a blast off…

Posted on Friday 16 September 2016

by Kathy L. Hudson, PhD; Michael S. Lauer, MD; and Francis S. Collins, MD, PhD
September 16, 2016.
New England Journal of Medicine
by Deborah A. Zarin, M.D., Tony Tse, Ph.D., Rebecca J. Williams, Pharm.D., M.P.H., and Sarah Carr, B.A.
September 16, 2016
STAT politics
By Charles Piller
September 16, 2016
Well, speaking of launches! Francis Collins [Director of the NIH], Deborah Zahn [Boss at ClinicalTrials.gov], Robert Califf [new FDA Commissioner] and Ben Goldacre [ClinicalTrials Everyman] in the STAT piece – big guns all around. And then add this to the mix:
Promoting innovation and access to health technologies
September 2016
A lot of good words in these reports. The spirit is there in all of them at first reading. It’s not yet time to pick apart those encouraging words and see if they will translate into actionable changes in the Clinical trial process. That’s for a close reading of the official documents when they’re fully available. But we can frame some important things to look for.

In the past, there have been reforms that should have worked, at least helped. They have failed us for several reasons, but one stands out. After the trumpets stopped blaring, they were just forgotten. The people doing the trials either didn’t do them, or didn’t do them right, or didn’t do them on time. The people in charge didn’t keep up with them or do anything in response to infractions if they even knew about them. They sounded good, but they flunked compliance, surveillance, and enforcement. So as we’re looking over these various changes and reforms, these provisions are paramount. Without these elements, it’s just another failed exercise.

I’m just going to be glad they’re doing something, and that the agencies seem to be working together for a change. These links are here for starters, but now it’s time to read them and their official versions and see what’s behind the good words, with an eye out for compliance, surveillance, and enforcement. Feel free to join in the fun…
Mickey @ 9:29 PM

an anniversary…

Posted on Friday 16 September 2016

Today is an anniversary for me. This post from a year ago today …

Posted on Wednesday 16 September 2015

Well, our RIAT article, Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence, is finally published online at the British Medical Journal. It’s fairly straightforward. The emphasis is on the harms analysis for obvious reasons – an accurate representation of a drug’s safety is always the first order of business…

… marked the end of an intense couple of years, all focused on our RIAT team getting to say this in print:

by Le Noury J, Nardo J, Healy D, Jureidini J, Raven M, Tufanaru C, & Abi-Jaoude E.
British Medical Journal. 2015 …

Conclusions: Neither paroxetine nor high-dose imipramine demonstrated efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data available to increase the rigour of the evidence base.

I first happened onto Paxil Study 329 in 2010 reading a letter from Paul Thacker then at the Project on Government Oversight [POGO] exposing it as ghostwritten [see roaches…]. The more I learned about it, the worse it looked. Over time, I had come to admire Jon Jureidini who had mounted the first challenge to the article in 2003 and David Healy who had pioneered our awareness of akathisia and suicidality with the Antidepressants. So I was honored to be asked to join them on the RIAT reanalysis team.

There are layers and layers of stories to tell about the writing of this article. It’s a story I expect will ultimately be told in detail. This is just an outline. We had originally planned to reanalyze the data already released by court order strictly following the a priori protocol [from before the study began]. We were able to stick with that plan in the efficacy analysis, supplementing it with a more modern correction method for missing values requested by the peer reviewers [Multiple Imputation]. But that wasn’t possible with the harms analysis. The method for cataloging harms wasn’t specified in the protocol, and the one used in the original paper obscured  the findings. So we apploed to GSK for the CRFs [original case report forms] and after another saga in its own right, we were granted remote access [50,000± pages]. The process of gaining the access and using the constricting remote access system are some of those other stories – partially documented on our web site [study329.org].

When it was finally completed and submitted, it wasn’t an ending, but the beginning of another story. Over the next year, it went through seven major resubmissions, multiple peer reviews and independent analyses. Acceptance was never assured until near the end of the process. And there were plenty of frayed nerves within and among everyone involved, particularly near the end of that year. It was something new for the authors, the journal, and the genre – and that showed in the process. I only wish other clinical trial reports were as closely looked at as this one. So the prepublication year was another whole story unto itself.

In an area where people question how involved the listed authors are in the production of a published article, or whether the journals are thorough in their review, our paper stands on its own. It was unfunded research. The authors on the byline were the only act in town. We did the negotiating, extracted the data, ran the analyses, checked each others work, wrote and edited the narrative, drew the graphics, made the submission, fielded the correspondence, etc. No ghosts anywhere in [or out of] sight. As mentioned, it was vetted like none other by the BMJ. And the final paper was well received and is widely quoted. It was definitely all well worth it. I got to work with some amazing colleagues on something that mattered. Who could ask for more than that? I hope others will follow the principles of a RIAT anaysis and take a look at many other questioned studies.

