in the land of sometimes[1]…

Posted on Sunday 8 November 2015

This is just some fluff. After all this time looking at the industry-funded clinical trials [RCTs], I’ve learned a few tricks for spotting the mechanics of deceit being used, but I realize that I need to say a bit about the basic science of RCTs before attempting to catalog things to look for. Data Transparency is likely coming, but very slowly. And even with the data, it takes a while to reanalyze suspicious studies – so to these more indirect methods. I expect there will be a few more of these posts along the way – coming mostly on cold rainy week-end days like today when there’s not much else going on. If you’re not a numbers type, just skip this post. But if you’re someone who wants to contribute to the methodology of vetting these RCTs, email me at Examples appreciated. It’s something any critical reader needs to know how to do these days…

The word sta·tis·tics is derived from the word state, originally referring to the affairs of state. With usage, it has come to mean general facts about a group or collection and the techniques used to compare groups. In statistical testing, we assume groups are not different [the null hypothesis], then calculate the probability of that assumption. If it’s less than some value called alpha [0.05], we reject the null hypothesis and assume the groups are significantly different.

In statistical testing, assumptions abound. For continuous variables, we assume that the data follow a normal distribution, so we can simplify the dataset into just three numbers: the mean [μ], the standard deviation [σ], and the number of subjects [n]. In an RCT, with just those numbers for the placebo group and the drug group, we can calculate the needed probability. In the normal distribution, all the items between two standard deviations on either side of the mean make up 95% of the sample. Values outside those limits make up only 5% of the sample. In doing statistical testing for the difference between two groups [assuming for the moment an equal σ and n], when the probability of the null hypothesis is 0.05 or less [p < 0.05], we feel confident that the groups are significantly different. But that only tells us that the groups are different – not how different.

In this simple two group example, calculating the p value depends on having the means [μ1 and μ2], the standard deviations [σ1 and σ2], and the two sample sizes [n1 and n2]. And this is about as far as they got in my medical school version of a statistics course in the dark ages called the 60s [only scratching the surface of the field]. So those of us doing research had to add some other degrees. They do a better teaching job in these modern times [with computers to do the heavy number crunching instead of the calculators that shook the table and sounded like Gatling guns]. And with the increased computer power came much more sophisticated statistical testing allowing the evaluation of many more factors in the models.

This is a case where one wonders if the technological advances have been all that helpful. In the past, medications were evaluated on clinical grounds. The efficacy scale was simple. It had it doesn’t work, it sometimes works, and it works – a scale suited to an effective medications. With the modern clinical trials, much smaller differences are the rule – sometimes in the range of absurdity. So, as most people know in the abstract, a p < 0.05 doesn’t necessarily denote clinical significance. It may mean absolutely nothing or conversely something of real value. But in spite of that knowledge, our eyes are invariably drawn to the ubiquitous p value like a magnet.

One attempt to get at a more relevant index of efficacy is to standardize the magnitude of the difference between the means of the two samples in some way – for example Cohen’s d [a way to compute the strength of the effect]. It’s the difference in the means expressed as a percent of the pooled standard deviation. Back to assuming an equal σ and n in the two groups, it would be:

d = 1 – μ2) ÷ σ

While there’s no strong standard for d like there is for p, the general gist of things is that: d = 0.250 [25%] is weak, d = 0.50 [50%] is moderate, and d = 0.75 [75%] is strong. Note: for groups of unequal size or distribution, the pooled σ is:

This graphic makes this point better, and gets around to why I’m writing this:

Even a strong  Cohen’s d isn’t a huge separation – plenty of overlap still in the picture. So when you’re looking at Effect Sizes, don’t think it looks like the figure on the left [d = 4]. You’re usually still back in the land of sometimes when you’re looking at these Effect Sizes in a Clinical Trial report in a journal article.

Another point. You may have noticed that you need μ, σ, and n to calculate statistical significance, but only μ and σ to calculate Cohen’s d. The strength of effect is independent of the sample size. You can figure out how these thing relate to each other. With a drug that has a moderate effect [eg d = 0.50] you need only a small sample size to achieve statistical significance [even less if it’s strong]. But with a weak effect [d = 0.250], you need to have a whole lot more subjects in your study. Again, assuming two groups with equal size and distribution, the relationship looks like this:

While these are the nuts and bolts of how one does Power Analysis when planning a clinical trial to figure out the needed sample size, that’s not why this graph is here. Most RCTs have p values listed, but many don’t have any version of the Effect Size [Cohen’s d, Odds Ratio, NNT, etc], probably because they’re weak sisters. So one thing to look for is that they have very large sample sizes. It’s in order to get that magic p < 0.05 they’re looking for to legitimize a weak effect. When the Effect Size is missing, you often have enough information to calculate it using the formulas above. Note: It’s common to have the Standard Error [se   or   sem] rather than the Standard Deviation [sd   or   σ]. But it’s easily converted using the formula:

se = σ ÷ √n    or    σ = se × √n

A common way to get those large samples is by having many sites with small numbers from each [from all over the world]. That introduces another covariate [number of sites], so it’s important to see if SITE is included in the statistical model and testing. But more about that part next time there’s a cold and rainy lost weekend…
Mickey @ 9:11 PM

quite a day!…

Posted on Sunday 8 November 2015

Mickey @ 12:03 AM

under the bushel…

Posted on Saturday 7 November 2015

Silicon Valley offers a fresh way to tackle conditions such as schizophrenia says US mental-health expert Thomas Insel
The New Scientist
By Sally Adee
Nov 4, 2015

