get here however you can!…

Posted on Saturday 18 October 2014

"We look forward to welcoming you to sunny San Diego for AACAP’s 61st Annual Meeting!

Gabrielle Carlson, MD, AACAP’s Program Chair, welcomes you to San Diego from the USS Midway, the site of the Welcome Reception on Wednesday, October 22. All are invited to attend!"

In the spirited video from the deck of the USS Midway, Gabrielle Carlson sporting a sailor’s cap, welcomes us to the AACAP Annual Meeting, ending with the words, "Get here however you can!" You may not recognize her name right off. Here’s a reminder:

Is it fair to haunt Dr. Carlson with her being an author on the by-line of the infamous Paxil Study 329 report in the Journal of the American Academy of Child and Adolescent Psychiatry back in 2001? She is, after all, a valued academic at Stony Brook, decorated for her research contributions in psychopharmacology. She’s obviously right-thinking on some areas of the issue of over medicating children. In a recent Commentary, she decries the overmedication with Atypical Antipsychotics…
The Dramatic Rise in Neuroleptic Use In Children:
Why Do We Do It and What Does It Buy Us?
Theories from Inpatient Data 1988-2010
by Gabrielle A. Carlson, MD

…It is ironic that the most noxious and impairing behavior, namely explosive outbursts in children, has no ‘‘home’’ in the DSM no- sology. Recognizing that explosions can occur in many conditions, neither intermittent explosive disorder nor, if it is accepted into DSM-V, DMDD, allows the diagnosis if the explosions are ‘‘better explained by’’ another condition. There is not even a consistent way in which one can find information about rage outbursts. In PubMed, there are almost completely different databases for terms like rages, rage outbursts, anger outbursts, rage attacks, explosive outbursts, and meltdowns. Irritability, the term that seems increasingly to be adopted, like aggression, may sub- sume these behaviors, but is not synonymous. Therefore, we speculate that the behavior that most drives the most use of AAPs does not even have a label that can be consistently used, and will certainly, without a "home," never be an indication for FDA approval….

In conclusion, the meteoric rise in the use of AAPs in children with ADHD and ODD reflects the fact that the traditional evidence-based treatments (stimulants and parent training/behavior modification) are either unsupported by providers and insurance (at least in terms of the intensity they require) or that these treatments are insufficient, because of the severity of the conditions being treated.

AAPs may be expensive, and clearly have important adverse effects. The question is whether society (and insurance companies) want to support the alternatives. If they do not, I feel that the rhetoric is disingenuous. I, for one, would be grateful if the AAPs could compensate for what we have lost in terms of other treatments, and were as powerful as the media imply.
… blaming the Managed Care payers for not supporting more appropriate treatments. Good for her.

However, I not only think that haunting these authors is justified, but is actually an imperative. Twenty of the twenty-two authors of Study 329 are still alive, six are in significant leadership positions in the American Academy of Child and Adolescent Psychiatry, and others dot the by-lines of other ghost-written industry-funded experimercials like this one. Gabrielle Carlson is AACAP’s Program Chair welcoming the attendees to the meeting. It is likely that many of the named authors were on the by-line of that article only because they were site primary investigators for the clinical trial itself and little involved in the writing or the extensive data manipulation involved in creating this masterpiece of deceit – now a monument to an era yet to be fully acknowledged.

In the case of Dr. Carlson, Stony Brook was in the group of sites added to Paxil Study 329 late because of slow recruitment and accounted for only 11 subjects in the trial. She’s not mentioned in any of the subpoenaed documents that I know of. Apparently it was simply a source of revenue for Stony Book, and another paper to add to her CV. But that’s the whole point. Other than the two SKB/GSK employees who directed the show creating the paper with ghost-writer Sally Laden, the actual non-involvement was true for the twenty academic authors whose names were on that author‘s list. They lent their academic credentials and the reputations of their institutions to the paper, a ticket insuring that it would be accepted in a prestigious journal and read by colleagues who respected those honorifics, without really participating in its creation. But even worse, in the decade during which the paper has been universally vilified, not one of those authors has come forward and said a word. They continue to occupy high places, adding an obvious irony to Carlson’s comment, "Get here however you can!"

Sure, Managed Care bureaucrats have pushed atypical antipsychotics over more intensive and expensive interventions [keeping the cost of medical care down]. Of course the Pharmaceutical Industry has promoted antidepressant medications for treatment of adolescent depression [in the business of selling FDA approved drugs]. Yes the professional organizations have created guidelines that recommend these practices [evidence-based medicine from peer-reviewed journals]. But without those names on the by-line certifying the articles, the papers wouldn’t have been published that allowed those things to happen. And when the authors sit in silence in their own careers even after it becomes clear, as in this case, that they lent their names, positions, and institutions to a fictional publication, they are the main force in the center of perpetuating what’s wrong.

So, is it fair to haunt Dr. Carlson with her being an author on the by-line of the infamous Paxil Study 329 report in the Journal of the American Academy of Child and Adolescent Psychiatry back in 2001? Of course it is. The whole profession and the patients we serve are haunted by publications like Paxil Study 329, and will continue to be haunted until  these authors, this journal, this organization, and this profession wakes up and starts talking and making needed changes…
Mickey @ 1:48 PM
Filed under: OPINION
the best presentation money could buy…

Posted on Friday 17 October 2014

October 17, 2014

A black box warning about suicide risks should remain on the anti-smoking drug Chantix® until it can be reevaluated using findings from thorough scientific studies, a U.S. Food and Drug Administration panel of experts said Thursday. Chantix® has carried the FDA’s strongest warning label since 2009 after it was linked to violent or suicidal behavior among some patients taking the drug.

Pfizer asked the FDA to drop the boxed warning, citing recent studies suggesting that patients taking Chantix® were not at increased risk for psychiatric problems, the Associated Press reported. However, the 11-member FDA advisory panel voted to retain the black box warning on Chantix®. One member voting in favor of removing the warning and six favored slight changes to the label. The FDA does not have to follow the advice of its expert panels, but typically does.
by Ed Silverman
October 17, 2014

“I think Pfizer took quite a chance trying to get the box deleted. They obviously wouldn’t have done it if they thought they could convince people, but they failed completely,” says Diana Zuckerman, the president of the National Center for Health Research, a non-profit advocacy group.

“They had the best presentation money could buy – very good analyses and complicated statistics to prove their point. And the company trotted out these studies and tried to make a very strong case for why the Black Box should be deleted, but only one person voted their way."

“Pfizer took a big chance, but I think they did so because they were afraid the next study wouldn’t be so favorable and maybe they could get rid of the Black Box warning now. Remember, if it were removed, it would be hard to get it reinstated later, even if a post-marketing study showed risk.”

Pfizer is not flinching. “The completion of our currently ongoing safety study will represent one more step forward in the process of accurately characterizing the neuropsychiatric safety of this important medication,” says Steven Romano, a Pfizer senior VP who heads the medicines development group.
I’ll be brief since I expect it will be all over the evening news tonight. This is one of those situations where I wonder why physicians are even in the loop. While quitting smoking is obviously an important preventive medicine maneuver, how would any single physician have any knowledge about whether a given patient should take Chantix®?

