··and sealing-wax…

Posted on Friday 1 July 2016

    “The time has come," the Walrus said,
    “To talk of many things:
    Of shoes··and ships··and sealing-wax··
    Of cabbages··and kings··
    And why the sea is boiling hot··
    And whether pigs have wings.”
    The Walrus and the Carpenter
    Lewis Carroll, 1832 – 1898

It seems like only yesterday, but it’s been three years since the DSM-5 was released [May 18, 2013]. Unlike Spitzer’s 1980 DSM-III, Kupfer and Regier’s DSM-5 was hardly cause for celebration. I was just glad to have it off of the front page. While the debates and harangues had gone on for years, the substantive questions about its basic structure were never even really addressed.

So when I saw the abstract below, I perked up. Dr Kendler was part of the DSM-5 Task Force and maybe he’s finally getting around to examining the flawed MDD category. However, in the days leading up to the DSM-5, Dr. Kendler wrote a report explaining the move to get rid of the Bereavement Exclusion in the DSM criteria for Major Depressive Disorder that I thought was an ill advised rationalization at best. My take is cataloged in depressing ergo-mania….
American Journal of Psychiatry
by Kenneth S. Kendler
Published online: May 3, 2016

How should DSM criteria relate to the disorders they are designed to assess? To address this question empirically, the author examines how well DSM-5 symptomatic criteria for major depression capture the descriptions of clinical depression in the post-Kraepelin Western psychiatric tradition as described in textbooks published between 1900 and 1960. Eighteen symptoms and signs of depression were described, 10 of which are covered by the DSM criteria for major depression or melancholia. For two symptoms [mood and cognitive content], DSM criteria are considerably narrower than those described in the textbooks. Five symptoms and signs [changes in volition/motivation, slowing of speech, anxiety, other physical symptoms, and depersonalization/derealization] are not present in the DSM criteria. Compared with the DSM criteria, these authors gave greater emphasis to cognitive, physical, and psychomotor changes, and less to neurovegetative symptoms. These results suggest that important features of major depression are not captured by DSM criteria. This is unproblematic as long as DSM criteria are understood to index rather than constitute psychiatric disorders. However, since DSM-III, our field has moved toward a reification of DSM that implicitly assumes that psychiatric disorders are actually just the DSM criteria. That is, we have taken an index of something for the thing itself. For example, good diagnostic criteria should be succinct and require minimal inference, but some critical clinical phenomena are subtle, difficult to assess, and experienced in widely varying ways. This conceptual error has contributed to the impoverishment of psychopathology and has affected our research, clinical work, and teaching in some undesirable ways.
I found this abstract confusing. I couldn’t quite land on what he was getting at. I thought the idea of surveying the textbooks historically for their take on the symptoms of depression was clever. At the end, I couldn’t agree more that people have reified the DSM Disorders, or that there’s a categorical error in the woodpile with MDD. But his main point eluded me, so I read the whole article. Alas, neither of those things is what Dr. Kendler seems to be getting at here.

What I think he’s saying is that the fully nuanced clinical picture of Major Depressive Disorder may have many of the features he found in his textbook review that are being overlooked, symptoms like depersonalization or derealization. He tells us that the DSM criteria are simply an index to the Disorder, not the Disorder itself – ergo, there’s nothing wrong with the DSMs per se. The problem is a conceptual problem in the users. I guess he thinks we’ve gotten sloppy. And he apparently buys that there is a unitary Disorder behind these various symptoms. That’s hardly the serious look at Major Depressive Disorder I had hoped to read.

The categorical error that I see is that Major Depressive Disorder [MDD] isn’t a category in the first place, and never has been. When I think back to the 1980 days when the DSM-III first arrived, that’s what I thought on first reading. Gone was the psychiatric disease Depression, AKA Melancholia AKA Endogenous Depression AKA Endogenomorphic Depression. This is the stuff of psychiatry proper that has been with us since the dawn of recorded history. And then there used to be something else – a heterogeneous collection of patients with widely varying severity who had the affective symptom, depression, but not the illness Depression. The DSM [-I] had used the term depressive reaction. The DSM-II gathered them together under the term depressive neurosis. In the DSM-III, they were all included under MDD [my mistake, there were other categories included but they never caught on because they felt too made-up].

It’s easy to see the problem. There are really no boundaries on the much larger second group. I personally thought at the time that this second group had problems in their relationships, or their lives, or carried over from the past, or in the basic structure of their personalities, and that depression was a symptom, a signal to them and to the world that something wasn’t right. Most of my internal medicine colleagues looked into the symptoms that brought them to a doctor’s office. Finding no underlying physical cause, they reassured them and sent them on their way. I did that too, and for many, that was enough. But for a sizable number, it wasn’t, and I got interested in working with those cases [I still am]. So in that group, the gamut runs from unhappy in a lousy marriage to structuralized lifelong personality disorder. No clear borders. And that drives actuaries and third party payers crazy. So I suppose that conflating the Depressions and the severe depressions looked like a solution to many. Major Depressive Disorder then became a way of certifying or validating illness. That’s the only explanation I could come up with at the time for the faux category.

