1 Boring Old Man

SUMMARY TO DATE:

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.

THIS WEEK:

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.

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.

Why America’s top mental health doctor is moving to Google

FUSION

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.

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 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.

“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.

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.

Google’s Latest Hire Has a Creepy Plan to Track Your Mental Health

GIZMODO

by Annalee Newitz

10/27/15

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.

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."

New England Journal of Medicine Names Third Editor in a Year

New York Times

By LAWRENCE K. ALTMAN

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…

Califf for the FDA

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.

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].

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial

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?

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.

• R.K. Chandra’s infant formula study withdrawn by medical journal:
  Evidence entered in libel lawsuit over CBC documentary spurs retraction of scientist’s paper
  CBC News
  Oct 28, 2015
• After court verdict, BMJ retracts 26-year-old paper
  Retraction Watch
  by Shannon Palus
  October 28, 2015
• Ranjit Chandra: how reputation bamboozled the scientific community
  by Caroline White.
  British Medical Journal. 2015 351:h5683.
• A major failure of scientific governance
  by Richard Smith, former editor in chief, and Fiona Godlee, editor in chief
  British Medical Journal. 2015 351:h5694.

On has to be awed by blogger Neuroskeptic whose scope far exceeds the rest of us combined. Here, he clears up the dilemma I obsessed about recently. When the results of the RAISE study were published a few days ago, the extensive press coverage proclaimed that the NAVIGATE [NAV] patients received a much lower dose of antipsychotics than those with treatment as usual [TAU], yet the paper itself said nothing about the drug doses. That’s a hot issue at the moment. Traditional psychiatric teaching has been that maintenance medication [and plenty of it] was an important ongoing part of treatment to prevent psychotic relapses, whereas an initiative from Mad in America, the British Psychological Society, the studies of Wunderink and Harrow, etc. suggest that maintenance medication interferes with long term functional recovery. And the ideological and guild-driven overlay on this point hangs heavily over any and all opinions on this matter. So the difference between the media hype and the actual papers caught the eye of many [including yours truly – see raising a dilemma…]. Says Neuroskeptic on this point:

Medication for Schizophrenia: Less is More?

Neuroskeptic: Discover Magazine

By Neuroskeptic

October 27, 2015

According to the New York Times [NYT] a week ago, a major new study found that lower doses of antipsychotics are better for the treatment of schizophrenia:

The findings, from by far the most rigorous trial to date conducted in the United States, concluded that schizophrenia patients who received smaller doses of antipsychotic medication and a bigger emphasis on one-on-one talk therapy and family support made greater strides in recovery over the first two years of treatment than patients who got the usual drug-focused care.

The paper, by John M. Kane and colleagues and published in the American Journal of Psychiatry [AJP], is called Comprehensive Versus Usual Community Care for First-Episode Psychosis and it presents the results of the NIMH “RAISE” study. Three days ago the NYT accordingly issued a correction:

An article on Tuesday about a study of the treatment of first-episode schizophrenia referred incorrectly to the conclusions of the study. Though it studied a program intended to reduce medication dosages, the researchers do not yet know for sure if dosages were lowered or by how much. Therefore, the study did not conclude “that schizophrenia patients who received smaller doses of antipsychotic medication and a bigger emphasis on one-on-one talk therapy and family support made greater strides in recovery.”

Which is more like it.

Actually, it’s what I want to hear too. I never didn’t think that a broad intensive focus on the individual and the family with adequate resources [including brief hospitalization when required] along with the careful use of medications was the right approach to these patients. I thought it in the 1970s and in all the years in between. My only recent questions have been whether the RAISE version is the right version and whether it will convince the powers that be to implement some version widely.

The intervention was in fact a complex mix of family and individual support and therapy, supported activities and employment, and a computerized medication management system called COMPASS.

One of the features of COMPASS is that it recommends doctors to use lower doses of antipsychotics than they otherwise might. The COMPASS manual advises that people suffering their first psychotic episode are more sensitive to antipsychotics, and so lower doses will suffice, compared to chronic schizophrenia patients. However, Kane et al. report no information on dosage so we don’t know if the intervention group were actually taking lower doses than the controls.