But there’s something else to say. Pfizer’s sales of Chantix® are down. They obviously think it has something to do with the Black Box warning in the labeling. So they are spending tons of money trying to get the label removed – thinking more patients will "ask their doctor if…" and that more doctors will not be afraid to prescribe it. It’s a sign of their inflated sense that they can influence and control the world if they just play their cards right. It doesn’t occur to them that maybe their sales are down because Chantix® is only for the hardy. If you’ve prescribed it yourself, you know that it does exactly what that Black Box label says it does, and maybe more often than the label suggests. They can’t change that with a label eraser or even a piece of Robert Gibbons statistical sleight of hand [see way past time…].

It is what it is…
Mickey @ 4:16 PM
Filed under: OPINION
more Wagner et al

Posted on Friday 17 October 2014

I know I sometimes get kind of hung up on numbers, and it just happened. I was looking at Wagner et al in the last post because it was ghost-written, but I did read the abstract and something stuck with me. It’s highlighted in red below, "[effect size=2.9]". The effect size is a measure of the strength of an effect and is the simplest of calculations: it’s the difference in the means of the two groups divided by the standard deviation. Besides being an index of the strength of an effect, it also normalizes things so different studies can be compared. The usual range is 0.25 = weak, 0.50 = moderate, and 0.75 = strong. So what’s with effect size=2.9? It doesn’t make any sense. So I went back and pulled the whole paper to calculate it myself. Curious George, I guess…
by Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE.
American Journal of Psychiatry. 2004 161[6]:1079-1083.

OBJECTIVE: Open-label trials with the selective serotonin reuptake inhibitor citalopram suggest that this agent is effective and safe for the treatment of depressive symptoms in children and adolescents. The current study investigated the efficacy and safety of citalopram compared with placebo in the treatment of pediatric patients with major depression.
METHOD: An 8-week, randomized, double-blind, placebo-controlled study compared the safety and efficacy of citalopram with placebo in the treatment of children [ages 7-11] and adolescents [ages 12-17] with major depressive disorder. Diagnosis was established with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Patients [N=174] were treated initially with placebo or 20 mg/day of citalopram, with an option to increase the dose to 40 mg/day at week 4 if clinically indicated. The primary outcome measure was score on the Children’s Depression Rating Scale-Revised; the response criterion was defined as a score of < 28.
RESULTS: The overall mean citalopram dose was approximately 24 mg/day. Mean Children’s Depression Rating Scale-Revised scores decreased significantly more from baseline in the citalopram treatment group than in the placebo treatment group, beginning at week 1 and continuing at every observation point to the end of the study [effect size=2.9]. The difference in response rate at week 8 between placebo [24%] and citalopram [36%] also was statistically significant. Citalopram treatment was well tolerated. Rates of discontinuation due to adverse events were comparable in the placebo and citalopram groups [5.9% versus 5.6%, respectively]. Rhinitis, nausea, and abdominal pain were the only adverse events to occur with a frequency exceeding 10% in either treatment group.
CONCLUSIONS: In this population of children and adolescents, treatment with citalopram reduced depressive symptoms to a significantly greater extent than placebo treatment and was well tolerated.

Well, they give us the mean CDRS-R scores at the baseline and the standard deviations…
… Mean Children’s Depression Rating Scale Revised scores at baseline were 58.8 [SD=10.9] and 57.8 [SD=11.1] in the citalopram and placebo groups, respectively, indicative of moderately severe illness.
And they show us that there’s about a 5 point difference at week 8 on the graph, but they didn’t give us either the Means or the Standard Deviations at week 8 anywhere that I could find. Since the Formula is Effect Size = [Difference in the Means] ÷ [Standard Deviation], we could work backwards as in 2.9 = 5 ÷ [Standard Deviation] which comes out with a Standard Deviation = 1.72. Given they started with a Standard Deviation = ~11, 1.72 has to be wrong. As I scratched my head in confusion and pondered, I noticed these references below the abstract on PubMed:
These were comments on the article in the AJP. I wasn’t the first to wonder about that effect size. Commenter Andres Martin had named it the big bang [a bit of AJP humor]. In their response to comments, Wagner et al said:
Dr. Martin and colleagues inquire about the value of 2.9, which was calculated as the quotient of the least square mean, divided by the common standard error of the mean for each treatment group. With Cohen’s method, the effect size was 0.32.
I have no clue where that first part came from, but the effect size=0.32 is more like it – in the weak-to-moderate range. But then there were those other numbers:
… Citalopram treatment showed statistically significant improvement compared with placebo on the Children’s Depression Rating Scale — Revised as early as week 1 [F=6.58, df=l,150, p<0.05], which persisted throughout the study. At week 8, the effect size on the primary outcome measure, Children’s Depression Rating Scale-Revised [last observation carried forward], was 2.9. Additionally, at endpoint more citalopram-treated patients [36%] met the prospectively defined criterion for response than did placebo-treated patients [24%], a difference that was statistically significant [x²=4.178, df=l, p<0.05]. The proportion of patients with a CGI improvement rating <2 at week 8 was 47% for the citalopram group and 45% for the placebo group [last observation carried forward values]. For the CGI severity rating, baseline values were 4.4 for the citalopram group and 4.3 for the placebo group, and endpoint values [last observation carried forward] were 3.1 for the citalopram group and 3.3 for the placebo group.
They report 36% responders to Citalopram as opposed to 24% to Placebo. The NNT [Number needed to Treat] would be 1 ÷ [0.36 - 0.24] or NNT = 8.3. In prose, that translates to, "You have to treat 8 people with Citalopram before you get one that does better than they would’ve done on a Placebo" – which is lousy. And for the chi square, I got [x²=2.852, df=l, p=0.0912] with the Yates correction and [x²=3.439, df=l, p<0.0637] uncorrected. But there was also the CGI [Clinical Global Impressions] result which is the observation of improvement: Placebo 45%, Citalopram 47%. And the severity: Placebo 4.3, Citalopram 4.4 before, and Placebo 3.3, Citalopram 3.1 at 8 weeks. That’s no difference at all. So the subjects showed no overall observed improvement with Citalopram. My Conclusion: A weak at best and clinically insignificant signal. In their response to criticisms, Wagner et al said:
We believe that the results of our study, which demonstrated a significant difference between citalopram and placebo beginning at week 1, is clinically meaningful, particularly at a time when there have been so few antidepressants shown to have superiority to placebo for depressed children.

That final comment is pretty bizarre, given that by the time it was written, Dr. Wagner herself had authored three previous articles claiming the effectiveness of SSRIs in youth [collusion with fiction…].

I finally located this study [CIT-MD-18] under Lexapro in Drugs@FDA. The answer to Psycritic’s original point is pretty complicated. They allowed this study [Wagner et al] to count in the Lexapro application for the pediatric MDD Approval because it is a racemic mixture. Wagner et al and one Lexapro trial were used for approval in adolescents, but it was only Lexapro that was approved. The NDA found the CDRS-R difference significant [p=0.038] but not the CGI [no mention of 'responders']. The bottom line is that this [shaky] clinical trial was essential to the pediatric approval.

How was that for a wild goose chase? Actually, I kind of enjoyed it. I had originally just looked at the graph in Wagner et all and assumed it was a positive study. Coming back to it after seeing that [effect size=2.9] value and realizing how shaky it really was was a good reminder that with these clinical trials, "all that glitters is not gold." It was only a positive study by the letter of the law, not by direct observation [CGI].

