1 Boring Old Man

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Among other things, one major change from the psychiatry I began with and the modern era was that I didn’t know which company produced which drug – or for that matter, which ones were on or off patent. I thought of the TCAs [Tricyclic Antidepressants] and the MAOIs [Monamine Oxidase Inhibitors] as primarily drugs for patients with Major Depression [what we called Major Depression back then meaning Melancholia, Manic Depressive Illness with a Depressive Episode, etc] and not for the outpatients where my own focus had landed. I don’t remember discussing them for children or adolescents. In my six month fellowship on an adolescent treatment unit, no kid was on antidepressants. I certainly recall talking about "kids being depressed," but never about them "having" a depressive illness. Recently, on an impulse, I found an old $0.01 copy of the late 1960s GAP [Group for the Advancement of Psychiatry] Psychopathological Disorders of Childhood we used and ordered it. It was as I recalled. The only mention of depression was in a listing of symptoms, but no diagnostic entity.

So I’m pretty sure that the existence of the then newer antidepressants created the diagnostic entity «Depression» in children and adolescents, and I’m even more sure that the hype that built around the drugs perpetuated the diagnosis «Major Depressive Disorder» in Adults. As things developed, the phrase «Treatment Resistant Depression» [with an acronym of its own – TRD] found wide usage in both kids and adults, as if it was itself also a diagnostic entity. I can’t right off think about other such situations, places where a treatment had such a profound effect on the creation and shaping of a diagnosis. I also wonder if there has ever been a single drug class that has been so heavily studied or had so much energy, time, or money spent trying to magnify a weak effect [sequencing, combining, augmenting, "personalizing", etc].

Since finally finishing the Study 329 RIAT project, I’ve been thinking about what else this Antidepressant Era in psychiatry might have to tell us for the future – assuming it’s finally drawing to a close. PHARMA seems to have genuinely flown the coop, moving away from CNS research for the most part. I hope, on psychiatry’s side, that free of the influences of PHARMA and KOLs, these drugs can be evaluated for their true worth and indications. We’re all so locked in to the polarized rhetoric that it may be a while before all the meta-analyses and retrospectives might offer some clarity. But I think that there’s perhaps a larger contribution that can be made to Medicine in general.

I had no idea that such a thing could happen, that the tools of scientific investigation could be so regularly perverted in plain sight. For example, that by withholding negative studies, one could actually create the illusion of a clinically relevant medication from a compound with a trivial effect. It makes perfect sense if you’ve seen it before. I just never would’ve thought to look.

Paroxetine resulted in significantly greater rates of response (defined as Hamilton Rating Scale for Depression [HAM-D] score <8) compared with placebo in the last observation carried forward population. Response rates were higher for paroxetine (76%; P=.02), imiprarmine (64%), and placebo (58%) among those patients who completed the 8-week trial. There was no statistically significant difference between paroxetine or imipramine and placebo on the HAM-D total score at end point. However, there was a significantly greater increase in the Clinical Global Impression (CGI) improvement scores for the paroxetine group compared with the placebo group.

In every specialty, a lot of the clinical side of medical training is learning to see a lot of patients in a practice day, process a ton of information, and get to the point where you almost automatically hear bells go off when some small piece of information comes your way that says, "stop, look, and listen" – some symptom that doesn’t fit, a hint that this cough is the early symptom of tumor instead of a cold, this rash is going to turn into a Stevens-Johnson syndrome in an hour, this back pain is an aneurysm about to dissect. Over these last few years of reading the psychiatric Clinical Trial literature, I’m beginning to hear those same bells when I scan through a Clinical Trial journal article. And I wish my training for reading these articles had been as rigorous as my bedside and consulting room training.

As peculiar as it might sound, I think that a big segment of the literature [particularly the industry funded Clinical Trial literature] that came out of the antidepressant era spanning the time in that top figure needs to be formally re-evaluated, not just to get a more accurate picture of these drugs, but also to familiarize all of us to the subtle ways it can be distorted – something like clinical training in journal reading. It’s certainly a treasure trove of tricks that ride just this side of fraud. While I’ve yet to find one of these studies where the data has been directly changed, I can’t think of any, off-hand, that played it totally straight in the analysis/presentation/conclusion realm either. We’ve always said doctors should be taught critical reading. It’s obvious that we’re woefully off the mark in that area when it comes to Clinical Trials. This kind of shenanigans isn’t just a problem in psychiatry. It’s medicine-wide. But psychiatry sure has the biggest library of examples on the block. We might as well find a way to use those papers to some decent purpose.

Clinical study reports of randomised controlled trials: an exploratory review of previously confidential industry reports

BMJ Open

by Peter Doshi and Tom Jefferson

26 February 2013

[full text on-line]

Objective To explore the structure and content of a non-random sample of clinical study reports [CSRs] to guide clinicians and systematic reviewers.

Search strategy We searched public sources and lodged Freedom of Information requests for previously confidential CSRs primarily written by the industry for regulators.

Selection criteria CSRs reporting sufficient information for extraction [‘adequate’].

Primary outcome measures Presence and length of essential elements of trial design and reporting and compression factor [ratio of page length for CSRs compared to its published counterpart in a scientific journal].

Data extraction Data were extracted on standard forms and crosschecked for accuracy.

Results We assembled a population of 78 CSRs [covering 90 randomised controlled trials; 144,610 pages total] dated 1991–2011 of 14 pharmaceuticals. Report synopses had a median length of 5 pages, efficacy evaluation 13.5 pages, safety evaluation 17 pages, attached tables 337 pages, trial protocol 62 pages, statistical analysis plan 15 pages and individual efficacy and safety listings had a median length of 447 and 109.5 pages, respectively. While 16 [21%] of CSRs contained completed case report forms, these were accessible to us in only one case [765 pages representing 16 individuals]. Compression factors ranged between 1 and 8805.

