ombudsman envy…

Posted on Sunday 15 November 2015

When it’s all said and done, I’m not impressed that our kvetching about the state of affairs with clinical trials, regulatory approval, pharmaceutical marketing, and the corruption and glitches along these processes will be particularly effective in the long run. We now know the problems, and we know they are sustained by a powerful set of forces. Furthermore, we know the solution [or at least an important part of the solution] – Data Transparency – and for that, we need structural reform. If the trial data is available, we can bypass all the spin and sin and see for ourselves [of course that depends on some "we" who is willing to do the surveillance and re-analysis]. So for a number of reasons, that has focused my attention on the goings-on in the European Union:
  • The European Medicines Agency [EMA] has embraced the concept of Data Transparency [a no-brainer] and is working out its policy.
  • The EMA is centralized, seems more transparent, more distant from the "powerful set of forces" and is more accessible than our FDA.
  • The same drugs are independently evaluated by the EMA and FDA, so transparency in one becomes transparency for both.
  • And then, there’s the European Ombudsman.
British Medical Journal
by Tom Jefferson
13 Nov, 2015

The institution of the European Ombudsman celebrated its first 20 years of activity with a party for staff and all those who have and still are contributing to its work. The shindig was held in the European Parliament. In the words of the current Ombudsman, Emily O’Reilly, the Ombudsman’s function “was born out of the debate on the emerging European citizenship in the early 1990s, and its purpose precisely is to enable those European citizens to hold the ever more powerful EU institutions to account, as the direct effect of what they do impacts more and more on the daily lives of the people. It acts in a complementary way to the courts and to the parliament, as a check on EU institutional power.

In the current climate, O’Reilly’s words may seem like a wish rather than reality. Except that the office’s record in the matter of access to secret clinical data is exemplary. It is to the Ombudsman that the Nordic Cochrane Centre referred in its attempt to access clinical study reports from the European Regulator, the European Medicines Agency [EMA], and it was the Ombudsman who sided with Peter Gotzche and colleagues. This led to the recognition that data relating to clinical trials cannot be considered confidential, as it is a public good.

I have chronicled the evolution of the EMA’s policy and its forthcoming release of large quantities of reports. Reports have also been released since the Ombudsman’s ruling in 2010. The visibility of such documents has finally lead to the realisation that clinical trials published in journals may not be trusted because they do not provide sufficient information and detail to understand the strengths and weaknesses of a trial…
If you’ve tried to deal with the FDA or the ORI or our other agencies, I hope you have better luck than I have. Responses are sluggish and rarely lead one anywhere. On the other hand, the European Ombudsman’s office responds quickly and is quite a contrast to the tired bureaucracy of our equivalent agencies [give me a young government every time]. And as the links above document, they’re on a roll with Data Transparency. Here‘s my crude timeline. In my humble opinion, if we are to get somewhere with Data Transparency, it will be coming from the EMA. Hopefully, they’ll pull us along. Nothing but Kudus for the European Ombudsman! [and her supporters] from the 1boringoldman campus]…
Mickey @ 12:57 PM

a simple truth…

Posted on Saturday 14 November 2015

In psychiatry, we’re rarely afforded the definitive data enjoyed in a lot of science. It’s just the way things are. But that doesn’t mean we can’t be glad when some definitive graphs come along – particularly when they support clinical experience. The data in this 2004 paper is an example. I received this link from multiple directions when I wrote about the recent article claiming increased efficacy with increasing dose [an inconvenient truth…]. The graphs are of 5-HTT transporter occupancy at varying doses of five different SSRI/SNRIs [the minimal effective dose marked with the dotted vertical lines]:
by Jeffrey H. Meyer, Alan A. Wilson, Sandra Sagrati, Doug Hussey, Anna Carella, William Z. Potter, Nathalie Ginovart, Edgar P. Spencer, Andy Cheok, and Sylvain Houle
American Journal of Psychiatry 2004 161:826–835.