This actually mirrors my own experience. When I first started volunteering after retirement, I worked in a Child and Adolescent clinic for a while. I tried SSRIs in a few depressed adolescents [actually Celexa®] without any luck. Then I had a case of Akathisia [unknown to me at the time], and that was the end of that little experiment. Actually, it was that case that got me looking at the psychopharmacology literature and ultimately lead to this blog. I looked at it initially to "catch up," but ended up "catching on." I did use SSRIs in a few adolescents with OCD-like symptoms [compulsive "cutting"] with notable success – though after the Akathisia case, I saw them frequently [and worried]. I actually stopped working in that clinic because I was being pressured to prescribe more. In those several years, I never saw a depressed adolescent who was just "depressed." They were all cases with complex family and interpersonal issues – way more psycho·social than bio·
Mickey @ 10:28 AM
Filed under: OPINION
collusion with fiction…

Posted on Thursday 16 October 2014

After the last post [a betrayal…], Psycritic commented that Celexa® had also been approved for adolescent depression by the FDA [I had said "Only Prozac®"]. I had a vague memory that something had happened, but was confused, so I took a look in Drugs @ FDA and got more confused. Then I tried Google and found a 2011 Canadian review of Celexa/Lexapro in adolescents that was illuminating. The part that got my attention was towards the end:
by Carlo Carandang, Rekha Jabbal, Angela MacBride, and Dean Elbe
Journal of the Canadian Academy of Child and Adolescent Psychiatry. 2011 20[4]: 315–324.

FDA Approval Process & Legal Action
While only one RCT for escitalopram was statistically superior to placebo on the primary outcome measure, according to Forest Laboratories, Inc. [US manufacturer of Lexapro] the FDA decision to approve escitalopram was based on two RCTs – the escitalopram RCT with positive results and an earlier trial with citalopram. “Escitalopram is the only active enantiomer of the racemic drug citalopram, so we considered it reasonable to [deem] the positive citalopram study along with the positive escitalopram study as sufficient evidence to support the approval,” said Karen Mahoney, an FDA spokesperson. A 2002 application for a pediatric indication for citalopram had previously been rejected by the FDA, and the US patent for citalopram expired in 2003.

The FDA approval decision for escitalopram came shortly after filing of a federal civil suit alleging Forest Laboratories, Inc. had illegally marketed escitalopram and citalopram for off-label use in children and adolescents from 1998 to 2005. The suit also alleged the company suppressed publication of a negative citalopram trial, and reports of increased suicidality in pediatric patients. This lawsuit was joined with another lawsuit regarding another Forest Laboratories, Inc. product levothyroxine, and was eventually settled in September 2010 for the sum of $149 million.

The citalopram trial [Wagner et al., 2004] that formed part of the basis for escitalopram FDA approval was alleged to have been written and submitted by a medical “ghost-writer” on behalf of Forest Laboratories, Inc. In April 2009, one month after the FDA approval for escitalopram in adolescents was granted, Forest Laboratories, Inc. admitted that a medical communications company, Prescott Medical Communications Group was not acknowledged as a contributor to the article at the time of publication. This practice is not allowed by the American Journal of Psychiatry, and an editor’s note regarding correction of this matter was published in August 2009…

At this point, I will admit that I had lost interest in my initial quest [FDA Approval of Celexa/Lexapro] because I’d run across something that was far more interesting. So let’s start over. The new topic is the 2009 Editor’s Note in the American Journal of Psychiatry about their earlier 2004 article on Celexa:

Editors’ Note

The article "A Randomized, Placebo-Controlled Trial of Cilalopram for the Treatment of Major Depression in Children and Adolescents," published in the June 2004 issue of The American Journal of Psychiatry [vol. 161, pp 1079-1083] is alleged by the United States Department of Justice in an ongoing suit to have been written and submitted to the Journal by a commercial medical writer on behalf of Forest Laboratories, Inc.

We requested responses from Drs. Karen Dineen Wagner, Adelaide S. Robb, and Robert L Findling [authors in their role as investigators in the clinical trial at their respective universities], Dr. William E. Heydom [the senior Forest laboratories study director], and Forest laboratories. Drs. Wagner, Robb, and Findling reported that they had received an initial draft from Dr. Heydom to which they contributed through several drafts, This paper was submitted as a Brief Report, which the Journal’s editors requested be resubmitted as a full-length Article. Drs. Wagner, Robb, and Findling report that they contributed with Dr. Heydorn to the resubmission and that they were not aware that Dr. Heydorn was working with a commercial writer. Dr. Heydorn did not respond to our request for comment.

A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. Hie manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

We are satisfied that the named contributors of this article satisfy the criteria for authorship as set forth in the "Uniform Requirements for Manuscripts Submitted to Biomedical Journals" from the International Committee of Medical Journal Editors. However, the Journal’s Instructions to the Authors in 2004 and our policy today do not allow contributions by unnamed writers to the preparation of a paper. Thus, the editorial contributions of Prescott Medical Communications Croup should have been acknowledged in the published article as required at the time the article was published.

Furthermore, Forest Laboratories failed to disclose to the Journal that it was aware of data from a study by Lundbeck that showed increased suicidality in children and adolescents who were treated with citalopram. Authors and sponsors are expected to disclose the existence of all data that affects the interpretation of their study. This note will appear in Medline and other databases as a Comment on the paper.

The official complaint [United States and Christopher R. Gobble v. Forest Laboratories Inc. and Forest Pharmaceuticals Inc. Civil Action No. 03-10395-NMG] is posted at …

Robert Freedman, M.D.

Michael D. Roy
Editorial Director
American Journal of Psychiatry. 2009 166[8]:942-943.

I’d never seen this before. It’s like a picture window into how much competition there was for the adolescent depression market, and how corrupt the whole enterprise had become. While we can respect Editor Robert Freedman for publishing this Editor’s Note, his certification of authorship is, of course, a sham – as is Dr. Wagner’s claim that she knew nothing of the ghost authoring. In the first place, the paper was presented to her already drafted. Whether it was written by Forest senior study director Dr. William Heydorn or someone else, it certainly wasn’t Wagner’s or her co-investigator’s work. And since she was in the author role in multiple other ghost-written trial reports at that time, her claim of naïveté about hired professional writers holds no water. She was everywhere in those days – Paxil, Prozac, Zoloft, Celexa – an author on each of these of ghost-written journal articles – all four claiming efficacy and safety in depressed adolescents for their respective drug:

Paradoxically, Karen Wagner and some of her co-authors in these studies were later on the ACNP [American College of Neuropsychopharmacology] Task Force convened to report on these questions after the Black Box Warning was added by the FDA in 2004:
And this kind of hyperbole was standard fare whenever ghost-writing was exposed:
    A Forest laboratory official in a letter of April 17, 2009, acknowledged that: "Forest retained a medical communications company to assist with preparation of the manuscript, a practice we understand to be common among pharmaceutical companies. Following discussion with the article’s named authors, the medical communications company created an initial draft of the manuscript. Over the course of time, however, from the initial draft to the final publication, the manuscript went through multiple iterations with the input of the named authors, as well as others who reviewed and commented on the manuscript; throughout this process, the medical communications company continued to provide copy editing, formatting, referencing and other editorial support. The manuscript was then submitted to AJP by Dr. Wagner, who, along with the other named authors, maintained control over the final content of the manuscript."