Why did you leave the National Institute of Mental Health to work for Google?
I have to confess that after giving heart and soul to mental-health problems over the last 13 years working in government, I have not seen any improvement for either morbidity or mortality for serious mental illness – so I’m ready to try a different approach. If it means using the tools available in the private sector, let’s go for it.

Are you saying Google is a better place to do mental-health research than the NIMH?
I wouldn’t quite put it that way, but I don’t think complicated problems like early detection of psychosis or finding ways to get more people with depression into optimal care are ever going to be solved solely by government or the private sector, or through philanthropy. Five years ago, the NIMH launched a big project to transform diagnosis. But did we have the analytical firepower to do that? No. If anybody has it, companies like IBM, Apple or Google do – those kinds of high-powered tech engines…
I keep thinking I’m done with Tom Insel, but then he says something else and …

I was raised in a different research environment in my Internal Medicine days in Memphis Tennessee than I’ve seen in these years of research in Psychiatry. Memphis is in the upper reaches of the Mississippi. West Memphis Arkansas was once the Malaria capital of the US – the point being Mosquitoes. And where there are Mosquitoes, kids get Impetigo [a skin super-infection with Streptococci]. So we saw more Glomerulonephritis and Rheumatic Fever in kids and the chronic deadly versions in adults than anywhere. These are post-streptococcal diseases [once endemic but now rare]. The hemoglobinopathies like Sickle Cell disease were also prevalent in our area. So a lot of our researchers were Streptococcologists and Hematologists. The point is that research often starts with observations, like these epidemiological findings. The researchers flock and make other observations with clinical immersion.

Another example: My mentor had noticed some odd inclusions in electron micrographs of the capillaries of Lupus patients. We started a study doing electron microscopy of capillaries in Lupus, and the controls were other patients with non-Lupus connective tissue disorders. The study was a great success. The inclusions turned out to be insignificant artifacts, but what he found was that the patients with Scleroderma [in the control group] had a Alexander Flemingdramatic decrease in capillary density. That was a significant finding, but hardly the point of the study – an observation along the way. The classic example is the discovery of Penicillin. Alexander Fleming, a veteran of WWI, was involved in looking for antimicrobial agents, having seen so much sepsis in that war. He sure wasn’t studying dirty petri dishes. But when he saw a bacteria-free ring around a mold in a dirty petri dish, he knew what he was looking at – an observation along the way.

Insel’s and Hyman’s NIMH was built aiming for results. Translational research, meaning something that could race from bench to bedside. Focused research, meaning that one looked at what the higher-ups wanted and made up a proposal to fit. No career researcher grants – locating people with "the knack" and supporting them to follow their noses [eliminating the explorer class]. Insel’s NIMH was big on technology [like his comments above]. So the ordinate axis of his grand clinical neuroscience plan was literally technologies:

Clinical Neuroscience timeline [2005]

Here, he’s blaming the failure of his RDoC on inadequate technology [I think it’s more likely just a lousy idea myself]. So we have technology driven projects. He may be closer to the mark with identifying pre-psychotic states, but if he is, it’s a lucky guess without confirmation so far – exploratory. But I hold my point. He starts with the desired end rather than where we are. And that’s what his NIMH has produced – flat predictable results. The recent RAISE study is an example. Pay a lot of attention to initial episode psychotic patients and it helps. The earlier you start, the better the outcome. I knew that already. So did you.

As in love as he is with academic/industry partnerships, he has ended up with an NIMH that has done a lot of PHARMA’s work for them and colluded, if even unwittingly, with the rise of an academic/pharmaceutical complex the likes of which we’ve never seen; in a specialty [psychiatry] that we would’ve never dreamed might go down that path; achieving pockets of corruption beyond our previous imagination. And to my knowledge, Insel has never even mentioned any of that.

Finally, his comments that the NIMH hasn’t lived up to his expectations and his disavowal of his own responsibility in his complaints is a bit of hubris that he would have been well advised to leave out of his remarks altogether. It exposes an arrogance that he’d best keep under the bushel…
Mickey @ 2:00 PM

how quaint…

Posted on Saturday 7 November 2015

These are some links to articles I’ve reviewed in the recent past – industry funded, professionally-ghost-written, clinical trials of the newer atypical antipsychotics published in highly ranked, peer reviewed, academic journals. There are some other things they share in common [I made it easy with my red highlighting]:
Each article has only one academic author [all of whom have conflicts of interest specific to the drug being studied]. So only five of the forty-four authors are academics. Since the studies were conducted by Contract Research Organizations at multiple Clinical Research Centers all over the world, it is also even possible that none of the forty-four listed authors ever met a one of the subjects involved in these studies.

