a remembrance of things past…

Posted on Friday 3 June 2016

by L M Williams, C Debattista, A-M Duchemin, A F Schatzberg and C B Nemeroff
Translational Psychiatry. (2016) 6, e799. Published online 3 May 2016

Overall, the higher rate of trauma observed in the present MDD sample is in line with registry and observational studies.Thus, childhood trauma and especially abuse may contribute to the development of depression observed in routine practice in multiple outpatient settings spanning primary and specialist care settings. Our findings suggest that abuse in particular, and not overall exposure to traumatic events, predicts a lower rate of acute response and remission after antidepressant therapy. Sexual, physical and emotional abuse compared with other types of trauma psuch as death of a parent/sibling, personal life-threatening illness/injury, or disaster], may have a specific impact on the neurobiological mechanisms of non-response to treatment. Neuroimaging studies suggest that there may be a differential effect of childhood sexual abuse on the subsequent functioning of emotional brain circuits in adulthood depression. Childhood abuse has also been associated with a greater sensitivity to stress, cognitive impairment, alterations in brain morphometry and immune and metabolic abnormalities that may impact the course of depression and capacity to respond to antidepressants. It is also possible that abuse may recur and that it is the recurrence of the trauma that produces poor treatment outcomes.

In addition to the type of stressor, our results suggest that there is a critical period [4 to 7 years] in which childhood trauma occurs and has the most significant impact on subsequent poor response to antidepressants in adulthood. There is a rapidly growing body of work to suggest that gene polymorphisms and epigenetic modifications interact with childhood trauma to exert their effect on risk for depression, and that this effect is greatest at critical neurodevelopmental periods. This evidence is consistent with the view that the extent of brain plasticity varies during development, such that trauma occurring during critical neurodevelopmental periods may alter brain morphometry, circuit function, endocrine regulation, immune function and subsequent physiologic reactions to stress in an enduring way.

Abuse occurring at age 4 to 7 years was associated with significantly poorer outcomes following the treatment with sertraline compared with the other selective serotonin-reuptake inhibitor escitalopram and the SNRI venlafaxine-XR. The participants who were abused at this age showed significantly less improvement in both clinician and self-rated symptoms following 8 weeks treatment with sertraline. Sertraline, in contrast to other serotonin-reuptake antidepressants, has an additional relatively specific effect on inhibiting dopamine. There is some evidence that subgroups of patients are also characterized by dopamine circuit dysfunction and number of traumatic events has been associated with higher ventral striatal dopamine response to amphetamine. Although speculative, these lines of evidence suggest that a possible dopamine-related mechanism might contribute to our specific observation of especially poor outcomes following sertraline in those exposed to early abuse.

Clinical translational significance
Here, we provide evidence from a well-powered study that outpatients with MDD have a fourfold higher incidence of childhood abuse than their healthy peers, and a twofold higher incidence of early exposure to other traumatic events. The greater the exposure to trauma, the less likely these depressed patients were to remit following antidepressant response. Thus, the translational significance of these findings is that in routine clinical management of depression it may be important to screen for childhood trauma to identify those patients that may not benefit from standard first-line antidepressants and may require additional therapy to more directly address the impact of trauma.
This was surprisingly difficult for me to read, particularly coming from Dr. Nemeroff. It just brings up too much to pretend objectivity. It’s hard for me to hear this as some big discovery because it’s something we were teaching in the Department Dr. Nemeroff took over before he arrived twenty-five years ago. Their findings were clear – depressed adults who had a history of physical or sexual abuse between the ages of four and seven were unresponsive to treatment with the usual symptomatic medications like antidepressants.

This is one of my slides from the late 70s/early 80s showing a few lines of development plotted by age. The pictures are typical self portraits from various ages [some from my daughter] paralleling the formation of the self representation. The bottom line shows attachment/separation schema [Mahler] and the stages of cognitive development [Piaget].

The four year old sees himself "out of his eyes" with the arms and legs coming out of the head [Mr. Potato-head]. It’s not until around age seven that the child will see herself as we see her, a whole person. In-between, Mr. Potato-head gets some hair, and has some "felt" body parts [here, a heart or genitals]. It’s a vulnerable work-in-progress period, and abuse can disrupt multiple vital developmental processes. Logical constructs aren’t available in the preoperational cognitive set so the child has no tools to understand abuse. It can and does have a profound impact on the developing self image, the templates for relating to others, and the general experience and understanding of the world. Whether these unfolding developmental sequences and the toll of abuse are the result of or cause actual changes in the brain itself or take place in a psychological domain is as unknown now as it was forty years ago. But the particular vulnerabilities of the preschool child and the enduring consequences remain a paramount concern whether hardware or software. And by the way, their finding highlights the inadequacy of the Major Depressive Disorder categorical diagnosis.

Translational message? Take a history!…
Mickey @ 7:00 AM

key opinion leaders: a profession…

Posted on Thursday 2 June 2016

In the last post [key opinion leaders:  an example…], I said of Dr. Thase that "… most of us think of him not in any specific role as an expert professional, but rather as a Professional Expert" – implying that being a KOL is itself is a profession. And it’s the ability to lead the opinion of others that matters, not some particular expertise itself. It was, in fact, around the drug Vortioxetine that I finally started to ponder what being a KOL actually meant. About this time three years ago, I read this in Medscape:
by Deborah Brauser
May 20, 2013

The experimental antidepressant Vortioxetine is safe and effective for treating major depressive disorder [MDD], findings from several new phase 3 randomized controlled trials [RCTs] suggest. Three studies of a total of 1545 US patients with MDD showed that those who received 20 mg of Vortioxetine had significantly decreased symptom scores on the Montgomery–Asberg Depression Rating Scale [MADRS] after 8 weeks of treatment compared with those who received matching placebo. However, there was no difference in symptom scores between the 10-mg and the 15-mg dose compared with placebo.