It’s time to stop arguing with such nonsense as if it might be credible. By now, we all know what happened in these trials. The contract CRO organized and ran the trials. The sponsoring/funding pharmaceutical company analyzed and manipulated the data, then turned it over to the contract medical writers. The named authors may or may not have done some editing along the way after it was written, but their main function was to provide the academic credentials needed for a ticket into the peer-reviewed medical journals or a poster at a meeting. These heavily worked-over studies regularly amplified efficacy while downplaying adverse events. When the FDA finally added the black box warning, it put a glitch in their profit projections, so the involved industries set about publicly debunking the FDA warnings in their now decade-long campaign [as described in a betrayal…].

As for the specific suit that brought this particular bit of ghost-writing into the public eye? The case against Forest Laboratories ultimately settled [see September 15, 2010: Drug Maker Forest Pleads Guilty: Will Pay More Than $313 Million to Resolve Criminal Charges and False Claims Act Allegations]. But even in this instance where the ghost-writing was exposed and admitted, the American Journal of Psychiatry, official journal of the American Psychiatric Association, chose to collude with the fiction that the academics on the by-line were genuine authors, and the journal left the study in place.

The American Psychiatric Association seems to be poised to engineer yet another identity shift in psychiatry [the prequel…, anything but over…, the sequel I…], apparently intending to proceed without acknowledging the misadventures of the last makeover, without participating in the reform efforts like Data Transparency or revised Conflict of Interest policies, without correcting or at least flagging the large fiction sections of our journal libraries. The American Academy of Child and Adolescent Psychiatry meeting in San Diego next week appears to be moving along the same silent path. Beside the obvious moral and ethical tangles involved, it seems to me that there’s an enduring liability being assumed by the professional organizations, the academic community, and our peer reviewed journals when they incorporate this attitude of denial and rationalization. The active participants in the deceit and corruption that accompanied the industrial invasion of academic and organized psychiatry actually represented only a segment of psychiatrists, albeit a segment in high places. Many of their names are already on this page, most are cataloged throughout this blog. And while too many in the specialty followed their lead, it was also the only major highway open to traffic, and it’s easy to forget how little many of us knew of this before the last six or seven years. That’s not intended as an excuse, but rather a commentary on the state of play.

If our professional organizations, our academic departments, and our peer reviewed journals continue to leave this big piece of history and its published record unexamined and uncorrected, the specialty of psychiatry incorporates it as its own rather than seeing it as the foreign body it deserves to be. And any of our current leaders who participate in this strained policy of rationalization and denial might just as well have been among the ranks of the worst of the KOLs, the guest authors, or on the advisory boards and the speaker’s bureau payroll – complicit in creating and perpetuating a fiction in a space reserved for scientific and therapeutic intention…
Mickey @ 1:00 PM
Filed under: OPINION
a betrayal…

Posted on Wednesday 15 October 2014

New York Times
by Robert Gibbons and J. John Mann
October 7, 2014

The changes in treatment and attitude brought on by Prozac prompted two colliding points of view. One was that antidepressants were overprescribed and people were encouraged to turn to a pill to solve all their problems. Another viewpoint was that major depression was one of the most debilitating illnesses in the world and was mostly untreated or undertreated, and even though we were now prescribing a lot of antidepressants there were still too many people with moderate to severe depression that remained untreated.

A third claim intruded into this debate, namely that the efficacy of antidepressant medications is overstated and the best evidence of effectiveness was in only the most severely ill patients. In an effort to shed light on this question, we obtained much of the world’s complete longitudinal data on randomized controlled trials of the antidepressants fluoxetine [Prozac] and venlafaxine [Effexor] in depressed patients conducted by Lilly, Wyeth and the National Institute of Mental Health. We included studies regardless of whether they demonstrated the medications were effective in order to get the clearest picture possible of the efficacy of these widely used antidepressants.

From the statistical model that synthesized these data across all studies separately for each age category, we computed estimated response and remission rates. We found an improvement in depression regardless of age in both medications relative to a placebo pill. Interestingly, the greatest benefit in terms of response and remission rates was seen in children, followed by adults, and then by more modest effects in the elderly. There was no evidence that severity of depression made a difference to how well the antidepressant medication worked. Based on these findings we concluded that antidepressants work across the lifespan, in patients with moderate or severe depression.
In a recent blog post, I reviewed Dr. Gibbons’ most recent paper, yet another assault on the Black Box Warning, this time using commercial databases [gibbons everlasting...] and cataloged his many previous attempts to cast doubt on the 2004 FDA Black Box Warning. He has made similar attempts to debunk the warnings on Neurontin® and Chantix® [very monotonous…].. This recent NYT comment is based on his 2012 articles with the same intent. I had offered a strong criticism at the time of those 2012 articles [an anatomy of a deceit 1… etc.], as did many others. But in gibbons everlasting…, I left out something important, something mentioned by Dr. Bernard Carroll both in his comment here and to the New York Times. So I thought I’d just run it around again:
by Gibbons RD, Coca Perraillon M, Hur K, Conti RM, Valuck RJ, and Brent DA
Pharmacoepidemiologic Drug Safety. 2014 Sep 29. doi: 10.1002/pds.3713. [Epub ahead of print]