I’ve been thinking about this ever since we wrote the RIAT 329 article. It felt odd to me that our group was writing about subjects we’ve never seen. But then it occurred to me that it’s the standard in a lot of the Contract Research Organization managed studies. The other thing that occurred to me over and over was that our group had no direct contact with any of the twenty-two authors of the original Paxil Study 329 – only with the sponsoring pharmaceutical company. And reading through the Clinical Study Report, it was obviously written by and analyzed by the sponsor. Even the professional ghost-writer worked off of some version of a summary document prepared by the sponsor. I would suspect that the same is true about the articles above. I guess we’re just so used to the primacy of the sponsors, in spite of the fact that we anachronistically still refer to these articles as "Kane et al" or "Keller et al" [how quaint!].

It just doesn’t seem to register anymore that this class of articles reporting clinical trials is published in academic journals, but it has no real connection to anything "academic." I’ve referred to the authors highlighted in red as "tickets," as if their function is to certify admission to the journals. I recently suggested facetiously in maybe nowhere… that…
It would be fine with me if there were a specific journal for that kind of paper – the Journal of Industry Financed Reviews and Clinical Trials in Psychopharmacology… If the peer reviewed academic journals absolutely need the revenue, they could at least put these articles in a labeled, dedicated section of their publications with a heading [I suggest Industry Financed Reviews and Clinical Trials in Psychopharmacology].
…but maybe I should have taken myself more seriously. I’m beginning to wonder if we are perpetuating the myth that these articles are the productions of an ethical academic author or set of authors. Perhaps we should insist that they be clearly identified as non-academic industrial productions – which is what they are – and published in a section of their own that makes that fact crystal clear. Why not? It’s the truth…
Mickey @ 8:00 AM

photo·shopping science

Posted on Friday 6 November 2015

Latuda ad images
Four years ago, shortly after it became apparent that PHARMA was exiting CNS  drug development en mass, there was a new Atypical Antipsychotic approved by the FDA for Schizophrenia – Lurasidone [Latuda®]. Since my interest in the FDA and the psychoactive drugs had come after all the previous approvals, I had never gotten in on the ground floor. So I resolved to follow the next new drug that came along, and that was Latuda®. I had something of a hypothesis: people seem to assume that new means better; but my guess is that at this late date, new means left-over.


Lurasidone [Latuda®]

0109/27/2011 ought to know by now… 0702/14/2014 or both…
0211/28/2011 in the shadows… 0802/15/2014 creepy…
0311/30/2011 hiding uptown, more…
0902/16/2014 sign it now!…
0412/01/2011 wait… 1002/20/2014 on time…
0512/01/2011 their choice… 1108/14/2014 under some of the rocks…
0607/01/2013 the mother of meta… 1202/15/2015 a perfectly good nap…

The first article in the American Journal of Psychiatry had only one academic author [Vanderbilt’s Herbert Meltzer]. The remainder were industry employees, a ghost writer, and a vice president of the Quintiles Contract Research Organization. The study itself showed "spotty" efficacy. Looking at the FDA’s New Drug Application evaluation, the results of all five submitted studies were equally "spotty" – so much so that the FDA evaluator recommended against approval. But the head of the FDA over-rode her conclusion and the drug was approved.

Because a Quintiles vice-president was an author, I originally assumed that Quintiles had done the study, but it turned out that it was actually conducted by a Clinical Research Center in the wrong part of Chicago affiliated with the notorious Dr. Michael Reinstein. Known as the Clozaril King,: he finally lost his medical license over his shady [and lethal] dealings. Quintiles had entered the picture after the study was completed, I presume to legitimize the study and clean it up for publication. The molecule itself had been developed by a small group, gone through several companies and mergers, and finally ended up being marketed by a company formed out of the various mergers and aquisitions, Sunovion Pharmaceuticals.

[01-05] So in that first round, my own conclusion was that this was at the bottom of the barrel: a molecule that had been passed around for years; shaky trials; guest·authored, ghost·authored, and jury-rigged articles; topped off by shifty handling by the FDA – a shameful chronicle and testimonial to the worst of CNS PHARMA. The ad campaign featured a smiling after patient and his beaming mother which was then photo·shopped to provide the before image. I thought of this whole story as photo·shopped science.

[06-12] A meta·analysis a few of years later located it at the bottom of the list, so I was kind of surprised when I read [again in the American Journal of Psychiatry] that Sunivion was promoting it through the the indication creep pipeline, seeking approval for bipolar disorder etc. The articles  were as obscure as the earlier set, but the FDA documents were not in Drugs@FDA like for the earlier Schizophrenia submission. So I submitted an FDA Freedom of Information Act [FOIA] request in February 2014 – sticking to my resolve to follow Latuda® through its patent life. A couple of weeks later, I was awakened from a nap. The FDA was calling. The lady on the phone got right to the point. She was calling to try to get me to withdraw that request – the FDA being so busy and all. I declined, asking how long it would take. She said a year and a half to two years. She seemed irritated.