Conclusions Clinical study reports represent a hitherto mostly hidden and untapped source of detailed and exhaustive data on each trial. They should be consulted by independent parties interested in a detailed record of a clinical trial, and should form the basic unit for evidence synthesis as their use is likely to minimise the problem of reporting bias. We cannot say whether our sample is representative and whether our conclusions are generalisable to an undefined and undefinable population of CSRs.

One runs into the most interesting people in the oddest of ways, looking into the most unlikely of topics. Tom Jefferson and Peter Doshi are the Tamiflu guys, the ones that spent years running down an epidemiology story that needed to be told, and at least for me, began to unravel the torturous and kind of boring story of how Clinical Trials are cataloged and documented. Tom is a British Epidemiologist with the Cochrane Collaboration in Rome, Italy. Peter, his colleague, is on our side of the pond in Maryland and now an editor with the BMJ. But this blog isn’t about their interesting story with Tamiflu and other things. It’s about a topic they’ve tried to clarify for all of us – the Clinical Study Reports that become part of the record of Clinical Drug Trials – a should·be·simple topic that’s complex·and·confusing [perhaps deliberately so].

After a few years being preoccupied with evaluating the documents from a single Clinical Trial [Paxil Study 329] for a RIAT project [A Milestone in the Battle for Truth in Drug Safety, Restoring Study 329], I made this diagram trying to clarify things for myself. The upper part is clear – the a priori PROTOCOL and the SAP [Statistical Analysis Plan] – are evaluated by the Institutional Review Board [IRB] and, and if approved become the directives for the Clinical Trial. That part’s blinded [dark glasses]. Once the blind is broken, the Raw Data as Case Report Forms [CRFs] are assembled and organized. They’re transcribed into data tables known collectively as the IPD [Individual Participant Data]. Notice there aren’t any glasses there [yet] because these nuclear document have rarely ever been seen. Then someone uses the IPD to write an exhaustive CSR [Clinical Study Report]. Later all of this becomes the highly condensed published ARTICLE usually under the byline of academic authors. I put the glasses there because it’s seen and unblinded, but notice they’re "rose colored glasses." The important part is how to get untinted glasses in the IPD and CRF quadrant where they’re needed, without the "rose coloring" of conflict of interest:

Doshi and Jefferson explain some of why this eyes-on view of the Raw data is so hard to get hold of. The issue is that the meaning and requirements of CSR varies from company to company and agency to agency – and it’s not at all clear whether the CSR must contain the IPD [ergo, Raw Data] or not. In the study we looked at [Paxil Study 329], the IPD was listed in Appendices to the CSR, but in GSK’s initial release – the Appendices were nowhere to be found in the 2004 posting, only appearing 8 years later [2012] at the insistence of Peter Doshi working with the NY Attorney General. And apparently, there’s a lot of variability. So if this is a remote interest, by all means read their paper [maybe even if it isn’t, because this at the heart of the Data Transparency question].

ABSTRACT- This article provides an overview of the use of paroxetine in the treatment of mood and anxiety disorders in children and adolescents. Although not currenty approved for use in patients younger than 18 years of age, the efficacy and safety of paroxetine have been studied in several pediatric mood and anxiety disorders. The epidemiology, diagnosis, and course of major depression, obsessive-compulsive disorder, social anxiety disorder, and panic disorder are discussed briefly. Current available data on the safety and efficacy of paroxetine based on double-blind placebo-controlled tnais and open-label studies for Ihe treatment of mood and anxiety disorders In children and adolescents are reviewed Clinical guidelines for the use of paroxetine in children and adolescents and recommendations regarding future directions of study are discussed. Psychophamacology Bulletin 2003;37[Suppl 1]: 167-175.

It’s easy to forget what it was like in 2003. We think of something like the Keller et al paper we know as Paxil Study 329 in isolation, a decidedly negative Clinical Trial published as positive. But we forget that it was just the launching pad for a much larger campaign. This Psychopharmacology Bulletin Supplement was published in the Spring of 2003, financed by GSK, moderated and assembled by Dr. Charlie Nemeroff, then Chairman of Psychiatry at Emory University and a major GSK Adviser. Now take a look at the Supplement’s Authors and the Journal’s Editorial Staff here, a veritable Who’s Who with multiple Departmental Chairmen and future alumni of Senator Grassley’s Senate investigations into fiscal corruption. And in the Supplement, Dr. Wagner’s version of the Keller et al paper [that she co-guest-authored] is certainly beyond generous:

The findings of one of the largest randomized, double-blind, multicenter, controlled trials of an SSR1 in the treatment of adolescents with major depression was reported by Keller and associates in 2001. The efficacy and safety of paroxetine was demonstrated in 275 adolescent outpatients with major depression ranging in age from 12 to 18 years. Patients were randomized to paroxetine, imipramine, or placebo for an 8-week trial Dose ranges for paroxetine were 20 to 40 mg per day, with a mean daily dose of 28 mg. Dose ranges for imipramine were 200 to 300 mg per day, with a mean daily dose of 205 mg. Paroxetine resulted in significantly greater rates of response (defined as Hamilton Rating Scale for Depression [HAM-D] score <8) compared with placebo in the last observation carried forward population. Response rates were higher for paroxetine (76%; P=.02), imiprarmine (64%), and placebo (58%) among those patients who completed the 8-week trial. There was no statistically significant difference between paroxetine or imipramine and placebo on the HAM-D total score at end point. However, there was a significantly greater increase in the Clinical Global Impression (CGI) improvement scores for the paroxetine group compared with the placebo group. Of patients in the paroxetine group, 66% were much or very much improved (P=02 versus placebo) compared with 52% of patients in the imipramine group (P=64 versus placebo) and 48% of patients in the placebo group.

Conclusion

In double-blind, placebo-controlled trials, paroxetine has demonstrated efficacy and safety in the treatment of major depression in adolescents, and in the treatment of OCD and social anxiety disorder in children and adolescents. Selective serotonin reuptake inhibitors such as paroxetine are currently the first-line treatment for children and adolescents suffering from major depression and anxiety disorders. Additional well-controlled studies are needed to further advance the treatment and outcome of children with depression and anxiety disorders.