Objective: Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin [5-HT] transporter [5-HTT]. The authors used [11 C] DASB positron emission tomography to measure occupancies of three other selective serotonin reuptake inhibitors [SSRIs] at minimum therapeutic doses. The relationship between dose and occupancy was also investigated.
Method: Striatal 5-HTT binding potential was measured in 77 subjects before and after 4 weeks of medication administration. Binding potential is proportional to the density of receptors not blocked by medication. Subjects received citalopram, fluoxetine, sertraline, paroxetine, or extended-release venlafaxine. Healthy subjects received subtherapeutic doses; subjects with mood and anxiety disorders received therapeutic doses. Percent reduction in 5-HTT binding potential for each medication and dose was calculated. To obtain test-retest data, binding potential was measured before and after 4 weeks in six additional healthy subjects.
Results: Substantial occupancy occurred at subtherapeutic doses for all SSRIs. Compared to test-retest data, each drug at the minimum therapeutic dose had a significant effect on striatal 5-HTT binding potential. Mean occupancy at this dose was 76%–85%. At higher plasma SSRI concentrations, 5-HTT occupancy tended to in- crease above 80%. For each drug, as the dose [or plasma level] increased, occupancy increased nonlinearly, with a plateau for higher doses.
Conclusions: At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.

hat tip to alto et al… 
In spite of 25 years of dreams and schemes, if these drugs don’t help on the first shot, they’re unlikely to do much better with prestidigitation. Because of the escalating side effects with increased dose, these drugs, like many in clinical medicine, have a therapeutic window. I’m awed with the number of patient dosed well beyond the window. Getting them to come down slowly is often a major undertaking, though there’s rarely a complaint once on a more rational dose. More doesn’t seem to be better, at least in my hands…
Mickey @ 9:55 PM

Posted on Saturday 14 November 2015

Later: At the end of a three year Air Force assignment to the USAFE hospital in Lakenheath England, it was about time to come home to our real lives. For our last trip to the Continent, we decided on camping through France. I had several weeks of leave and though we’d been to France often, we hadn’t ‘toured.’ So we loaded our diminutive Morris Minor with camping gear and took the Ferry to Calais. It couldn’t have been a more perfect trip. Somewhere in the middle we awoke in our tent and simultaneously noticed that our teeth were slightly purple [so we changed to white wine]. The trip back to Paris from the South was our only autorouteMorris Minor leg [superhighway], and our top-speed-low-sixty-miles-per-hour Morrris was definitely out classed, but we made it to the outskirts of Paris at midnight. The next morning, we decided that a ride down the Champs-Élysées would be  a nice way to end our European adventures before getting on the Ferry, and soon onto the plane home.

Totally by chance, without our even really noticing, we were the last car allowed onto the boulevard that day. It was inauguration day for Giscard d’Estaing who had defeated François Mitterrand. Neither of us spoke anything more than "menu" French, so after two weeks of wandering, we were news-dumb and had no clue we were crashing a presidential parade. The streets were lined with spectators who were as amused as we were with our toy British car as a one-car parade. They waved their flags, laughed, and clapped as did we – basking in our short-lived fame. It was, indeed, one fine Swan Song.

I’m telling my little story because I don’t know what else to do to say I love France the country, France the culture, and France the people – even the Parisians [though I’m not sure that was mutual]. I wasn’t even mad when France passed on our invitation to Iraq. Afghanistan seemed right but Iraq didn’t, so I agreed. I hate it that they’re about to have to go through what we experienced after 911. There’s no other choice now, but there’s really no point…
Mickey @ 6:53 AM

an inconvenient truth…

Posted on Friday 13 November 2015

While I was writing this earlier post [it just is what it is…] about a man who had had his Paxil dose inappropriately raised in response to withdrawal symptoms, I wondered why I was even writing it. Was I patting myself on the back for having developed a high level of suspicion about withdrawal symptoms? or about looking into over-medication? I thought about that recent book, "Mistakes were made, but not by me" that I recently ordered. Was I pointing out the mistakes of others but not looking in the mirror at my own? But later, a few more sensible things occurred to  me. For one, I had seen the article below in the advanced publications in the AJP before going to work, and I wondered what it was going to conclude. My eyes had landed on some particular phrasings [in red]…
by Ewgeni Jakubovski, M.A., Anjali L. Varigonda, M.D., Nicholas Freemantle, Ph.D., Matthew J. Taylor, Ph.D., Michael H. Bloch, M.D., M.S.
American Journal of Psychiatry. Published online: November 10, 2015.