The DVD arrived in Wednesday’s mail from the FDA, some 19 months after submitting the request. At first, I didn’t even know what it was. I’ve spent the last couple of days reviewing what I wrote about previously and looking at the linked documents. It has been so long that I only recalled the high points [maybe I should say, the low points] along the way. I haven’t yet looked at what’s on the disk, figuring there’s no emergency in this little quest of mine. If you’ve even made it to this point in this post, I expect that you’d agree that this is pretty boring and monotonous stuff. And I doubt that anybody is waiting with bated breath to hear what the disk has to say [myself included]. And I sure don’t know how to photo·shop these posts into something flashy and interesting.

The earlier Schizophrenia submission was so obfuscated that I couldn’t really even say that the drug was a loser with confidence. The way the trials were conducted in the world of professional patients and at overseas sites, even a decent drug’s efficacy could’ve been masked [it was negative at the US sites]. So far, the only real scientist I’ve located on my Latuda® journey was Cara Alfaro, Pharm.D., the initial FDA reviewer. And so sometime soon, I’ll look at the disk and see what the bipolar studies have to say – probably producing another post as monotonous as the ones already cataloged above [and here]. It’s the only thing I know to do in the absence of a Data Transparency policy that allows independent analysis of the raw data to keep PHARMA honest. Sunovion is hardly bored. Latuda® brought in $540 M in 2014…
Mickey @ 10:28 AM

chasing rainbows…

Posted on Wednesday 4 November 2015

I should’ve just let things lie with my last post – stuck with my bit of sarcasm and moved on. Instead, I clicked on the link that lead to Fusion‘s interview of Dr. Insel, and it wound me up all over again. I’ve characterized Dr. Insel as a breakthrough·freak…– moving from one shiny object to another without every landing on something that endures, chasing whatever rainbows are on the horizon. Early in his time at the NIMH, I suppose he could get away with that occupying himself with his Clinical Neuroscience fantasies, following the pop-science concepts of the day – evidence-based medicine, translational medicine, personalized medicine, proteionomics, neuroimaging, etc. and riding on the back of the matriculation of various medication trials started by Steven Hyman, his predecessor. His blogs and speeches were like the article below, filled with future breakthroughs just around the corner. And then there was the parallel DSM-5 initiative, funded in part by the NIMH, holding symposia with the same future-think  aiming to transform psychiatric diagnosis by linking clinical syndromes to biological markers.

But instead of biomarkers, there were other kinds of markers that said that there was a need for a change in direction. In 2004, there was the Black Box warning. Then the results of the big NIMH studies trickled out. None were exciting. The Atypicals were no better tolearated than the first generation antipsychotics. TADS and STEP-BD were lackluster and heavily "spun." STAR*D was too garbled and became quite easily forgotten. By the summer of 2011, the pharmaceutical companies were obviously fleeing CNS drug development in droves, moving to greener pastures [myopia – uncorrected…]. Later that year, the DSM-5 Task Force threw in the towel [class action in the air…] and admitted that the hoped-for biomedical transformation of psychiatric diagnosis wasn’t going to happen – the long sought data just wasn’t there. Dr Insel made a speech in London trying to keep the dream alive [Brain circuitry model for mental illness will transform management, NIH mental health director says] – but his examples were fanciful. The chemical imbalance meme was replaced with the neural circuitopathies, but by then, no bands were playing anymore. As the DSM-5 became increasingly disfavored, the NIMH abandoned it and introduced its own RDoC, a nebulous concept. If the biology wouldn’t map to diagnosis, they would map the diagnosis to the biology [my own unapologetic paraphrasing], or something like that. In spite of  meetings, task forces, and multiple schemes to get PHARMA to recant, the death of the pipeline has not been averted. Are these misadventures the reason he’s leaving?
by Casey Tolan
October 26, 2015

After 13 years as the director of the National Institute for Mental Health, Dr. Thomas Insel is starting a new job next week. But it’s not a job you might expect for a respected neurologist and psychologist: Insel will be working at Google, as a leader of the Google Life Sciences division, an independent company under the tech giant’s Alphabet umbrella.

clinical neuroscience avatar...Insel is moving from the government to Silicon Valley, he told me last week, because he sees the tech sector as the answer to detecting, diagnosing, and treating mental illness. “Technology can have greater impact on mental healthcare than on the care for heart disease, diabetes, cancer or other diseases,” he said in an interview at Chicago Ideas Week. “It could transform this area in the next five years.”

At the national institute, Insel prioritized funding for research of the most severe mental illnesses, like schizophrenia. He was previously the director of the Center for Behavioral Neuroscience at Emory University, where he studied how brain chemicals affect behavior like infidelity and parental attachment.

The details of his new job description are still under wraps. “I don’t know what I’m going to be doing, and I think they don’t either,” he said. “They’re an amazingly secretive company.” But he said it was an offer he “couldn’t refuse.” He sees potential in using Google’s analytics and data-mining tools to pilot new research on mental health.

