1 Boring Old Man

“To a man with a hammer, everything looks like a nail.”

“Can we develop a clinically useful diagnostic system based on neuroscience and genetics?  Not yet.  But, in the spirit of beginning a long journey, NIMH is taking its first step with the Research Domain Criteria [RDoC] project. RDoC makes no assumptions about current categories”…

“Our vision is a new classification with high reliability and validity based on a deep understanding of the neural basis of mental disorders.”

Re-Thinking Classification of Mental Disorders |February 1, 2010|

“While the focus of wearable technology and online apps has thus far mostly been for managing heart disease and diabetes, the tech approach may be best suited for mental health. The biomarkers for depression and psychosis and post-traumatic stress disorder are likely to be objective measures of cognition and behavior, which can be collected by smartphones. Some of our most effective interventions are psychosocial treatments that can be delivered or extended by smartphones and tablets. Most important, the sensors and the interventions can be integrated into a closed loop so that care is continuous and iterative. Increasing symptoms, suicidal impulses, and paranoid thoughts lead immediately to an intervention.”

Look who is getting into mental health research |August 31, 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…

Brain expert: Why I jumped ship to Google |Nov 4, 2015|

Somebody in the NIMH must’ve known some of us were thinking these thoughts, because this month’s issue of Psychophysiology is devoted entirely to the RDoC. It starts with a couple of articles explaining the RDoC and how it came to be in existence, followed by a number of investigators using this new system. The whole issue is freely avaliable on-line. So I guess we can’t complain that they haven’t really told us what’s going on. The ball’s in our court now, and here are the links:

The Physicians Desk Reference [PDR] has grown since it was introduced in 1947, the year I started the first grade. It was still pretty thin when I started medical school in 1963, just a year after the Kefauver-Harris Drug Efficacy Act passed in the aftermath of the Thalidamide affair. The Act charged the FDA with certifying efficacy by at least two well conducted clinical trials in addition to its traditional safety evaluations. Then in the 1980s, again in response to pressure, this time from the HIV victims, there was a movement to publicly register Clinical Trials. Those efforts culminated in the FDA Modernization act of 1997 that created clinicaltrials.gov – a public registry. It was originally conceived as placing parentheses around a trial [a registration database up front and reporting database when completed], but only the registration actually caught on. The post-completion reporting database cupboard is bare, and has been, even in situations where reporting is mandatory within one year, like in government funded trials. They just didn’t do it. My accounting only covers high points, but it gives the flavor of how things have gone – a chess game that doesn’t seem to end. And a PDR that just keeps on growing – filling with drugs some of whose efficacy and safety have been exaggerated…

Publication and reporting of clinical trial results: cross sectional analysis across academic medical centers

by Ruijun Chen, Nihar R Desai, Joseph S Ross, Weiwei Zhang, Katherine H Chau, Brian Wayda, Karthik Murugiah, Daniel Y Lu, Amit Mittal, and Harlan M Krumholz

British Medical Journal 2016 352:i637

[full text on-line]

Objective: To determine rates of publication and reporting of results within two years for all completed clinical trials registered in ClinicalTrials.gov across leading academic medical centers in the United States.

Design: Cross sectional analysis.

Setting: Academic medical centers in the United States.

Participants: Academic medical centers with 40 or more completed interventional trials registered on ClinicalTrials.gov.

Methods: Using the Aggregate Analysis of ClinicalTrials.gov database and manual review, we identified all interventional clinical trials registered on ClinicalTrials.gov with a primary completion date between October 2007 and September 2010 and with a lead investigator affiliated with an academic medical center.

Main outcome measures: The proportion of trials that disseminated results, defined as publication or reporting of results on ClinicalTrials.gov, overall and within 24 months of study completion.

Results: We identified 4347 interventional clinical trials across 51 academic medical centers. Among the trials, 1005 [23%] enrolled more than 100 patients, 1216 [28%] were double blind, and 2169 [50%] were phase II through IV. Overall, academic medical centers disseminated results for 2892 [66%] trials, with 1560 [35.9%] achieving this within 24 months of study completion. The proportion of clinical trials with results disseminated within 24 months of study completion ranged from 16.2% [6/37] to 55.3% [57/103] across academic medical centers. The proportion of clinical trials published within 24 months of study completion ranged from 10.8% [4/37] to 40.3% [31/77] across academic medical centers, whereas results reporting on ClinicalTrials.gov ranged from 1.6% [2/122] to 40.7% [72/177].

Conclusions: Despite the ethical mandate and expressed values and mission of academic institutions, there is poor performance and noticeable variation in the dissemination of clinical trial results across leading academic medical centers.