You can’t learn clinical medicine from just reading books. You ultimately learn it in a clinic. After this experience, I’d say the same about clinical trials and their results. The process of being on this team was an invaluable way to understand their ins and outs, how to evaluate them, and to see how easily they can be distorted. For me, it’s an anniversary to remember…
Mickey @ 1:37 PM


Posted on Friday 16 September 2016

The Onion. 2015 51[7]:1-2.

Noting that similar outcomes were achieved under both approaches, a landmark decade-long study of mental health treatment options published Tuesday has found that talk therapy and antidepressant medications are equally effective at monetizing clinical depression. “Our data indicate that regular counseling sessions and prescription drugs have similarly high success rates in generating large sums of money from the clinically depressed,” said Katherine Hutton of the University of Oklahoma, the study’s lead author, noting that both methods demonstrated consistent positive earnings across chronic, episodic, and seasonal depression cases. “While some people make tremendous profits with drugs, others see substantial revenues from therapy. Together, these are two very powerful tools for improving the health care industry’s bottom line.” The study concluded that when both approaches are combined, financial results are likely to be reached far more quickly than with one method alone.
Don’t we wish this was just a joke? When I tell my friends that I like volunteering, working for free, this is what I’m talking about. Money is the root of most COI…
Mickey @ 12:19 PM

say amen…

Posted on Wednesday 14 September 2016

I first heard the term ghost-writing used in the scientific literature at the end of 2010 [see roaches…]. I must’ve known what was coming because I added added the roach to the ad image [from something our exterminator said, "For every roach you see, there are a hundred behind the walls"]. Sure enough, six months later I got hold of The Rothman Report [see detestable…] that described a medical writing firm ghost-writing Risperidone® articles faster than they could find guest authors to front them. I guess one can only take in so much at a time. I exhumed that old STI ad to show the top line, the significance of which eluded me at the time – publication planning, advocacy development.

If you read the content of that STI ad, it talks about a lot more than just medical writing, but I was slow to catch on – apparently a lot of us were. By the time I saw the ad in 2010, Scientific Therapeutics Information Inc had been at it for a very long time [for example, managing the Paxil Launch in 1993]. Since then, it has gradually dawned on us that most all of the industry funded clinical trial articles in psychiatry are ghost-written. And these days, it’s right there in the Acknowledgments under editorial-assistance-provided-by. So exposing professional ghost-writing hasn’t made much of a difference [see rebranding…]. Industry and journal editors just adapted.

But I don’t think I personally got the full extent of industry’s modus operandi until recently, first from reading Lisa Cosgrove et al‘s article and the idea of ghost management
by Lisa Cosgrove, Steven Vannoy, Barbara Mintzes, and Allen Shaughnessy
Accountability in Research. 2016 23[5]:257-279.

The relationships among academe, publishing, and industry can facilitate commercial bias in how drug efficacy and safety data are obtained, interpreted, and presented to regulatory bodies and prescribers. Through a critique of published and unpublished trials submitted to the Food and Drug Administration [FDA] and the European Medicines Agency [EMA] for approval of a new antidepressant, vortioxetine, we present a case study of the "ghost management" of the information delivery process. We argue that currently accepted practices undermine regulatory safeguards aimed at protecting the public from unsafe or ineffective medicines. The economies of influence that may intentionally and unintentionally produce evidence-biased-rather than evidence-based-medicine are identified. This is not a simple story of author financial conflicts of interest, but rather a complex tale of ghost management of the entire process of bringing a drug to market. This case study shows how weak regulatory policies allow for design choices and reporting strategies that can make marginal products look novel, more effective, and safer than they are, and how the selective and imbalanced reporting of clinical trial data in medical journals results in the marketing of expensive "me-too" drugs with questionable risk/benefit profiles…

… and then reading one of Karen Dineen Wagner‘s depositions [see author·ity…] –

by Michael Baum, Esq., of Baum, Hedlund, Aristei & Goldman
on Tuesday, July 16, 2013, page 28 [pdf page 8]

QUESTION Okay. So do you recall whether you had access to patient level data when you were working on this publication?
  ANSWER No. We have access — well, as an individual investigator, you have access to your patients. But the individual patient data from other sites, usually when the data is presented, it’s put together. So I don’t — I just don’t recall if I saw individual — individual data.
QUESTION When you say "put together," does that refer to the pharmaceutical company compiling information and providing it to you?
  ANSWER The data is the property of the pharmaceutical company.
QUESTION And so they collect it and provide some form of summary of it to you?
  ANSWER Correct.
QUESTION And except for the patient level data that you had from your own particular site, you relied upon the information conveyed to you by the pharmaceutical company regarding the other sites. Is that correct?
  ANSWER In multicenter studies, each individual investigator has their own data and then it depends who sponsors the study. This was a Forest-initiated and Forest-sponsored study, so all of the data from the sites go to Forest.
QUESTION Then they compiled it and then did statistical evaluations of it?
QUESTION Did you do any of the statistical evaluations yourself?
QUESTION It was essentially provided to you by Forest statisticians?
  ANSWER Correct. I’m not a statistician.