Right now, he said, America’s system of treating mental illness is “dysfunctional.” He’s disappointed at the high levels of people who don’t get treatment and his failure during his time at the national institute at driving down suicide rates. “We’re not seeing any reduction in mortality in terms of suicide because we’re not giving people the care that they need,” he said. “We would never allow this to happen for cancer, for heart disease, for diabetes.”
He has repeatedly said things like this last paragraph without acknowledging that perhaps some of the dysfunctionality has something to do with his own policies. In spite of calls from everywhere, including his own advisory board within the NIMH, he never backed away from his focus on basic neuroscience research over more service oriented projects. Posing the dichotomy in the winter of 2012 [Balancing Immediate Needs with Future Innovation], there was little question where the NIMH was determined to be heading – characterizing basic neuroscience research as investing in the future. And even now, he’s still in the breakthrough mode:
Google mood sensors...He imagines creating “sensors that give you very objective measures of your behavior.” “We do that already for how many steps you’ve had and your activity,” he said, pointing to the Fitbit strapped to his wrist, “but this would be doing it for mood, for cognition, for anxiety. It’s really actually very doable.” The sensors would measure sleep, movement, and have you take clinical tests in order to measure mental health. Other tools could analyze someone’s language use for early signs of psychosis.

Technology can also be used to treat mental health as well as help detect symptoms. Insel cited the success of companies like Big White Wall, a startup in the United Kingdom. Members post anonymously about their struggles with depression, anxiety, or other mental health concerns, take clinical tests online, and videochat with therapists. It’s been supported by the National Health Service and has made therapy available to people who might never have had it before.

“This is really potentially transformative,” Insel said. Some research has shown that “giving that treatment online is as effective as face-to-face treatment, and in some cases better, because there are so many people with these disorders who will not come in for treatment.” Other research projects have used digital avatars as stand-ins for human therapists: A potentially life-saving innovation would be making it possible for people to get online therapy right when they’re having a crisis, even if that’s in the middle of the night.

Google therapy avatar...

“So much of what we’ve done in the mental healthcare system is you have a bad night, you make it through till morning and you call and they say, ‘We’ll give you an appointment in two weeks.’ That’s just not how you treat these disorders,” Insel said. Innovations like these are the future of mental health, he said—a future he hopes to keep pursuing at Google.
I think most clinicians would agree that there some basics shared across specialties that have to do with a personal engagement, a willingness to listen, and the natural empathic bond that occurs between people. Dr. Insel is not a clinician and never has been. I think that’s why I have such a negative reaction when he begins to talk about matters clinical. So many of the things he comes up with are surprisingly naive. Instead of coming up with ideas like Avatar Therapy or saying things like “giving that treatment online is as effective as face-to-face treatment, and in some cases better,” it would’ve been helpful if he had spent more time and more of the NIMH money on ways to improve our mental health care delivery  and increasing access to systems of care [with actual people].

Beyond that, this kind of promo-talk has characterized his blogs and speeches throughout his tenure. Phrases like “potentially transformative” dot every interview and they might as well retire the word "innovation" with him as he has worn it out [along with "novel"]. It’s hard to understand why he has the longest time in grade of any NIMH Director unless the gift of spin has become a requirement for the job.

A lot of what he seems to be proposing has an NSA-esque flavor, applying text analysis or big data techniques to online communications looking for signs of mental illness. Like waiting room screening and other such proposals, these are intrusive ideas being floated on uncharted waters. I sure hope Google has thought long and hard about allowing America’s highest ranking "breakthrough freak" loose with their data-gathering capabilities.
Mickey @ 8:30 PM

alert from your computer!…

Posted on Monday 2 November 2015

by Annalee Newitz

Google’s parent company Alphabet has just hired Thomas Insel, the former head of the National Institute of Mental Health, who has some pretty weird ideas about what his new job will entail. Insel told a crowd at Chicago Ideas Week that he still isn’t sure what Alphabet wants him to do. But then he explained what he’d like to be doing, which is using Google’s data-mining tools to research mental health at time when suicides in the US are on the rise. Insel told Fusion’s Casey Tolan:
    We’re not seeing any reduction in mortality in terms of suicide because we’re not giving people the care that they need. We would never allow this to happen for cancer, for heart disease, for diabetes.
So how would we reduce suicides, using technology? Insel says that he’d like to develop a wearable sensor to measure mood, cognition and anxiety. This device would track “sleep, movement” and even “language use” for red flags that could indicate mental health problems. Basically, he suggests, it would be a kind of FitBit for your moods and sanity levels.

But there are a lot of problems with this idea. Unlike a fitness tracker, which keeps tabs your physical activity and heart rate, Insel’s mood tracker would try to correlate your physical state with a possible mental state. And that’s where things get dicey, because not everyone experiences stress in the same way. For example, I recently bought the Spire, a wearable that does some of the mood tracking that Insel suggests his device would: it monitors heart rate and breathing, and then tells you whether you’re “focused” or “anxious” or “active.”