«Randomized clinical trials are the ideal means for evaluating the efficacy and safety of a drug or device. Timely dissemination of the findings of clinical trials is not only essential to support evidence based decision making by patients and providers, but is required to fulfill the ethical obligation that investigators and sponsors have to study participants, professional values, and the mission of academic medical centers. Recent work has examined issues of data sharing more broadly, including the questions of which data would be made available, to whom, when, and under whose oversight. Our analysis represents the first systematic examination of the publication of clinical trials and reporting rates for results across academic centers. Though the Institute of Medicine, the National Institutes of Health, the European Medicines Agency, and the World Health Organization have helped spur the discussion about expanding the frontiers of data transparency, our findings suggest that far more basic elements of transparency in the clinical trial enterprise – the need to publish findings and report results – remain elusive.»

True enough the academic principle investigator might be involved in the protocol and the approval by the Institutional Review Board, But the Sponsor whose product is being tested is never far away. In most cases, the trial itself is conducted by Contract Research Organizations, some of which are associated with an academic institution though most aren’t. The study itself is often conducted in multiple clinical research centers and the data is processed and analyzed by the sponsor’s scientists and statisticians. The writing is provided by a contracted medical firm. The principle investigator is variably involved in some of that process, but likely more as adviser than any real head honcho.

There was a time in our lifetime when clinical trials were actually done solely by academic departments, but they were slow, not particularly interested, and couldn’t meet the demand. It was a way of supplementing the departmental income. But now, the academics are only important on the front end, and operate mainly as a spokesperson after publication if there’s a positive outcome. It’s still a revenue generating endeavor for the academic departments, but the PIs and authors act as a public face for an industrial effort.  While I expect there is a lot of variability in the story as I describe it, we can’t really parse that from the outside.

So as the world of drug testing has become increasingly distant from academic influence and control, why are the academic authors still involved? My guess is that they bring the aura of an academic standard and a medical ethic to the trials, and, of course, serve as a ticket into the traditional academic journals. To my mind, this meta-analysis is just further evidence that that influence is simply a mirage. There are many other more effective ways to insure that product testing is on the up and up. The academic community would be more usefully engaged in vetting the data that these trials produce, disconnected from the manufacturers.

I suppose a "pardon my French" apology is in order for my outburst in the  last post on seeing that Rexulti® television ad yesterday. I’m not big on profanity and I apologize, but sometimes bold, underlined, italicized , or multiple repetitive posts just aren’t loud enough. As I’ve acquainted myself with what I think of as these tainted studies, most of the really egregious stuff has been in the past, a Paxil Study 329 or a Seroquel Study 15, things that happened a long time ago. I think I had the fantasy that if one could catch them early, they could be headed off. But in this case, that’s apparently just a fantasy. Here’s the ad that evoked that response:

Major Depressive Disorder isn’t an entity, a noun. In practice it’s an adjective describing a feeling. Its variant, Treatment Resistant Depression, is a tautology, even less a noun, more an adverb modifying the verb to treat. Yet the FDA has elevated it to a category, an entity for drug approval. And they went along with approving Rexulti®, a clone of the antipsychotic Abilify [just off patent], for Treatment Resistant Depression in spite of having only one study that achieved their minimal standards [statistical significance]. The second required study decidedly did not, unless you smeared your lens with vasoline and fell for some outrageous sleight of hand in plain view. If you look up the cost of Rexulti® on the Internet [which lists costs with a discount coupon], it sells for about $30/pill. And Abilify, the drug it replaces in-patent, is generic but still costs ~$10/pill.

If you are a prescriber or a patient who is tempted by that ad, at least read the material in the last post and look at the NNTs before you leap. Also, for the mathematically inclined, take a look at john henry’s hammer: continuous variables III…:

I was writing about Harlan Krumholtz’s paper in the BMJ, and took a break to watch The Blacklist episode I missed [on the DVR]. About two-thirds through, I was fast-forwarding through the commercials but I was stopped in my tracks as a logo I recognized flashed by – Rexulti®. So I watched the ad and found myself screaming at the television set. In case you forgot about it, it’s the Abilify clone, the one that had two articles in succession in the JCP that were cut and paste copies, only one academic author [KOL Michael Thase], and was approved by the FDA as an adjunct for Treatment Resistant Depression, in spite of not making it without jury-rigging the results. For review:        

December Tales
1. creative funding I…
2. creative funding II…
3. creative funding III & some other things…
4. skepticism unchanged…
5. the extra mile…
6. a worksheet post…
7. extending the risk…
8. a postscript…
9. a story: starting in the middle…
10. a story: the end of the middle…
11. a story: the beginning of the end…
12. a story: getting near the ending[s]…
13. a story: the first ending…
14. a story: the second ending…
15. a story: the epilogue…

Both Seroquel® and Abilify® are now off patent, so the ads will disappear. But now the FDA has approved Rexulti® for this indication based on these lackluster-at-best clinical trials I’ve been reviewing, so we can count on seeing in Rexulti®-in-Depression ads soon. Even worse, it has gotten that approval at the beginning of its patent life, so it will be with us for a very long time, perpetuating this practice of Atypical-Antipsychotic-Augmentation-of-Treatment-Resistant-Depression. Can the Direct-to-Consumer ads be far behind?