Objective: Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors [SSRIs] in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder.
Method: The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder.
Results: Forty studies involving 10,039 participants were included. Longitudinal modeling [dose-by-time interaction=0.0007, 95% CI=0.0001–0.0013] and endpoint analysis [meta-regression: β=0.00053, 95% CI=0.00018–0.00088, z=2.98] demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects [meta-regression: β=0.00207, 95% CI=0.00071–0.00342, z=2.98] and decreased likelihood of all-cause dropout [meta-regression: β=–0.00093, 95% CI=–0.00165 to −0.00021, z=−2.54].
Conclusions: Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents [50 mg of fluoxetine] The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.
[I make no apology for being somewhat skeptical maybe even slightly paranoid when I read our literature. The recent track record of psychiatric Clinical Trials and Meta-analyses more that justifies that stance imho…]

This study uses some fancy statistical manipulation to conclude that higher doses of antidepressants might be a little more likely to be effective in treating depression. The psychiatric literature is filled with articles about schemes to get more mileage out of the antidepressant treatment. There was the pharmaceutical pipeline that regularly released a new molecule every couple of years. There were several different classes of drugs [TCAs, MAOIs, SSRIs, SNRIs, Buproprion]. We studied sequencing [STAR*D, TMAP], combining [CO-MED], and augmenting [thyroxin, Atypical Antipsychotics]. Here we have the suggestion to try a higher dose. The group a UT Southwestern [Rush, Trivedi] insisted that if we pushed the doses and treated to remission, we would up our odds back when they designed STAR*D, and Dr. Rush is still talking about it [Isn’t It About Time to Employ Measurement-Based Care in Practice? AJP October 2015]. So far, the notion that genetic testing would refine our prescribing remains just that – a notion. Along the way, we’ve had Vagus Nerve, Transcranial Magnetic, and Deep Brain Stimulators. One would think that with such a heavily studied toolkit literally dominating twenty-five years of our journal literature, offering so many combinations and permutations, we would’ve arrived in the promised land. The inconvenient truth is that we haven’t – we haven’t even come close.

Skeptics like me would say it’s because most depression arises in response to psychological, biographical, and social forces that don’t fit the current DSM model of Major Depressive Disorder – that instead of Treatment-Resistant-Depression, we’d be best advised to turn our attention back to Non-Biomedical-Responsive-Depression with a bigger toolkit than simply Cognitive Behavior Therapy – a direction strongly opposed by the Managed Care/Collaborative Care/Integrative Care models. But even Biomedical Devotees like Dr. Insel aren’t satisfied with the current state of play and he has prattled on endlessly about his disappointment with our lack of progress.

Another facet of this inconvenient truth is that the therapeutic zeal accompanying the attempts to expand the effectiveness of the medications has fueled an epidemic of iatragenic illness [illnesses caused by treatment] – overmedication, adverse effects, dysinhibition, violence, withdrawal syndromes, etc. Which brings me back to my starting place. After I saw that abstract suggesting higher antidepressant doses before I headed off to the clinic, I recall thinking about how much time I spend dealing with patients who have iatragenic illnesses from their medications or who show up seeking a change in their medications. I mentioned a mega-overmedicated case recently [blitzed…, some truths are self-evident…] and this man I saw later in the day [it just is what it is…], but that’s just the tip of an iceberg of how many such cases I see. We’re beginning to see Obamacare and Medicaid patients now in the clinic, and I think the local doctors and contract mental health center are beginning to send those cases my way [for me to try to get straightened out]. That obviously can’t go on forever, even at the moment it’s barely manageable. But the point is, the inconvenient truth for me is that I appear to be developing a sub-specialty I would never have imagined – medication untangler.