Interestingly, a fourth study conducted in Europe and South Africa with 608 patients showed that both the 15-mg and 20-mg doses of Vortioxetine were associated with significantly lower MADRS scores than placebo. "We wanted to address the correct dose, and across the studies, the 20-mg had the most consistent findings over placebo," principal investigator Madhukar Trivedi, MD, professor of psychiatry at University of Texas Southwestern Medical Center in Dallas, told Medscape Medical News. Dr. Trivedi noted that "it’s very hard to figure out why" the 15-mg dose did well in the European study but not in the US studies, "but this often happens in antidepressant trials"…
I don’t know what it was about that particular day, but instead of following the article’s narrative, all I could see was «We» and «principal investigator Madhukar Trivedi». I felt absolutely sure that he was not the «principal investigator» on this study. And «We»? He hadn’t been any part of «We». He was looking at all of this post hoc – after the fact. I spent an inordinate amount of time looking for any evidence that either Dr. Trivedi or Dr. Thase [presented an earlier APA poster in 2011] had been directly involved in any of these studies ongoing, and it just wasn’t there [see way past time…]. ie:
Planners want KOLs to appear to have done much or all of the important work behind an article, presumably because many readers would be less inclined to give credence to an article that had only pharmaceutical company authors…
Sergio Sismondo
in Corporate Disguises in Medical Science: Dodging the Interest Repertoire

Since then, I’ve just assumed that being a KOL is a profession in and of itself. In this case, the professionals would be Michael Thase, Madhukar Trivedi, and the group that signed on to the review [Schatzberg, A.F., Blier, P., Culpepper, L., Jain, R., Papakostas, G.I., and Thase, M.E. 2014. An Overview of Vortioxetine. Journal of Clinical Psychiatry. 75[12]:1411–1418.]. Today, I decided to look over the 13 RCT articles, the review article, and the meta-analysis funded by the sponsors, Takeda and Lundbeck. Recalling the figures from Cosgrove et al‘s paper, I repeated their compilation of the authors’ COI declarations with the review and meta-analysis included. The 15 articles had 60 by-line author cites spread among 31 authors. 13 of the authors were employees, making up 36 cites. Of the remaining 18 authors, only one didn’t have a financial COI with at least one of the sponsors, so 23/24 of the non-Employee cites had a COI. All 15 articles were ghost-written. And then I read them and looked over Thase and Trivedi’s presentations at the Institute of Medicine and at the FDA hearing.

I’m not totally sure why I did all of that today. I never doubted Cosgrove et al‘s excellent paper. I think I just had to see it for myself, kind of like going to the TMAP Trial in Austin a few years back to make it real. I suppose it’s still hard for me to imagine that smart people like Michael Thase, Madhuklar Trivedi, or all the other Professional KOLs would participate in such foolishness, or that the other tainted authors would sign on to papers written by professional writers being paid to make something look better than it can ever be. But it looks just like it did last time through. Sismondo’s title was well chosen, Corporate Disguises in Medical Science: Dodging the Interest Repertoire.
Mickey @ 6:58 PM

key opinion leaders: an example…

Posted on Wednesday 1 June 2016

    you can’t learn it from books,
    you can’t learn it without books.
    …………………….zen saying…

I grew up on the Tennessee River near Lake Chickamauga where I swam, picnicked, camped, boated, fished, skied, etc. Then I left for college and those things stayed with the lake. As an adult in Atlanta, I discovered Lake Sydney Lanier an hour north of the city renown for its sailing conditions. After one outing with a friend, I found myself reading every book about sailing I could get my hands on and haunting boatyards on the weekends. If being a sailor could be measured by a written test, by the time I bought my boat, I’m pretty sure I would’ve scored in the expert range. But on the water in my new boat, I was an anxious dunce. It would be several years before sailing became an intuition, and I could call myself a sailor…

As an internist and later as a psychiatrist, I read about drugs, but I really learned about them from teachers, colleagues, and patients. When I came back to that part of psychiatry after retiring, I encountered something new – the people I now call KOLs. They were a class of experts, academics who published drug studies and wrote endlessly about them. I figured out that their recommendations came from the data from clinical trials, not from their experience. I knew enough of them personally to know that they didn’t see that many patients, certainly not to follow them long term. So it was a new class for me, not one I’d encountered in my wanderings through medicine and I was wary of their advice. Since I also found the text-books unhelpful and out-of-date the day they came out, I started reading the Clinical Trial reports myself – and that’s what got me here today.

One of the early papers I read was Barriers to implementation of a computerized decision support system for depression: an observational report on lessons learned in "real world" clinical settings. The author, a Madhukar Trivedi, had a computer program with an algorithm for using the antidepressants. He was trying to study his program, but what he found was that if he didn’t look over the clinicians’ shoulders, they didn’t use it. So the paper was a sort of amateurish speculation about what psychic conflicts they might have that kept them from using his program [and scuttling his study]. Then I got to the end and read his Conflict of Interest declaration, and it was his psychodynamics I started thinking about! I wouldn’t have used his computer program either. Here’s what I had to say back then [evidence-based medicine I…]. Madhukar Trivedi, it turns out, is a KOL extraordinaire.