– that she hadn’t actually seen the data or participated in the analysis, even as a Principle Investigator for the study. And it wasn’t just that fact itself. It’s that she said it in such a matter-of-fact way, like what she was saying was some kind of explanation that we should understand. It reminded me of a piece from several years back that addressed what happened when a recruited author insisted on actually seeing the study data. See selling seroquel VII: indication sprawl… for a telling example in which Nassir Ghaemi did exactly that, and was summarily unrecruited.

I synopsized my own dawning awareness here because without having gone through that process, I doubt I could’ve read Alastair Matheson’s papers and really understood them. I might have seen his waving us off of focusing so much on ghostwriting [Ghostwriting: the importance of definition and its place in contemporary drug marketing] as a bias from his years working in industry. But that’s not how I see his writings now. He brings a fresh point of view to the discussion of this pharmaceutical invasion of the medical literature, having spent close to twenty years doing many of the things we write about [see rebranding… and directly as he proposes…]. He’s an "insider":

"I worked on over one hundred drugs, most of which were, in my estimation, mediocre products that could be better pitched if a more persuasive scientific angle could be found for them. I visited corporate headquarters and congresses; analyzed markets, products, and competitors; groomed key opinion leaders; ghostwrote manuscripts; developed publications plans; and devised marketing strategies."
He’s cataloged his writings on a website:
In The Disposable Author: How Pharmaceutical Marketing Is Embraced within Medicine’s Scholarly Literature, Matheson makes a number of points: First, the academic authors are recruited based on reputation and status. They can be disposed of and replaced. In a way, they’re "ghosts" too. While he validates that Pharma does all kinds of egregious stuff, behind the scenes, but he warns against getting preoccupied with that. It reinforces an evil pharma meme that takes attention away from his next point. It’s a system and every part of it gains something. There aren’t any innocent victime in the system as it now stands [except maybe the patients]:
Such devices are widespread in medicines peer-reviewed journal literature. But who is behind them, and whose interests are served? Here we come to the crux. Everyone is behind them, and each party benefits in its own way. Companies get the elixir of endorsement on which advocacy marketing depends; academics reap the rewards of authorial status and generally fed that they deserve top billing; journals sell reprints; and culturally I believe, academic medicine and its journals crave the sense that the research scene remains in their hands. It is customary for academic “investigators" to be placed at the front of the byline, and indeed, it is understandable that readers who will prescribe the drug want to read the opinions of qualified peers who have used it in their patients…
The net result is that the academic and commercial interests merge. He suggests that by demonizing one or another element in the system, for example Pharma, one doesn’t pay attention to the journal editors who allow these jury-rigged articles to be published as a way of funding their journals. But his argument is nuanced and should be read in full rather than in snippets. His suggested solution is simple:
"Let me then define contemporary advocacy-based marketing punctiliously, as a practice in which content with potential commercial or promotional utility is planned, convened, funded, influenced or owned by a company, but communicated by, or disproportionately attributed to, the peers or opinion leaders of the intended customers. Advocacy marketing thus defined is routine in medicine and its scholarly literature, and the chief policy conclusion of this essay is that it should be banned outright."
Of course that’s right. So long as the academic authors are essentially functioning as a  sales force, there is no meaning to the word academic. How can we refer to Karen Dineen Wagner as an academic author when she signs on to a study where she’s neither seen the data, nor reviewed the analysis, nor even come into the writing process until after it’s drafted? How can we call a journal part of the scholarly literature when the editor doesn’t retract articles that are clearly wrong by wide-ranging consensus. Rather than academic medicine being a watchdog, a counterpoint to commercial interests, the academic is disappearing as it merges with the powerful commercial forces. So he sees "integration, not subterfuge, as the danger."

I say "Amen"
Mickey @ 10:35 PM


Posted on Wednesday 14 September 2016

So what… Miles Davis

Mickey @ 9:26 PM


Posted on Wednesday 14 September 2016

I was once a Primary Care Physician of sorts, an internist seeing referrals from general medical officers in a military hospital so I saw a lot of people whose physical complaints reduced down to matters psychological. I think it’s very different now, but thise the latter days of the Viet Nam War, and there was a reduction in force going on. It was hard to get active duty soldiers or even their dependenys to accept a mental health referral. They were afraid if would affect their promotions and retirement. I have no clue if that was true, but what I thought didn’t much matter. It’s what they thought. Detecting mental health problems and treating them became part of my job, so I had a some experience with the older generation antidepressants in non-melancholic "everyday" depression.