But the Spire didn’t accurately read my moods, despite its accurate readings of my physical state. At one point while wearing the Spire, I had to do something that made me anxious. Despite my stress, the Spire claimed I was “focused”–most likely because I was forcing myself to concentrate and breathe slowly. My mental state did not match my physical one.

And that’s a relatively benign example. If we’re going to be judging people’s mental health based on things like heart rate, sleep patterns, breathing, and word choices, there are all kinds of confounding factors that might make a person seem stressed when they are just excited, or feeling awkward or jetlagged. And vice versa. None of this would be a big deal, however, if it weren’t for the fact that Insel wants to use these wearables to intervene in people’s mental health.

It’s easy to see why Insel would want to use Google’s infrastructure to do this. Suicide rates are up in the US, and studies show that early intervention can save lives. Often people who are depressed will withdraw from the world, isolating themselves from help until it’s too late. In that situation, a tracker that could alert health authorities when somebody is depressed might help. Just wear your device – or something more futuristic, like a skin circuit–save your data to the cloud, and any aberrant readings will be analyzed and sent to a mental health professional.

Except, of course, you’re now sharing a lot of hard-to-interpret health data with … whom? Your company’s psychologist? Your local health department? A doctor chosen from your insurance network? Then there’s the question of what healthcare workers will do when they believe you’re not in an optimal mental state. One can easily imagine a message popping up on some poor desk jockey’s monitor: “You’re not in the right mood today. Please take a day of unpaid leave.” Or, worse: “We’ve detected signs of mental instability, based on how you’ve been talking and sleeping. Please report to a doctor immediately.”

This is all made so much worse when you consider the kinds of specious correlations that Insel has already worked on in his previous job as a research neuroscientist at Emory University. There, he tried to show a correlation between genes, hormones, and a predilection for infidelity. I shouldn’t need to spell out how many problems there are with trying to find a physiological measure for something like “fidelity,” which is an idea that comes from culture in humans, and is interpreted in wildly different ways across social groups.
The fact is, we don’t have a technology that can accurately measure emotional turmoil. We have tech that can offer hints, certainly. There are predictable patterns to mental illness, but they aren’t universal. The idea of a mental health monitor whose data is being analyzed by algorithms should make us wary.

Insel wants to prevent people from suffering when they experience mental illness, which is a worthy goal. But his ideas about how to do it may cause more harm than good.
Mickey @ 12:58 PM

predictable repetitions

Posted on Monday 2 November 2015

While it is not fashionable to talk of psychoanalysis or other mind theories these days, I can think of no other way to approach this editorial by the editor of the New England Journal supporting Robert Califf’s nomination for the leadership of the FDA. And the particular mind theory isn’t really psychoanalytic, it’s just what’s called common sensepeople do the same things over and over. Freud called it the repetition compulsion and tried to explain it in a variety of ways, but his speculations are immaterial. It’s the phenomenon that matters. If you read this blog frequently, or even occasionally, you can predict what I’m going to write about and what I’m going to say with surprising accuracy. Likewise, you can look at the name of a frequent commenter and predict their response. Watching the presidential debates, you can do the same thing for the candidates you know [and you’ll be able to do it for the ones you don’t know by the next debate]. We call that character.

The word character can be used in a number of contexts. In the moral sphere, it means that a person who has been principled in the past will be principled in the future [predictable repetition]. In drama, the predictable repetitions of the characters are what drive the plot. When you say "He’s a real character," you’re referring to a person with unusual predictable repetitions. But in a psychotherapeutic context, it simply means the individual collection of predictable repetitions, no matter what the context. For a trivial example, when I write these blogs, I invariably use colors, bolds, italics to emphasize certain words. I know it’s kind of annoying, but try as I might, the habit [a predictable repetition] persists. These character traits we all have are enduring, and changing them, even if you know what they are, is a real undertaking. It’s the stuff of psychotherapy, and it’s plenty hard work. It’s not hard to identify maladaptive character traits in others. It easy to see how they account for a person’s own difficulty in negotiating life happily. But there’s nothing slightly easy about helping a person change them – the wisdom of "a leopard can’t change his spots."

Dr. Jeffrey Drazen’s appointment to editor of the NEJM was characterized by intense debates about the whole question of Conflicts of Interest. I wrote about them around his recent play to lighten the NEJM policy for review articles [a contrarian frame of mind…, wtf?…, wtf? for real…, a narrative…, not so proud…]. This is just one reminder among many of that episode when he was appointed:
New York Times
May 12, 2000

…Dr. Drazen, 53, helped pioneer asthma drugs now taken by four million asthmatics worldwide. In today’s news conference, he strongly defended the need for doctors to work closely and carefully with the drug industry. He called the industry a powerful force without which basic research findings made through taxpayer grants from the National Institutes of Health could not be converted into new therapies to improve patient care and public health. Last February, after an internal investigation prompted by articles in The Los Angeles Times, The Journal found that it had violated its own rules in publishing 19 articles by Dr. Drazen and other authors with industry ties. The Journal said the articles should have been written by scientists without such connections, but its editors blamed themselves and said Dr. Drazen had disclosed his industry support.