Apparently, Marcia Angell had the same kind of reaction when she wrote Is Academic Medicine for Sale? in 2000 after reading this paper in the journal she edited:
by Martin B. Keller, James P. McCullough, Daniel N. Klein, Bruce Arnow, David L. Dunner, Alan J. Gelenberg, John C. Markowitz, Charles B. Nemeroff, James M. Russell, Michael E. Thase, Madhukar H. Trivedi, Janice A. Blalock, Frances E. Borian, Darlene N. Jody, Charles DeBattista, Lorrin M. Koran, Alan F. Schatzberg, Jan Fawcett, Robert M.A. Hirschfeld, Gabor Keitner, Ivan Miller, James H. Kocsis, Susan G. Kornstein, Rachel Manber, Philip T. Ninan, Barbara Rothbaum, A. John Rush, Dina Vivian, and John Zajecka.
New England Journal of Medicine. 2000 342:1462-1470.

Background: Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain.
Methods: We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone [maximal dose, 600 mg per day], the cognitive behavioral-analysis system of psychotherapy [16 to 20 sessions], or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients’ treatment assignments.…
She was struck by the COI declaration [it’s online and it is definitely impressive]. However, I’m interested in the By-Line. Martin Keller has included even more KOLs than he mustered for his Paxil Study 329 paper. Notably, here are four of the six "thought leaders" mentioned in key opinion leaders: the new millennium… [Charlie Nemeroff, Martin Keller, Alan Schatzberg, and Robert Hirschfield]. There are the two gurus from TMAP and STAR*D [John Rush and Madhukar Trivedi]. There’s the Board of Directors of the Corcept® Corporation [Alan Schatzberg and Charles DeBattista]. And then there’s Michael Thase.

Dr. Thase was on the faculty of the Western Psychiatric Institute in Pittsburgh from 1984 to 2007 when he moved to the Perlman School of Medicine in Philadelphia as Chief of the Division of Mood and Anxiety Disorders Treatment & Research Program. He writes broadly about the diagnosis and treatment of these disorders and so most of us think of him not in any specific role as an expert professional, but rather as a Professional Expert – a KOL who is everywhere. He still may not have caught up with Charlie Nemeroff in total publications, but he’s closing in fast [he got off to a late start].

This is from a paper by Sergio Sismondo who attended a KOL management meeting to see what was up [Corporate Disguises in Medical Science: Dodging the Interest Repertoire][see Howard Brody on Sismondo‘s paper]:
Invited to a pharmaceutical industry conference on relationships with key opinion leaders was Dr. Michael Thase, a representative KOL. Thase, who was introduced as having authored over 500 publications and being “one of the brightest stars in neuroscience,” was a smiling and confident speaker, comfortable giving his narrative to this audience of mostly pharmaceutical company managers

Thase gave his disclosures in a practiced move. As he explained, In the past decade, I have been a consultant to the manufacturer of every compound that has been developed for the treatment of depression or the treatment of bipolar disorder, and some number of other compounds that haven’t made it through the multi phases stages of development.

Normally, he said, he presents this as two slides. He added a list of six pharmaceutical companies that had paid him to give talks in the previous 3 years, and another four that have recently funded research projects. He does not believe, he opined, that academics are very often dishonest, but he does recognize that “who you spend time with, where you make money, and so on,” can influence what you believe to be true. Dr. Thase is the quintessential KOL, a nationally recognized expert who is personable and a good public speaker. As one insider defines them, KOLs are well-known specialists who “can influence other physicians”…
When he took the reins as editor of the Psychopharmacology Bulletin in 2002 [occasioned by Charlie Nemeroff’s moving up to edit Neuropsychopharmacology – the journal of the American College of Neuropsychopharmacology], Thase wrote of his relationship with industry:
A particular area of interest of mine is the increasingly acrimonious [and often sanctimonious] furor about the relationship between academic medicine and the pharmaceutical industry. Let me be up-front about my position: I am a libertarian by nature and firm believer in personal accountability, free markets, and limited regulatory interference. Unlike the editors of some of medicines more prestigious journals, however, I do not plan to write editorials broadly condemning a pseudomonolithic pharmaceutical industry while the publisher’s business office collects money for advertisements or academic supplements. Let me also be clear about this little economic fact: the Bulletin is a product of the publisher’s business, and it must at least break even to stay afloat. This means that it is essential to maintain honest, yet mutually beneficial relationships with the industry. Moreover, as "Big Pharma* is responsible for the development and introduction of virtually all new psychotropic medications, it seems an act of epic foolishness to try to impose some sort of hands-off relationship between our editorial board and the pharmaceutical industry…
I picked Michael Thase as my example because he’s so omnipresent and so tangled up in this Vortioxetine story I’ve been following – all the way along its history. Parenthetically, looking at those Vortioxetine papers collectively, the KOL business must be declining, because they’ve been able to collect quite an assortment of known KOLs to pair-up with their company doctors on the By-lines…
hat tip to even more librarians   
Mickey @ 6:43 PM

key opinion leaders: the new millennium…

Posted on Monday 30 May 2016

Having become preoccupied with the newer antidepressant, Vortioxetine, I was going to talk some about the KOL’s [Key Opinion Leader] place in psychiatry using Michael Thase, one of the main such figures in the Vortioxetine story, as an example. But then I received a copy of an older article I’ve heard about but never seen. It’s as good an introduction to the topic as one might wish for…
hat tip to the librarians   
Boss of Bosses: Charles B. Nemeroff, MD, PhD
by James La Rossa Jr. and Genevieve Romano
TEN: The Economics of Neuroscience. 2000 2[9]:8.