I found them to be a sometimes effective treatment, but there was the a effect burden. Most of the soldiers were on the flight line and the side effects interfered with work, so they stopped them. And even among dependents, long term use wasn’t much of a question because even responders wanted to stop them as soon as they could. The party line in those days was "if you respond to an antidepressant, you should continue it for six months to prevent relapse." I said it, but that didn’t mean they did it. Constipation, blurry vision, and dry mouth are pretty annoying. Later, as a psychiatry resident, I was much more impressed with the drugs in hospitalized cases, but not so much in the outpatient clinic.

Even later, in practice, almost all my referrals were people who came for what I did – psychotherapy. As the new antidepressants appeared, I used them some but mostly adjunctively. So the majority of my experience with the newer drugs comes from my post-retirement years in a general outpatient clinic. In "virgins" [kind of rare], when I prescribe Antidepressants, I always present them as a "therapeutic trial." I warn about side effects, particularly libido and akathisia. I talk about the withdrawal syndromes. And I do my "finger thing."
"As much as we’d like our antidepressants to help this much or this often, they’re more in this range, and it may take several weeks before you notice any change."
Now to the point. In responders, I say:
"I’m glad it’s helping. Depression in most cases is time limited, so after a while, if everything’s going well, we’ll taper the drug and get you off of it. Some people have withdrawal symptoms and worry "the depression is coming back!", and get stuck on the meds. That’s why we taper off the drug."
That prep works fine. Unfortunately, a majority of people I see aren’t "virgins." They’ve been on SSRIs for a long time and see them as either ongoing treatment or a preventive. Getting them to stop isn’t easy. So I’ve learned to wait until I know them better [and vice versa] and suggest a trial taper. That works for the  willing. But I have to admit, there are plenty who just don’t want to stop, so I go for a lower dose and don’t push it [guiltily]. I was glad to see this article that brings some science to bear [from a reputable source]:
by Carvalho A.F , Sharma M.S., Brunoni A.R, Vieta E., and Fava G.A.
Psychotherapy and Psychosomatics. 2016 85:270-288.

Newer generation antidepressant drugs [ADs] are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents. In this critical review, we evaluated the literature on adverse events, tolerability and safety of selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, bupropion, mirtazapine, trazodone, agomelatine, vilazodone, levomilnacipran and vortioxetine. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms [nausea, diarrhea, gastric bleeding, dyspepsia], hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances [heart rate, QT interval prolongation, hypertension, orthostatic hypotension], genitourinary symptoms [urinary retention, incontinence], sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system disturbances [lowering of seizure threshold, extrapyramidal side effects, cognitive disturbances], sweating, sleep disturbances, affective disturbances [apathy, switches, paradoxical effects], ophthalmic manifestations[ glaucoma, cataract] and hyperprolactinemia. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. Other areas of concern involve suicidality, safety in overdose, discontinuation syndromes, risks during pregnancy and breast feeding, as well as risk of malignancies. Thus, the rational selection of ADs should consider the potential benefits and risks, likelihood of responsiveness to the treatment option and vulnerability to adverse events. The findings of this review should alert the physician to carefully review the appropriateness of AD prescription on an individual basis and to consider alternative treatments if available.
There was a time when I read most review articles that were ever put in front of me – just a way of keeping up. But the KOL/PHARMA era ended all of that a long time ago. This one is like they used to be, information that I might trust enough to use.
Mickey @ 5:04 PM

stuck with me…

Posted on Sunday 11 September 2016

Unless you’re a race car driver with a manual transmission, you don’t notice the dashboard gauge on the far right. You just glance at the speedometer on the left that tells you how fast you’re going [mph]. The tachometer on the right tells you how fast the motor’s turning [rpm]. It lets the speed demon know to shift before it gets "in the red" or the motor will self destruct.
    It was an example I used in a lecture in the 1970’s for new residents called "Crisis Intervention: A Psychotherapy". The thumbnail version goes like this: Anxiety is our built-in early warning system to alert us to danger. If you’re a rabbit in the woods and hear a twig snap, the anxiety system focuses your attention, alerting you that there may be a predator about and mobilizes you to run for your life. It’s the same with bipeds – anxiety mobilizing our attention and emergency coping skills. But if those fight or flight mechanisms don’t work and the danger persists, there may come a point where the problem changes. Instead of the anxiety helping us mobilize to solve our problem, the emotion itself becomes overwhelming and becomes the problem itself. We call it panic, or terror, something dire – it’s a crisis – and all we can think about is escaping the intolerable emotion. We’re running "in the red."