We all know what happened. Instead of tightening a boundary, the DSM-III loosened it [maybe better said, destroyed it]. So the valuable research on Melancholia was stymied by dilution, and the huge number of symptomatically depressed people became fair game for the pharmaceutical industry and the [carpetbagger] KOLs who jumped at the chance to annex them as an eager market for the antidepressants. The scientifically sound ideas that were developing about Melancholic Depression [that it has a biologic basis, that it responds to medications or ECT, that it is a brain disease, that it has a genetic component] flowed into the whole population of people with depressive symptomatology who were told they had a chemical imbalance or a brain disease. And what flowed out was untold billions of dollars in sales of largely unnecessary and sometimes dangerous medications. And in the mix, millions of dollars of unnecessary and unproductive research depleted the funds available for continuing research pathways that might have clarified some more focused piece of the puzzle. In the process, progress in the psychological and social treatments also ground to a halt. We all went backwards.

Dr. Kendler’s offering seems to be an attempt to help us be more forgiving about the short-comings of the DSM and its Major Depressive Disorder category. What I’m able to follow about his idea seems trivial and off the mark – more "cabbages and kings". I found it particularly annoying that this is one of the few commentaries on the DSM-5 from an official and that it continues to skirt the real problems. In my opinion, as shepherds of the DSM, it would behoove he and his colleagues to take another tack. Fix the DSM rather than us, and restore the boundaries to more reasonable scientific domains so we can pick up where we left off 36 years ago and bring some kind of much needed clarity to the current sea of misinformation. And as a corollary, the place of medication in the symptomatic treatment of depression can only be clarified by clinical trials conducted without the epidemic corruption of our current era. The fact that the pharmaceutical industry, the clinical trial industry, and the third party carriers like things just the way they are right now is really not our concern.

So like Lewis Carroll’s Walrus, I think "the time has come … to think of many things." But right now, we’re sure not thinking about the right ones. We’re in the "whether pigs have wings" range. Somewhere on the other side of the morass of commercial interests, ideological differences, guild wars, and a sea of other bias, there’s some system that will deliver the best we’ve got with the resources available. And there’s some path that allows productive researchers to be in an environment that optimizes progress. Neither of those things are likely to happen without a sensible classification system that fits a lot better than the one we have now, without an insistence on honesty in the science we bring to bear on the problems, and without an oversight function that insures that we never again allow what’s happened here to repeat.
Mickey @ 5:50 PM

adolescence…

Posted on Wednesday 29 June 2016

    ad·o·les·cence   [ad-l-es-uh ns]
    noun: adolescence
       the period following the onset of puberty when a young person develops from a child into an adult.
Home after a long bus ride on a choir trip, she was in an agitated state. Apparently one of the neighborhood girls had been telling increasingly exaggerated tales, stories our daughter knew were untrue. "She’s just a liar! Why does she do that?" And nothing we said made a dent in her consternation.

The next day, we were on the front porch and my wife mentioned another neighborhood kid, an adopted girl who was headed for trouble. She’d announced to my wife that she’d met her "real" mother who was a "street walker" – this time something we knew wasn’t true. Our daughter, piped up from across the porch where she had seemed lost in a magazine and said matter-of-factly, "Oh she didn’t really meet her real mother. That’s just what she wishes was true," and returned to her magazine. But there was more to come.

On the weekend, she decided to go sailing with us – a rare treat in an age where being with friends had moved center stage. It was a good sailing day, and we’d had a fine adventure getting tangled up in a regatta of smaller boats – "gnats!". We were on a long tack back to the dock when she announced out of the blue, "All lies are wishes. I think I’m right about that." It was said as a challenge, so we joined in the game. We offered counter examples that she shot down with increasing confidence. "I’m telling you, I’m right about this."
We usually think of adolescence in terms of puberty with its physical, emotional, and identity changes:
    pu·ber·ty   [pyoo-ber-tee]
    noun: puberty
       the period of life when the sexual organs mature and he or she becomes able to have children
But there’s a concomitant cognitive leap that’s every bit as dramatic. Piaget described it as a move from Concrete Operations to Formal Operations, focusing on the use of logic and classification. But it’s more clearly described as the acquisition of the capacity for abstract thought. So the arithmetic of elementary school gives way to algebra, where a symbol like X can be any number. Or the jump from a book report that says "Black Beauty was very black and pretty. That’s why they called him Black Beauty." to one that says "Black Beauty is a story about a horse’s encounters with cruelty and kindness." It’s the cognitive leap hopefully illustrated in my daughter’s reflections on the meaning of lies [she was thirteen].

With the acquisition of meta-thought [abstract reasoning], the adolescent finds him-or-her-self in a new world [or an old world with a new look]. They may not yet have a knowledge or experience base, but they can think as well as their parents, and seem to know it ["I’m telling you, I’m right about this."]. And they can drive parents to distraction with their endless arguing and logic games. Little wonder Anna Freud pointed to rationalization as the primo defense mechanism of adolescence. But beyond that, they now can see our flaws and foibles and gladly point them out if given half a chance, as the former authority of parenthood fades.