Charlie Nemeroff is sitting quietly at the speaker’s table, ignoring the bustle going on around him. His face betrays nothing — neither boredom* nor interest, or apprehension. Only the blinking of his eyes distinguish him from a statue. When he hears his name he rises very slowly, and begins to move to the lectern with deliberate strides, gathering speed as he goes, brightening now. He breaks into a grin and begins speaking the minute he approaches the microphone and, before the hush of the room takes hold, he has won the crowd with a disarming and deliberate manner that cuts simply to the heart of the most complex issues in neuropsychiatry.

Charles B. Nemeroff, MD, PhD, chairman of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta, finds himself addressing a room of crowded colleagues hundreds of times each year. Even in the ultra-competitive world of medicine and academia, Nemeroff is admittedly the most coveted academic speaker in psychiatry in the United States. His prolific authorship [he has published 600 research reports and reviews] along with a sheer enormity of research grants, awards, and scientific board appointments, has afforded him unprecedented celebrity within the psychiatric community. Nemeroff’s academic and intellectual largess translates to a small and influential group of close friends, including fellow department chairmen Alan Schatzberg [Stanford], Marty Keller [Brown], Dwight Evans [U-Penn], Bob Hirschfeld [U. of Texas, Galveston] and NIMH heavyweight Dennis Charney, all of whom spend a great deal of professional and personal time together. Psychiatry is a highly charged topic these days, and these six thought leaders walk a fine line between controversy and political correctness, often made possible by their strong allegiances both to topics and to one another.

The ethics surrounding the implementation of placebo-control trials is one of psychiatry’s most super-charged political issues, as is addressed in more detail in this issue of TEN. "From a scientific point of view, the best data on efficacy of any treatment is best derived from placebo-controlled trials," Nemeroff says. But with diseases like cancer and stroke, placebo trials become unethical. Thus, "the FDA in most cases has allowed for comparison between novel treatments for devastating disorders with traditional already-approved treatments." If a novel agent proves efficacious against en existing agent, it gets approved. But "that has not been the case in psychiatry. And we have to raise questions about the use of placebo in conditions like mania, where patients are terribly ill. [In these cases] one wonders why it isn’t sufficient to have evaluation based on ‘just-as-good-as’ or ‘better-than’ currently available treatments and better side effect profile."

Nemeroff is among the most coveted advisors to the pharmaceutical industry. Predictably, rumors about his alliances, or lack thereof, abound. It is safe to say that his views are expressed in a forceful manner — he is a passionate person — and he fully expects to lead the corporate strategy of those he advises. Those who do not heed his advice are often recipients of his wrath. Consequently, Nemeroff is often in favor with the most successful drug makers, since those firms are doing the lion’s share of research, which he often directs.

Privately, Nemeroff is circumspect about the role between private and public funding. Working with industry can "he a win-win. There is a shared vision but also separate mission – The university mission is a troika: research, teaching, clinical service; whereas the pharmaceutical industry [mission is to] discover new drugs and to market them effectively. Sometimes those goals are simpatico and sometimes they’re not." As an example of a situation where industry funding works to the benefit of the scientific community, Nemeroff recounts a new teaching council that he started recently with a grant from Janssen called The Young Faculty Development Program, where young professors get the opportunity to learn about clinical issues and academic life. And he talks also about the differences he sees between today’s young clinicians and those of his generation, "in the past, there was a clear schism between psychoanalytically oriented psychiatrists and so-called biological psychiatrists. Today, this mind-brain dualism seems silly … Patients of course have both minds and brains." The fact of the matter is that psychosocial factors … can certainly affect how the brain functions and we also know that the brain itself changes. The nature/nurture controversy is really no controversy, as we’ve improved our understanding of the brain."

The Bronx-NY-born Nemeroff is most content being both a researcher and a physician. As an example, he recounts a part of the very day of this phone interview. "[Earlier today] I saw four patients, one on emergency consult; at the same time, I was dealing with a number of issues related to an NIMH grant of the psychobiology of early trauma. What can be better than being a teacher and a researcher and a physician?"
When I left academic and mainstream psychiatry in the mid-1980s, we had experts – people who were known and knowledgeable about some particular topic in the field. When I returned several decades later, we had a different breed – Key Opinion Leaders [KOLs]. They too were well known and knowledgeable, but they were something else as well. The term comes from the PHARMA marketing lingo and was well chosen – they can lead the opinions of others. So they are in high demand by industry as advisors, authors, speakers, grantees, etc. And the pay, though sometimes indirect, has been excellent, both to them and their institutions. Some did actual research, but most referred to themselves as researchers by defining Clinical Trials as research. And they published like crazy – authoring and co-authoring hundreds of articles.

By the turn of the century when this piece was written, Charlie Nemeroff was at at the top of the heap and the top of his game – the quintessential KOL. This article mentions some of the other major KOLs of the time, a core group of his friends and fellow chairmen. So as the new drugs flowed from industry at a steady rate, there was plenty to talk about, and the promise of future breakthroughs was always fertile ground for their stream of presentations and review articles. But that’s just the very public part. There were the advisory positions [left below] and those paid pharma speaker engagements to small groups all over the country [right below] generating personal income.

While this article was not written as an exposé, it offered a candid look behind the scenes at how Dr. Nemeroff and his colleagues occupied a formidable power-base in psychiatry in 2000, and hinted at how the boundary between academia and industry was disappearing. In the same year, responding to an article in the NEJM where Nemeroff and three other authors came from the group mentioned above [of the 29], editor Marcia Angell wrote an editorial, Is Academic Medicine for Sale? [after looking at the voluminous COI declarations]. Perhaps she could’ve even substituted bought and sold for for Sale, at least in the psychiatric literature on RCTs.