He was a portly New Englander with a gravelly voice [from many allergies] and a sarcastic wit. He was a Corpsman in the Air Force for four years [to avoid serving two years as an Army private in Viet Nam]. There may have been a war going on, but it didn’t have much to do with our day to day life on a base in the UK. He had married a knock-dead gorgeous British girl [we wondered why she’d married a jolly fat guy]. In the Ward chatter in the mornings, he entertained us with a running dialog about his family back home, all Morticians for generations.

One morning, he showed up in an agitated state. Some relative had died, and that meant a prime Mortuary was up for grabs if he could get out of the Air Force. He thought about claiming homosexuality [this was pre-Don’t Ask, Don’t tell, but he’d heard that didn’t work anymore [correct, particularly with that wife]. Then one day, he was jolly again. He had a plan. The Air Force had weight standards, and like many he was way over his limit. That meant a monthly visit to the weight control officer. He’d been the day before, and he’d asked what would happen if he didn’t make the weight loss goal. "Out you go!" was the answer. So he set about eating his way out of the Air Force with a vengeance. He was rarely seen without ice cream [quarts], a mega-bag of potato chips, and Kandy Korn [sugar with coloring]. His progress seemed visible almost daily, and within a couple of months, he was being mustered out of the service.

A few months after he left, we got a letter about his exciting new job at the family Mortuary [and about his trouble losing all that extra weight]. Soon after they got to the US, his wife smiled, said goodbye, and took off never to be seen again. But he was a good sport about it "I always figured something like that was coming. It was good while it lasted" [I told you he was Jolly]…

While it’s an absurd example, it was a time [early 70s] when guidelines were really beginning to flower – weight, blood pressure, cholesterol, exercise, blood glucose, etc. The yearly physical was in vogue. Traditionally, doctors had treated diseases, but things were changing and the new version of the preventive medicine meme was on the ascendancy – nothing like now, but heading our way. I remember thinking that the "risk factor" talk that was emerging sounded sort of like a good idea, but I hadn’t signed on to be a health counselor, and it looked like that’s where we were headed. It didn’t seem like what doctors were for, at least not this doctor. And I actually recall fantacizing about something like a health counselor as  an allied health profession. I particularly balked at treating minimal blood pressure and lipid elevations because the medications of the day made people ill [and I wasn’t really convinced that I was doing something of worth for the patients].

I was thinking a lot about how I was going to spend my life back then. The thought of being a health  cop  counselor just didn’t appeal to me, but I felt guilty for having the thought. How much that had to do with changing specialties is lost in the mists of time – but I know it was, at least, part of the story. After running a few services and programs along the way, I changed my tune about feeling guilty about taking my own interests into account. The key to a successful program is to protect the staff from burning out, almost inevitable when dealing with chronic conditions [and bureaucracies]. Now, when I think about spending my time doing what’s proposed as a role for me in Collaborative Care, I shudder. Even if I thought it was a good idea, I’d pass [but it isn’t a good idea].

Benefits of Early Detection and Intervention and Treatment
The USPSTF found no studies that directly evaluated whether screening for MDD in adolescents in primary care [or comparable] settings leads to improved health and other outcomes. However, the USPSTF found adequate evidence that treatment of MDD detected through screening in adolescents is associated with moderate benefit [for example, improved depression severity, depression symptoms, or global functioning scores]…

Harms of Early Detection and Intervention and Treatment
The USPSTF found no direct evidence on the harms of screening for MDD in adolescents. Medications for the treatment of depression, such as selective serotonin reuptake inhibitors [SSRIs], have known harms. However, the magnitude of the harms of pharmacotherapy is small if patients are closely monitored, as recommended by the U.S. Food and Drug Administration [FDA]. The USPSTF found adequate evidence on the harms of psychotherapy and psychosocial support in adolescents and estimates that the magnitude of these harms is small to none…

I’ve read all the studies reviewed in 2009 and this current version. There’s not even a hint of a rational reason to recommend a preventive intervention in adolescent depression, and what these USPSTF papers conclude is as much bull-shit as some of the papers themselves. I’ve read a lot of the papers in the adult  articles too. Same deal. So when I think back on my soldier days in the early 1970s, I wish I’d had my present mind and spoke it. Our Base Commander wasn’t thinking about his troops’ health. He was thinking about how they looked on inspections, or about being strong on the "regs," or about getting that star he wanted on his epaulets. And the reason he wasn’t going to get the star was widely known by all – his affinity for bourbon – which made his subsequent campaign even sillier.