Disclosure

This work was supported by an unrestricted educational grant from GlaxoSmithKline. Dr. Wagner serves as scientific adviser and consultant for and receives research support from Abbott Laboratories, Eli-Lilly, Forest laboratories, GlaxoSmithKline, Pfizer, and Wyeth-Ayerst. She also receives research support from Bristol-Myers Squibb, Organon and the National Institute of Mental Health. Dr. Wagner serves as scientific adviser and consultant for Janssen, Novartis, Otsuka, and UCB Pharma.

Dr. Nemeroff’s star had begun to droop in the sky by then. He had become the Editor in Chief of Neuropsychopharmacology, the ACNP Journal, in 2001 – quite an honor. First, he published a review article in Nature Neuroscience [Treatment of mood disorders] in 2002 recommending three treatments that he had a direct financial interest in without declaring those interests. This omission was exposed by Drs. Bernard Carroll and Bob Rubin resulting in a change in policy for all Nature journals. He did it again in 2004! [see hubris… for the details]. But the growing crack turned into a canyon in 2006 when Dr. Nemeroff published a ghost-written review of a vagal nerve stimulator for treating depression [VNS Therapy in Treatment-Resistant Depression: Clinical Evidence and Putative Neurobiological Mechanisms – full text] in his own journal [Neuropsychopharmacology] with a raft of other colleagues, all of whom were involved with that nerve zapper’s company [including him] without any  acknowledgment. He was confronted again by Drs. Carroll and Rubin. In quick succession, he stepped down [was removed] as Editor and his activity was heavily restricted by his University. The final blow came in 2008 when Senator Grassley and Staffer Paul Thacker started a Senatorial investigation into academic psychiatrists with undisclosed pharmaceutical income, and Nemeroff was on the top of the list. That was the nail that ended his career as Chairman of Psychiatry at Emory. Many of the people on the editorial board and the Supplement above were on Senator Grassley’s list, including Dr. Martin Keller of Keller et al and Dr. Karen Dineen Wagner, author of this article.

Finally, the in-your-face version of the alliance between PHARMA by this segment of academic psychiatry came out of the shadows. When Dr. Nemeroff was confronted by Emory, his defense was that he was just doing his job with all of his industry connections – cataloging the money he’d raised to support his department at Emory through educational grants. And that makes a strange kind of sense, as convoluted as it seems. Dr. Nemeroff was hired because he could [and would] bring in the money from unrestricted educational grant[s] from any number of pharmaceutical companies. The changes – managed care, the closing of psychiatric hospitals, the collapse of the Community Mental Health Centers, the failure of the States to provide public psychiatric care – had devastated psychiatric departments in medical schools. And so they hired the likes of Dr. Nemeroff and his colleagues who could [and would] solve the problem by alliances with PHARMA. It’s really that $imple. And if you think about it, the dethroning of Dr. Nemeroff and hi$ colleague$ wa$ not becau$e of hi$ rai$ing PHARMA money for hi$ department. It was becau$e he wa$ rai$ing money for him$elf. And that was true of all the people on Senator Grassley’s list. It was their undeclared personal income that brought them to grief. If you want to hear what that sounds like from inside, check out Conflicts of Interest, an extremely telling blog by Psycritic [Update: Here‘s a public version].

^{hat tip to Psycritic and many others…} 

Is Mandatory Prospective Trial Registration Working to Prevent Publication of Unregistered Trials and Selective Outcome Reporting?

An Observational Study of Five Psychiatry Journals That Mandate Prospective Clinical Trial Registration

PLoS | ONE

by Amelia Scott, Julia J. Rucklidge, and Roger T. Mulder

August 19, 2015

Objective: To address the bias occurring in the medical literature associated with selective outcome reporting, in 2005, the International Committee of Medical Journal Editors [ICMJE] introduced mandatory trial registration guidelines and member journals required prospective registration of trials prior to patient enrollment as a condition of publication. No research has examined whether these guidelines are impacting psychiatry publications. Our objectives were to determine the extent to which articles published in psychiatry journals adhering to ICMJE guidelines were correctly prospectively registered, whether there was evidence of selective outcome reporting and changes to participant numbers, and whether there was a relationship between registration status and source of funding.

Materials and Methods: Any clinical trial [as defined by ICMJE] published between 1 January 2009 and 31 July 2013 in the top five psychiatry journals adhering to ICMJE guidelines [The American Journal of Psychiatry, Archives of General Psychiatry/JAMA Psychiatry, Biological Psychiatry, Journal of the American Academy of Child and Adolescent Psychiatry, and The Journal of Clinical Psychiatry] and conducted after July 2005 [or 2007 for two journals] was included. For each identified trial, where possible we extracted trial registration information, changes to POMs between publication and registry to assess selective outcome reporting, changes to participant numbers, and funding type.

Results: Out of 3305 articles, 181 studies were identified as clinical trials requiring registration: 21 [11.6%] were deemed unregistered, 61 [33.7%] were retrospectively registered, 37 [20.4%] had unclear POMs either in the article or the registry and 2 [1.1%] were registered in an inaccessible trial registry. Only 60 [33.1%] studies were prospectively registered with clearly defined POMs; 17 of these 60 [28.3%] showed evidence of selective outcome reporting and 16 [26.7%] demonstrated a change in participant numbers of 20% or more; only 26 [14.4%] of the 181 the trials were prospectively registered and did not alter their POMs or the time frames at which they were measured. Prospective registration with no changes in POMs occurred more frequently with pharmaceutical funding.

Discussion: Although standards are in place to improve prospective registration and transparency in clinical trials, less than 15% of psychiatry trials were prospectively registered with no changes in POMs. Most trials were either not prospectively registered, changed POMs or the timeframes at some point after registration or changed participant numbers. Authors, journal editors and reviewers need to further efforts to highlight the value of prospective trial registration.