We all know how this story finally came to something of a close, though Nemeroff’s reign didn’t exactly end because of his industry connections – it was personal greed. In 2002, he published a review article recommending three different treatments all of which he had a personal financial stake in without disclosing that interest – easily seen by watchdogs Bernard Carroll and Bob Rubin. In spite of being publicly exposed and censured by Emory, in 2006 he did it again with a review of a treatment he and his coauthors all had financial interests in, again with no COI declarations [and in a journal he edited to boot], again seen by Drs. Carroll and Rubin. He was forced to step down as editor of the prestigious journal, Neuropsychopharmacology, and was put on a tight rein by Emory. But in 2008, when he was investigated by Senator Grassley for unreported pharma income, he lost his chairmanship [as did two of his cohorts on Senator Grassley’s list, Drs. Schatzberg and Keller].

So at the turn of the century, the academic·industrial complex was going strong in psychiatry, but largely out of sight. Clinical Trials were conducted by Contract Research Organizations [CROs]. The data was analysed by the sponsors and written up by contracted medical firms [ghostwriters]. The publication authors were editors and window dressing for the industry·dominated process. Inside academic psychiatry, there was a powerful coalition of KOLs and a boss·of·bosses running the show with pharma allies [or vice versa].
Mickey @ 6:02 AM

1776 – 2016…

Posted on Monday 30 May 2016

Mickey @ 6:00 AM

on being boring…

Posted on Sunday 29 May 2016

I recognize when I get on a topic and beat it in the  ground, I’m living up to my 1BORINGoldman moniker. And right now, I’m doing that with Vortioxetine [Brintellix® AKA Trintellix®]. But I’ve got my reasons [actually two of them]. But neither reason is to prove to you that this latecomer is a particularly weak addition to an already weak class of drugs – the SSRI/SNRI antidepressants. You already know that.

One reason is in my own history as an eight year amateur Clinical Trial vetter. When I first started looking into these psychopharmacology trials, in spite of having had more than the usual amount of statistical training and experience, the clinical trial motif was new territory – and there was much to learn. But early on, like many of you, I could see that the industry funded trials were regularly distorted. And then there was the absurdity that the data itself was hidden [proprietary property of the sponsor]. And in those few instances where one could nail down the misreporting [because of subpoenaed internal documents or court-ordered data release] by the time those facts were available, they were old drugs either off-patent or nearly so. The profits were already in the bank and the drugs were established and in use. So I resolved to take a look at new drugs that came along, and if the reports looked shaky, perseverate on what was wrong – hoping to join a chorus that might finally move us away from such things in our academic journals. Vortioxetine is both new and shaky, ergo, one of my reasons to stick to it like glue.

But the second reason is that the more I read these clinical trial articles, the more aware I become of how much work goes into putting the commercial spin into every graph, table, sentence, calculation, statistical test, omission, etc. I’ve already mentioned a few in smoke and mirrors…, but there are others everywhere. In one of the the main data tables, I mentioned things like how it was sorted and which units were shown graphically.

[click image for full size]

But then notice the absence of a p-value column, for example. And they show the aggregate results for all studies [Meta-analysis], but then they break out the aggregate for the non-US studies [Meta-analysis (non-US)]. How come? Remember that they make a big deal out of there being a dose response effect and there it is in the non-US data. But why not also break out the US studies? Well because they don’t show a dose response effect – and, for that matter, they don’t show much of any effect at all! a significant omission:

These studies involve thousands of subjects – the kind of numbers required to detect the kinds of small differences they’re reporting. The way they get these big numbers is to use a lot of sites. With the US studies, we know the cities where they were gathered. With the non-US studies, we only know the countries, not the number of sites in each. But even at that, there are many, many sites, in diverse places, each with its own staff and raters. That’s a lot of room for a lot of variability, invisible to the reader [go ahead, click on the image to see what I mean by many, many and diverse].

[click image for full size]

I used to just pass over these presentation quirks because I couldn’t prove they were deliberate, what with this being the age of evidence based medicine and all. But they’re so universal, I give them more valence now. But the most damning finding in the industry funded trials and their reports is something that’s hard to quantify, but plain as the nose on your face. It’s the narrative itself, and this is a fine example. It’s a sales pitch, that sings that old song: accentuate the positive, eliminate the negative, latch on to the affirmative, and don’t mess with mister in-between. Just read the discussion. You can’t miss it.

So, when I have a boring-attack and get stuck on this drug and these deceptive articles, it’s just my small attempt to neutralize how it is being advertised. Vortioxetine’s not something new, some kind of advance. It’s just a particularly weak addition to an already weak class of drugs trying to follow a tired old marketing strategy to an undeserved success…
Mickey @ 8:54 PM

smoke and mirrors…

Posted on Friday 27 May 2016

When I began to look at Clinical Trial reports a few years back, I had to relearn how to approach our literature. The studies are now industry funded, and that turned out to mean that the pharmaceutical companies control every step of the process, resulting in distorted and unreliable efficacy and side effect profiles. One might think that with all of the focused attention and attempts at reform, things might’ve changed more. But the beat just goes on.