I don’t know what drives the current mania about prevention [that has a spot now on most evening news broadcasts] other than the timeless fear of death, but it’s not about a sensible and effective adherence to public health and preventive medicine principles – nor is it about making the health care professions, particularly front line specialties, something people want to do with their lives.

What would you like to see if you had your druthers?

I work in an institution that is trying to employ a collaborative-care kind of model. Where PCPs do the prescribing but they consult with a psychiatrist, and they work with a non-licensed person who is trained to do behavioral activation therapy and administer the PHQ-9.

I don’t worry that much about the guy who does it at the practices, I’m familiar with. He’s smart and thoughtful and will probably go to grad school in psychology. He’s only supposed to work with people with mild to moderate depression, but the PCPs frequently use him to facilitate access to psychiatric care – so getting someone with a serious psychosomatic illness, who is burning through specialists, in to see a psychiatrist. But a fair number of patients who have been diagnosed by their primary care docs as having mild-moderate depression have quite a lot more going on – most often substance abuse but also cutting. He promptly refers them to the right level of care, though getting them in can be hard.

Personally, I’d feel better training psychologists in psychopharmacology and having them, rather than PCPs, prescribe psychotropics to the medically uncomplicated [I’m sure I’ll get a lot of blow back on that].

What I would advocate for, is a kind of annual visit with a psychologist that’s comparable to an annual with an internist. Someone who can track your mental health over time, encourage good care and know patients so that if things start to go awry, either that general practitioner or a different kind of specialist can be called in quickly. So, say, if a young person starts to develop psychosis, it can be watched for a while, and if it really does get serious, there’s already a mental health professional in the picture that s/he has known for a long time and trusts.

We overscreen for depression and overprescribe, but a lot of the patients with much more serious illnesses are falling through the cracks.

Mickey, what would you advocate instead of the questionnaire-based screening to help those who are not getting care get it?

He’s only supposed to work with people with mild to moderate depression, but the PCPs frequently use him to facilitate access to psychiatric care – so getting someone with a serious psychosomatic illness, who is burning through specialists, in to see a psychiatrist. But a fair number of patients who have been diagnosed by their primary care docs as having mild-moderate depression have quite a lot more going on – most often substance abuse but also cutting. He promptly refers them to the right level of care, though getting them in can be hard.

A lot of medical care and particularly psychiatric care is already preventive medicine. I keep people out of jail and out of emergency rooms. I write more prescriptions than I’d like because it’s all I’ve got, for one thing, but also because with a little safe medication and support, I can prevent people from going to the GP/PA offices where they throw medicine at them [adding without subtracting]. And when those with more serious mental illness come along, I have to stand on my head to get them what they need – and even then, I have to settle for much less than is really necessary.

Reading those papers on screening or collaborative care, there are multiple conflicting streams. Don’t let a single patient fall through the cracks and keep people away from services that will cost a mint. Treat all the depression and serious mental illness that’s out there and don’t overmedicate them with anxiolytics, antidepressants, and antipsychotics. I personally think that a major force behind the overuse of medications is that everything else has been eliminated as being not "evidence-based" – meaning getting people "well." The truth is that like the rest of medical practice, "well" is not available in most cases. "Better" isn’t guaranteed. Often, the best we can do is keep people from getting "worse." With physical disease, chronic and ongoing care can’t be ignored. In mental illness, it can be ignored – and has been to an alarming degree. The powers that be decimated mental health care because they could, not because it was a good idea.

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

by D. Jeffrey Newport, Linda L. Carpenter, William M. McDonald, James B. Potash, Mauricio Tohen, and Charles B. Nemeroff, The APA Council of Research Task Force on Novel Biomarkers and Treatments

American Journal of Psychiatry. 2015 172:950–966.

… Other NMDA antagonists failed to consistently demonstrate efficacy; however, two partial agonists at the NMDA coagonist site, D-cycloserine and rapastinel, significantly reduced depressive symptoms without psychotomimetic or dissociative effects.

Conclusions: The antidepressant efficacy of ketamine, and perhaps D-cycloserine and rapastinel, holds promise for future glutamate-modulating strategies; however, the ineffectiveness of other NMDA antagonists suggests that any forthcoming advances will depend on improving our understanding of ketamine’s mechanism of action. The fleeting nature of ketamine’s therapeutic benefit, coupled with its potential for abuse and neurotoxicity, suggest that its use in the clinical setting warrants caution.

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial

by Maurizio Fava, M.D., Asli Memisoglu, Sc.D., Michael E. Thase, M.D., J. Alexander Bodkin, M.D., Madhukar H. Trivedi, M.D., Marc de Somer, M.D., M.P.H., Yangchun Du, Ph.D., Richard Leigh-Pemberton, M.D., Lauren DiPetrillo, Ph.D., Bernard Silverman, M.D., Elliot Ehrich, M.D.