Now I remember that on the drive home, I was thinking of my training director days, and fantacizing that I would now add a seminar on iatragenic illness as a way of teaching about how to recognize and manage the situations I’m talking about here [and also as a way of teaching what not to do and how to keep therapeutic zeal in check]. We could alternate readings and cases, and I’d bet it would be both popular and helpful. Hopefully, there will come a day soon when we won’t need medication untangler specialists. And maybe there will come a time when one can again simply say:
    "Let’s take another look at your story. Maybe there’s something going on in you or your life that needs much more attention, something contributing to your depression that medication can’t possibly change."
Mickey @ 11:45 AM

the curse of insel’s legacy…

Posted on Thursday 12 November 2015

I was reading along in Dr. Makari’s Opinion piece in the New York Times when I got to the final paragraphs where he artfully articulated something I’ve been trying to say for a very long time:
New York Times – Opinion
NOV. 11, 2015

Unfortunately, Dr. Kane’s study arrives alongside a troubling new reality. His project was made possible by funding from the National Institute of Mental Health before it implemented a controversial requirement: Since 2014, in order to receive the institute’s support, clinical researchers must explicitly focus on a target such as a biomarker or neural circuit. It is hard to imagine how Dr. Kane’s study [or one like it] would get funding today, since it does not do this. In fact, psychiatry at present has yet to adequately identify any specific biomarkers or circuits for its major illnesses.

Critics worry that this new stipulation will limit clinical studies and foster what has been all too familiar in psychiatry — unwarranted speculation aimed at prematurely reducing many layers of intersecting causality to one. If so, the institute will become the latest in a long, unhappy line of those who pressed for a simple solution to the Janus-faced problems of mind-brain illness. In the meantime, Dr. Kane’s study provides pragmatic clinicians with strong new evidence for an old idea: Individuals with mental illness should be fully engaged as beings whose rich psyches and ever-present social worlds are just as real as their brains.
I’ve been hard on Tom Insel and tried to say why every time I write about him, but I don’t ever feel like I get it said. But it’s simple. He thought he owned the NIMH and its directions. Last week in an interview, he blamed the NIMH’s inadequate analytic fire-power for not confirming his nebulous RDoC:
Five years ago, the NIMH launched a big project to transform diagnosis. But did we have the analytical firepower to do that? No. If anybody has it, companies like IBM, Apple or Google do – those kinds of high-powered tech engines…
Clinical Neuroscience, RDoC, Neural Circuits: These are some things he decided would lead us to the promised land, and so he made them preconditions for receiving NIMH grant money! No offense, but the Director of the NIMH is supposed to create an environment where our best and brightest researchers can pursue their ideas. It’s fine to keep them out of the stratosphere and insist that they propose projects that have some general value and realistic goals, but that’s not what Tom Insel did. He essentially told them what things he was interested in having them work on. Is the RDoC something of value? Who knows? Mainly because it doesn’t even exist. And would it transform diagnosis? Who knows? Again, because it doesn’t exist. And about those Neural Circuits, take a look at this earnest resident pretending to talk to a patient [the talk that matters…] about her Neural Circuits [instead of confronting her about her addictive behavior]:

Dr. Insel’s replacement will need to start by de-Inselizing the NIMH, and that’s going to be a big task. He micromanaged everything to follow his agendae. I wonder if it ever occurred to him that the reason that the NIMH didn’t give him what he wanted is that maybe it wasn’t there to find. He may have kept the researchers from spinning off and following some idiosyncratic path, but he did it by forcing them to follow his own idiosyncratic path.
Mickey @ 10:09 PM


Posted on Thursday 12 November 2015

An open letter to all US Presidential candidates

Medical experiments on humans [clinical trials] are carried out in the hope of improving health and furthering science. By their very nature they entail uncertainty about potential harms and benefits of a treatment or a procedure. This is why following WWII, prior ethics review by an independent committee has gradually been introduced as a key condition.

No benefit can be derived from trials which are either invisible or reported partially or selectively.

To avoid this risk, a growing number of organisations have made efforts to allow access to clinical trial results in a detail hitherto unknown.