Erickson described the developmental task of adolescence as identity formation. The adolescent’s abstract musings quickly turn to the question of "What am I?" Blos described it as the second separation/individuation [the first being the coming into personhood at age two]. And like the two year old’s "No" as the harbinger of change, the adolescent often starts the identity process with something similar, the rebellious "I don’t yet know what I am, but I’m sure not what you think!" And there may be any number of trial identities before one fits. In my vignette about my daughter, the first girl [the "liar" on the bus] is now a successful gay married woman and I suspect her self-important exaggerations at thirteen were related to not knowing how to fit into the culture of the time. The second girl did go on to prostitution and other such, dying in her late twenties from a unintended narcotic overdose during a relapse – all in spite of her parents somewhat heroic attempts to turn things around. With the identity comes the related character or personality formation. In adolescence, all of those character traits that seemed kind of fluid in childhood begin to condense into the a predictable and fixed set of ways of doing, being, and reacting that we call the person·ality.

And finally, there’s interpersonal life ["… a rare treat in an age where being with friends had moved center stage"]. The adolescent drifts away from family life into that place of their own called adolescence, where the people that matter are peers [and the dominant culture is guaranteed to differ from the teen culture of their parents]. Even for the introvert who stays apart, peers remain the audience being played to in the mind. Adults think of it as a phase they’re going through on the way to a place in society, but for many occupants, it feels like [and may actually become] a final destination. In the finale of the classic teen musical "Grease," they sing exuberantly "We’ll always be together" – which is rarely true in fact. Yet for many, it’s etched in memory just as the song describes it. If you don’t know that, go back to your high school reunion and be awed by the floods of memories and emotions.



So what’s a quasi-psychodynamic overview of some broad issues of adolescence doing here in the middle of a blog about corruption in Randomized Control Drug Trials? I try to stick to that topic, even though I’m really speaking in my second language [mostly acquired in my latter years]. But as I’ve read all these RCTs about antidepressants in youth, I’ve had a growing frustration which came to a head with the PSYCHIATRICNEWS article about Karen Dineen Wagner’s remarks at the recent APA meeting [see a blast from the past…].

By my read, adolescence is a critical crossroad in development. It’s a period when change is in the air, a time with an opportunity to set right the unnecessary baggage carried forward from childhood. It’s also a time with its own shoals and pitfalls that may become incorporated into the adult personality structure and carried forward for a lifetime. Some change in adolescence is luck – an encounter with a teacher, a reparative friendship, a romance, and a myriad of other possibilities. But other adolescents flounder helplessly – developing symptoms, acting out, acting up, withdrawing, becoming depressed – signals for needed help.

Reading about Dr. Wagner’s talk about treatment [Child Psychiatrists Look at Specialty From Both Macro, Micro Perspectives] that only addressed the use of the antidepressants [which are hardly robust, more likely closer to inert in adolescents, and can be dangerous] or CBT [useful for some cases where you can find a C that needs some BT], and making arguments based on her tainted RCTs from ancient history [that we’ve been over a gajillion times], I got pissed off. Surely there’s more to say about adolescent mental pain than that, particularly by the President Elect of the American Academy of Child and Adolescent Psychiatry. When my kid gets depressed and I don’t know what to do, I want her to see someone who knows the landscape of that place called adolescence frontwards and backwards; someone who has taken the time to learn how to be invited inside its borders where parents are rarely allowed to go; and someone who will help my child find out where her unique tangles are and help her find a way to get on a road that can lead to a fulfilling adulthood [if that takes some pill, fine, but please hold the generic alogrithms!]. I couldn’t think of any way to say that except to speak in my native tongue…
Mickey @ 5:18 PM

a blast from the past…

Posted on Monday 27 June 2016

I’ve been called out at times for focusing on these older Clinical Trials like Paxil Study 329 or the Citalopram CIT-MD-18 study. I’m kind of tired of talking about them myself. However, there are substantial reasons for dwelling on these trials. For one thing, we’re finally getting to see the back story – the raw data in Paxil Study 329 and the internal emails from the Citalopram CIT-MD-18 study. For another, these trials were very much in Dr. Karen Dineen Wagner‘s memory at the recent APA Meeting in Atlanta:
PSYCHIATRICNEWS
by Aaron Levin
June 16, 2016

Children are not just small adults, and clinical practice and the overall health care system need to take notice of that reality, said speakers at APA’s 2016 Annual Meeting in Atlanta in a session on child and adolescent psychiatry in the 21st century….

In the clinic, managing mental illness in young people requires subtle but significant shifts in thinking, said Karen Dineen Wagner, M.D., Ph.D., a professor and chair of psychiatry and behavioral sciences at the University of Texas Medical Branch, Galveston…

As for treatment, only two drugs are approved for use in youth by the Food and Drug Administration [FDA]: fluoxetine for ages 8 to 17 and escitalopram for ages 12 to 17, said Wagner. “The youngest age in the clinical trials determines the lower end of the approved age range. So what do you do if an 11-year-old doesn’t respond to fluoxetine?”

One looks at other trials, she said, even if the FDA has not approved the drugs for pediatric use. For instance, one clinical trial found positive results for citalopram in ages 7 to 17, while two pooled trials of sertraline did so for ages 6 to 17. Another issue with pediatric clinical trials is that 61 percent of youth respond to the drugs, but 50 percent respond to placebo, compared with 30 percent among adults, making it hard to separate effects.