PURPOSE: In the 2004, FDA placed a black box warning on antidepressants for risk of suicidal thoughts and behavior in children and adolescents. The purpose of this paper is to examine the risk of suicide attempt and self-inflicted injury in depressed children ages 5-17 treated with antidepressants in two large observational datasets taking account time-varying confounding.
METHODS: We analyzed two large US medical claims databases (MarketScan and LifeLink) containing 221,028 youth (ages 5-17) with new episodes of depression, with and without antidepressant treatment during the period of 2004-2009. Subjects were followed for up to 180 days. Marginal structural models were used to adjust for time-dependent confounding.
RESULTS: For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses. Marginal structural models revealed that the majority of the association is produced by dynamic confounding in the treatment selection process; estimated odds ratios were close to 1.0 consistent with the unadjusted and simple covariate adjusted association being a product of chance alone.
CONCLUSIONS: Our analysis suggests antidepressant treatment selection is a product of both static and dynamic patient characteristics. Lack of adjustment for treatment selection based on dynamic patient characteristics can lead to the appearance of an association between antidepressant treatment and suicide attempts and self-inflicted injury among youths in unadjusted and simple covariate adjusted analyses. Marginal structural models can be used to adjust for static and dynamic treatment selection processes such as that likely encountered in observational studies of associations between antidepressant treatment selection, suicide and related behaviors in youth.
In gibbons everlasting… I listed Dr. Gibbons previous articles on this topic since the Black Box Warning was issued by the FDA in 2004. While the FDA meta-analysis supported the case that suicidality is an uncommon but dangerous side effect of the use of SSRIs in adolescents, it was the case reports heard by the panel that lead them to append the warning. Dr. Gibbons statistical analyses have chased disproving the warning all over the map – from multi-country comparisons, the CDC statistics, proprietary databases, VAH statistics, drug company clinical trials, etc. always chasing the same hypothesis, the same one recently espoused by Lu et al [all databases are not created equal…]:
    The Hypothesis [my version]:
    The Black Box Warning is wrong. It scared doctors who prescribe fewer antidepressants to adolescents, depriving them of needed treatment, thereby increasing the incidence of suicidality.
In his previous outings, over the last decade, Gibbons has stuck to attempts at using population meta-analyses to show that antidepressants don’t increase the incidence of suicidality. His articles are difficult because they can’t be vetted [not enough information] and they involve complicated statistical analyses that he describes, but does not show. They are invariable followed by media reports, The ones mentioned in the NYT above were followed by a media blitz [the campaign…]. Invariably he finds no evidence of suicidality in adolescence on SSRIs. There are several points to make about these papers:
  1. There is no strong evidence that SSRIs are even effective in adolescent depression. Only Prozac was approved, and that was early on before these questions were raised. So the notion that effective treatment is being withheld is unsubstantiatable.
  2. This syndrome is not common, but once you see it, you have no question of causality [at least I didn't]. It’s not a population study thing, it’s a case report thing. And there are plenty of cases of completed suicides among those reports. I don’t even treat adolescents, but I personally know of several such cases. The cases are substantiatable.
Now to the most recent paper and Dr. Carroll’s point. After a decade of trying to prove it doesn’t happen, in this new study, it seems that it does happen after all:
    "For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses."
And then Dr. Gibbons undoes it with some kind of factor analysis that is opaquely described and unintelligible to any physician no matter how statistically sophisticated. Carroll calls it "voodoo statistical hand waving," but even that is forgiving because Gibbons’ presentation is effete and insulting to the reader. So the question really comes down to Why do these recurrent articles against the Black Box Warning keep coming? with each study more questionable and convoluted than the last. They are presented as being in the service of child advocacy – hardly likely. One hint about their persistence is in looking at the authorship:
by Nemeroff CB, Kalali A, Keller MB, Charney DS, Lenderts SE, Cascade EF, Stephenson H, and Schatzberg AF.
Archives of General Psychiatry. 2007 64[4]:466-72.
Three authors on Senator Grassley’s list, chairmen who lost their chairs in the following years; four customers of Sally Laden, notorious ghost-writer; and the medical director and emplyees of Quintiles, a major CRO. Then:
News coverage of FDA warnings on pediatric antidepressant use and suicidality
by Barry CL and Busch SH.
Pediatrics. 2010 125[1]:88-95.
These studies were financed by the National Bureau of Economic Research, a think tank founded by a member of the Eli Lilly Board at the time [see pretty loud coi…, the NBER study, and tortured numbers…]. Then there are the numerous studies of Dr. Gibbons who has testified for Pfizer in the cases involving SSRIs, Chantix, and Neurontin. Throw in the recent study by Lu et al [see all databases are not created equal…], employed by Harvard’s Managed Care conglomerate. There are others, but nowhere among them are the expected child psychiatrists or psychologists. This is pretty much an industry effort all the way through.

This is a strange story about an unlikely collection of people diligently pursuing the debunking of a clear, if uncommon, adverse effect of a class of medications when given to youth – a potentially fatal complication. It proposes to be advocacy for teens being denied effective treatment, yet even the evidence for its effectiveness is decidedly underwhelming. The people producing these studies are not from the community of people actively involved in treating the populations studied, and the evidence they present is at some distance removed from the actual patients [claims databases, population statistics, etc.], invariably connected with some industry [PHARMA, Managed Care, etc.], and generally accompanied by some kind of prominent media coverage like the NYT piece I started with above. The important question is Why? Why do they keep at it? Of course we can’t truly know their motives, but it’s a pretty good guess that it’s not what the articles say. And though unprovable, we can easily hypothesize for ourselves what drives this campaign. Almost anyone reading this could come up with a set of motives, but I want to say a few of them out loud:
  • PHARMA: Depressed adolescents are common – a lucrative market for the sale of antidepressants.
  • PHARMA: The suicidality Adverse Event was downplayed in the original reports – a litigation liability.
  • Managed Care: The cost of delivering care other than drugs to depressed teens would be expensive.
  • Psychiatry: The KOL psychiatrists have based their reason d’etre on the effectiveness of the SSRI drugs, talking about ‘depression’ as if it’s a ‘disease entity’ and the SSRIs as the ‘treatment’ for that ‘disease entity’. They essentially define psychiatry by this disease/treatment dyad. 
In my mind, this is an affront to the biological psychiatrists who have given us effective treatments for the subset of depressed people who have the depressions that fit the disease model – eg Manic Depressive Illness, Melancholia. It is an affront to the psychotherapists from a variety of disciplines who work with adolescents who present with depression. It is an affront to psychiatrists who don’t subscribe to the neoKraepelinian dictum that all mental illness is biological. And it is an affront to the scientists who adhere to the scientific method and use its tools carefully – hypervigilant to the introduction of bias, including their own. But first and foremost, it is a betrayal of the trust of the depressed adolescents, their parents, and the practitioners who treat them…
Mickey @ 2:00 PM
Filed under: OPINION
«evidence-based medicine» some evidence

Posted on Tuesday 14 October 2014

In my medical lifetime, I’ve watched medicine turned into a business enterprise. I was fortunate to be able to hide in the cracks and mostly evade that myself – haunting places like training programs, academia, military service, a solo practice off the grid, a charity clinic. It’s not that I’m averse to systems. I’m just specifically wary of systems for-profit being involved with anything that purports to give care. And I’m wary of systems not-for-profit that are funded as start-ups that are slated to later carry the ball on their own. The best medical system I ever worked in was an overseas military hospital. The worst was everything else. These are all acquired feelings at the end of a career, not something I started with.

The top graph tells the story. The relative cost of medical care in the United States has doubled [since the days I first heard of Managed Care around the late 1970s]. And the reasons are obvious everywhere you turn. Fee churning Emergency Rooms in for-profit Hospital Corporation owned facilities; Direct-to-Consumer ads increasing drug sales six-fold; inflated guidelines fueling unnecessary testing and treatment; controlling Managed Care monitors demanding evidence of efficacy but giving no evidence of their own [efficacy]; abusive pharmaceutical advertising and pricing; the constant whirr of the MRI machines in the background pouring out normal studies. The sick and those of us who treat them are a captive audience with no clear alternatives in sight. We’ve been an easy mark for decades. And it’s as if there’s an inertia from a more benevolent time, memories of a different ethic – something that keeps us naive about the impact that the business·i·fi·ca·tion of medicine has had on our lives and our healthcare. And speaking of evidence, the bottom graph is one of the many that make the same indictment – it hasn’t been worth it.

It’s funny, the cynicism in that last two paragraphs is evanescent. I can get to feeling it in spades, work myself up into a righteous froth – and then watch it evaporate within minutes. It happened today. I hadn’t worked in a couple of weeks – weddings, funerals, other things – but when I went to the clinic today, the cynical gloom lifted and I had fun. Maybe that’s not the right word. I got into the problems that came my way and did what I’ve learned to do. Some might say I wrote too many prescriptions. Others might say I didn’t write near enough. Some would say I didn’t need all those years of training to do what I actually spent my time doing today. Since I don’t get paid, it would be hard to say I didn’t earn my keep. My point is that I felt none of that uncomfortable cynicism I can feel at other times. The Licensed Professional Counselor I worked with and I saw several cases together we pass back and forth in our version of Collaborative Care, the same with the Internist and the Nurse Practitioner.