Despite the growing international effort and a notable legislative effort in the EU, the US lags behind.

Study results posted on are, by definition, incomplete and unverified. Even so, eight years after the introduction of federal law FDAAA 2007 a very small number of results of registered trials have been made available and updated.

No detailed regulatory documents are available from the FDA. Physicians and patients require access to clinical study reports and anonymized individual patient data from trials of approved drugs and biologics.

US law and regulations globally affect organizational and professional behaviors with huge impact on health worldwide. The international composition of this letter’s signatories reflect this reality.

We call for a statement by all US presidential candidates on whether they support access to clinical trial data held by federal agencies, irrespective of topic, sponsor, country in which the trial was run or results.

We ask that they state what measures they would put forward, if elected, to address the scandal of invisible and distorted clinical trials.

Kudos to Tom Jefferson for drafting our consensus letter to the presidential candidates published today in the British Medical Journal. I feel honored to be included in this list of heavyweights. Some may think that such gestures are ineffective, but I disagree. We’ve had years of silence and the results speak for themselves. Now people are speaking out, there’s movement – actually fairly rapid movement for the usual pace of things in medicine and science.

For example, here’s recent article in the PLoS Mind the Brain Blog by  James Coyne that says:
    A university and clinical trial investigators must release data to a citizen-scientist patient, according to a landmark decision in the UK. But the decision could still be overturned if the University and investigators appeal. The scientific community needs the decision to be upheld. I’ll argue that it’s unwise for any appeal to be made. The reasons for withholding the data in the first place were archaic. Overturning of the decision would set a bad precedent and would remove another tooth from almost toothless requirements for data sharing.
We didn’t need Francis Collins, Director of National Institutes of Health to tell us what we already knew, the scientific and biomedical literature is untrustworthy.

And there is the new report from the UK Academy of Medical Sciences, Reproducibility and reliability of biomedical research: improving research practice.

There has been a growing unease about the reproducibility of much biomedical research, with failures to replicate findings noted in high-profile scientific journals, as well as in the general and scientific media. Lack of reproducibility hinders scientific progress and translation, and threatens the reputation of biomedical science.

Among the report’s recommendations:
  • Journals mandating that the data underlying findings are made available in a timely manner. This is already required by certain publishers such as the Public Library of Science (PLOS) and it was agreed by many participants that it should become more common practice.
  • Funders requiring that data be released in a timely fashion. Many funding agencies require that data generated with their funding be made available to the scientific community in a timely and responsible manner
A consensus has been reached: The crisis in the trustworthiness of science can be only overcome only if scientific data are routinely available for reanalysis. Independent replication of socially significant findings is often unfeasible, and unnecessary if original data are fully available for inspection.

Numerous governmental funding agencies and regulatory bodies are endorsing routine data sharing.

The UK Medical Research Council (MRC) 2011 policy on data sharing and preservation  has endorsed principles laid out by the Research Councils UK including:
    Publicly funded research data are a public good, produced in the public interest, which should be made openly available with as few restrictions as possible in a timely and responsible manner. To enable research data to be discoverable and effectively re-used by others, sufficient metadata should be recorded and made openly available to enable other researchers to understand the research and re-use potential of the data. Published results should always include information on how to access the supporting data.
The Wellcome Trust Policy On Data Management and Sharing opens with:
    The Wellcome Trust is committed to ensuring that the outputs of the research it funds, including research data, are managed and used in ways that maximise public benefit. Making research data widely available to the research community in a timely and responsible manner ensures that these data can be verified, built upon and used to advance knowledge and its application to generate improvements in health.
The Cochrane Collaboration has weighed in that there should be ready access to all clinical trial data:
    Summary results for all protocol-specified outcomes, with analyses based on all participants, to become publicly available free of charge and in easily accessible electronic formats within 12 months after completion of planned collection of trial data; Raw, anonymised, individual participant data to be made available free of charge; with appropriate safeguards to ensure ethical and scientific integrity and standards, and to protect participant privacy (for example through a central repository, and accompanied by suitably detailed explanation).
Many similar statements can be found on the web. I’m unaware of credible counterarguments gaining wide acceptance. Yet, endorsements of routine sharing of data are only a promissory reform and depend on enforcement that has been spotty, at best. Those of us who request data from previously published clinical trials quickly realize that requirements for sharing data have no teeth. In light of that, scientists need to watch closely whether a landmark decision concerning sharing of data from a publicly funded trial is appealed and overturned…
And he goes on to describe several important cases to follow as the voices for Data Transparency grow stronger…
Mickey @ 10:59 AM