[see also Is Mandatory Trial Registration Decontaminating the Psychiatric Literature? by Julia Rucklidge, Ph.D. on Mad in America].

So to my post-it notes. They add one other vital thing, the a priori study protocol [I’m 100% serious about the vital part]. Among many other things, it lays out what variables will be assessed and exactly how they will be analyzed. Most, if not all, RCT distortion involves not following the a priori study protocol [or having a biased protocol from the start]…

«declare the Primary Outcome Measures»
«register the trial including an a priori protocol»
«conduct the blinded trial»
«break the blind»
«analyze the Primary Outcome Measures according to the a priori protocol»
«report the results»

^{[truncated and rearranged to fit]}

And of the 60 that were preregistered and carried into the  publication, only 26 POMs were used without some evidence of jury-rigging [14.1 %]! Pitiful!

And ~half of those retrospectively registered trials were registered over a year after the study began. Also pitiful!

And more…

Twenty-one [11.6%] of the 181 studies were deemed unregistered, 61 [33.7%] were retrospectively registered, 37 [20.4%] had unclear POMs either in the article or the registry and 2 [1.1%] were registered in an inaccessible trial registry. Only 60 [33.1%] studies were prospectively registered with clearly defined POMs.

But seventeen of these 60 [28.3%] properly registered trials showed evidence of selective outcome reporting – this means that there had been changes to POMs based on a comparison of the trial registry and the publication. In total, only 26 [14.4%] of the 181 trials were prospectively registered and did not alter their POMs or the time frames at which they were measured. Prospective registration with no changes in POMs occurred more frequently with pharmaceutical funding.

As I’ve mentioned before, back in the early days of SSRIs, I was lucky to have a good friend whose wife, a sophisticated Social Worker, had taken Paxil shortly after it came on the market. When she stopped, she got ill and was perceptive enough to recognize that it wasn’t anything like her "depression coming back." It was something else. It was a withdrawal syndrome. She described it clearly back then, including "brain zaps," just like we’ve come to know it now that it’s more recognized and well characterized. So I knew about withdrawal early, and began slow tapering off of SSRIs a long time ago with all of them [never prescribing Paxil]. When I mentioned it to colleagues, they didn’t know what I was taking about.

• The Seroxat/Paxil Yugoslavia Trial Part I July 8, 2015
• The Seroxat/Paxil Yugoslavia Trial Part II July 9, 2015

At this time, SKB were seeking approval of Paxil and the Yugoslavia trial was to show the FDA (the US drug regulator) how effective Paxil was in treating depression – they would also try to show the FDA how it was important to keep taking Paxil and not to stop… because if you did stop then you would go into relapse, in other words, SKB were trying to prove that stopping Paxil meant the patient’s original illness would return.

With the results they wanted, SKB then provided the FDA with apparent evidence that showed patients staying on Paxil continued to enjoy a normal, "depression free" life, but that those abandoning the drug would  suffer relapse back into a depressive state. One thing that was irksome to SKB was that they had to convince the FDA that the relapses shown in the study were not simply patients suffering withdrawal.

• MHRA Missing Key Seroxat/Paxil Withdrawal Information August 18, 2015

That brings up something that has nagged at me for years. I still see depression in two major categories, just as I did before I even came into psychiatry. Depression [with a capital "D"] meaning Melancholia, the Depressive Episodes of Manic Depressive Illness, Post-Partum Depression, etc. And depression [with a little "d"] as in everything else [formerly known as Neurotic Depression]. Whichever the case, depression is a time-limited condition – and medication for depression is a time limited medication. The guideline I recall from the days of the Tricyclics and MAO Inhibitors was that patients who had responded to these medicatiuons should continue them for 6 months before stopping to prevent a relapse [I have no clue how that guideline got into my mind so long ago].

I followed that practice even after the SSRIs came along. Years later, when I retired and started seeing patients in a clinic where patients had been medicated by someone else, it was apparent that the rest of the world saw things differently. Patients had been on an antidepressant for years and obviously thought it was keeping their depression away. And getting them to give it up required knowing them for a while, and withdrawing slowly as a trial. Otherwise, it was like taking away a talisman, or a comforting blanket. I’ve wondered how that idea of antidepressant as preventative-forever ever came about. Avoiding withdrawal may well be the answer…

This time last year, I was feeling steamed that the pharmaceutical companies had been granted the right to treat the data from Clinical Trials as proprietary, private property, in the first place. That Law needed to be overturned! So I couldn’t find the Law and I wrote people in the know for help. They agreed to help, but nobody could remember. As it turned out, they couldn’t remember because there wasn’t any Law, PHARMA just assumed ownership and that was that [see repeal the proprietary data act… and except where necessary to protect the public…]. I wrote Canadian Law Professor and expert Trudo Lemmens who confirmed that, mentioning that it was loosely based on Trade Agreements and PHARMA was trying to strengthen their position. I knew I was way into something I could never master, so I moved on. But today, this article came my way:

Five Reasons Why TPP Countries Should Unite To Oppose The US Pharmaceutical IP Agenda

Intellectual Property Watch

By Deborah Gleeson and Ruth Lopert

18 AUG 2015

Failure to reach agreement over expanded intellectual property [IP] protections for medicines has proven to be a stumbling block to completion of the 12-country Trans Pacific Partnership negotiations. As expected, the US is continuing to pressure negotiating partners to adopt broader and longer monopoly protections for medicines. But the risks for their health systems are very high – and will be much higher if they don’t stick together in rejecting the US demands.

A leaked draft of the agreement’s IP chapter from May 2014 showed that, with the exception of Japan, the other countries had been consistent in rejecting the US proposals. But more recently, another leaked draft dated 11 May 2015 and published by Knowledge Ecology International last week demonstrated a splintering of this opposition. Rather than pushing back collectively, individual countries appear to be attempting to craft creative language and qualifying footnotes to give the appearance of conceding to US demands while preserving existing standards where possible.