    People on the top of a burning building often jump to their deaths even if they see the fireman’s ladder coming up to save them. Panicking soldiers leave their foxholes and go running across the battlefield, becoming sure targets. Crisis emotions really are intolerable, and people do irrational things just to feel better. Worse, instead of learning a new coping skill when faced with a problem they can’t solve, they may develop an avoidant phobia for the situation, or learn a maladaptive pattern that persists. So when you see a person in crisis, it’s a marker that they’re in a situation they have no skill to handle and they are likely to act irrationally. And while it’s a great opportunity for learning something new, there’s a very real danger of acting irrationally and learning something unhelpful.

    So the goal as a crisis interventionist isn’t necessarily to solve their problem, nor is it to just get rid of the intolerable feeling. It’s to do something to dial the emotion down into the tolerable range, to help them clearly identify the problem at hand, and if possible figure out why they ended up in a dysfunctional panic state rather than staying in the problem-solving mode. Obviously, if the problem is something that would discombobulate anyone, like a natural disaster or an assault, you will lean way into the patient and help in any way possible. But in many cases, the crisis state has something to do with the patient’s unique life experience.

The reason I was thinking about an ancient lecture from my teaching-residents days was a person I saw in the clinic last week. A counselor had come to my office with a worried look, saying she’d seen a patient who might be suicidal. We don’t see many "crisis" patients in our outpatient clinic. This is a fictionalized-for-privacy version that hopefully retains the flavor of the case:
    She was an unusual looking 56 y/o who appeared younger. She was agitated, and complained of having "that feeling" she’d had years before when she’d attempted suicide by shooting herself in the chest. She recalled "that feeling" from two other times in her life resulting in brief psychiatric hospitalizations. She had moved to our area a year or so ago after divorcing her second husband – living alone, supported by a monthly check from her first husband. She knew no one here, and was emphatic that she didn’t want to get to know anyone. She had been depressed for several months and had been tried on several antidepressants by her primary care doctor [currently on Prozac 80mg/day] without much effect. She’d gotten "that feeling" – escalating over the previous week.

    Like most people in crisis, she wasn’t at all forthcoming with her history, preferring to talk about needing to get rid of "that feeling" – afraid of what she might do. So at first, getting the history took some real doing. When I inquired about her marriages, she said they’d lasted 28 years and 12 years respectively with 4 kids by the first husband, now grown, "scattered," and doing well. She had initiated both divorces, the first so she could be with the man who became her second husband. One of the things that came later in that lecture about Crisis Intervention was the importance of constructing a timeline. Here, I’d done my math: 56 years [her age] – 28 years [her first marriage] – 12 years [her second marriage] – 2 years ["a year or so"] = 14 years old. So I asked, "Why did you get married so young?" She responded, "I was just barely 15" and finally volunteered her story.

    She was adopted and in an unusual way. She was Japanese. Her adoptive father was stationed in Japan and brought her home as an "orphan" to his wife at age two. The adoptive couple had talked about adopting "a boy," but he brought her instead. When she was older, she’d figured out that she was only half Japanese ["unusual looking"] and that he was actually her biological father, but "he’d never admit it." She was mistreated as a child [I’ll omit the details] and consciously married [became pregnant] to escape. While she was grateful to her husband for the rescue, she was never happily married. The three episodes of "that feeling" were marital crises when she "couldn’t stay and she couldn’t leave." After her kids were grown, she met future husband number two and thought she could finally "be happy." When he turned out to have some deal-breaking problems of his own, she "gave up" – defeated. The "depression" she presented to her primary care doctor would be better characterized as an embittered loneliness.

    So where was the crisis? A month earlier, she’d signed up on a dating web site and met someone that she really liked. A week ago, he’d begun to press for them to meet in person. Caught between hope and fear, she was overwhelmed with the weight of her biography and experience, and presented in crisis.

I would anticipate that she’ll do well. She’d learned in her recent isolation that she could, in fact, live alone. She had reached out [the dating site, coming to the clinic] instead of acting out. She made a good connection with me and the counselor, and scheduled follow-up appointments. She had never put her narrative together before as above. She’d seen her struggles as just a bad fate rather than a threaded story she could understand and perhaps do something about.

Obviously, the case stuck with me. Partly, it was the nostalgia of an old man [me] being reminded of my first job a director of a Crisis Unit, and later teaching crisis intervention techniques to residents and trainees from other disciplines. I really enjoyed working with them as they developed "the knack" of doing this kind of interview. Some were "naturals," some took a lot of work, and a few… well it’s just not for everyone. Crisis Intervention was a vital component of the Community Mental Health Movement [secondary prevention], but now it’s rarely even mentioned. A lot of the cases I see in our clinic are not in full blown crisis, but they still need that same kind of "sorting out" to get anywhere. But I put it here for another reason. I got to thinking about how such a case might be handled now in some of the currently proposed systems.

