1 Boring Old Man

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

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

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

by Le Noury J, Nardo J, Healy D, Jureidini J, Raven M, Tufanaru C, & Abi-Jaoude E.

British Medical Journal. 2015 …

[full text on-line]

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.

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.

New Study Finds Therapy, Antidepressants Equally Effective At Monetizing Depression

NEWS IN BRIEF

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.

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.

Under the Influence: the Interplay among Industry, Publishing, and Drug Regulation.

by Lisa Cosgrove, Steven Vannoy, Barbara Mintzes, and Allen Shaughnessy

Accountability in Research. 2016 23[5]:257-279.

[full text on-line]

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…] –

– 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."

• Published articles on science, commerce and publication ethics
• Unpublished empirical investigations
• Themes and reflections

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…

"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."

So what… Miles Davis

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.

"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."

"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."

The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature

by Carvalho A.F , Sharma M.S., Brunoni A.R, Vieta E., and Fava G.A.

Psychotherapy and Psychosomatics. 2016 85:270-288.

[FullText PDF]

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.

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.

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.

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?

^{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!"

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]:

A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

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.

NMDAR inhibition-independent antidepressant actions of ketamine metabolites.

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.

Ketamine and Depression: A Breakthrough?

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.

• Real Psychiatry: Latest on Ketamine
• Slate Star Codex: Ketamine Research In A New Light

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 71^st 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.

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

^{Once, when asked why I retired to a rural area in the mountains, I joked, "So I don’t have to buy flood insurance." But I guess I didn’t take being closer to the sky where lightning comes from into account. When we were hit a few years ago, I had to replace all things electronic and many things electric. So I subscribed to a surge protection option with our power provider. At other times, when friends from Atlanta asked how I liked living in a rural area in the mountains, I had joked, "Fast internet and cable television enhance my wilderness experience." Well, that one was righter than I knew. After the first time lightning struck, I didn’t take the time to learn how to also protect the cable that delivers our telephone/television/internet connections. I thought about it, but I got busy and it just evaporated. Perhaps I was lulled into a false sense of security by that old saying. So when we were hit again on the final day of the Olympics, my power protection worked just fine. The lights didn’t even blink. But the lightning traveled down the telephone/television/internet cable like Sherman’s march to the sea – cable television modem, wireless phone system, internet modem, router, both computers, and the ATT gizmo that boosts our cell phones from one bar to six – all were terminal casualties. During the time it has taken to rebuild our electronics, we’ve been reduced to sharing an old tiny notebook computer [which had I used as a travel machine before the days of smart phones and tablets] connected to the new internet modem directly [no router, wifi, or cell phone amplifier yet]. I thought I was up and running with the new equipment on Thursday, but alas, "complications". Now we’re aiming for the day after Labor Day. Needless to say, the new system has a gaggle of lightning arresters all along its path [a false sense of security now morphed into full bore PTSD, lightning-wise]…}

The Disposable Author: How Pharmaceutical Marketing Is Embraced within Medicine’s Scholarly Literature

by Alastair Matheson

Hastings Center Report. 2016 46[4]:31-37.

The best studies on the relationship between pharmaceutical corporations and medicine have recognized that it is an ambiguous one. Yet most scholarship has pursued a simpler, more saleable narrative in which pharma is a scheming villain and medicine its maidenly victim. In this article, I argue that such crude moral framing blunts understanding of the murky realities of medicine’s relationship with pharma and, in consequence, holds back reform. My goal is to put matters right in respect to one critical area of scholarly interest, the medical journal publication.

Pharma relies on peer advocacy to sell its wares to prescribing doctors. This is an arrangement in which clinicians’ qualified colleagues, including “key opinion leaders,” are recruited by pharmaceutical corporations and marketing agencies to deliver commercially expedient content to their professional fellows. Precisely how this practice works in the setting of publications is not well understood because ethicists studying the problem have made too much of the narrative of corporate villainy and medical victimhood. Accordingly, criticism of industry publications has been preoccupied with the crudely dishonest practices of ghostwriting, ghost authorship, and “ghost management,” vices condemned as “dirty little secrets” perpetrated from “behind the scenes” with the connivance of academic “shills” or “guest authors,” in contempt of standards set by the International Committee of Medical Journal Editors. This account is appealing, and yet it is wrong or, at the very least, seriously incomplete, with only limited relevance to the actualities of contemporary industry practices. In truth, many commercial publications are not developed in secret but fashioned within a culture of open collaboration, where academic authors make substantial, independent contributions; pharmaceutical companies are showcased rather than hidden; and medicine’s editorial standards assist rather than impede the workings of commerce.

…Following a brief career as a biologist, I worked in pharmaceutical marketing between 1994 and 2010, first in a “medical communications” company and then as a freelance consultant working directly or indirectly for most of the major pharmaceutical corporations and over thirty marketing agencies in North America and Europe. 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.

Is medicine the manipulated victim of the pharmaceutical corporations, or their colleague in corruption? The answer, of course, is both…Yet most scholarship has pursued a simpler, more saleable narrative in which pharma is a scheming villain and medicine its maidenly victim… I argue that such crude moral framing blunts understanding of the murky realities of medicine’s relationship with pharma and, in consequence, holds back reform.