American Journal of Psychiatry. Published online: February 12, 2016

Objective: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of an m- and k-opioid partial agonist, buprenorphine, and an opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression.

Method: A multicenter, randomized, double-blind, placebo- controlled, two-stage sequenti al parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2mg/2mg of buprenorphine/samidorphan [the 2/2 dosage group], 8mg/8mg of buprenorphine/samidorphan [the 8/8 dosage group], or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale [HAM-D], the Montgomery-Åsberg Depression Rating Scale [MADRS], and the Clinical Global Impressions severity scale [CGI-S].

Results: Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures [HAM-D: -2.8, 95% CI= -5.1, -0.6; MADRS: -4.9, 95%CI= -8.2, -1.6; CGI-S: -0.5, 95% CI= -0.9, -0.1]. There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation.

Conclusions: The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.

Buprenorphine  along with Naloxone are the ingredients in Suboxone® – the sublingual film used in the treament of Opioid addiction. The Buprenorphine is a morphine agonist similar to Methadone. The Naloxone is there to prevent IV use as it will throw users into withdrawal [not necessarily true in people not already addicted]. In the combination described in this paper, Buprenorphine is combined with Samidorphan, another narcotic antagonist. This combination showed promise in treating depression in its early phase trials, but then failed in two later trials reported just last month [Alkermes Depression Drug Disappoints in Trials, Alkermes shares plunge after drug misses trial goals, Alkermes depression drug fails, shares plunge, Alkermes Falls Most Since 2002 as Depression Drug Trials Fail]. And the closely watched stock tanked in a day.

The study above, reported in the American Journal of Psychiatry  today was Received: July 15, 2015 and Accepted: November 30, 2015. It was one of those earlier studies that generated all that excitement on Wall Street. It was a "Two-Stage Sequential Parallel Comparison Design Study" – it’s something of a crossover design but too complex to explain without reproducing the whole article. The same for the analysis. Speaking of complex, they had a fancy way of evaluating their crossover data that included this $50 formula:

[I sure didn’t get it]. In the end, they reported a significant difference for the lower but not the higher dose of their drug combo [HAM-D p=0.02, MADRS p=0.005, CGI p=0.03]. Of note, there were no significant differences in the patient self rating scales [Inventory of Depressive Symptomatology Self-Report, the Sheehan Disability Scale, or the SF-12].

It’s hard for me to imagine that they’ll ever succeed in engineering an opiate that has some therapeutic effect without the obvious problem of abuse and addiction – the kind that practitioners already deal with every day. I literally surrendered the narcotic part of my narcotic license in order to be able to say "I can’t prescribe pain pills." I was just so weary from being hit on for narcotics. And frankly, it feels a lot like the deepest theory herein is to over-ride depressive affect with the euphoric effect of opium. That experiment has already gone on for centuries without coming to any good end.

AUTHOR AND ARTICLE INFORMATION

From the Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston; Alkermes, Inc., Waltham, Mass.; the Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia; McLean Hospital, Belmont, Mass.; and the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas. Address correspondence to Dr. Fava [mfava@partners.org].

Presented at the 53rd annual meeting of the New Clinical Drug Evaluation Unit, Hollywood, Fla., May 28 – 31, 2013.

Supported by Alkermes, Inc., Waltham, Mass. The authors thank Mark S. Todtenkopf, Ph.D., for assistance in the preparation of the manuscript; the ALKS 5461 investigator study group; and Richard S. Perry, Pharm.D., for editorial assistance in the preparation of the manuscript, which was supported by Alkermes, Inc.

ClinicalTrials.gov identifier: NCT01500200.

Dr. Fava has received research support from and/or served as an adviser or consultant to Acadia, Alkermes, AstraZeneca, Avanir, AXSOME Ther- apeutics, Biogen, Bristol-Myers Squibb, Cerecor, Dinippon Sumitomo Pharma, Eli Lilly, EnVivo, Euthymics Bioscience, Forest Pharmaceuticals, FORUM Pharmaceuticals, GenOmind, GlaxoSmithKline, Intracellular, Janssen R&D, Johnson & Johnson Pharmaceutical Research and De- velopment, Lundbeck, Merck, Methylation Sciences, MSI Methylation Sciences, the National Center for Complementary and Alternative Med- icine, the National Coordinating Center for Integrative Medicine, NIDA, NIMH, Naurex, Nestle Health Sciences, Neuralstem, Novartis AG, Nutrition 21, Osmotica, Otsuka Pharmaceuticals, PamLab, Pfizer, PharmoRx Therapeutics, Photothera, PPD, Puretech Ventures, PsychoGenics, RCT Logic [formerly Clinical Trials Solutions], Reckitt Benckiser, Ridge Diagnostics, Roche Pharmaceuticals, Sanofi-Aventis, Servier Laboratories, the Stanley Medical Research Institute, Sunovion, Taisho, Takeda, Tal Medical, and VistaGen; he has had speaking or publishing roles for the American Society of Clinical Psychopharmacology, Belvoir Media Group, CME Institute/Physicians Postgraduate Press, and MGH Psychiatry Academy; he has equity holdings in Compellis and PsyBrain; he is named on patents for sequential parallel comparison design, licensed by MGH to Pharma- ceutical Product Development and a patent application for a combination of ketamine plus scopolamine in major depressive disorder, licensed by MGH to Biohaven; and he is a copyright holder for the MGH Cognitive and Physical Functioning Questionnaire, the Sexual Functioning Inventory, the Antidepressant Treatment Response Questionnaire, Discontinuation-Emergent Signs and Symptoms, the Symptoms of Depression Questionnaire, and SAFER and has publications with Lippincott Williams & Wilkins, Wolkers Kluwer, and World Scientific Publishing.