After work, I came home and saw those graphs up there on my desktop, prepared before I left town for the weekend. They seemed far away from the morning’s activities. It took a bit to recall why I’d hunted them down. I’ll get back to that I’m sure. But right now, I think I’ll just let the good feeling linger…
Mickey @ 8:44 PM
Filed under: OPINION
a thing to share…

Posted on Monday 13 October 2014

from ChopstiX restaurant
Raleigh NC
Mickey @ 7:09 PM
Filed under: OPINION
the sequel I…

Posted on Sunday 12 October 2014

The order of things:
  1. the prequel…
  2. unanswered questions…
  3. the sequels
Whether you think the introduction of the DSM-III in 1980 was a necessary specialty-saving intervention, a hostile take-over, a revolution, a bloodless coup d’état, right or wrong, isn’t what this post is about. It’s about the long term ramifications of a professional organization itself orchestrating a major change in the direction of a profession. Here’s what the architect of that change had to say about how that came to be:
    "How could a professional organization engineer a scientific revolution that changed its core? According to conventional wisdom, organizations respond; they do not initiate. By the 1970s psychiatry in the United States had begun to undergo massive changes. The postwar glow had been replaced by the new pressures for accountability on all of medicine. Many leaders in psychiatry deplored the ideological rifts that had divided the field, and they called for a more unified, scientifically based profession. They deplored the "demedicalization" of psychiatry and its severe loss of credibility. I was one of the young leaders who had criticized the ideological divisions within psychiatry and had been searching for ways to improve the scientific status throughout my career. The field’s ideological schisms had weakened us seriously, and psychiatrist’s bitter public disagreements were self-destructive. To cover up these differences or to act solely because of the criticism was not in and of itself sufficient; psychiatry had to adopt a genuine commitment to science rather than to ideology. It needed to change the profession fundamentally if it was to become a respected part of medicine. To accede to the pressure without radical modifications of the field would not have convinced others that the profession had changed. A new strategy was essential! Producing the DSM-III stated emmphatically that psychiatry in America chose an evidence-based practice rather than ideology."
    Dr. Mel Sabshin in Changing American Psychiatry: A Personal Perspective
As one who was much younger in the profession at the time, but not in-the-know, I was oblivious to all of that. So what happened over the next several years was dramatic and unexpected, at least to me [irony I…, irony II…, irony III… ]. Independent of the reasons, the correctness, or the content of what happened in those days, the changes resulted in a consolidation of power within the APA [American Psychiatric Association] that persists to the present – a "top down" power structure as described by Dr. Sabshin.

The turn of the century saw a very different psychiatry from the days that produced the DSM-III. Most practicing psychiatrists were doing medication management using a host of new drugs that had poured from the pharmaceutical industry pipeline. The journals were filled with clinical drug trials and biological research articles. What started in the DSM-III as an open question…
    For most of the DSM-III disorders, however, the etiology is unknown. A variety of theories have been advanced, buttressed by evidence – not always convincing – to explain how these disorders came about. The approach taken in DSM-III is atheoretical with regard to etiology or pathophysiological process except for those disorders for which this is well established and therefore included in the definition of the disorder. Undoubtedly, with time, some of the disorders of unknown etiology will be found to have specific biological etiologies, others to have specific psychological causes, and still others to result mainly from a particular interplay of psychological, social, and biological factors.
    DSM-III Introduction – page 7.
… wasn’t so open any more, at least in mainstream psychiatry, and the research thrusts were to solidify the dominant view of biological causality and treatment. An example of the continued centralization of power within the APA was the commissioning of a Task Force at the turn of the century to produce a DSM-5 that was directly keyed to the hypothesized biological substrate of the various disorders.

As mentioned in the prequel…, the 2014 landscape in psychiatry is very different from the year 1980 or even the year 2000. Exposures of scientific and commercial misconduct swept through academic psychiatry and the pharmaceutical industry; the psychopharmacology pipeline ran dry; PHARMA took "a runner" from CNS drug development altogether taking its liberal support of academic institutions and the APA with it; the DSM-5 Revision floundered in something of a public spectacle; and there was a growing backlash against the monocular biomedical directions in psychiatry in general and the efficacy and safety of the widely used medications in specific. Most psychotherapy had been handed off to other disciplines in the 1980s. These days, most medication is being prescribed by Primary Care Physicians. Most Psychiatric hospitals are closed. Many chronically mentally ill patients are in jail, prisons, or shelters. And the ACA [Affordable Care Act] looks to turn the third party system further upside down. After a frantic year or so trying to woo PHARMA back without success, the place and fate of psychiatry are again in question – endangered species? obsolete? severe shortages? train more? train less? train none? are the kind of phrases being thrown around [or hurled].

Most practicing psychiatrists have grown up in the post-1980 era – by which I mean that within the body of the APA, there’s little apparent turmoil or faction. If there’s much of a call for change or reform coming from inside the ranks, I don’t know about it. Incidentally, there are many psychiatrists who are off the grid for a multiplicity of reasons, suggesting that there’s not much room for discord, controversy, or dialog within the APA. And so to the subject: the APA’s continued assumption that it is tasked with defining, rather than representing, the body psychiatric – persistent since the the days of Sabshin and Spitzer.

In unanswered questions…, I was mentioning several articles in the PsyciatricNews where Presidents of the APA are talking about the future of psychiatry being in Integrative Care, Collaborative Care, and Population Health. I added another in which the APA is offering a course on Recovery [with a capital R] meaning Recovery as it is formulated by SAMHSA [Substance Abuse Mental Health Services Agency] or as you might read about it on many websites opposed to the current medication-heavy brief-contact psychiatric practices. That is a huge topic that I’m not going to talk about substantively in this post, not because I don’t have something to say or don’t want to say it, but for the opposite reason. It’s too big for a simple blog post [and there are too many distracting rants along the way]. Right now I want to talk about just one simple thing. There is a growing trend in what’s coming from the upper levels of the APA that the redirection of psychiatry and the redefinition of psychiatrists is what the organization is setting out to do – what it’s supposed to be doing.

That’s a bad habit that needs a great deal of reflection, because that’s what the APA did in 1980 – created a psychiatry that fit the prevailing vision of what physicians should do in the face of Managed Care’s insistence – see sick people, make a diagnosis, give them the treatment for their sickness, then send them on their way. So the APA created a dictionary to catalog those diseases in concrete terms, and industry went about coming up with a compendium of treatments keyed to the catalog. There are some mental diseases that can be classified in that way, and some treatments that can be used in that way. But being the only model in town, it inappropriately generalized to be the model for all comers. Then the medication makers jumped on board, engaged with psychiatry, and made an ill-gained fortune. We now live in a world where the system that the APA actively created, encouraged, and maintained is currently a very big problem – and psychiatrists are villified for going along with it.