When parents express anxiety about using SSRIs and ask for psychotherapy, Wagner explains that cognitive-behavioral therapy [CBT] takes time to work and that a faster response can be obtained by combining an antidepressant with CBT. CBT can teach social skills and problem-solving techniques as well. Wagner counsels patience once an SSRI is prescribed.

A 36-week trial of a drug is too brief, she said. “The clock starts when the child is well, usually around six months. Go for one year and then taper off to observe the effect.” Wagner suggested using an algorithm to plot treatment, beginning with an SSRI, then trying an alternative SSRI if that doesn’t work, then switching to a different class of antidepressants, and finally trying newer drugs.

“We need to become much more systematic in treating depression,” she concluded.
Not many days after Dr. Wagner’s lecture, we read a meta-analysis of antidepressants in youth by Cipriani et al in the Lancet [Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis] that included the reports listed in Wagner’s presentation that reached a very different conclusion:
When considering the risk–benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated.
On the other hand, Wagner speaks of antidepressants as a first line treatment and suggests prescribing off-label based  on the RCTs that are well over a decade old, even including younger children in her recommendation. There’s no mention of the Black Box Warning or anything else that’s happened since then. Hers is an anachronistic presentation, one that might have been given over ten years ago when hopes were higher for the antidepressant drugs in kids.

But thinking further, that didn’t really capture the thrust of this presentation. Then it hit me, it was even older than that. The emphasis on coming on strong, using a sequence of drugs until you hit one that worked, treating for a long time, an algorithm [all without an evidence-base] – those things sounded like the catechism of John Rush and Madhukar Trivedi in their STAR*D Protocol. And STAR*D came directly from TMAP [Texas Medical Algorithm Project] – the industry seeded treatment scheme derived from Expert Opinion that required State Physicians to use on-patent drugs rather than Generics until it was finally exposed as corrupt by Allen Jones in 2004.

And finally I remembered that there was a similar program for kids – TCMAP [Texas Childrens Medical Algorithm Project] and guess who were on the expert panel? Graham Emslie and Karen Dineen Wagner. Here’s what I said previously [the answers to those questions…]:
Perhaps the biggest pharmaceutical scam to date was TMAP [Texas Medical Algorithm Project]. Before it was stopped, it had nearly bankrupted the Texas Mental Health system, had spread to 17 other States, and was on its way to Washington. It should make us all shudder when we hear the word "Guidelines." It was shepherded into being by John Rush and Madhukar Trivedi in Dallas. Basically, they controlled guidelines for the huge Mental Health system in Texas. It had a child piece [TCMAP] and Karen Dineen Wagner and Graham Emslie  were both involved in setting the Algorithms. The TMAP program was exposed in 2004 largely through the work of one man, Allen Jones, an Inspector for the Pennsylvania OIG [who was fired for his work] but who never gave up. Below is just a snippet from a report he published on the Internet in 2004 with the bare bones of Dr. Wagner’s involvement [A more complete version about her goes from pages 10-14, and tells quite a story]:
    In 1997-98, TMAP, with pharmaceutical industry funding, began working on the Texas  Children’s Medication Algorithm Project [TCMAP]. An "Expert Consensus" panel was assembled to determine which drugs would be best for the treatment of mental and emotional problems in children and adolescents. The panel consisted almost exclusively of persons already involved in TMAP or associated with TMAP officials. A survey was not necessary. These persons simply met and decided that the identical drugs being used on adults should also be used on children. There were no studies or clinical trial results whatsoever to support this consensus…

    One of the members of the children’s "expert consensus panel" was Graham J. Emslie,M.D., Professor and Chair, Division of Child and Adolescent Psychiatry. University of Texas Southwestern Medical Center, [a TMAP site] and Director. Bob Smith Center for Research in Pediatric Psychiatry, Dallas, TX…

    The panel also included Dr. Karen Dineen Wagner

    In 1998, without any published trial data and based on the "consensus opinion" of Emslie, Wagner and others, TCMAP began widespread usage of these SSRIs and other drugs on children within the Texas state Juvenile Justice system and state Foster Care System…

    Between 1998 and 2003, state doctors following the TCMAP guidelines routinely and regularly prescribed these antidepressant drugs to children in accordance with the TCMAP algorithm requirements…
After the first year, they published periodic updates in the JAACAP:
    by CARROLL W. HUGHES, GRAHAM J. EMSLIE, M. LYNN CRISMON, KAREN DINEEN WAGNER, BORIS BIRMAHER, BARBARA GELLER, STEVEN R. PLISZKA, NEAL D. RYAN, MICHAEL STROBER, MADHUKAR H. TRIVED, MARCIA G. TOPRAC, ANDREW SEDILLO, MARIA E. LLANA, MOLLY LOPEZ, A. JOHN RUSH, AND THE TEXAS CONSENSUS CONFERENCE PANEL ON MEDICATION TREATMENT OF CHILDHOOD MAJOR DEPRESSIVE DISORDER
    Journal of the American Academy of Child and Adolescent Psychiatry, 1999 38[11]:1442-1454.