One could be forgiven for thinking that this might seem like a reasonable outcome. But there are at least five good reasons why this is a risky approach – and why pushing back collectively through the final stages of negotiations would be a wiser strategy.

1. The US demands are inherently unreasonable. It is widely recognised that the US is seeking monopoly protections that will frustrate and delay access to affordable medicines in countries that are party to the agreement – and due to spillover effects, potentially to others that are not…
2. Bargaining with the US is risky business. Under pressure from the US, and anxious to secure gains in market access in exchange for apparent concessions on medicines, negotiators seem to be pursuing solutions in creative wording…
3. Adopting prescriptive obligations in a trade agreement constrains future policy options,even if creative wording averts substantive changes. Tight specification of IP obligations locks countries into existing regimes and prevents the kinds of reforms recommended by the former Australian Government’s Review of Pharmaceutical Patents – such as winding back patent term extensions or reducing effective patent life.
4. The obligations in the TPP will become the template for the next trade agreement. What countries accept – or appear to have accepted, footnotes and exemptions notwithstanding – will then form part of the standard template for the next trade agreement negotiated by the US…
5. Developing countries will undoubtedly get the raw end of the deal. Vietnam, as the lowest income country, is likely to be worst affected. While the TPP parties have agreed to a transition period for developing countries, it does not cover all of the pharmaceutical obligations. In the latest leaked draft, earlier proposals for a transition period based on development indicators seem to have been abandoned in favour of a time-based transition…

Implications of the Trans-Pacific Partnership Agreement on Equitable Access to Healthcare

Mad In America

By Erik Monasterio, MD

November 20, 2014

As a piece of their support of the movement for Data Transparency in Randomized Clinical Trials [RCTs], the BMJ featured a particular article [Restoring invisible and abandoned trials: a call for people to publish the findings] with this cover graphic [minus my added post-it notes] on their June 22, 2013 print edition:

Since then, I have learned a lot more about the details of Clinical Trial reporting and have talked about it here ad nauseum. Two of the authors, Peter Doshi and Tom Jefferson, went the extra mile in their quest to vet the studies on Roche‘s Tamiflu® for their Cochrane Collaboration review [Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments] – spending literally years chasing down the raw data for the published and unpublished trials. Then they were joined by Kay Dickersin, David Healy, and Swaroop Vedula to collect even more data at large and launch the RIAT Initiative, a move supported by the BMJ and PLoS editors [see “a bold remedy”…]:

Restoring invisible and abandoned trials: a call for people to publish the findings
Analysis
British Medical Journal
^{by Peter Doshi, Kay Dickersin, David Healy, S Swaroop Vedula, and Tom Jefferson}
June 13, 2013
^{[full text on-line]}

Restoring the integrity of the clinical trial evidence base
Editorial
British Medical Journal
^{by Elizabeth Loder and Fiona Godlee [BMJ] and Virginia Barbour and Margaret Winker [PLoS Medicine]}
June 13, 2013
^{[full text on-line]}

Restoring Invisible and Abandoned Trials: A Creative Approach to a Public Good; Now a Creative Approach to Implementation is Needed
Blog
PLoS Medicine
^{By Margaret Winker and Virginia Barbour}
June 13, 2013
^{[full text on-line]}

Data Transparency proposes to reform it by skipping the system altogether. Allow independent investigators to see the same thing the system sees as soon as the blind is broken and reanalyze it, checking the work of the Sponsor/Journal. So that’s the reason for my post-its upstairs. When the RIAT paper was written, I presume they looked for the clinical study report, the electronic patient level datasets, and the completed case report forms.

Having spent some time on a RIAT Team, here two+ years later, I would revise that cover slightly. The CSR is an exhaustive report on the study, but it’s not "raw." It’s something prepared by human beings, the same human beings responsible for the published article – thereby as prey to distortion and corruption as the paper itself. What they got as electronic patient level datasets are one type of IPD [individual patient data]. It’s the compiled database derived directly from the forms filled out as the study progressed – forms called the case report forms [CRFs]. Unless one suspects fraudulent transcription, the IPD is what matters – then you need the CRFs to check with. The CSR is only useful if it contains the IPD. Otherwise, it’s just the long form of the paper you already suspect has something awry.

So to my post-it notes. They add one other vital thing, the a priori study protocol [I’m 100% serious about the vital part]. Among many other things, it lays out what variables will be assessed and exactly how they will be analyzed. Most, if not all, RCT distortion involves not following the a priori study protocol [or having a biased protocol from the start]. So remember these post-it notes when evaluating a RCT or a RIAT reanalysis:

STAR*D was an elaborate NIMH study aiming to define some sequencing method that would improve the response to antidepressants using the algorithm on the left [as seen from space]. The main outcomes were a database mined for several hundred publications, a self-rating depression scale [QIDS-SR], and a template for future studies called naturalistic at the time – no control group, no blinding, and progress was monitored by a telephone version of the QIDS-SR. From my point of view, it was a thirty-five million dollar misunderstanding…

Depression Subtypes in Predicting Antidepressant Response: A Report From the iSPOT-D Trial

by Bruce A. Arnow, Christine Blasey, Leanne M. Williams, Donna M. Palmer, William Rekshan, Alan F. Schatzberg, Amit Etkin, Jayashri Kulkarni, James F. Luther, and A. John Rush.

American Journal of Psychiatry. 2015 172[8]:743-750.

Objective: The study aims were 1] to describe the proportions of individuals who met criteria for melancholic, atypical, and anxious depressive subtypes, as well as subtype combinations, in a large sample of depressed outpatients, and 2] to compare subtype profiles on remission and change in depressive symptoms after acute treatment with one of three antidepressant medications.

Method: Participants 18–65 years of age [N=1,008] who met criteria for major depressive disorder were randomly assigned to 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine. Participants were classified by subtype. Those who met criteria for no subtype or multiple subtypes were classified separately, resulting in eight mutually exclusive groups. A mixed-effects model using the intent-to-treat sample compared the groups’ symptom score trajectories, and logistic regression compared likelihood of remission [defined as a score ≤5 on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report].