it just is what it is…

Posted on Tuesday 10 November 2015

It was towards the end today’s clinic. He was a big guy, friendly, seemed neither anxious nor depressed. He had come to have his meds refilled. He was on Paxil 60mg in the morning and Remeron 45mg at night. He launched right into his story:
He had always worked Construction, but when the housing market crashed, so did his livelihood. He couldn’t find work anywhere. His [sort of] wife was out of work as well. He got depressed and was started on Paxil 10 mg by a nurse practitioner. When it looked like he was going to lose his house, he went into the breaking and entering business for the first time in his life. After some early successes, he got caught in the act and found himself with no [sort of] wife, no house, and a five year prison sentence. I asked how the Paxil dose had gone from 10 to 60 milligrams. He asked me if I’d been to prison [first time I’ve ever been asked that]. But what he wanted to explain to me was how boring prison life can be and wondered if I already knew.

He said, "It’s like a grammar school playground. A bunch of guys with nothing to do except watch t.v., eat, and get in fights with each other. When you get in a fight, you end up on solitary for a few days. And I got really depressed in solitary so the doc increased my meds." That happened several times, and up went the medication dose. I asked if they gave him medications on solitary, but that was what he’d already figured out on his own – that it was withdrawal symptoms. "But by the time I figured it out, I was on 60 —-ing milligrams." The Remeron had been started because of insomnia, something he had never had before. His description of the withdrawal symptoms was classic, down to the brain zaps [for which he had a more colorful but less printable name]. He had tried to come down on the Paxil dose, but invariably got the symptoms late in the day and so he took the skipped pills. He would squirrel away a half pill here and there to build a "stash" in case of getting sent to solitary, and he had definitely learned to avoid fights. He was terrified that he wouldn’t be able to get the medication. The withdrawal symptoms were that bad. And he was convinced that he’d never sleep again without the Remeron.

He had already given a few hints along the way about how to proceed. He was on two drugs with withdrawal syndrome possibilities, one he knew about – Paxil. So Paxil seemed the place to start. His own attempts failed at "the end of the day." With the short acting drugs, people taking them only once a day often get evening symptoms and I even wondered if that was part of why the dose was so high [and maybe even wondered if that had something to do with the Remeron addition]. Something I’ve learned is that if one comes on too strong with the tapering meme, the patients get scared go elsewhere to someone who will just write the refills. So I suggested that the first order of business was to get him to a twice daily Paxil dosing. Move a half pill to the afternoon every week or two. When I explained why, he liked to idea. Once we got to a twice daily dose [30 mg twice a day], we could start a taper with  less fear of evening withdrawal symptoms. And if half a pill doesn’t work, I told him to try moving by quarters. But the real point is that he seemed to be on-board once he felt comfortable I wasn’t going to "cut him off."
My own experience is that you are often flying by the seat of your pants tapering these drugs. And I’ve found that it’s always important to convey that you’re not going to pull the rug out from under the patient. The other thing is that if I can engage the patient in the enterprise, they often find schemes on their own you wouldn’t have thought of. For a few patients, they never get off. For others, it’s a long slow process. And then there are many who can get off pretty quickly once they see that it’s possible to come down on the dose. But the rate seems to be a physically determined individual difference. Certainly, this is not a majority phenomenon. Even though I try to taper everyone, many just stop on their own with no problems. I know I can’t tell in advance who will fit into what group. I’m absolutely sure that most of the difficult cases are like this – where withdrawal has been misunderstood and some clinician has chased symptoms with escalating doses.