Dr. Sabshin’s retrospective above makes it clear he knew that leveraging the DSM-III Revision to change to direction of psychiatric practice was highly unusual…
    "According to conventional wisdom, organizations respond; they do not initiate."
My point is that the resulting consolidation of power persisted to the present along with the role of the APA in a defining psychiatry. And as to the goal of reducing discord …
    "The field’s ideological schisms had weakened us seriously, and psychiatrist’s bitter public disagreements were self-destructive."
… it was achieved in spades. Many psychiatrists converted and others just left – having no place at the table. Third Party payment schedules moved psychiatrists into the medication management slot while psychotherapies and counseling went to panels of other mental health specialties, tightly controlled by Managed Care. There has been little controversy or debate among the membership of the APA since those days. Even in these later years of scandal over conflicts of interest, ghost writing, jury-rigged clinical trial publications, false advertising, speaker’s bureaus, distorted reporting of efficacy and adverse events, etc., the outcry and movements for reform have come from outside the APA, mostly outside psychiatry. And as the chronic mental patients filled up our prisons in the years after de-Institutionalization, the APA has had little to say. We could’ve used a lot more discord along the way.

The APA’s assumption of power may well have been justified in the 1970s, but holding onto it wasn’t. The APA was heavily supported by the Pharmaceutical Industry, and supportive in kind. When the ethical misbehavior, the conflicted commercial connectedness, and the invasions of our literature became crystal clear to the whole world, the APA was silent or defensive. Ironically, the revolution launched with the cry against ideology…
    "Producing the DSM-III stated emphatically that psychiatry in America chose an evidence-based practice rather than ideology."
… has created a professional organization that is a bastion for a particular notion of overall causality and treatment that has all the earmarks of a fixed ideology, and in spite of a massive research effort, an ideology that operates with little in the way of a strong confirming evidence base except in limited areas.

And now the APA is making noises about another major redefinition as we move into the future, and appears to be pitching it to its membership. While there’s much to be said about what’s being pitched [next post], there’s a question that comes before that. Should the APA even be on the pitching mound at this point. The suggested changes aren’t coming from the floor of the membership. They’re not coming from some subgroup of psychiatrists intensely studying a problem, nor a subgroup of practitioners who have long-occupied the suggested roles, nor the halls of physical medicine, nor being introduced as a topic for general debate within psychiatry itself. My premise is obvious, that the centrality of the APA upper echelon in defining psychiatry has been maintained and used to keep psychiatry on a path controlled by industrial and ideological forces – a legacy from Sabshin, Spitzer, and 1980s DSM-III – whether that was their intent or not and it’s being exerted once again.

Now, the APA is pushing a major change in the directions of the profession in the face of the exhaustion of the current paradigm that will have not only an effect on practice and third party reimbursement, it does nothing to deal with the plight of the chronic patients now incarcerated; it does nothing to curb overuse of psychiatric medications particularly by primary care; it moves clinical psychiatry to a non-patient-contact role; it’s based on a theoretical role originating from outside the specialty; and it looks as if it will perpetuate the very things in need of change. These are goals that have been pushed by Managed Care and PHARMA, hardly by psychiatrists or even its opponents – more like retiring the side than reform. And it’s coming from the APA – the only negotiating force in town. Is this to be the legacy from the 1980 revolution? Is the APA representing psychiatry, our patients, or simply itself and some inappropriate assumptions of power and misguided decisions all along the way? Will practicing psychiatrists continue to leave their fate in the hands of an organization that unilaterally lead us down this path?

Undoubtedly, changes need to be made once again. But these changes? as being presented? dictated by the APA? It sounds like the decision of a group that has painted itself into a corner and further abandoned the practice of clinical psychiatry, taking charge at a time it needs to be taking stock, and operating on an anachronistic centralization of power whose utility has long passed…
Mickey @ 9:00 AM
Filed under: OPINION
anything but over…

Posted on Thursday 9 October 2014

Tom Jefferson is a researcher/reviewer with the Cochrane Collaboration. He was involved throughout in the Tamiflu story and the Cochrane meta-analysis of the Tamiflu Trials. He’s as good a resource as we might find for understanding what the EMA’s recent policy decision really says:
British Medical Journal blog
by Tom Jefferson
7 Oct, 14

The European Medicines Agency [EMA] has now released the final version of its policy on the prospective release of clinical reports of trials, which are submitted by sponsors to support marketing authorisation applications [MAAs]. The agency has said that it will—at a future date—determine how to release individual participant data [IPD].

The policy—to become effective from 1 January 2015—explains what will be released and how. Full clinical study reports will not be released. Rather, selected parts of clinical study reports will be released, including the “core report” [although this is not labelled as such in the text], the statistical analysis plan, protocol and its amendments, and a blank case report form. [To those familiar with clinical study reports, these are sections 1-15, 16.1.1, 16.1.2, and 16.1.9 of the ICH E3 guidelines.] The policy document does not explain why full clinical study reports will not be released.
This «core report» for the CSR [Clinical Study Report] is what I was worried about [beyond the blind…]. And it for sure won’t have the IPD [Individual Participant Data]. Having the «statistical analysis plan, protocol and its amendments» is a good thing. But does it pass the Rolling Stones test?
    You can’t always get what you want
    But if you try sometimes
    Well you just might find
    You get what you need
Ask me in February 2015…
The EMA’s policy states: “The Agency respects and will not divulge CCI [commercially confidential information]. In general, however, clinical data cannot be considered CCI.”  That said, commercially confidential information will be redacted, “where disclosure may undermine the legitimate economic interest of the applicant/market authorization holder” and in items that may facilitate identification of trial participants. Sponsors will have primary responsibility for redacting study reports for EMA’s approval prior to their being made accessible under the new policy.
This is the part that got to AllTrials:
    The policy puts primary responsibility for redacting information into the hands of trial sponsors. This means that they get to suggest which information submitted to the EMA should be kept hidden. The EMA has a policy that the information in clinical trial reports should not generally be considered commercially confidential [this is echoed in the EU Clinical Trials Regulation] but it may never become clear which information is being kept hidden.
As it should…

The policy is a landmark, as for the first time it ensures access to clinical study reports of drugs that have obtained a MAA or on which a decision has been made. The EMA may be the first regulator to allow such access and the Nordic Cochrane Centre, the European Ombudsman, and the EMA deserve credit for that.

There’s a lot of good news for researchers in the final version of the policy. Gone is the “Peeping Tom” clause of “viewing only” access to data—described by users of comparable policies as “science through a periscope”—and there is no trace of a threat of legal proceedings for those who produce research that is disagreeable to sponsors.

In a previous post I urged users to adopt Reagan’s maxim of “trust but verify” when reading the EMA’s policies. Ultimately, we will not know how usable and transparent this policy is until it has been in use for some time.
I was prepared to say at this point that Tom’s report adds some disappointments, but that I stick to my guns that it’s a leap forward [beyond the blind…]. But when I went to the AllTrials site to clip their comment, I found this [see also a coup d’état…, the other shoe]:
    Yesterday, the likely European Commissioner for industry who will oversee the regulation of medicines and the EMA said there are risks that need to be balanced with greater clinical trial transparency. MEPs have been questioning the candidates for the new European Commission and, if approved by MEPs, Elzbieta Bienkowska will lead the industry department [DG ENTR].