Results: Thirty-nine percent of participants exhibited a pure-form subtype, 36% met criteria for more than one subtype, and 25% did not meet criteria for any subtype. All subtype groups exhibited a similar significant trajectory of symptom reduction across the trial. Likelihood of remission did not differ significantly between subtype groups, and depression subtype was not a moderator of treatment effect.

Conclusions: There was substantial overlap of the three depressive subtypes, and individuals in all subtype groups responded similarly to the three antidepressants. The consistency of these findings with those of the Sequenced Treatment Alternatives to Relieve Depression trial suggests that subtypes may be of minimal value in antidepressant selection.

ABCB1 Genetic Effects on Antidepressant Outcomes: A Report From the iSPOT-D Trial

by Alan F. Schatzberg, Charles DeBattista, Laura C. Lazzeroni, Amit Etkin, Greer M. Murphy, Jr., and Leanne M. Williams

American Journal of Psychiatry. 2015 172[8]:751-759.

Objective:: The ABCB1 gene encodes P-glycoprotein, which limits brain concentrations of certain antidepressants. ABCB1 variation has been associated with antidepressant efficacy and side effects in small-sample studies. Cognitive impairment in major depressive disorder predicts poor treatment outcome, but ABCB1 genetic effects in patients with cognitive impairment are untested. The authors examined ABCB1 genetic variants as predictors of remission and side effects in a large clinical trial that also incorporated cognitive assessment.

Method:: The authors genotyped 10 ABCB1 single-nucleotide polymorphisms [SNPs] in 683 patients with major depressive disorder treated for at least 2 weeks, of whom 576 completed 8 weeks of treatment with escitalopram, sertraline, or extended-release venlafaxine [all substrates for P-glycoprotein] in a large randomized, prospective, pragmatic trial. Antidepressant efficacy was assessed with the 16-item Quick Inventory of Depressive Symptomatology–Self-Rated [QIDS-SR], and side effects with a rating scale for frequency, intensity, and burden of side effects. General and emotional cognition was assessed with a battery of 13 tests.

Results:: The functional SNP rs10245483 upstream from ABCB1 had a significant effect on remission and side effect ratings that was differentially related to medication and cognitive status. Common homozygotes responded better and had fewer side effects with escitalopram and sertraline. Minor allele homozygotes responded better and had fewer side effects with venlafaxine, with the better response most apparent for patients with cognitive impairment.

Conclusions:: The functional polymorphism rs10245483 differentially affects remission and side effect outcomes depending on the antidepressant. The predictive power of the SNP for response or side effects was not lessened by the presence of cognitive impairment.

To account for the testing of multiple SNPs, SNP p values of 0.05/18<0.0028 ere considered significant using a Bonferroni correction for nine SNPs, each tested for one main effect and one interaction effect. All p values <0.05 are reported for completedness, because of the possibility of false negative results at this significance level.

Remission. In the modified intent-to-treat sample, age [p=0.01] and baseline QIDS-SK score [p<0.001] were significant predictors of remission. Hence, genetic analyses were performed covarying for both.

Within the significant overall model [X²=67.58, df=29, p<0.001] only rsl0245483 contributed significantly to prediction of remission. For rsl0245483, there was a significant main effect on remission using multiple testing correction [W=12.64, p<0.001; main effect odds ratio=3.48] and a significant interaction by treatment arm [W=11.18, p=0.001; interaction odds ratio=1.73]. Common allele homozygotes for rsl0245483 responded significantly better to escitalopram [p=0.032] and sertraline [p=0.020] than did minor allele homozygotes. Minor allele homozygotes responded significantly better to venlafaxine [p=0.018]. There were no effects noted in the heterozygotes. The specific contribution of rsl0245483 as a predictor of remission was also verified in univariate models assessing each SNP one at a time.

The effect was similar in whites and nonwhites. In white participants in the modified intent-to-treat sample [N=423], within the significant overall model [X²=61.51, df=29, p<0.001] rsl0245483 had a significant main effect on remission [W=7.22, p=0.007; main effect odds ratio=3.54] and a significant interaction by treatment arm [W=6.99, p=0.008; interaction odds ratio=1.78], which did not pass the multiple testing threshold. For nonwhites, within the significant overall model [X²=55.79, df=28, p=0.001], there was a main effect of rsl0245483 on remission [W=11.42, p=0.001; main effect odds ratio=14.38] and a significant interaction between rsl0245483 and treatment [W=9.81, p=0.002; interaction odds ratio=3.54] that met the multiple testing correction threshold.

My take on this whole line of thinking is suffused with suspicion. It seems to me that the assumption that there will be biomarkers that predict antidepressant response is widely held, but I’m in the dark as to why. At least this study has a hypothesis – the transport of drugs across the blood-brain barrier.  This article is accompanied by a Perspective article from the NIMH Intramural Research Program [Clinically Useful Genetic Markers of Antidepressant Response: How Do We Get There From Here?] that suggests [you guessed it] more research.

STAR*D began in 2001 as an outgrowth of the TMAP program [often referred to as the infamous TMAP program] and has spawned a steady stream of both public and industry financed research into super-charging antidepressants ever since – now chasing the dream of predictive genetic biomarkers [which might lead to a productive enterprise in commercial testing]. Meanwhile, back at STAR*D, it looks as if someone’s going to have another shot at it:

End of ‘Trial and Error’ Approach to Depression, Schizophrenia?

Medscape Medical News

by Kenneth Bender

August 14, 2015

… Somaia Mohamed, MD, PhD, VA Connecticut Health Care System, and coauthors of the article describing the VAST-D study credit the Sequenced Treatment Alternatives to Relive Depression [STAR*D] study for highlighting the frequent inadequate response to initial treatments, but point out that the study did not ultimately identify optimal interventions after initial treatment failure.