Dr. Thase has served as an adviser or consultant to Alkermes, Allergan [includes Forest Laboratories and Naurex], Avanir, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Lundbeck, Johnson & Johnson [includes Ortho-McNeil and Janssen], MedAvante, Merck [includes Schering-Plough and Organon], Nestlé [includes Pamlab], Neuronetics, Novartis, Otsuka, Pfizer [includes Wyeth Ayerst], Roche, Sunovion, and Takeda; he has received grant support from Agency for Healthcare Research and Quality, Alkermes, Avenir, Eli Lilly, Forest, Johnson & Johnson, NIMH, Otsuka, Phar- maNeuroboost, and Roche; he has equity holdings in MedAvante and receives royalties from American Psychiatric Foundation, Guilford Publications, Herald House, and W.W. Norton; his spouse is employed by Peloton Advantage, which does business with Pfizer.

Dr. Bodkin has received payment for participation in advisory panel meetings related to the investigation of ALKS 5461 as a potential treatment for psychiatric disorders and has served as a consultant and received research support from Bristol-Myers Squibb, Otsuka, and CeNeRx, served as a consultant to MyTomorrows, has received research support from Shire, and has received grant support from NIH/NIMH.

Dr. Trivedi has served as a consultant to or received fees from Alkermes, AstraZeneca, Bristol-Myers Squibb, Cerecor, Eli Lilly, Forest, Johnson & Johnson, Lundbeck, Merck, Naurex, Neuronetics, Otsuka, Pamlab, Pfizer, Rexahn, Roche, and Shire and has served on a scientific advisory board for Rexahn; he has received research support from NIMH and NIDA.

Drs. Memisoglu, de Somer, Du, Leigh-Pemberton, DiPetrillo, Silverman, and Ehrich are or have been full-time employees of Alkermes, Inc., and have stock options.

 

Screening for Depression in Children and Adolescents:

U.S. Preventive Services Task Force Recommendation Statement

by Albert L. Siu, MD, MSPH, on behalf of the U.S. Preventive Services Task Force

Annals of Internal Medicine. Published online 9 February 2016

[full text on-line]

Description: Update of the 2009 U.S. Preventive Services Task Force [USPSTF] recommendation on screening for major depressive disorder [MDD] in children and adolescents.

Methods: The USPSTF reviewed the evidence on the benefits and harms of screening; the accuracy of primary care–feasible screening tests; and the benefits and harms of treatment with psychotherapy, medications, and collaborative care models in patients aged 7 to 18 years.

Population: This recommendation applies to children and adolescents aged 18 years or younger who do not have a diagnosis of MDD.

Recommendation: The USPSTF recommends screening for MDD in adolescents aged 12 to 18 years. Screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. [B recommendation] The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for MDD in children aged 11 years or younger.

Screening for Major Depressive Disorder in Children and Adolescents:

A Systematic Review for the U.S. Preventive Services Task Force

by Valerie Forman-Hoffman, PhD, MPH; Emily McClure, MSPH; Joni McKeeman, PhD; Charles T. Wood, MD; Jennifer Cook Middleton, PhD; Asheley C. Skinner, PhD; Eliana M. Perrin, MD, MPH; and Meera Viswanathan, PhD

Annals of Internal Medicine. Published online 9 February 2016

[full text on-line]

Background: Major depressive disorder [MDD] is common among children and adolescents and is associated with functional impairment and suicide.

Purpose: To update the 2009 U.S. Preventive Services Task Force [USPSTF] systematic review on screening for and treatment of MDD in children and adolescents in primary care settings.

Data Sources: Several electronic searches [May 2007 to February 2015] and searches of reference lists of published literature.

Study Selection: Trials and recent systematic reviews of treatment, test–retest studies of screening, and trials and large cohort studies for harms.

Data Extraction: Data were abstracted by 1 investigator and checked by another; 2 investigators independently assessed study quality.