    The new president of the European Commission, Jean-Claude Juncker, recently moved the responsibility for the regulation of medicines from the health to the industry department. When asked whether this move would allow industry lobbying to affect drug regulations, Ms Bienkowska said, “All my professional experience shows that I am lobbyist-proof. I’m absolutely lobbyist-proof”. Glenis Willmott MEP said, “It is disappointing Ms Bienkowska didn’t answer directly whether or not she thinks pharmaceutical and medical devices should really be in the health commissioner’s portfolio.”

    Ms Willmott also asked Ms Bienkowska if she will ensure the EMA’s commitment to greater clinical transparency will continue. Ms Bienkowska replied that clinical trial transparency is important for Europe; “however, you have to look at the other side and ensure there are adequate levels of safety when it comes to the potential misuse of data.” We’ve heard this claim before and we responded on our “Myths & Objections” page. MEPs will vote to appoint the candidates to the European Commission on 22nd October.

This battle is anything but over.  In the other shoe I ended with a picture of Niccolò di Bernardo dei Machiavelli, the author of The Prince – the Renaissance treatise on how to gain and wield power at any cost. I think of him once again this evening. There is no stopping place for the cause of Data Transparency. PHARMA is always in the background. They have unlimited resources and teams of people being well-paid to spend their days working whatever angles are necessary to win the day and allow PHARMA to hold onto control of the data from clinical trials. It’s not paranoia that leads me to this cynical conclusion, it’s self-evident experience. The only thing to say is that their offering this much consistent resistance says that we’re fighting the right battle. And by the way, endless thanks to MEP Glenis Willmott [see on the right track…]. She’s a true champion for the cause [and it is a cause]…
Mickey @ 12:15 AM
Filed under: OPINION
the prequel…

Posted on Wednesday 8 October 2014

I wrote this before the last post. Even as I wrote it, I knew I was writing it to myself, mainly to get things straight in my own thinking. But I changed my mind about posting it for two reasons. First, many of you aren’t psychiatrists and may not know the chronology so intimately – and I think it might help. History always seems to help me. Second, there’s something I want to say that has to do with George Dawson’s comment to the last post that won’t make sense without this. I apologize for the redundancies, where I lifted phrases to write the last post.

I was only casually aware of matters psychiatric during the 1960s. For me, it was the era of medical school, Internal Medicine training, and bench research. But from what I recall, the psychiatric residents got a generous government bonus for choosing the specialty. There was a shortage, it seems. In retrospect, that was because of de·Institionalization, and psychiatrists were needed to staff the Mental Health Centers that were to take their places as patients were moved from the hospitals into the community. By the latter half of the 1970s when I was in psychiatric training and early on the faculty, public mental health services were in crisis as the community services and hospital resources disappeared, even as the patient load from de·Institionalization grew [it was before they started filling up the jails and prisons]. Within psychiatry, there was a backlash against the prominence of psychoanalysts. Outside of psychiatry, the criticisms of psychiatry had a broad base: the heavy use of medications in treating psychosis; both the psychoanalytic and medical models; charging third party payers for psychotherapies; the question of whether mental illness was disease; the power of psychiatrists in involuntary commitment and medication. It was a tumultuous time. In the background, the revision of the diagnostic manual was marching towards release in 1980, a force that would make massive changes in the specialty and its practice. One part of that oft-told story is that those changes in psychiatry were orchestrated by the American Psychiatric Association [APA] under the guidance of its Board of Trustees, its Medical Director Dr. Melvin Sabshin, the chair of the DSM-III Task Force, Dr. Robert Spitzer, and the strong influence of the neoKraepelinians centered at Washington University in Saint Louis. Dr. Sabshin further consolidated the power of the APA by founding the American Psychiatric Publishing, Inc. [APPI].

The course of psychiatry in the US has been steered by the American Psychiatric Association since those 1980 changes. I don’t know if that central control was present before then, but it has certainly been true during my time. Many of us have withdrawn our membership for a variety of reasons in that time period. The medical·ization and medicine·ization of the specialty built through the ensuing quarter century, an era when much of academic and organized psychiatry was actively engaged with the pharmaceutical industry and the neuroscientific focus of the NIMH. It was a period of dramatic change with third party payers paying psychiatrists for outpatient medication management, and contracting with other specialties for psychosocial treatments. Another change – our prisons filled with chronic mental patients creeping toward the numbers of the confined prior to de·Institionalization.

The first decade of the new century began at the apogee of the now aging new psychiatry. The APA embarked on a DSM Revision that would realize a dream of connecting clinical diagnosis with measurable biology. Dr. Tom Insel of the NIMH advocated reframing psychiatry as Clinical Neuroscience. And the pharmaceutical industry was maintaining a steady pipeline of new medications coming onto the market [along with a publishing arm of its own]. But by the end of the decade, things were once again changing dramatically, as we all know. The involvement of academic psychiatrists with industry came to public attention with the revelations of Senator Grassley about unreported income, but the focus soon generalized to the whole issue of a corrupted alliances between a prominent sector of psychiatry and drug manufacturers – and we began to learn about ghost writing, and guest authorship, and industry financing out-front and in the background. Suits against pharmaceutical companies flourished exposing false advertising, exaggerated efficacy, minimizing of adverse reactions, and the involvement of the "KOLs" with industrial interests which became a source of public shame for us all. Meanwhile, the enthusiasm for a "biologic" DSM-5 choked in a desert of non-confirmation. Then the pipeline dried up, and PHARMA began to exit CNS drug development en masse. Quite an impressive decade of changes in fortune.

Here at the near midpoint of the second decade of the century, it would be hard to summarize the current state of play. We’ve seen several years of intense efforts to reform the clinical trials of drugs through Data Transparency, though at least in psychiatry, at present there’s not a lot of actual action in that arena with a dry pipeline – so, the "closing the stable door after the horse has bolted" adage seems to apply. The DSM-5 effort mercifully limped to its lackluster conclusion, but not before being abandoned by the NIMH, now creating a diagnostic system of its own – the Research Domain Criteria project [RDoC]. If anything, the DSM-5 Task Force process exposed the APA to further scorn – particularly with it’s chairman being exposed as involved in an entrepreneurial enterprise. And to complexify matters further, there’s another huge general issue on the table at the moment, the changing landscape of practice, finance, and health policy coming with the Affordable Care Act [ACA] among other things.

Where is the American Psychiatric Association in all of this? The DSM-5 is certainly not the catalyst for a paradigm shift like its predecessor, the DSM-III. It’s a code book at best, one still haunted by the process of its creation. While there’s continued wide usage of the medications from the earlier decade, the accompanying enthusiasm for psychopharmacology has undergone considerable dampening in recent years. The mainstay triad of promising future biological discovery [proteinomics, neuroimaging, and genomics] has lost some of its star-power. Likewise, the publicity around the ubiquitous conflict of interest issues have taken a heavy toll on the reputation of psychiatry in general, as they should. As I mentioned above, the APA has been the prime driving force for the direction of American psychiatry since at least 1980. While still in the leadership position, the APA is now operating in a dramatically different environment with the only clarity being that change is inevitable, though the shape and direction of that change is unclear…
Mickey @ 4:35 PM
Filed under: OPINION