They also note that the STAR*D study did not include an atypical antipsychotic augmentation treatment arm, because the study was conducted prior to FDA approval of that indication for an agent in this class.

The VAST-D study will incorporate atypical antipsychotic augmentation in the protocol, and the authors indicate that it will answer two principle questions unanswered by STAR*D: "For which patients, under what circumstances, is switching to vs augmenting with other antidepressants the most effective ‘next-step’ strategy, and how does augmentation with atypical antipsychotics compare to either switching or augmenting with antidepressants?"

The VA augmentation and switching treatments for improving depression outcomes (VAST-D) study: Rationale and design considerations

by Somaia Mohamed, Gary R. Johnson, Julia E. Vertrees, Peter D. Guarino, Kimberly Weingart, Ilanit Tal Young, Jean Yoon, Theresa C. Gleason, Katherine A. Kirkwood, Amy M. Kilbourne, Martha Gerrity, Stephen Marder, Kousick Biswas, Paul Hicks, Lori L. Davis, Peijun Chen, Alexandra Mary Kelada, Grant D. Huang, David D. Lawrence, Mary LeGwin, and Sidney Zisook

Psychiatry Research. Published Online: August 05, 2015

Highlights

• Over 2/3s of Major Depressive Disorder cases do not achieve remission on initial treatment.
• Urgent need to identify effective next step treatments for MDD.
• Switching to bupropion-SR vs. augmenting with bupropion-SR or aripiprazole.
• Compare 12-week remission and relapse for up to 6 months after remission.
• Seven methodological issues to balance efficacy and effectiveness.

Abstract

Because two-thirds of patients with Major Depressive Disorder do not achieve remission with their first antidepressant, we designed a trial of three “next-step” strategies: switching to another antidepressant [bupropion-SR] or augmenting the current antidepressant with either another antidepressant [bupropion-SR] or with an atypical antipsychotic [aripiprazole]. The study will compare 12-week remission rates and, among those who have at least a partial response, relapse rates for up to 6 months of additional treatment. We review seven key efficacy/effectiveness design decisions in this mixed “efficacy-effectiveness” trial.

Stepping Up to Address Our Nation’s Shame

PsychiatricNews

by Renée Binder, M.D.

July 13, 2015

… In June, I arranged for the Board of Trustees to tour San Quentin in northern California. It was a powerful, moving, and formative experience, and I’m thankful to Dr. Paul Burton, the chief psychiatrist, and to the California Department of Corrections and Rehabilitation for giving us that access. Our visit was important because, if one wants to understand firsthand the toll mental illness is taking on our country, one just needs to peer beyond the bars of our nation’s jails and prisons. It’s also important to have a detailed and nuanced understanding of the situation. Our tour was a no-holds-barred look at San Quentin State Prison. For three hours, we were shown various aspects of prison life…. We specifically saw the psychiatric facilities, which are highly used by the inmates. In many ways they are state of the art. As you’d expect, sharp angles in the halls and cells, down to the door hinges and door handles, were filed smooth to prevent inmates from using them to aid in a suicide attempt. Many cells provided a sanctuary for inmates, nearly always curled up on a plain bed with a blanket covering them head to toe.

But the rooms that captivated our group were the group therapy rooms. Separate enclosures or “modules” formed a semi-circle for people who are at once both dangerous and needing and deserving of help. We briefly observed one group. Those participating highly praised the care they were getting. One patient’s body language told us when he had enough of our interruption; in a visceral way, it was clear he valued his treatment.

The four psychiatrists with whom we interacted were obviously compassionate and concerned about each of their patients. At each stop, it was abundantly clear that the care provided by the staff psychiatrists was superb and professional. Even if incarceration itself is likely a detriment to many individuals’ mental health, the physician-patient interactions we witnessed gave us hope…

Jails and prisons have become the front lines of treatment for mental illness. The data indicate that San Quentin is an anomaly in the quality of care that’s available in such a setting. This is likely due to its proximity to a highly desirable metropolitan area and its affiliation with the University of California, San Francisco, Department of Psychiatry.

According to a 2010 study by the Treatment Advocacy Center and the National Sheriff’s Association, there was one psychiatric bed for every 300 Americans in 1955. By 2005, that rate dropped to one psychiatric bed for every 3,000 Americans. Over time mental illness has been criminalized, and our jails and prisons take up the slack, despite being seriously ill-equipped to do so. Our jails and prisons have turned into warehouses for those with mental illness; the number of people with mental illness in jails is three to six times higher than that of the general public.

This is why APA and the American Psychiatric Association Foundation have joined forces with the National Association of Counties and the Council of State Governments Justice Center in the “Stepping Up” Initiative. The initiative seeks to reduce the number of people with mental illness in our prisons and jails by promoting the use of mental health courts and diverting minor offenders who have mental illness to treatment resources rather than incarceration…

We must reduce the use of our jails and prisons as warehouses for Americans with mental illness, partly to help our patients, but also because of what this tragedy says about the kind of nation we are. This is an effort for our patients, for our profession, and for our nation.

… psychiatry’s concern about the imprisonment of the mentally ill is being used by advocates of forced outpatient treatment as a Trojan Horse.  The advocates for forced treatment in outpatient settings [such as the Treatment Advocacy Center] argue that forced drug treatment would prevent the mentally ill from ending up in prison, and thus their legislation, which in fact curbs the civil rights of citizens in profound ways, comes cloaked in the rhetorical garb of “humanism.” If we are going to have an honest societal discussion about the shame of imprisoning the “mentally ill,” then it needs to be completely decoupled from that legislative agenda. Indeed, an argument can be made that the growing imprisonment of the “mentally ill” is yet another example of how our drug-based paradigm of care has failed us. The use of psychiatric medications in our society has exploded over the past 25 years; there is great societal pressure put on people diagnosed with schizophrenia or bipolar disorder to take their medications; and yet we now have this problem of hundreds of thousands of “mentally ill” in prisons and jails…