Asked today at the news conference about that episode, Dr. Drazen said that as The Journal’s new editor in chief he would hand over all manuscripts dealing with his specialty or products made by the nine companies to deputies "and make sure that they are on the agenda at a time when I do not come to the editorial meeting." In such cases, Dr. Drazen said he wanted "The Journal to be able to judge the science that comes in, if it is good or bad, without me having anything to do with it."

"I do not want to influence things in either a positive or a negative way,” he said. ”We want the good science and good information to get out there” in The Journal, which is one of the most influential in the world. Dr. Drazen, who will leave his Harvard post, will be the Journal’s third editor in chief in less than a year. His selection follows several years of turmoil between the editors of The Journal and its owner, the Massachusetts Medical Society, concerning the society’s increasing business ventures…
I don’t question Dr. Drazen’s character in the moral context – nor, for that matter, Dr. Califf’s. I would expect that they are decent human beings who pay their taxes, don’t text while they drive, and don’t litter. But I do question their predictable repetitions. Dr. Drazen’s appointment was questioned because of his consistent bias in favor of business and industry. He assured us that it would not affect his editorship. And yet here we are fifteen years later and he’s making a major assault on the NEJM’s [exempary] COI policy. And now he’s using his pulpit as NEJM Editor to support a nominee for head of the FDA who is similarly afflicted with industry bias. Like I said, predictable repetitions
New England Journal of Medicine
by Jeffrey M. Drazen, M.D.
October 28, 2015

Robert M. Califf, M.D., has been nominated to be the next head of the Food and Drug Administration (FDA); he currently serves as Deputy Commissioner for the Office of Medical Products and Tobacco. We think his confirmation as commissioner should proceed as quickly as possible. Because the FDA oversees the safety and, in some spheres, the efficacy of products that constitute about 25% of our economy, the country needs a strong and experienced leader who can keep the FDA focused on its mission.

Since Califf was nominated to succeed Margaret Hamburg, numerous individuals and groups have endorsed his candidacy. His noted strengths include his experience in the testing of new and established drugs for efficacy; his successful career at Duke University, where he was the founding director of the Duke Clinical Research Institute, by many measures one of the premier academic research organizations in the world; and until his FDA nomination, his tenure as head of the Duke Translational Medicine Institute and professor of medicine at Duke University. Over his 30-year academic career, he has published more than 1200 peer-reviewed publications, work he has authored has been cited over 50,000 times, and his Web of Science h-index is 118. But academic output has not been his primary goal; instead, he has worked to accrue the data needed to improve patient care. Despite this laudable aim, a few concerns have been expressed about his associations with industry, and these concerns may have caused some to withhold support for his nomination.

Like Califf, we believe that our actions should be driven by data, not innuendo. Since 2005, Califf has reported, as an investigator, the outcomes of seven clinical trials sponsored solely by industry in primary publications in major general medical journals. Of these trials, four had a negative outcome [i.e., not favoring the intervention], two favored the intervention, and one, with a factorial design, had a mixed outcome. Given this performance, it is impossible to argue that Califf has a pro-industry bias. On top of this, for the past 3 years the vast majority of his funded salary came from leadership roles in the Clinical Translational Science Award from the National Institutes of Health [translational medicine], the NIH Collaboratory, the Patient-Centered Outcomes Research Network [large-scale population health research], and the Duke Center for Medicare and Medicaid Innovation [CMMI] project, which developed a model approach to health care disparities in diabetes, using geospatial mapping to deliver clinical care and social support more effectively.

Our association with Califf grows from a decade of mutual service on the Forum on Drug Discovery, Development, and Translation of the Institute of Medicine [now the National Academy of Medicine]. Through this decade of service, Califf’s primary interest was clearly in gathering and using solid information to promote the health and well-being of people suffering from disease. His aim was always to find better ways to diagnose and treat illness. He wanted well-gathered data on which to base all our clinical decisions and wanted to design and implement health systems that worked effectively to improve the outcomes of individuals and populations. Califf’s experience, his proven leadership abilities, his record of robust research to guide clinical practice, and his unwavering dedication to improving patient outcomes are unsurpassed qualifications for the post of commissioner of the FDA; we strongly endorse his nomination and urge the Senate to act favorably on it.
Drazen says of Dr. Califf, "…it is impossible to argue that Califf has a pro-industry bias." I would conclude the opposite, that it’s impossible to reach any other conclusion. My own bias notwithstanding, I hardly think this is a good time to have a pro-industry biased head of the FDA, no matter how accomplished or moral. Neither is it a time to have a leader with an anti-industry bias. We need a just plain old scientist with no record of predictable repetitions in this area – that’s called common sense
Mickey @ 10:36 AM

maybe nowhere…

Posted on Thursday 29 October 2015

I have no real information about Ketamine as a treatment for depression, though it does seem beyond peculiar to be writing about a club drug in the context of treating a mental illness. But I’m writing about it for another reason nonetheless – a ethical reason. As common as it has become, I protest peer reviewed academic journals publishing articles that are primarily commercials. And my protest extends to publishing articles written by people with strong financial ties to the treatment under discussion in the article. It would be fine with me if there were a specific journal for that kind of paper – the Journal of Industry Financed Reviews and Clinical Trials in Psychopharmacology. I expect there already are a few [or some unacknowledged candidates].