    The consensus panel agreed on categorizing 3 levels of "data" hierarchically in formulating stages and differential branching of the treatment algorithm. Level A data consist of both child and adult randomized controlled clinical trials, level B data consist of open trials and retrospective analyses, and level C data are based on case reports and panel consensus as to recommended current clinical practices. Level A takes precedence over level B, and B over C…

    The recommended monotherapy antidepressant for stage 1 are SSRIs [fluoxetine, paroxetine, or sertraline]. [Fluvoxamine and citalopram may be added to the list at a future date with additional research.

    SSRIs are deemed first-line treatments because of supporting efficacy data for fluoxetine in children and adolescents and paroxetine in adolescents [level A], open trials of sertraline [level B], and clinical experience [level C]. Information extrapolated from adults further supports the initial use of SSRIs given the minimal need for dosage titration [level A in adults and level C in children/adolescents] and favorable side effect profiles [levels A and C]…
Only fluoxetine was a published paper [paroxetine was an abstract of Study 329 posted at the 1998 APA]. There was a consensus meeting recorded in 1998, with no details [wayback machine]. With the coming of Jones’ whistle blower suit and the mounting awareness of adverse effects that lead to the Black Box Warning, TCMAP just disappeared. TCMAP was never adjudicated, and the only specific TMAP suit I know of was the settlement in Allen Jones and the State of Texas v. J&J.
No wonder I kept thinking this was an anachronistic presentation. It is literally a blast from the past, almost twenty years ago. The fact that it has been reincarnated at the 2016 APA meeting in spite of all the intervening evidence and dialog to the contrary is remarkable. I guess she thought we would forget [and I almost did!]…
Mickey @ 1:34 PM

timeless…

Posted on Sunday 26 June 2016

PHARMABIZ.COM
June 24, 2016

Nonmedical use of prescription opioids more than doubled among adults in the United States from 2001-2002 to 2012-2013, based on a study from the National Institute on Alcohol Abuse and Alcoholism [NIAAA], part of the National Institutes of Health. Nearly 10 million Americans, or 4.1 per cent of the adult population, used opioid medications in 2012-2013 a class of drugs that includes OxyContin and Vicodin, without a prescription or not as prescribed [in greater amounts, more often, or longer than prescribed] in the past year. This is up from 1.8 per cent of the adult population in 2001-2002.

More than 11 per cent of Americans report nonmedical use of prescription opioids at some point in their lives, a considerable increase from 4.7 per cent ten years prior. The number of people who meet the criteria for prescription opioid addiction has substantially increased during this timeframe as well, with 2.1 million adults [0.9 per cent of the US adult population] reporting symptoms of “nonmedical prescription opioid use disorder [NMPOUD],” according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5].

“The increasing misuse of prescription opioid pain relievers poses a myriad of serious public health consequences,” said Nora D. Volkow, M.D., director of the National Institute on Drug Abuse [NIDA], which contributed funding for the study. “These include increases in opioid use disorders and related fatalities from overdoses, as well as the rising incidence of newborns who experience neonatal abstinence syndrome. In some instances, prescription opioid misuse can progress to intravenous heroin use with consequent increases in risk for HIV, hepatitis C and other infections among individuals sharing needles.”

Scientists analyzed data from NIAAA’s National Epidemiologic Survey on Alcohol and Related Conditions-III [NESARC-III], ongoing research that examines alcohol and drug use disorders among the US population, as well as associated mental health conditions. The study appears online in the Journal of Clinical Psychiatry…

If you don’t know the story of the Opium trade and the Opium wars in China, or the role of the British, now would be a good time to take a look [see History of Opium in China, How China got rid of opium]. China literally became a nation of addicts and the China we know today was shaped by its history with Opium. Not worried about this problem? Click on the bottle and look at what’s advertised. Ask your kid how hard is it to get pain pills in their school.

If you are a physician who is not in a specialty absolutely requiring the use of narcotics [surgery, etc.], you can do what I did. Surrender the narcotic part of your DEA licensure to guarantee that you don’t contribute one pill to this problem. And expunge the idea that Narcotic abuse is like alcoholism, something that only afflicts certain people. Narcotic addiction is for anyone.

My view? Narcotics are like Uranium. The only solution is to control the supply. The demand is timeless…
Mickey @ 10:00 PM

an ink blot…

Posted on Sunday 26 June 2016

Boston Globe
by Michael Rezendes, Jenna Russell, Scott Helman, Maria Cramer, and Todd Wallack
June 23, 2016

I didn’t try to summarize this article because I challenge you to read it all the way through to the end on your own. The only thing wrong with it is that it’s missing an "s" in the title. It should read, "Closing psychiatric hospitals seemed humane, but the states failed to build a system to replace them."