However, I do agree with Allen Frances on this point: Any effort to remake mental health care in this country needs to include a focus on what can be done to help the multitudes of poor people and disenfranchised people who show up in distressed emotional states in emergency rooms and homeless shelters, and the eventual routing of many such people to jails and prisons.  But, in my opinion, if we want to find a solution, we should focus on providing housing, social support and jobs that help people lead meaningful lives. If we want to reduce the number of people said to be mentally ill and in jail, then we should focus on reducing poverty in this country. Substantially raising the minimum wage would, undoubtedly, be a good first step in addressing this problem…

A Debate Between Allen Frances and Robert Whitaker
Robert Whitaker

For some time now I have maintained that commitment—that is, the detention of persons in mental institutions against their will—is a form of imprisonment; that such deprivation of liberty is contrary to the moral principles embodied in the Declaration of Independence and the Constitution of the United States; and that it is a crass violation of contemporary concepts of fundamental human rights. The practice of "sane" men incarcerating their "insane" fellow men in "mental hospitals" can be compared to that of white men enslaving black men. In short, I consider commitment a crime against humanity. In the first place, the difference between committing the "insane" and imprisoning the "criminal" is the same as that between the rule of man and the rule of law: whereas the "insane" are subjected to the coercive controls of the state because persons more powerful than they have labeled them as "psychotic" "criminals" are subjected to such controls because they have violated legal rules applicable equally to all…

The fundamental parallel between master and slave on the one hand, and institutional psychiatrist and involuntarily hospitalized patient on the other, lies in this: in each instance, the former member of the pair defines the social role of the latter, and casts him in that role by force…

In this therapeutic-meliorist view of society, the ill form a special class of ”victims” who must, both for their own good and for the interests of the community, be "helped"  — coercively and against their will, if necessary — by the healthy, and especially by physicians who are "scientifically" qualified to be their masters. This perspective developed first and has advanced farthest in psychiatry, where the oppression of "insane patients" by "sane physicians" is by now a social custom hallowed by medical and legal tradition. At present, the medical profession as a whole seems to be emulating this model. In the Therapeutic State toward which we appear to be moving, the principal requirement for the position of Big Brother may be an M.D. degree.

Involuntary Mental Hospitalization: A Crime against Humanity
Thomas Szasz,

Right now, there’s an enormous and somewhat understandable back lash to the recent era of psychopharmacological/neuroscientific goings on, and pressing ahead without addressing all the conflicts in the air is likely to be a lesson in futility. The sentiment expressed above by Robert Whitaker and in the British Psychological Society’s Report suggests that psychotic conditions aren’t, in fact, mental illness at all, but rather some barometer of social ills and imbalances, or even a sign of psychiatrists not listening.

If Dr. Binder is serious about approaching this problem, she’s going to have to address all of the views. The official mouthpieces in psychiatry right now seem to think that they can just ignore what’s happened in these last 20 or 30 years if they start behaving in more rational ways now. They think that they can avoid acknowledging the sins of the fathers. That is unlikely to help anyone at this point.  All they’re going to hear about is forced drugging, imprisonment, overmedication, "bio-bio-bio," medical models, the DSM-whatever, pharma this and pharma that.

I’ve had a lot to say about that Report along the way myself, the views of the retired old psychiatrist I see in the mirror. But Dr. Coyne used a YouTube video of Kris Kristofferson singing The Silver Tongued Devil and I to illustrate Dr. Carroll’s wordsmithery – and posted Janis Joplin’s Me and Bobby McGhee [a Kristofferson classic] below it. Those videos reminded me of an earlier and much different time. Kristofferson himself embodied the contrasts of those years – a Rhodes Scholar, Air Force Captain, Ranger, and helicopter pilot who turned down an English Instructorship at West Point to become a songwriter in Nashville. Those were interesting times.

I had already thought about the 1960s mentality reading the BPS Report. The anti-establishment tone, the discounting of the dire changes in mental functioning, the simple solutions to complex phenomena were all familiar from those salad days in my own past. But Dr. Coyne’s musical interlude helped me remember the time when my own sixties naiveté first met the stark reality of psychosis, and I understand more fully what bothers about that BPS [British Psychological Society] Report. It’s as reductionistic as that of the other pole of the antipodes, those psychiatrists who talk as if antipsychotic medication compliance is all there is to treating people with psychotic illness. Dr. Carroll’s term is dead center – "Domesticating Psychosis" – as are Dr. Pies’ “Trivializing the Suffering of Psychosis…” and Dr. Pierre’s “Romanticizing psychosis”.

Much of the BPS Report was about empathy and collaboration, about kindness and respect, about the humanistic values that are an integral part of any interaction with the people who come looking for help – essential ingredients of medical care from long before science caught up. These are hardly new discoveries or unique to the profession of psychology. They are the bedrock of the values I’ve known for my fifty years in medicine, psychiatry included.

So the notion that there’s some concrete impersonal ‘disease model‘ as it’s presented in this Report or in the anti-psychiatry blogs can’t help but grate. I have to actively remind myself that it’s true that there are psychiatrists [that I sarcastically refer to as the KOLs] who do naively speak as if brain science is all there is; who have abetted an epidemic of inappropriate overmedication [that I’m as pissed off about as any psychologist]; who, by the way, are the negative stimulus for this blog in the first place; and who discredit the legitimate biological psychiatrists that have contributed so much to our knowledge and patient care. So I’m mad too. With that reminder, I can usually back off from reacting.

But this BPS report has obviously gotten to me, gotten to a lot of us. I said my emotional response was complicated. Even now, I can still feel those 60s feelings that were perhaps appropriate for things like Segregation, the Cold War, or our misbegotten war in Southeast Asia. But they don’t come close to encompassing the magnitude that is psychotic illnesses – back then or now. This Report was too much the polemic, too "sixties", too politically correct, and too simplifying. It attempted to "make nice" with one of the more painful and devastating afflictions that can befall a human being, particularly the young. And while we can all be excited with the cases that recover, there are many who have a very different trajectory.