The newest antidepressant on the block, Vortioxetine [Brintellix®, now Trintellix®], is sticking to the same old formulas. The publications’ authors are all either employees or otherwise tainted. A ghosted review article has an army of KOLs on the byline [see the recommendation?…]. They made a yeoman’s attempt at indication creep, including an all day KOL-rich Institute of Medicine production and a special FDA re-hearing trying [and failing] to create a new indication, Cognitive Dysfunction in Depression [see more vortioxetine story… and a parable…]. There have been a number of independent meta-analyses and critiques:
Now we have yet another Vortioxetine meta-analysis, this time by the manufacturers [Takeda/Lundbeck], again with their [everyman’s] KOL, Michael Thase, and four company employees on the byline:
Thase ME, Mahableshwarkar AR, Dragheim, M, Loft H, and Vieta E.
European Neuropsychopharmacology. Mar 25, 2016 [Epub ahead of print]
2014/2015 Impact Factor 4.369

The efficacy and safety of vortioxetine, an antidepressant approved for the treatment of adults with major depressive disorder (MDD), was studied in 11 randomized, double-blind, placebo-controlled trials of 6/8 weeks? treatment duration. An aggregated study-level meta-analysis was conducted to estimate the magnitude and dose-relationship of the clinical effect of approved doses of vortioxetine [5-20mg/day]. The primary outcome measure was change from baseline to endpoint in Montgomery-Åsberg Depression Rating Scale [MADRS] total score. Differences from placebo were analyzed using mixed model for repeated measurements [MMRM] analysis, with a sensitivity analysis also conducted using last observation carried forward. Secondary outcomes included MADRS single-item scores, response rate [≥50% reduction in baseline MADRS], remission rate [MADRS ≤10], and Clinical Global Impressions scores. Across the 11 studies, 1824 patients were treated with placebo and 3304 with vortioxetine [5mg/day: n=1001; 10mg/day: n=1042; 15mg/day: n=449; 20mg/day: n=812]. The MMRM meta-analysis demonstrated that vortioxetine 5, 10, and 20mg/day were associated with significant reductions in MADRS total score [Δ-2.27, Δ-3.57, and Δ-4.57, respectively; p<0.01] versus placebo. The effects of 15mg/day [Δ-2.60; p=0.105] were not significantly different from placebo. Vortioxetine 10 and 20mg/day were associated with significant reductions in 9 of 10 MADRS single-item scores. Vortioxetine treatment was also associated with significantly higher rates of response and remission and with significant improvements in other depression-related scores versus placebo. This meta-analysis of vortioxetine [5-20mg/day] in adults with MDD supports the efficacy demonstrated in the individual studies, with treatment effect increasing with dose.
The article has a number of figures, forest plots of the parameters they compiled from the various Clinical trials. The two below are from Figures 2B and 4B. Take a look at the versions in the paper first. In the ones below, I’ve removed some of the columns that were irrelevant to the points I wanted to make, and I’ve sorted them differently – first by region [US, mixed, non-US] and then by dose [my apologies for the "waviness" – an artifact of my graphic capabilities]. In both of my versions, I see nothing of the "dose response" effect they advertise in the text. Instead, heterogeneity seems to be the order of the day. Another thing that appears obvious is that there’s a big difference between the US and non-US sites in both tables.

In the MADRS Total Score Differences [above], the forst plot abscissa is plotted as the raw difference. While that’s a legitimate way to show Effect Size, the units are unfamiliar, at least to me. In the far right column, they show the more familiar Standardized Effect Size [Mean Difference ÷ Standard Deviation] roughly scaled as 0.25=weak, 0.50=moderate, and 0.75=strong. Only one of the US sites reaches something that might remotely be clinically significant.

The MADRS Remission data is similar: Dose response curve? Not so much. And in the US sites, nothing achieves significance [p<0.05] or has an NNT or an Odds Ratio that is the range of a clinically solid antidepressant.

Is it fair to imply as I have done here that the US data is more reliable? I know that’s sure what I think. But my real point in redoing these figures is to show that the way the data is presented can be [and often is] easily used to guide the reader towards some preferred conclusion. Omission is another way to lead the reader. What’s missing here is that six of these studies had active comparators, included in some of the other papers listed above. In this paper, they explain why they left them out in the text…
This meta-analysis centers on the comparison between vortioxetine and placebo in the 11 individual studies and does not evaluate differences between vortioxetine and the active references [duloxetine and venlafaxine XR]. The results of the active references can be found in the publications for the individual studies. In two of the previous meta-analyses of the vortioxetine data, direct comparisons between vortioxetine and the active reference were included. Direct comparison of vortioxetine and the active reference is not appropriate, as the individual studies were not designed or powered to enable this comparison. Rather, the rationale for including an active reference in these studies was for the internal validation of the study design [i.e., assay sensitivity]. To evaluate the efficacy of vortioxetine relative to another antidepressant would require a study that is specifically designed for that purpose, that is, an active-comparator study. In addition, in the six studies that include an active reference, patients were excluded – for ethical reasons – if they had known hypersensitivity or a history of lack of response to previous treatment with the active reference, which introduces the potential for bias in favor of the active reference.
… which is baloney. This plot of those comparisons from Cosgrove et al [see publication bias III – close encounters of the second kind…] is the likely explanation for why the active comparators were omitted. Vortioxetine just doesn’t come out very well:

It’s sort of unusual to see an industry produced meta-analysis of their own clinical trials. I’ve given just a few examples where the way things are displayed or omitted falsely inflate the overall picture of how the drug performs. There are others, but even without the window dressing, this is a weak antidepressant on the best of days [if that]. I would speculate that this industry created meta-analysis is intended to neutralize the less than enthusiastic findings of the independent meta-analyses.