He seems pleased as punch to be out of prison and I doubt he’ll ever go back [even as I wrote that, I remembered that my track record predicting criminality has not been stellar]. But I’d bet the house that his illness started as situational and is now iatrogenic [caused by his medications]. I know nothing about SSRI being associated with non-violent crime, but who knows if that Paxil had something to do with his later life new profession?

I wish I could say that this was an unusual kind of case. It’s not at all unusual. I spend a surprising amount of time trying to figure out how to deal with medication messes like this. Because of time pressures, there’s not a lot of psychotherapy of any classic sort going on in the clinic, but I do have time to do a reasonable diagnostic evaluation though it’s often spread over multiple meetings. With the coming of Obamacare and Medicaid, I now see more patients that I can refer to local therapists, who will accept the low fees [if you don’t send too many] – and there are some decent ones around. While it’s an irony that a way overtrained psychoanalyst spends so much time untangling medication snafus, I actually kind of enjoy it. If it were a full time job, I think I would meet Mr. Burnout quickly, but it isn’t [a full time job], and I don’t [feel those burnout signs and symptoms that say "time to move on"]. I would love to live in a world where the medications were mostly solutions rather than frequently the problem, but for now, it just is what it is…
Mickey @ 8:48 PM

have no place…

Posted on Tuesday 10 November 2015

O! be some other name:
What’s in a name? that which we call a rose
By any other name would smell as sweet;
So Romeo would, were he not Romeo call’d,
Retain that dear perfection which he owes
Without that title.
William Shakespeare

It’s hard to imagine that the Journal of the American Medical Association can publish something like the viewpoint piece on the right and expect anything except mockery, and plenty of it. The notion that changing the name of Conflict of Interest to a Confluence of Interest might change the fundamental truth that whatever passes for objectivity in science [or for that matter anything else] evaporates when there is a personal stake involved. This is a bit of wordplay that belongs in the category of "the dog ate my homework."

9 November 2015

Disingenuous denial

JAMA. 2015 314:1791. “Confluence, Not Conflict of Interest” now appears in print, and leads me to break my rule and comment on this article a second time, because I think it marks a low point for JAMA. It aligns the journal with the disingenuous deniers who pretend that conflicts of interest don’t arise when authors and investigators write about work that they have a vested interest in promoting. It joins together JAMA with the NEJM which took a similar stance in a series of opinion papers earlier this year. This is a sort of Republican Tea Party of the soul, where you know you are saying something false and daring people to contradict you, knowing that their very engagement is a form of legitimation. And besides, you have power over them and they don’t over you. Blake called this place Ulro, and it leads to nothing but harm and barrenness — for those involved as well as for everyone else. But it is perfectly possible to get out of Ulro and build a better world.
Richard Lehman’s column in the BMJ usually hones in on the central issues in his journal reviews, but this time he’s especially quick to get to the heart of the matter. This absurd piece in the JAMA goes against an essential feature of "human nature" and the authors seem to think that surrounding an obviously wrong premise with several pieces of forced logic might fool someone. They begin:
Given the broad array of stakeholders, the diversity of approaches, and the concern that such policies might restrain innovation and delay translation of basic discoveries to clinical benefit, the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania recently convened an international meeting on conflict of interest…
If you follow Conflict of Interest issues in psychiatry, you are unlikely surprised that this viewpoint article comes from the University of Pennsylvania. Psychiatry Chairman Dwight Evans has himself been involved in several COI investigations. In a particularly egregious example involving Paxil Study 352, the University exonerated Evans with a remarkable comment:
By Ed Silverman
March 1st, 2012

The University of Pennsylvania has denied allegations made by one of its professors that several other academics – including his department chair – allowed their names to be added to a medical journal manuscript, but gave control of the contents to GlaxoSmithKline, according to his attorney. The study, which was funded by the drugmaker and the National Institutes of Health, looked at the impact of the Paxil antidepressant on patients with bipolar disorder.