I suppose some would see this as treatment resistant depression. She had a history of depressions and she’d presented complaining about being depressed. She hadn’t responded to antidepressant drugs – even titrated to a maximum dose. Would she be a Ketamine candidate? Atypical Antipsychotics? CBT? What would’ve happened in Collaborative Care? When she didn’t respond to drugs from the Primary Care Clinician, she would’ve been passed on to the Clinical Coordinator. Would that Clinical Coordinator have known how to evaluate her? had the experience and training to get at the pertinent story? know how to take a focused history? And when the Coordinator presented the case to me as the consultant Psychiatrist, what could I possibly suggest without having that story, without seeing the patient?

I can’t, by any stretch of the imagination, find a way to see this as a brain problem. And I’ve never had any idea how to describe cases like this in DSM terms. I just wonder what happens to people like her in today’s managed mental health climate….
Mickey @ 6:36 PM

sliced bread…

Posted on Friday 9 September 2016

No matter how comprehensive the  back-up system for your computer, when lightning strikes, things get lost. After I got my new machine Wednesday afternoon, I commenced reconstituting things – reinstalling software, restoring backed-up documents, email files, graphics, etc. By last night I was pleased with my progress [though cringing at the thought of going through the email threads I’d missed in my three week exile]. But then I noticed something, my Bookmarks were gone with the wind. I apparently never included them in my backing up, and that was just that. I had an elaborate collection of folders where I kept frequently visited places – resources, web sites, places to remember in general. Oh well, and I started reconstructing it [Note to self: Back it up this time!]. The place I started was with Resources: ClincalTrials.gov, Drugs@FDA, the FDA ‘Orange Book", PubMed, my university ejournals, DIDA, psychrights, NIH RePORTER, etc]. Those are the places I haunt…

It’s hard to remember that the Internet as most of us know it is only a little over twenty years old. Tim Berners-Lee developed his hyper-linked text documents for CERN’s internal use in the early 1990s. Then Marc Andreessen introduced the graphic-based browser Mosaic [1993], and later Netscape [1994], and we were off and running. The capacity to store, retrieve, and search huge databases of information on the web came even later. My point being that the Internet still contains its own history. Many of the large data-based systems were built at a time when the technology was less standardized, so they’re hard to use. Plus, as soon as a system gets put in place, somebody thinks of something else to add. So most systems are layered with "add-ons", making them even more confusing. When my wife posted something about our lightning strike on Facebook, lamenting the troubles we were having getting things going, a friend commented, "Get a 12 year old." People who’ve grown up on the web just seem to intuitively know how to navigate its rapidly changing landscape.

ClinicalTrials.gov and anything having to do with the FDA [including Drugs@FDA] are examples of such difficult-to-navigate systems, particluarly the latter. Both were created in the spirit of transparency but have their own share of opacity. Sometimes, I’m amazed at what’s available from the FDA, but finding it [or if it’s there] can be a nightmare and contribute to a receeding hairline. Fortunately, others have the same frustration and are aiming to do something about it [see OpenTrialsFDA: Unlocking the trove of clinical trial data in Drugs@FDA and OpenTrials: towards a collaborative open database of all available information on all clinical trials]:

Well Ben Goldacre isn’t still 12 years old, but he’s certainly in the generation that can see the possibilities. And he’s hooked up with the right people. This is one of those ideas that many of us have had, but it looks like he and his colleagues may bring it off – an example for the saying, "best thing since sliced bread!"

Ben Goldacre has come under fire for including pharma and other commercial types in his projects – sleeping with the enemy. The fear is that they will become Trojan Horses that will corrupt the enterprise from within. I’m in the innocent until proven guilty camp myself [with vigilance]. Like Bad Science, Bad Pharma, AllTrials, and COMPare, OpenTrials is a really good idea…
Mickey @ 11:59 AM

of mice and men…

Posted on Thursday 8 September 2016

Nosing around about Ketamine, I ran across this draft that I never posted from 2½ years ago:

from February 19, 2014: Neuroskeptic has an interesting thing going trying to figure out if the effect on depressed people from Ketamine is because Ketamine is a pharmacologic antidepressant, or, to put it in my own worlds, does getting stoned ripped dissociated feeling something psychodelic help depressed people? He starts by  discounting studies that compare Ketamine to Placebo since Ketamine is obviously psychoactive and a Placebo isn’t. Then he moves to a study that compared Ketamine to a Benzodiazepine – another psychoactive drug. That’s difficult because though Benzodiazepines are psychoactive, they’re sedatives. Ketamine is something else. He mentions a study that’s not in depressed people, but it’s pretty interesting. The subjects were Cocaine addicts who wanted to quit. They compared Ketamine to a benzodiazepine too. Here are the results of the questions they asked:
That’s going to be a hard comparator to find! And it begs the question if it’s helping because it gets the depressed "out of themselves." If you’ve worked an ER where people have been brought having taken Ketamine, it’s just hard to imagine using it as a therapeutic agent. They are way "out of themselves!" So here’s what Neuroskeptic said:
    In summary I think the question is still very much open whether ketamine’s antidepressant effects are ‘psychological’ or ‘physiological’ in origin. I’m genuinely agnostic on the issue; I would love to know the answer, but at present we don’t have it.
I’m going to vote ‘psychological’…