We’re so used to these industry prepared, ghost managed papers that there are some aspects of these articles that we don’t even notice. All along the way, when there’s something that looks negative, the narrative explains it away as in the omission of the active comparators. They’re written and presented aiming towards a conclusion rather that trying to clearly present the facts and allowing the reader to reach their own conclusions. Also, it’s worth noticing that this article is published in European Neuropsychopharmacology which is the publication of the European College of Neuropsychopharmacology, a scientific organization – a place where one might expect the most rigorous of scientific papers to appear rather than what looks to be a ghost-managed commercial advertisement…
Mickey @ 11:41 PM

“that’ll preach”…

Posted on Wednesday 25 May 2016

My good friend Andy died a couple of years back. By education, he was a minister, but he did other things instead, mostly good. Maybe he’d left the pulpit, but his way of saying things betrayed his history, so when he ran across something that really mattered or was unusually right, he’d smile and say "That’ll preach!" Reading this editorial, I heard his voice…
There are better solutions to the “reproducibility crisis” in research
by Eric J. Topol
British Medical Journal. 2016 353:i2770.

Money back guarantees are generally unheard of in biomedicine and healthcare. Recently, the US provider Geisenger Health System, in Pennsylvania, started a programme to give patients their money back if they were dissatisfied. That came as quite a surprise. Soon thereafter, the chief medical officer at Merck launched an even bigger one, proposing an “incentive-based approach” to non-reproducible results — what he termed a “reproducibility crisis” that “threatens the entire biomedical research enterprise.”

The problem of irreproducibility in biomedical research is real and has been emphasised in multiple reports.  In the same vein, the retraction of academic papers has been rising, attributable, in nearly equal parts, to irreproducible results or data that have been falsified. But this problem is not confined to basic science or animal model work from academic laboratories. Clinical trials, the final common pathway for the validation and approval of new drugs, have been plagued with serious drawbacks.

The bad science in clinical trials has been well documented and includes selective publication of positive results, data dredging, P hacking, HARKing, and changing the outcomes that were prespecified at the beginning of the study [below]. Indeed, the high prevalence of switching outcomes in drug industry funded trials led Ben Goldacre and colleagues at the University of Oxford to organise Compare, an initiative to track this considerable problem. Furthermore, the disparity between what appears in peer reviewed journals and what has been filed with regulatory agencies is long standing and unacceptable.
    Bad science
  • Data dredging — Mining a dataset with innumerable unplanned analyses
  • P hacking — Repetitively analysing data in ways not prespecified to find a significant P value
  • HARKing (hypothesising after the results are known) — Retrofitting the hypothesis after the results are known to portray an exploratory, retrospective analysis as if it was prospectively declared
In case you don’t recognize the name, Eric Topol is the Cardiologist who started the ball rolling that exposed the dangers of Vioxx®. He later left the Cleveland Clinic in a conflict over corporate influences and now directs the Scripps Institute [among other things].
Transparency is key

What is missing is the deep commitment—across academia and the life science industry—for open science and open data. Everyone asks for accountability of research findings, which can be vastly promoted by making them fully transparent. But compliance is poor. Even the mandatory requirement for publishing results on Clinicaltrials.gov within two years was evaded for 87% of 4347 clinical trials in academic centres.

When we start to see all the protocol, prespecified hypotheses, and raw data available for review, along with full disclosure of methods and analyses and what, if anything, changed along the course of experiments, be it at the bench or in clinical trials, we’ll have made substantive progress. A promising, low cost digital solution exists to capture all of the data and promote trust and reproducibility in biomedical research. Use of blockchain technology has recently been shown to provide an immutable ledger of every step in a clinical research protocol, and this could easily be adapted to…

Until we develop the right system, we don’t need or want money back guarantees on research reproducibility. But I’d be interested to pick up on that refund offer for my medications or any medical care that doesn’t work.
Maybe I should just say "Amen, brother!"That’s all Andy would’ve said…
Mickey @ 5:24 PM


Posted on Tuesday 24 May 2016

David Healy‘s blog has a guest post called The Pill That Steals Lives: One woman’s terrifying journey to discover the truth about antidepressants by Katinka Blackford Newman – an introduction to a book about her experiences with psychiatric medications due out in early July. It’s one of those all too familiar stories where a negative reaction to one medication was interpreted as an illness that was treated by adding other medications in an escalating cycle:
It had started when I had hit a wall of despair while going through a divorce. Sleepless nights took me to a psychiatrist who prescribed an antidepressant. Within hours I was hallucinating, believed I had attacked my children and in fact attacked myself with a knife. I ended up in a private hospital where doctors clearly thought I had a screw loose when I told them I was being filmed and that there was a suicide pact with God. The psychosis ended when I said I wanted to stop taking the escitalopram but doctors insisted I take more pills. This began a terrible decline where I couldn’t leave the house, dress myself, finish a sentence. But the worst thing of all was that I couldn’t feel love for my children, Lily and Oscar, who were 10 and 11 at the time. At the end of a year I was about to end it all. As a last resort I tried to get myself readmitted to the same private hospital, but my insurance had run out. And that was how I ended up sectioned at this NHS hospital that had made the decision to take me off all the drugs [Lithium, Olanzapine, Sertraline, Prozac, Lamotrigine]. I was climbing the walls, screaming, shouting, and begging my family to get me out of there. If I’d been suicidal while on the drugs, withdrawal made me far worse…
It looks to be an interesting book [and advertises a revelation along the way]. But that’s not why it’s here. It’s this:
[Lithium, Olanzapine, Sertraline, Prozac, Lamotrigine]
No matter what you believe about mental illness [disease or not] or about psychopharmacology [disease specific or symptomatic], it’s hard for me to imagine when…
[two antidepressants plus two mood stabilizers plus an atypical antipsychotic]
…would ever be an appropriate drug regimen for any condition I know of. What illness does that treat? How about with the new NpN terminology they’re so excited about? Would renaming it …
[glutamate with yet to be determined enzyme interaction plus a dopamine, serotonin receptor antagonist [D2, 5-HT2] plus a serotonin reuptake inhibitor [SERT] plus a glutamate voltage-gated sodium channel blocker]
…make things any better? [one shudders to think what it would become in RDoC talk]. I’m being sarcastic and I shouldn’t be because this is a deadly serious point. A case like this transcends the usual discussions about efficacy or indication. There’s just no rational rationale for this drug cocktail that I can think of for anything. And I’ve seen cases like this over and over. I recently catalogued such a journey [good news bulletin… see case number 3 and its links].