If the peer reviewed academic journals absolutely need the revenue, they could at least put these articles in a labeled, dedicated section of their publications with a heading [I suggest Industry Financed Reviews and Clinical Trials in Psychopharmacology]. And speaking of Ketamine, I would nominate the review I recently discussed [a touch of paralysis… and infomercials…] for my new journal. Here’s another Ketamine article that may or may not be a prime candidate:
by J. W. Murrough L. Soleimani, K. E. DeWilde, K. A. Collins, K. A. Lapidus, B. M. Iacoviello, M. Lener1, M. Kautz, J. Kim, J. B. Stern, R. B. Price, A. M. Perez, J. W. Brallier, G. J. Rodriguez, W. K. Goodman, D. V. Iosifescu and D. S. Charney.
Psychological Medicine. 2015 45:3571–3580.

Background. Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation [SI]. We have previously shown that a single dose of ketamine, a glutamate N-methyl-D-aspartate [NMDA] receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression.
Method. We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI [n = 24]. Patients received a single infusion of ketamine or midazolam [as an active placebo] in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation [BSI] 24 h posttreatment represented the primary outcome. Secondary outcomes included the Montgomery–Asberg Depression Rating Scale – Suicidal Ideation [MADRS-SI] score at 24 h and additional measures beyond the 24-h time-point.
Results. The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h [p = 0.32]; however, a significant difference emerged at 48 h [p = 0.047]. MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h [p = 0.05]. The treatment effect was no longer significant at the end of the 7-day assessment period.
Conclusions. The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.
Declarations of Interest:
In the past 3 years, Dr Murrough has served on advisory boards for … and is named on a patent pending for neuropeptide Y as a treatment for mood and anxiety disorders, on a patent pending for the combination of ketamine and lithium to maintain the antidepressant response to ketamine, and on a patent pending for the combination of ketamine and lithium for the treatment Ketamine for suicidal ideation…
… Dr Charney [Dean of Icahn School of Medicine at Mount Sinai], and Icahn School of Medicine at Mount Sinai have been named on a use patent on ketamine for the treatment of depression. The Icahn School of Medicine has entered into a licensing agreement for the use of ketamine as therapy for treatment-resistant depression. Dr Charney and Icahn School of Medicine at Mount Sinai could potentially benefit if ketamine were to gain approval for the treatment of depression. Dr Charney is named on a patent pending for ketamine as a treatment for PTSD…
It appears to me that an academic appointment is generally a requirement to publish an article in a peer reviewed academic journal [there’s good reason for that]. I’ve called it a ticket, one that has, in my opinion, been heavily abused – bought and sold way too frequently. An academic appointment isn’t intended to be a commercial commodity.

But here we have something even more confusing, both the academic author and his academy are on an entrepreneurial adventure. It doesn’t quite belong in an academic journal. But there doesn’t seem to be a traditional industry involved to get it into my proposed new journal. Maybe a better question to ask is, "What is Mount Sinai up to here?" Clearly it’s a potential money-making venture being spearheaded in consort with one of its academic department heads [or vice versa]. That being the case, are we to assume that this self-same department and its faculty are in any position to evaluate the drug’s effectiveness. And what does it say when the two articles on Ketamine are being touted by Department Chairmen [Nemeroff and Charney] who are notoriously KOLs heavily involved in commercial products?

This story blurs the meanings of academic, of industry, and of patents. To add to that, Ketamine itself blurs the distinction between drugs [as in street drugs] and medication. I can’t even make up the name of the journal where this paper belongs – maybe The Journal of Entrepreneurial Academics? Or maybe it belongs nowhere…
Mickey @ 8:00 AM


Posted on Thursday 29 October 2015

Below is a collection of references to everything you might want to know about Dr. R. K. Chandra, a Canadian researcher whose 1989 paper, Influence of maternal diet during lactation and use of formula feeds on development of atopic eczema in high risk infants, was retracted by the BMJ yesterday. It was originally published by the British Medical Journal on July 22, 1989. It appears that this paper and many others written by Dr. Chandra are simply fabrications – reports on studies that were never done at all. And some had co-authors who were unaware that the trials had never even taken place.

Why would you want to spend your time reading about this? We talk here a lot about studies that have been "spun" – subtly twisted to accentuate efficacy or downplay toxicity. Why bother to read about a case where the whole thing is simply made up? An outright lie? I think it might be worth your while to see how the various institutions failed to act, passed the buck, dropped the ball. Those things are most easily seen in the videos of the CBC television’s investigation below. Pay particular attention to the university officials. It took a media expose and a court decision to get this story out…

Mickey @ 12:42 AM