So where did the focus on medication dosage come from? Possibly from this NIMH press release from 20th October, the same day the NYT story ran, which says that RAISE

Featured a team of specialists who worked with each client to create a personalized treatment plan. The specialists offered recovery-oriented psychotherapy, low doses of antipsychotic medications, family education and support…Featured a team of specialists who worked with each client to create a personalized treatment plan. The specialists offered recovery-oriented psychotherapy, low doses of antipsychotic medications, family education and support…Featured a team of specialists who worked with each client to create a personalized treatment plan. The specialists offered recovery-oriented psychotherapy, low doses of antipsychotic medications, family education and support…

Which is technically true, but a little ambiguous. “Offered low doses” could be read as implying “provided low doses”, and presumably the NYT article was based on such a reading, yet there’s no evidence to suggest that the doses provided were actually lower than in the control group. Even if the doses were lower, we don’t know if the low doses were contributing to the better outcomes in the intervention group, because that group got all kinds of other extra treatments as well [e.g. family therapy, supported education]. Theoretically the lower doses might have been harmful if the harm was outweighed by the other beneficial stuff. Or equally, the lower doses might account for all the benefit. We just don’t know.

Looking over their Manuals [COMPASS, INDIVIDUALIZED RESILIENCY TRAINING] and the NIMH Press Release, I have complaints. The COMPASS Manual is algorithmic and recommends only second generation antipsychotics. I’m not at all sure I agree with that. The metabolic syndrome is not always less ominous than the neurological side effects of the first generation drugs in my hands. And I’m not at all in love with the IRT approach which is not as focused on the Schizophrenic cognitive problems as I would prefer. However, I’m no expert, and there’s plenty of room for iteration in both areas.

But as much as I appreciate Neuroskeptic’s detective work, I don’t buy that "we just don’t know" about the medication doses. I’m suspicious that "we just weren’t told." That data is in some perfectly adequate computer database and there are more than enough statisticians involved in this project to extract it for us. So I’m suspicious that it doesn’t quite show what they want it to show, and  that’s why "we just don’t know." Likewise, that confusing Table 2 in the paper is unnecessarily obtuse. There are a lot more intelligible ways to display the outcome that they didn’t choose. So I smell something fishy, hear something spinning. Time will tell.

She was brought to the clinic by her aunt who was taking care of her temporarily. She was a woman in her fifties with a cast on her lower leg from a fall. She was calm, alert, but couldn’t answer many questions. She was blitzed. She told me she’d fallen and broken her hip. But she knew neither the date nor the season. By history, she was obviously the ‘black sheep’ of the family – a failed marriage, no contact with her kids, psych hospitalizations, multiple rehabs for alcohol, benzodiazepine detox, etc. – moving from family member to family member. Her aunt had a piece of paper with her medications written out neatly:

• Seroquel 600 mg/day
• Trazadone 450 mg/day
• Depakote 2.5 Grams/day
• Neurontin [I forget how much too much]/day
• Cogentin 4 mg/day
  among other things…

…an outrageous cocktail!

Over a couple of months, I got her down to…

• Seroquel 200 mg/day
• Depakote 500/day
• Cogentin 4 mg/day

…without incident. But she was still pretty fuzzy [season "yes" – month "no"]. That was two weeks ago. I had noted her pupils were dilated every visit but  wanted to decrease the Seroquel before taking on the Cogentin. This time they were so widely dilated I could barely tell her eye color [why it wasn’t that dramatic earlier isn’t clear to me] and she complained about her vision being blurred. So I stopped the Cogentin by coming down a mg/every couple of days. Yesterday, I had stepped out to return a phone call. When I got back, the nurse had put she and her Aunt in the office because she was so agitated. She was in the middle of a full scale hyperventilation episode with carpal-pedal-spasm – throwing her glasses across the room breaking them and yelling about…well, about everything.