I’m obviously not quite so agnostic as Neuroskeptic when it comes to Ketamine, but I’m open to being born·again given something really solid. The question remains, "Is the manifest improvement in depressive symptoms following the initial psychodelic experience ‘psychological’ or ‘physiological’?" and I have to concede that I don’t really know the answer. I certainly can’t argue that there’s not an effect [this Janssen article from the recent AJP]:

by Jaskaran B. Singh, Maggie Fedgchin, Ella J. Daly, Peter De Boer, Kimberly Cooper, Pilar Lim, Christine Pinter, James W. Murrough, Gerard Sanacora, Richard C. Shelton, Benji Kurian, Andrew Winokur, Maurizio Fava, Husseini Manji, Wayne C. Drevets, and Luc Van Nueten
«Janssen Employees, Janssen COI»
American Journal of Psychiatry. 2016 173:816–826.

Objective: Ketamine, an N-methyl-D-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.
Method: In a multicenter, double-blind study, adults [ages 18–64 years] with treatment-resistant depression were randomized to receive either intravenous ketamine [0.5 mg/kg of body weight] or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale [MADRS].
Results: In total, 67 [45 women] of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 [SD=12.0] for ketamine and -5.7 [SD=10.2] for placebo; in the thrice-weekly groups, it was -17.7 [SD=7.3] for ketamine and -3.1 [SD=5.7] for placebo. Similar observations were noted for ketamine during the open-label phase [twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5]. Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common [>20%] treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.
Conclusions: Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

In May, an article published in Nature got a lot of attention. It suggested that the psychodelic effects of Ketamine and the antidepressant effects came from different molecules. Great news, but the problem was that the finding was studied in mice, not people:
by Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD
Nature. 2016 533[7604]:481-486.

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR [N-methyl-d-aspartate receptor] antagonist [R,S]-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of [R,S]-ketamine to [2S,6S;2R,6R]-hydroxynorketamine [HNK] is essential for its antidepressant effects, and that the [2R,6R]-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors]. We also establish that [2R,6R]-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of [R,S]-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
Discover Magazine
By Neuroskeptic
May 7, 2016

In recent years there has been great research interest in ketamine as an antidepressant. Ketamine, a drug better-known for its use as an anaesthetic [and a recreational drug in lower doses] is claimed to have powerful, rapid-acting antidepressant effects, even in depressed patients who have not responded to more conventional drugs. However, its mechanism of action remains unclear.

Now, in a major new Nature paper, Baltimore researchers Panos Zanos and colleagues say that ketamine itself is probably not an antidepressant after all. Instead, the antidepressant effects can be attributed to a metabolite of the drug, formed in the body after taking ketamine. The metabolite is called [2S,6S;2R,6R]-HNK. But is this a real breakthrough or a red herring? Here’s how Zanos et al. describe their findings:
    Here we show that the metabolism of [R,S]-ketamine to [2S,6S;2R,6R]-hydroxynorketamine [HNK] is essential for its antidepressant effects, and that the [2R,6R]-HNK enantiomer exerts behavioural, electroencephalo-graphic, electrophysiological and cellular antidepressant-related actions in mice.

So how does HNK do this? Unlike ketamine, HNK is not an NMDA glutamate receptor antagonist. Rather, it acts to promote signalling via the AMPA glutamate receptor. NMDA antagonism is believed to underlie ketamine’s anaesthetic and psychoactive [dissociative hallucinogenic] properties. So HNK is not likely to have these undesirable effects, Zanos et al. say, making it more suitable as an antidepressant.