Note: I wrote a long narrative detailing my own history with the issues engendered by this article, but then I erased it. I suggest reading it and using it as an ink-blot for your own thinking like I did. They’ll ask for your email address to read it. Don’t worry, the worst that will happen might be a few offers easily dismissed with unsubscribe [I have a subscription to the Globe in order to get STAT and Pharmalot]…
Mickey @ 2:09 PM

this time…

Posted on Friday 24 June 2016

I almost feel like I ought to make an apology. For the last month, my head has been partially elsewhere – a wedding anniversary of note and a celebration cooked up by our daughters that drew a crowd from our earliest days forward. It’s over now, and things are edging their way back to normal. That picture above was taken by a visitor the morning after a gathering on the back porch over the weekend. I got an email asking if it’s a permanent change, did it have a meaning? I think I put it there because I liked it. It reminded me of the weekend and the coming together of friends from different times in our lives. But I can always generate a symbolic meaning in a pinch, and I thought of a couple immediately. First, in this enterprise of trying to clean up the mess made by the academic·pharmaceutical complex, it’s time for a coming together of people from different places and times with a shared purpose rather than a litany of differences.

But another meaning is actually closer to what I’ve been thinking over the last couple of weeks. I’ve been fortunate to be privy to a round·table discussion among some of our best and brightest, people who were around in the period of excitement and discovery when psychopharmacology was in its infancy – the days before those often-cataloged corrupting forces grabbed the wheel. I obviously can’t contribute much, having ridden my own train down a different track, but I can listen and learn. And there’s quite a story to be told. I hope that it gets written in all the complexity it deserves. A lot of it is in books already written, but not often read. The Antidepressant Era and The Creation of Psychopharmacology by David Healy and Before Prozac by Edward Shorter come to mind. They’re long and detailed, but that’s actually part of my point. This is one complicated story, one that deserves a thorough understanding rather than the simplified versions we hear so often – populated with trolls under the bridge, handsome princes, and fairy godmothers – those artificial and flattened characters people make up to drive home a point. This time, we need to get it right…
Mickey @ 3:02 PM

involuntary honesty…

Posted on Friday 24 June 2016

A Phase 3 Randomized Clinical Trial [RCT] of a medication isn’t really research. That’s already been done earlier. The RCT is product testing with two important elements – efficacy [does it work?] and safety [does it cause harm?] – and in either case, what is the strength of the effect?  Other things might become apparent along the way. Who knows? Maybe some day the secret of the universe might be serendipitously found in an RCT, but that’s still an incidental, exploratory finding – not why the trial is being done. 

Everything about a given trial is specified in two documents [often combined] – the Protocol and the Statistical Analysis Plan – prepared in advance [a priori] and submitted to an Institutional Review Board [IRB]. After the Clinical Trial is approved and the blinded study is underway, no changes can be made except under unusual circumstances, and then only by an official amendment to the Protocol approved by the IRB.

Why so rigid? It’s obvious. There’s never any guarantee that the sanctity of the blind hasn’t been breached, informing any after·the·fact changes. Anyone who has any experience with statistical analysis knows that with foreknowledge, one can have a field day with statistical testing. Shuffle some outcomes, select the right tests, ignore the negatives, etc. And that’s exactly what has happened – over and over. Weak signals without clinical significance have been turned into lucrative blockbusters. While it’s hard to prove, it can easily be prevented.

So some version of the proposal made by Dr. Carroll seems inevitable to me [see CORRUPTION OF CLINICAL TRIALS REPORTS: A PROPOSAL and out of this mess…]. We’ve had decades of proof that the pharmaceutical industry isn’t going to self·regulate. His suggestion is both feasible and goes straight to the heart of the matter:

Our primary defense against such perversions of scientific reporting is fidelity to the registered IND protocol and plan of statistical analysis. The solution is not hard to see: We need independent analyses of clinical trials because we cannot trust the corporate analyses. In effect, we need something like the Underwriters Laboratory to verify the statistical analyses of clinical trials. Nobody takes the manufacturing corporation’s word for it concerning the safety and performance of X-ray machines or cardiac defibrillators. Why treat the statistical analysis of drug trials any differently? It’s highly technical work. Who should assume that responsibility? Why not the FDA? After all, they alone see all the data. My specific proposal is for Congress to mandate that the FDA analyze all clinical trials data strictly according to the registered protocols and analysis plans. That requirement should apply to new drugs or to approved drugs being tested for new indications. It should apply also to publications reporting new trials of approved drugs. Corporations and investigators should be prohibited from publishing their own in-house statistical analyses unless verified by FDA oversight.

Interestingly, this was the direction we were headed in fifty years ago when the RCTs were in their infancy [see Evolution of Psychopharmacology Trial Design and Analysis: Six Decades in the Making and under fire I…]
    The 1950’s was an exciting decade for psychopharmacology, and in 1959, Jonathon Cole was appointed head of the new Psychopharmacologic Research Branch [PRB] at the NIMH where many of the rating instruments and Clinical Trial procedures were subsequently developed and tested. By 1967, the Early Clinical Drug Evaluation Unit [ECDEU] offered a centralized service for Clinical Trials to NIMH grantholders. This is from a 1976 ECDEU Manual:
    As originally conceived, the ECDEU program consisted primarily of grant- supported clinical investigators working in tine common area of psychotropic drug evaluation [both new and established compounds]. One of the problems they encountered, and task they accomplished, was the development of a uniform battery of clinical assessment instruments known as the ECDEU Standard Reporting System, first introduced for utilization in 1967. The rationale behind this effort was twofold. First, it was felt that such a system would enhance both the quality of early clinical drug research and allow greater generalizability of results across studies and investigating units. Second, data collected on common forms could be stored in a data bank for future study and research. Since the implementation of this Standard Reporting System and the Biometric Laboratory Information Processing System [BLIPS], the ECDEU program has evolved into more than an extramural grant support program for psychotropic drug research teams. In collaboration with The George Washington University Biometric Laboratory, the ECDEU Standard Reporting System has been made available to any investigator interested in conducting clinical trials, whether federally grant supported or not. To utilize these services, the investigator is requested to:

      1. Submit a Research Plan Report and agree to send the study data to the Biometric Laboratory.
      2. Collect sufficient information about the subjects in his study so that the data can be entered into the ECDEU data bank. This means, essentially, that a core of data must be collected for each patient…

    In return, he receives a sufficient number of assessment scales to conduct his research. Once the trial is completed, the forms are returned to the Biometric Laboratory for processing and data analyses, the results of which are sent to the investigator in the form of a standard data package. The rating scales and data processing services are provided at no charge – our sole "remuneration" being the opportunity to add the investigator’s data to the data bank. It should be stressed that an investigator’s data and/or results are never published or disseminated to others without his permission.
Back then, industry didn’t participate, and the program disappeared for political reasons, not because it was a bad idea. But the time for wishing for voluntary honesty has long passed. It’s time for some muscle.
Mickey @ 11:49 AM

X…

Posted on Friday 24 June 2016

 
Mickey @ 12:08 AM

out of this mess…

Posted on Wednesday 22 June 2016

David Healy, Jon Jureidini, Bernard Carroll, and Ben Goldacre

Some day there’ll be a best seller, a popular science book that will tell a story currently still in the making – and near the beginning the book will have a chapter about the interchange between David Healy and Charlie Nemeroff in Toronto in 2000 when Healy lost a new job because he talked about the potentially fatal side effects of SSRI [and Nemeroff, then boss of bosses] undermined his job change in retaliation. And there will be a piece about how Jon Jureidini, a pediatric psychiatrist, publicly protested a published study in 2003 that fraudulently claimed that a SSRI was safe and effective in adolescent depression. And that best-selling-author-to-be will add the efforts of Bernard Carroll and Bob Rubin in 2003 and later 2006 in exposing that same Charlie Nemeroff and others for promoting treatments they had a personal financial interest in without acknowledging those interests. Then there’s Ben Goldacre who will be cited for calling attention to the essential role of data transparency in bringing the truth to light with the AllTrials initiative, or getting at a major mechanism of deceit with his COMPare project. There will be so many more who will figure into this unfolding story. But right now, in spite of a lot of prequels, that book can’t be written because the story’s not over yet. Sure enough, there’s been progress but the main story line continues, lacking an in·place general solution…

Recently, the pioneers have been mighty busy. In September, David Healy, Jon Juriedini, and their colleagues republished the 2001 study that had become a paradigm for a jury-rigged Clinical Trial report, reanalyzing it from the original dataset using the author’s own Protocol and found that despite the earlier claims, the drug was neither effective nor safe in adolescents [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence]. Then in March, Jon Juriedini and some other colleagues were back with another SSRIs·in·adolescents·study, this time with access to internal documents showing again how a negative Clinical Trial had been published as positive [The citalopram CIT-MD-18 pediatric depression trial: Deconstruction of medical ghostwriting, data mischaracterisation and academic malfeasance]. This study had been used as a basis for FDA Approval, and used the same technique of altering the a priori protocol – something Ben Goldacre‘s COMPare project calls "outcome switching."

We now know that this problem of misreported Clinical Trials will never be solved so long as the raw data remains hidden. Without access to that information, we’ll never put a stop to these dark days of pseudoscience in the medical literature. But that’s not enough, because it’s the analysis of that data where the misbehavior has been centered. Today, one of those pioneers has a blog post that suggests a viable next step, a concrete general solution to the problem:
Health Care Renewal
by Bernard Carroll
June 22, 2015

There is a disconnection between the FDA’s drug approval process and the reports we see in medical journals. Pharmaceutical corporations exploit this gap through adulterated, self-serving analyses, and the FDA sits on its hands. I suggest we need a new mechanism to fix the problem – by independent analyses of clinical trials data.