It took a while to get her breathing slowed. In the barrage of things that followed  [a litany of a lifetime of woes and symptoms], I noticed that her pupils were down to size; that she was fully oriented with intact memory, past and present; and that she was mad as hell about many [if not all] things. As she calmed down, I could see that she had some subtle but none-the-less definite involuntary movements of her tongue. In addition, her legs were never totally still…

How did this woman get on such an outrageous cocktail? I wasn’t able to take as much history as I would’ve liked, but I think I got to the bottom of that question. She was being seen at our local contract mental health center. Every time she went, she left on more medication [both kinds of more – increased dose and/or new meds]. She was never seen by the same person twice. As as matter of fact, she was never seen by a person in the traditional sense. They have telepsychiatrists there, psychiatrists on television sets. She and her aunt had been to the center to complain about the overmedication themselves since our last visit, and the director was mega-apologetic – sheepishly admitting that this wasn’t the first time [duh!]. I’m going to give her a call myself later this week.

I’m not going to wind up on telepsychiatry today. I complain about enough things already. I think it’s a creation of some cost-cutting bean counter and ought to be outlawed as de facto malpractice rather than the subject of glowing articles in the Psychiatric News. I doubt I even have to explain why I think that, so I won’t. This is hardly my first encounter with such a case, and I’m sure it won’t be my last. Some truths are self-evident…

Most of us are aware that a number of the articles in our peer-reviewed journals reporting industry-funded Clinical Trials of CNS drugs have been distorted to a greater or lesser degree. I think it’s important to look at how they’ve been "spun" to play up efficacy and downplay harms. The distortions were no accident, but rather deliberate and sometimes skillful moves to maximize the commercial desirability of the drugs. In our paper on Paxil Study 329 [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence], we didn’t speculate on such things directly though I did address them in some blogs [study 329 vi – revisited…, study 329 vii – variable variables?…, study 329 viii – variable variables decoded…, study 329 ix – mystic statistics…, study 329 x – “it wasn’t sin – it was spin”…,  study 329 xi – week 8…, and study 329 xii – premature hair loss…].

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence: Response to Drs. Eriksson and Hieronymus

by Elia Abi-Jaoude

British Medical Journal. 2015 351:h4320.

[full text online]

[references on-line]

In scientific inquiry, there is a role for both hypothesis-driven and exploratory research. Research trainees have often heard one form or another of the saying, ‘If you torture your data long enough, it will tell you what you want to hear.’ Nevertheless, the practice of inappropriate data interrogation with the aim of obtaining a p value that is less than 0.05 pervades the literature[1–12]. Hence, prespecifying hypotheses helps protect against spurious findings, and also helps ensure that research pursuits are based on a rationale that is informed by known scientific evidence.

Nevertheless, clinical research endeavours typically demand considerable time and other resources, and the knowledge and interpretation of scientific evidence that may provide a basis for hypotheses is constantly evolving; thus, it is imperative that data from studies are adequately interrogated. The key, however, is that this is done in a transparent manner, both in terms of reporting the full extent of exploratory analyses, and in tempering interpretations of findings arising from such exploratory pursuits.

The study published by Keller and colleagues[13] is not transparent about the distinction between the prespecified outcome measures and the additional analyses carried out. In fact, one such exploratory variable is misleadingly described as a “[i.e., primary outcome measure]”[13][page 765]. An internal SKB memo describes the aim to “effectively manage the dissemination of these data in order to minimise any potential negative commercial impact”[14]. It described “no plans to publish data from Study 377” [a trial similar to Study 329 with similarly negative results][14] [pdf page 1], and that “Positive data from Study 329 will be published”[14] [pdf page 5]. Despite repeated requests from us, GSK was not able to produce adequate evidence for an analytical plan outlining the rationale for the exploratory analyses. Thus, there is nothing to indicate that the additional exploratory measures came about from a renewed understanding of the scientific merits of the additional exploratory variables.

Professor Ericksson and Dr. Hieronymus go on to propose the “depressed mood” item as a more sensitive and appropriate measure of antidepressant efficacy than the total sum of the Hamilton Depression Rating Scale [HDRS][15]. They refer to their recently published analyses of pharmaceutical company studies of SSRIs for adult depression, in which “whereas 56% of 32 comparisons failed to reveal a significant difference between groups when HDRS sum was used as effect parameter, only 9% failed to detect a significant superiority of the active drug with respect to the “depressed mood” item”[15,16]. However, whether the single “depressed mood” item is a more appropriate measure of antidepressant efficacy is debatable.