… On the other hand, pharmaceutical marketing is anathema to science, corrupting to medicine, wasteful to economies, and harmful to patients, and I must acknowledge the moral difficulty that for many years I sold my intellect in its service. Pharma itself, of course, has never truly acknowledged its underbelly of secrets, half-truths, corruption, power, and death, and it flaunts the language of ethics like a silk cummerbund over a paunch. If it is a lie to dissemble, distort, or omit, then pharma must be considered a liar whose subtle falsehoods stock the annals of medicine. It is to these annals — the peer-reviewed journals of the academic medical profession — that I now turn.

The art of publications development lies not in coating commercial content with an academic veneer, but in meshing commercial positioning and academic expertise as deeply as possible, creating content that is scientifically compelling but instilled with subtle commercial valence. Nonetheless, a diagnostic feature of this literature is that academic recruits and their institutions are readily replaceable by others without any decisive impact on the published product. Alternative academics and institutions might add varying intellectual content to the work, but its commercial functions will be served just as well. The leading problem with the use of academic authors in today’s industry publications is not passivity but disposability. Only the corporate project itself is fundamental, and particular academic contributions are exchangeable details.

The medical journal article should be a point of resistance and distinction between commerce and academia, but it operates instead as one of merger and ratification. The commercial-academic landscape is continuous.

Finally, although it is beyond the scope of this essay to consider the matter in detail, medicine’s editorial guidelines lend support to this culture of misattribution. In previous work I and others showed how the ICMJE authorship formula supports commercial byline avoidance. All the forms of spin I have discussed in this section are overlooked, tolerated, or mandated by ICMJE requirements. By complying with ICMJE diktats, industry literature may lay claim to the highest ethical standards. Far from a dirty little secret, drug marketing is ostentatiously robed in the standards of medicine itself.

"Ghost” metaphors have shamed some egregious marketing practices and been the basis of some important scholarship. Unfortunately, the critical weakness of the word “ghost” is that it steers attention to industry’s role, and industry secrecy, and away from the multistakeholder responsibilities for mercantile literature and its misattribution. Ghostly practices are merely part of the overall activities and continuous with the subtler and less secretive ones I have described. By focusing on them, publication ethics has missed the bigger picture. Worse still, it has become bogged down in problems of definition and, in consequence, has been outflanked by commerce.

Integration, Not Subterfuge, as the Danger
The overenthusiastic promotion of ghost metaphors serves the popular narrative in which the primary threat posed by pharma to medicine is one of deception and external manipulation. This threat is indeed important, but it is not the foremost danger. The greatest threat is blending and assimilation, such that the distinction between the commercial and academic is by slow gradations ceasing to be apparent or even important within medical culture. This transformation in the quality of medical science and discourse is not being driven by deception or trickery so much as cultural and institutional proximity of commerce and academia, involving philanthropy, patronage, and most importantly, the increasingly routine nature of industry-academic research partnership. The medical journal article should be a point of resistance and distinction between commerce and academia, but it operates instead as one of merger and ratification, its meticulous guidelines working not to differentiate but to bring the worlds of medicine and commerce more minutely together. As the distinction between the commercial and academic diminishes, marketing has progressively less need for ghostly subterfuge in communicating its propositions; the commercial-academic landscape is continuous. Contemporary industry literature positions academics, corporations, journals, and readers side by side in the pursuit of truth: public, civilized, rational, and humane, it leads today’s assimilated medicine naturally to the point of sale.

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. This is a matter for academic medical institutions and societies as well as journals, and the first step to achieving it is to understand the nature of attribution. This concept has never been adequately understood by medicine’s editors and is not even discussed in the ICMJE guidelines. Medicine’s construction of authorship has long envisaged a “two-sided coin” of credit and responsibility, and in thus focusing on the author has not adequately ad – dressed the needs of the reader; but in any case, as I have shown here, attribution runs far wider than authorship and turns on what readers perceive as much as what is disclosed. If a project is instigated and funded by a company and its data are privately owned, then it is a commercial project, and by means both of authorship and other attributive devices, it should be presented clearly to readers as commercial, not the ambiguous, supposedly academic-led fare that is a staple of medicine’s intellectual diet.

To ensure that readers perceive mercantile content for what it is, it would ideally be published separately from noncommercial research. Publishers could, for instance, restrict industry-funded content to new publications such as a “JAMA Commercial Medicine” or quarantine it in clearly labeled “Commercial Pages” within existing journals. Failing this, there should at least be conspicuous commercial attribution. Mercantile science should be welcomed with scholarly courtesy and respected on its merits but presented as commercial from the outset. Companies could, for instance, be identified in the titles of articles they finance [“A Pfizer Trial,” for example] or listed as corporate coauthors. Abstracts should clearly state commercial finance, instigation, planning and data ownership, and identify the product the article promotes. Ideally, such measures would be introduced in a cross-media standard. If every commercial article, web page, and lecture was introduced to its audience with stark labeling, this would encourage readers to think twice, expose the advocacy function of the academic authors, limit the unmarked seepage of marketing into medicine, and counter the creeping cultural merger of science and commerce. Differentiation can reverse integration…