Data Synthesis: Limited evidence from 5 studies showed that such tools as the Beck Depression Inventory and Patient Health Questionnaire for Adolescents had reasonable accuracy for identifying MDD among adolescents in primary care settings. Six trials evaluated treatment. Several individual fair- and good-quality studies of fluoxetine, combined fluoxetine and cognitive behavioral therapy, escitalopram, and collaborative care demonstrated benefits of treatment among adolescents, with no associated harms.

Limitation: The review included only English-language studies, narrow inclusion criteria focused only on MDD, high thresholds for quality, potential publication bias, limited data on harms, and sparse evidence on long-term outcomes of screening and treatment among children younger than 12 years.

Conclusion: No evidence was found of a direct link between screening children and adolescents for MDD in primary care or similar settings and depression or other health-related outcomes. Evidence showed that some screening tools are accurate and some treatments are beneficial among adolescents [but not younger children], with no evidence of associated harms.

I came to psychiatry drawn by the psychological struggles apparent in so many of the medical patients I’d seen along the way. I just didn’t get it. And learning to view them in the context of the person’s whole biography was, in itself, worth the price of admission for me. When the DSM-III with its expanded focus on distinct disorders came along, I was neither interested nor able to go back, so I went away. I understood and even agreed with many of the criticisms of what had been before, but I couldn’t live with the baby in the bathwater problem. I see non-melancholic depression as a signal that something’s wrong that needs attending rather than just a symptom to be treated. And that’s particularly true in adolescence and young adulthood. I really don’t think there’s a unitary disease, Major Depressive Disorder [MDD], even in adulthood, but I double-dog-really don’t think it exists in children and adolescents – certainly not in the way these articles imply. Five years volunteering in a Child and Adolescent clinic after retirement only reinforced these views.

So as important as I think it is to attend to depression in adolescents, this recommendation and the accompanying review just seem way off the mark. And to present this slide as an updated "Systematic Review" is ludicrous:

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I was sitting in the waiting room Friday morning waiting for an ENT appointment [to check a worrisome non-healing lesion in my nostril]. The big tv was looping through an animated description of some balloon thing they could do to your sinuses and a hearing aid spiel about why getting them from an ENT is better than [anywhere else]. I was reading on my phone about depression screening rather than from the various WebMD magazine-lets lying around. When the receptionist gave me the papers to fill out, I half expected there to be a PHQ-9 like at my internist’s office or in the waiting room at the clinic where I work. There wasn’t. But there was one about whether I needed that sinus balloon job and one in case I’m hard of hearing. When I went to the examining room, another tv set was silently mime-ing how to use an epi-pen and cycling through the various hearing aid batteries available at the front desk. The highlight of the visit was the pronouncement that it looked like "a wart" instead of all the ominous options that occurred to me when I found it. I gladly left my "wart" in a jar for the pathologist. On the way home, I wondered why I have such a strong visceral reaction against the idea of screening for depression in doctor’s waiting rooms. Here are some words:

Screening for Depression in Adults:

US Preventive Services Task Force Recommendation Statement

by Albert L. Siu, MD, MSPH and the US Preventive Services Task Force [USPSTF]

JAMA. 2016 315[4]:380-387.

[full text online]

Description: Update of the 2009 US Preventive Services Task Force [USPSTF] recommendation on screening for depression in adults.

Methods: The USPSTF reviewed the evidence on the benefits and harms of screening for depression in adult populations, including older adults and pregnant and postpartum women; the accuracy of depression screening instruments; and the benefits and harms of depression treatment in these populations.

Population: This recommendation applies to adults 18 years and older.

Recommendation: The USPSTF recommends screening for depression in the general adult population, including pregnant and postpartum women. Screening should be implemented with adequate systems in place to ensure accurate diagnosis, effective treatment, and appropriate follow-up. [B recommendation]

• Screening for Depression—A Tale of Two Questions
• US Preventive Services Task Force Recommendation Statement on Screening for Depression in Adults Not Good Enough
• Recommendations for Screening for Depression in Adults Michael Thase [full text]
  
• Patient Health Questionnaire [PHQ-9]
• Task force urges depression screening for all U.S. adults
• Universal Depression Screening Urged
• Missing in action: Did US journalists miss a huge opportunity to critically examine mental health screening?

Besides antidepressants, they’re talking about Cognitive Behavior Therapy. CBT is a legitimate and effective therapy, but it’s not generic. In my area, most mental health types would list it as their first line discipline. But I don’t think I’ve seen a full course of what Aaron Beck would call CBT in the eight years I’ve been involved. What happens in formal trials and what happens in the "natural world" are very different things. So I suspect that the majority of waiting room depression would be treated with medication.