I’ve been following the ketamine/depression story for nearly a decade and this paper is the most interesting piece of work I’ve seen. This is a really impressive set of experiments – but they were all in animals. Zanos et al. haven’t shown that ketamine’s antidepressant effects are mediated by HNK in people; rather they’ve studied the ‘antidepressant-like‘ effects of ketamine in rodent behavioural models such as the forced swim test. Bottom line: we don’t yet know whether HNK is a human antidepressant.
My own suspicion is that the antidepressant effects of ketamine may be driven not by a metabolite but as a kind of psychological reaction to its pronounced psychoactive effects. If HNK is non-psychoactive, I predict that it won’t turn out to mediate ketamine’s antidepressant effects in humans. HNK might nonetheless have some antidepressant activity but not as dramatic as ketamine. Then again I might very well be wrong, and I hope I am, because if Zanos et al. are right, they might just have discovered the next ‘miracle’ antidepressant.
Here are a couple of other commentaries on the HNK finding:
For ever-so-long, we’ve lived in a dream world in psychopharmacology. I call it future-think, what’s coming down the pipeline or shows promise. But the pipeline is dry, and HNK, mentioned above, hasn’t even made it into humans yet. This story has one of the classic signs of future-think, a review article from Dr. Charlie Nemeroff, KOL extrordinaire. In Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression, he was pushing Rapastenel, touted to be a Ketamine-ish drug with antidepressant properties but none of the club drug effects [see a touch of paralysis…]. Nemeroff earlier went out of his way to assure us he had no COI with the drug. However, right after the review article came out, the drug and its company was bought up by Allergan, one of Dr. Nemeroff’s COI companies [After a $560M Allergan buyout, Naurex vets regroup for CNS R&D] [up to his old tricks?]. It’s based on a single proof of concept study [Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent], marginal if even that, but somehow Allergan got it on the fast track [Allergan’s Rapastinel Receives FDA Breakthrough Therapy Designation for Adjunctive Treatment of Major Depressive Disorder [MDD]]. They advertize Phase III trials in the offing, but none are registered on clinicaltrials.gov that I can locate. So I wouldn’t say Rapastenel is either in the pipeline or yet even a drug of promise, but it’s being discussed as if it is the next great something-or-another.

And Janssen is certainly going forward full bore with Esketamine intravenous and intranasal [see the best predictor… and Esketamine Receives Breakthrough Therapy Designation from U.S. Food and Drug Administration for Major Depressive Disorder with Imminent Risk for Suicide]. When I looked at their recent study earlier [Intravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study], I focused on efficacy and didn’t pay enough attention to the club drug effect. They assessed it with both the Brief Psychiatric Rating Scale [BPRS] total score and the Clinician Administered Dissociative States Scale [CADSS] total score [which roughly paralleled each other]. The upper figure is the BPRS data from the paper and the lower versions are redrawn with an accurate x-axis timeline [because I am suspicious of irregular scales in graphic presentations]. It looks like about a 2 – 4 hour "high":

"Similar to ketamine, esketamine led to transient dissociative and psychotic symptoms. According to CADSS severity categories, the peak mean CADSS total scores at 40 minutes postinfusion on day 1 for the esketamine .20 mg/kg and .40 mg/kg groups would be categorized as high. However, symptoms subsided to baseline levels within 4 hours. The CADSS scores showed evidence of dose dependence on each DB dosing day. A similar pattern was observed for psychotic-like effects measured using BPRS total scores. These results are similar to results of IV ketamine studies."

The intranasal form [study not yet  published that I can find – reference: Canuso C, et al. "Esketamine for the Rapid Reduction of the Symptoms of Major Depressive Disorder, Including Suicidal Ideation, in Subjects Assessed to be at Imminent Risk for Suicide." Society of Biological Psychiatry 71st Annual Scientific Meeting. May 12-14, 2016] may be an improvement in terms of a delivery system, but it’s not apparent to me how Esketamine makes any advances over the already available racemic mixture of Ketamine in terms of either efficacy or absence of club drug effects.

I am perhaps even more skeptical than Neuroskeptic that the transient antidepressant effect that follows the psychodelic effect of these drugs can be isolated as the "the next ‘miracle’ antidepressant" – agreeing with him that the effect is likely a linked consequence of the drug’s mind-altering experience. But beyond that, I think of Ketamine as a feel good drug rather than an antidepressant, adding a good feeling instead of ameliorating the target emotion – depression. I question whether this is a rational direction for psychiatric treatment to pursue.

[click image for the SSRis, SNRIs, and Atypicals by the year of Approval]

While the debates about the psychoactive drugs that have flowed from the pharmaceutical pipeline [see the pipeline paradigm…] have covered lots of territory over the last thirty-five years, at least we haven’t had to deal so much with the problems of an earlier generation – drug abuse [Benzodiazepines, Barbituates, Meprobamate, etc.]. Ketamine adds that back into the equation. It is already a widely abused street drug, and there’s no reason to doubt that its use as an antidepressant will dramatically expand its abuse potential – particularly if there’s an intranasal a snortable version. It may be consistent with the goals of the pharmaceutical industry [sell more drugs] or managed care [cut hospitalization costs], but this feels like no country for psychiatry [or our patients] – like a time to be careful rather than in a rush. So I question the FDA fast-tracking either Rapastinel or Esketamine by granting Breakthrough Therapy Designation. If a non-psychodelic antidepressant actually comes from this line of thinking down the road, then that might be reasonable. But for the moment, Ketamine’s cousins remain inhabitants of the realm of speculation and entrepreneurialism, hardly candidates for the fast lane…
Mickey @ 11:55 PM


Posted on Thursday 8 September 2016

General Douglas MacArthur [1944]
If you’re too young to remember what this photo is, it means I’m back…
Mickey @ 9:06 AM