What can be made of the finding that statistical significance is reached on a single item – depressed mood – but not on the sum total of items representing the constellation of symptoms that we presently refer to as major depression[16]? Perusing the results presented in Table 2, almost all HDRS endpoint mean scores for the depressed mood item fall between ratings ‘1’ and ‘2’: the placebo arms mean scores are closer to ‘2’, i.e., ‘spontaneously reported verbally’, and the SSRI arms mean scores are closer to ‘1’, i.e., ‘indicated only on questioning’[16][Table 2]. This finding could be readily explained by SSRI-induced apathy, a common yet underappreciated effect of these drugs[17–23]. Thus, patients experiencing SSRI-induced apathy could be less likely to spontaneously report a depressed mood than patients on placebo, all the while there is no substantial difference between the two in terms of their overall symptoms of depression.

Furthermore, while the effect size based on this single “depressed mood” item is described as moderate, the change of much greater magnitude is that of the endpoint versus baseline mean scores, for both the SSRI and placebo arms[16][Table 2]. This highlights the important role of placebo and non-specific factors in the SSRI response. The additional effect from SSRI versus placebo could be partly a result of unblinding due to adverse effects. Both clinician and patient participants can tell with a high degree of accuracy whether they have been assigned to a drug or placebo arm in a trial[24,25], and this is rarely reported in clinical studies[26]. Further, adverse events have been shown to correlate with effect size in antidepressant trials[27,28]. Of note, in an early study by Thomson, whereas 43 of 68 trials showed tricyclic agents to be superior to inert placebo, only 1 out of 7 trials showed the antidepressant to be superior relative to atropine as an active placebo[28].

As an alternative to symptom-based scales, more meaningful, patient-relevant measures include those that assess function and quality of life. In Study 329, none of such protocol-defined measures showed paroxetine to be more efficacious than placebo, including the clinical global impression mean score, autonomous function check list change, self perception profile change, or the sickness impact profile[29].

In conclusion, while exploratory analyses can yield useful information, they can be – and very often are – used to fish for statistically significant results that are presented in a misleading manner[1–12]. It is worthwhile to explore more appropriate and meaningful alternatives to current popular measures to capture patient response to intervention. However, this necessitates full transparency, including access to clinical trial protocols and raw data. Otherwise, we will continue to subject our patients to interventions with a distorted impression of benefits and harms.

With adults, you’re dealing with ingrained character traits – maladaptive ways of approaching the world, of dealing with people. The task involves isolating those automatic mechanisms and then helping the patient find ways to become aware of and hopefully change them. With kids, it’s different because we’re dealing with a developing person. We look at a lot of psychopathology as developmental deviation. The kid has gotten off the track, and our task is to get them back on the road to healthy development.

I didn’t pursue a Child and Adolescent fellowship, but would’ve if I hadn’t used up my be-a-student quota on a couple of residencies and analytic training. But that idea of developmental deviation stayed with me. Years later I was working in a Child and Adolescent clinic and saw how important that concept really is. Most of the adolescents were brought because of behavioral problem or depressive symptoms and the main thrust of our work with the kids and their families was to help them get back to the business of developing an identity suitable for adult challenges.

When I woke·up after retiring and found how much the academic-industrial alliance had fueled something of a medication-mania, I was most surprised about how it had its fingers in the C&A literature and practice. The Bieder·mania epidemic of the Bipolar Child, the general use of the atypical antipsychotics in disruptive and developmentally challenged children, and the continued use of the SSRI andidepressants in adolescents in spite of the weak to negative clinical trials and Black Box Warning were unwelcome surprises. It was if the distinction between child and adult psychiatry, between children and adults, had eroded and the kids were being treated as little adults – reminiscent of the adultomorphic children of previous centuries.

I was disappointed that the official responses to our recent RIAT article [Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence] from the American Academy of Child and Adolescent Psychiatry [AACAP] and its journal [JAACAP] were so focused on their paper itself [aacap and jaacap respond…], rather than to the broader issues like data transparency of clinical trials or overmedicating children. The American Academy of Child and Adolescent Psychiatry [AACAP] is meeting in San Antonio Texas this week [AACAP’s 62nd Annual Meeting], and to my knowledge, Study 329 isn’t on the docket, though some members argue it should be [AllCapsUnlocked]. One of the authors of that 329 paper, Karen Dineen Wagner, is slated to be installed as president elect this week.