, for 12-week regimens, before discounts. But Gilead never replied to their requests last November for trial data, according to the lawsuit.

So last December, the groups turned to the FDA and submitted a Freedom of Information request for the data, since the drug maker had submitted the information to the agency as part of the drug approval process. However, the groups say the FDA denied their request for “expedited processing” and maintained it would take from 18 to 24 months to fork over the data, according to the lawsuit
So, the FDA treats the Treatment Action Group and the Global Health Justice Partnership just like they treated some curious old blogger – namely me [see a priori]:
"When I tried to look at more recent drugs, things were less smooth. For one of the last requests I submitted, I got a call from the FDA and the FDA lady tried to talk me out of making the request in the first place. When I refused and asked her how long it would take, she said about two years [that was three years ago] and I never heard from them again."
[I wonder if the same FDA lady called them that called me?]…

The irony here is obvious. We give Gilead an FDA break for the R&D work they didn’t do, fast track them to patent protection, so they can charge an outrageous fee to patients with Hepatitis C [most of whom can’t afford it so governments end up paying] so they can pay their head honcho $192+ M as a yearly salary, but we can’t expedite the NDA report from the FDA to allow some attempt at vetting the drug. I reckon Gilead has cut its business teeth on squeezing people with AIDS, and really knows how to play the system…

Mickey @ 1:53 PM