The way this happens is that a patient gets started on a medication and things go badly. So other medicines are tried without stopping the last. As the patient continues to go downhill, the medications get added irrationally. There may be akathisia and/or withdrawal mixed in with the medication effects. It ends like the story I think I’ll read when the book arrives – an impossible situation where the patient still may or may not have the problem they came with, are living in an obtunded mental state from all the medications, and have the added prospect of one or more withdrawal syndromes to face. One unholy mess!

The solution when a case is headed this way is to STOP adding things and gradually taper off of all medication, using something like a benzos for distress if you have to. LOOK at the patient as if it’s a brand new case. Perhaps get a consult from someone you respect, and LISTEN to what they say and the patient says. Unfortunately, the people who get into such messes are reticent to let them see the light of day so finally somebody else [family?] intervenes. And when you see a case like this – somebody on five medicines who’s getting or has already gotten worse – always think medication effects until proven otherwise.
Mickey @ 5:19 PM

a thorny problem, this one…

Posted on Monday 23 May 2016

Reading through Sergio Sismondo’s Ghosts in the Machine was confirming, validating my own impression that there is a  secretive commercially driven enterprise manipulating the processes by which we know about medications. I knew it was there, but I really didn’t know it was so ubiquitous, nor did I know it was a profession. But there were parts of his essay I just didn’t get. This was one of them:
Implicit in many of the exposes of ghostwriting in the medical science and popular literature is an assumption that ghostwritten science is formally inferior. Given the very high acceptance rates of ghost-managed papers, that assumption is questionable in general – though it may be right about important cases. Pharmaceutical company research, analysis, and writing results in knowledge. It is not different from other medical research, analysis, and writing in the fact that companies and their agents make choices in the running of clinical trials, in interpretations of data and established medical science, and in the messages they convey in papers and presentations. This point is straightforwardly suggested by STS’s longstanding commitment to symmetry. It is justified by the results of canonical studies that have shown how science is choice-laden. Thus, the work of pharmaceutical companies to produce research and place it prominently in medical journals is not merely a corporate use of the patina of science. It is science, though it is science done in a new, corporate mode.
It was one of those paragraphs you read over and over with the same question·mark look on your face. And apparently I’m not the only one [see Leemon McHenry’s Ghosts in the Machine: Comment on Sismondo]:
The commercial medical science that has created the ghostwriting industry is a corruption of science, and not merely as Sismondo puts it "science done in a new, corporate mode."
Which is what I think. Back to Sismondo, there was a part of Ghosts in the Machine that I really liked reading:
Everybody systematically connected with publication planning wants established formal rules of conduct. As sub-contractors, publication planners would like to reduce uncertainty, so that they can plan ahead and so that they can produce exactly the papers that will satisfy all of the different parties with whom they interact. Both publication planners and pharmaceutical companies want formal rules to guide and cover their work, to legitimize it so that its exposure does not amount to scandal…
In the course of life, I spent almost a decade as an educator/administrator. And as much as I enjoyed those years, there was one part I had no problem getting away from. It was hearing the question, "What is your policy about …?" To me, that meant "give me a rule so I’ll know how close to the line I can get without consequences" [and then the search for the loopholes began]. Here’s another solution that we might initially think we could agree with:
Bioethics. 2010 24[6]:273–283.

It is by now no secret that some scientific articles are ghost authored – that is, written by someone other than the person whose name appears at the top of the article. Ghost authorship, however, is only one sort of ghosting. In this article, we present evidence that pharmaceutical companies engage in the ghost management of the scientific literature, by controlling or shaping several crucial steps in the research, writing, and publication of scientific articles. Ghost management allows the pharmaceutical industry to shape the literature in ways that serve its interests.

This article aims to reinforce and expand publication ethics as an important area of concern for bioethics. Since ghost-managed research is primarily undertaken in the interests of marketing, large quantities of medical research violate not just publication norms but also research ethics. Much of this research involves human subjects, and yet is performed not primarily to increase knowledge for broad human benefit, but to disseminate results in the service of profits. Those who sponsor, manage, conduct, and publish such research therefore behave unethically, since they put patients at risk without justification. This leads us to a strong conclusion: if medical journals want to ensure that the research they publish is ethically sound, they should not publish articles that are commercially sponsored.

But then the doubts come creeping in. How would journals be financed? Industry is the only act in town able to finance trials. Where would physicians get information? package inserts? Who says the FDA Approval tells us enough to make clinical decisions? Who says the FDA is uncorruptable? And so on, and so on, and scooby-dooby-do…

A thorny problem, this one…
Mickey @ 2:09 PM