When they analyze and publish their clinical trials in medical journals, pharmaceutical corporations have free rein to shape the analyses. The FDA conducts independent analyses of the data submitted by the corporations, and it may deny or delay approval. But the FDA does not challenge the reports that flood our medical journals, both before and after FDA approval. It is no secret that these publications are routinely biased for marketing effect, but the FDA averts its gaze. That failure of the FDA – a posture known as enforcement discretion – has been well documented. The question is why? At the same time, exposing the biases has been difficult for outsiders because the data are considered proprietary secrets.
This is just a teaser. The whole post is on-line. In the next section, Carrol outlines the problem using Juriedini’s latest paper as a case example then proposes a solution:
A Specific Proposal
Our primary defense against such perversions of scientific reporting is fidelity to the registered IND protocol and plan of statistical analysis. The solution is not hard to see: We need independent analyses of clinical trials because we cannot trust the corporate analyses. In effect, we need something like the Underwriters Laboratory to verify the statistical analyses of clinical trials. Nobody takes the manufacturing corporation’s word for it concerning the safety and performance of X-ray machines or cardiac defibrillators. Why treat the statistical analysis of drug trials any differently? It’s highly technical work. Who should assume that responsibility? Why not the FDA? After all, they alone see all the data. My specific proposal is for Congress to mandate that the FDA analyze all clinical trials data strictly according to the registered protocols and analysis plans. That requirement should apply to new drugs or to approved drugs being tested for new indications. It should apply also to publications reporting new trials of approved drugs. Corporations and investigators should be prohibited from publishing their own in-house statistical analyses unless verified by FDA oversight.
There follows a section on why the time to act is at hand and the potential counterarguments:
It is time for Congress to grasp this nettle. The time for enforcement discretion is past, and we need Congress either to direct the FDA to act or to create a new mechanism of oversight. To do nothing would be unthinkable.

There are other suggested solutions beginning to appear and I’ll cover some of them in subsequent blog posts. But this one comes first because it’s the one that makes the most sense to me. In all of the work that went into our Paxil Study 329 paper where my part was the efficacy analysis, I became convinced that insisting that the analyses follow the a priori Protocol and Statistical Analysis Plan to the letter is the only way to insure that the analysis is worthwhile. After we finished our paper, I went back and looked and every questionable trial I’d looked at had suspicious variables. My problem was that finding those Protocols was spotty. My hat’s off to Goldacre’s team for being able to run them down. The other ubiquitous problem was from inappropriate statistical testing. So Carroll’s proposal seems right as rain. The FDA has the capabilities to do the analyses, and already does them in many cases.

I picked the four investigators up top, not because they work together, or even necessarily agree. I picked them because each has been a central part of my own growing understanding of a way out of this mess. My way of saying "thanks!"

Update: Dr. Carroll’s proposal was cross posted on Naked Capitalism with some interesting comments.
Mickey @ 7:57 PM

a summer reading list…

Posted on Wednesday 15 June 2016

I first ran across a paper by Cosgrove et al in February [Under the Influence: The Interplay among Industry, Publishing, and Drug Regulation] and have talked about it frequently. I think it’s an important article for a number of reasons:
  • It’s about a contemporary medication, Vortioxetine [Brintellix® now Trintellix®]. Our Paxil Study 329 article and the recent article about Karen Dineen Wagner et al’s Citalopram in Adolescents article are important windows into the deceitful publication practices in clinical trials of psychoactive drugs, but they’re about old studies [2001 & 2004] about drugs now long off-patent. No apologies about that. It took that long to get the information necessary to get to the bottom of things. But Cosgrove et al are writing about a drug that’s new and in-patent – a drug being detailed widely to doctors right now.
  • They didn’t have access to any special information like the other two articles [raw data & subpoenaed documents]. They were able to show how the published articles were misleading using available information from regulators etc., showing that with enough stick-to-it-ness, these RTCs can be vetted effectively. While we long for data transparency, as we learned with the 329 effort, there’s a lot of work involved in a reanalysis. Cosgrove et al show us that with another version of a-lot-of-work, even without special access, these tainted articles can be evaluated.
  • Their article doesn’t stop with demonstrating some of the methodology of the misreporting illustrated in the articles, but goes on to make suggestions about problems in the system and pathways to change. While you might not completely agree with all of them, they’re all valuable food for thought. That’s what academic publication is supposed to be about.
There’s another reason for focusing on this article. It’s a class act, yet it’s not published in a journal that has a wide readership, or as wide a readership as it deserves [journal and paper alike].
  • So the article brings up another issue: how hard it is to get a controversial or contrarian article published in the medical literature. With Paxil Study 329, even with a willing journal, we went through a prolonged review. While it was difficult, in the end I’m for that. I wish the original paper we were reporting on had been looked at anywhere near as closely as our submission and conflicts of interest as closely scrutinized. With the Citalopram in adolescents study, the authors gave us a narrative of the difficulties they encountered [background notes].
You’d think as much as I’ve said about these articles already, that I’d shut up about them. But there’s a reason I haven’t. Reading blog posts from a boring old man can’t possibly do strong articles like these justice. They need to be read in person rather than in summary. And I found out that Cosgrove et al is finally available full-text on-line so it can [and should be] read by all. Here are the three articles with their full text links, and a fourth similarly important recent clarifying meta-analysis thrown in for good measure:
    Summer Reading List
We are finally seeing articles published about the other side of the coin – evidence-based analyses of Clinical Trials that reveal the kind of bias and deceit that has come to characterize too much of our medical literature. These clarifying papers are still uncommon, published with much blood, sweat, and tears – sometimes in remote corners of the medical literature. It’s important to make sure we’ve read them [and spread them]. We can’t expect hard working clinicians to run across them, so pass them along. The time for simply decrying what’s wrong has passed. It’s time for reparative action, and there’s no stronger stimulus than articles like these that document the scientific misbehavior behind the original publications…
Mickey @ 12:06 AM