At the same time, the university has acknowledged a claim by the professor, Jay Amsterdam, that the 2001 study was ghostwritten by Scientific Therapeutics Information, his attorney tells us. However, he says the university is not planning on taking any action in connection with the ghostwriting. The study, which was published by the American Journal of Psychiatry [see here], did not mention that STI played any role.

“They said his allegations were not meritorius, although they did find that the publication at issue was ghostwritten,” says Bijan Esfandiari, the attorney, citing a letter and other documents he received from the university. “They acknowledged that a marketing firm was involved in drafting, and everything associated with, the issue. But in response to our complaint, they said that, at the time these events took place, which was between 1998 and 2001, ghostwriting was standard practice and everyone was doing this, so therefore, we’re not going to punish any individuals”…
While there was, indeed, a lot of corruption in the years around the turn of the century, to dismiss it with something tanamount to "but there was a lot of that going around" as if it were a fad or a pesky virus hardly rises to any reasonable medical or academic standard. It’s an argument as lame as "… such policies might restrain innovation and delay translation of basic discoveries to clinical benefit." Medicine arose in ancient history and survived for centuries not based on powerful scientific advances. Those advances are only in their second century. Medicine prevailed because it was among the few professions that was able to adhere to a consistent and enduring ethical stance. A resistance to outside Conflicts of Interest has been an implied element of that ethic throughout our history. Arguments such as those expressed in this JAMA viewpoint article simply have no place in our tradition or our literature. And to have these recent articles actually advocating for conflicted authorship in our two major journals [NEJM: Revisiting the Commercial–Academic Interface, JAMA: Confluence, Not Conflict of Interest] is cause for alarm…
Mickey @ 8:00 AM


Posted on Tuesday 10 November 2015

Aung San Suu KyiWhile I’ve given up political blogging for good, there is a story I followed in the past that may finally be coming to a long awaited resolution. It’s the story of Burma [Myanmar] which is under a military dictatorship backed by the world’s largest standing army. Since my summary in 2007 [getting up to speed on Burma…], much has changed, but one thing has stayed the same – Nobel Peace Laureate Aung San Suu Kyi. After years of prison and house arrest, she is free and her democratic reform party appears to be heading for a huge victory [Myanmar vote has opposition party confident of landslide, Myanmar’s Aung San Suu Kyi: NLD has won election majoritywith video interview]. The last time around [1990], the military shut the country down. It’s doubtful that they will be able to pull that off now. It will be a triumph for something decent in the world if she finally  prevails…
Mickey @ 6:23 AM

tom jefferson on data transparency…

Posted on Monday 9 November 2015

Tom Jefferson is an epidemiologist with the Cochrane Collaboration- a central figure in the reviews of Tamiflu® concluding that it was not the panacea for influenza claimed by the manufacturer. Later, along with Peter Doshi, David Healy, Kay Dickersin, and Swaroop Vedula, he authored the RIAT proposal [see Restoring invisible and abandoned trials: a call for people to publish the findings] which we followed in our article [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence]. In this video, he discusses the whole issue of Data Transparency, and then in the invited article that follows, proposes that public health policy rely only on independent trials and studies rather than the industry-influenced studies in the medical literature.

by Tom Jefferson
Drug and Therapeutics Bulletin of Navarre, Spain. 2015 23[2]:1-11.

Journal publications of randomised controlled trials [“literature”] have so far formed the basis for evidence of the effects of pharmaceuticals and biologics. In the last decade, progressively accumulating evidence has shown that literature is affected by reporting bias with evident implications for the reliability of any decision based on literature or its derivatives such as research synthesis. Instead of trying to reform the fields of research, industry, government, regulation and publishing, I propose basing public health decisions and reimbursement of any important intervention on independent trials and studies following the model pioneered by the mario negri Institute of Pharmacological research.
Note that the interviewer above mentions the TPP [Trans-Pacific Partnership] which is a multinational agreement currently being negotiated. It couldn’t be a bigger [and more crucial] deal. If you’re not up to speed on it, see this page on Public Citizen. Among many other things, it could potentially declare Clinical Trial Data a Trade Secret, undermining any and all attempts at reform…
Mickey @ 11:08 AM