And then there’s the question of what constitutes depression. Would it be people who say they’re depressed? – which is what unhappy people nowadays say to describe how they feel – bad marriages, no marriages, the burden of a difficult biography, personality disorders, situational crises, grief, lonliness, etc. The formal diagnosis of depression has become corrupted in the recent era – simplified to mean almost any constellation of discrete symptoms and causes. So even discussing it as if it’s a unitary entity is hard to justify.

But I don’t think those things are why depression screening evokes such a visceral "No" when I hear it. One part of that is the global burden of depression meme that introduces so many articles on antidepressants [and blogs by our former NIMH Director for one] implying that through some not-so-clear-mechanism, the incidence of depression-the-vaguely-biological-entity is accelerating. It makes  little sense. If there were a genetic or neural circuit etiology, why would it be increasing? And were that true, what does the symptomatic treatment with medications have to with that? Those arguments invariably precede a pitch for more funding for brain research or some new, innovative, treatment for depression, loosely based on a 2004 population study by the World Health Organization. And so this whole line of thinking seems flawed to me, a cascade of unproven and unexamined assumptions that have achieved an autonomous momentum that will only be amplified by waiting-room-depression-screening.

• Little interest or pleasure in doing things?
• Feeling down, depressed, or hopeless?
• Trouble falling or staying asleep, or sleeping too much?
• Feeling tired or having little energy?
• Poor appetite or overeating?
• Feeling bad about yourself – or that you are a failure or have let yourself or your family down?
• Trouble concentrating on things, such as reading the newspaper or watching television?
• Moving or speaking so slowly that other people could have noticed?
• Or being so fidgety or restless that you have been moving around a lot more than usual?
• Thoughts that you would be better off dead, or of hurting yourself in some way?

What would you call it if I gave a lecture for CME, unrelated to prescribing but it was sponsored by Big Pharma – even though I had nothing to do with the business end of it? I would definitely get listed in Open Payments web site.

There was a time when pharmaceutical sponsorship of all kind of things was common, even desirable. I didn’t actually think much about it back then – seeing it as a service provided by one member of the medical community to another. They gave us an endless stream of pens, cheesy models if knees and brains, note pads, prescription pads. F. Netter’s drawings in C.I.B.A. pamphlet’s were the gold standard for anatomical illustration – much revered. But I honestly didn’t know which company made which drug. A friend once quipped that the only drug company we all really knew was SKF, because they made the diet pills we took as med students to cram for exams [embarrassingly true in the mythic 60s].

As pharmaceutical and life-sciences companies search for the most effective, efficient ways to manage collaboration with the physicians who conduct research, write articles, or speak on their behalf, relationship management of the interaction with these elite physicians, or key opinion leaders [KOLs], has ultimately emerged as an individual business discipline. Similar to CRM, KOL management is an essential component for marketers and medical staff throughout the life-cycle process of a specific drug or product.

^{[NOTE: CRM stands for Customer Relationship Management]}

By sustaining a business process that creates and maintains meaningful and collaborative relationships between KOLs and business functions from marketing to medical affairs, pharmaceutical and life-sciences companies can experience increased share of voice and accelerated adoptions at the global, national, and regional levels. A CEO of a major pharmaceuticals company recently told a group of analysts that effectively managing KOL relationships was essential to companies’ future products and market expansion.

As physicians strive to choose from a myriad of drug options for their patients, they often turn to fellow key opinion leading physicians for knowledge and advice on specific drugs. Key opinion leaders possess a unique credibility, as their validity often stems from years of industry experience and medical affiliations. As a result, pharmaceutical and life-sciences companies have begun relying heavily on key opinion leaders to help establish the knowledge base about their drugs and expand their markets throughout all stages of life-cycle management.

^{[KOL Management in Pharma and Life Sciences:
The next wave of CRM applications – 2006]}

So I take George’s point, and I don’t mean that sarcastically. My radar just doesn’t work anymore. When I think about it, Megan’s Morning Rounds PhRMA and Johnson & Johnson sponsorship is more along the lines of what I recall from the past. It’s open and I expect [hope] that her clarification is on the up and up [explanation?…]. I’m sure that there are many hypotheticals that I wouldn’t have a clue how to classify, how to decide which side of the line they fall on. People like Dr. Nemeroff and the other ultra-KOLs on Senator Grassley’s list made that part easy. They were so far south of the border that the line drew itself. And there are plenty of others where that’s true.

I come from an era when even the possibility or appearance of a Conflict of Interest was exclusionary. I did a lot of speaking during my years. And though it was to trainees, graduate students, and peer groups in my own and other mental health specialties, I didn’t ask for honoraria, and if it appeared, I donated it back to the sponsoring organization. I did accept room and board if it was out of town. That wouldn’t have worked had I been on the circuit, but I wasn’t. Saying it now sounds kind of prissy, hyper-moral, maybe even pseudo-moral. But I was just following the lead of my own role models. I really liked talking about things I had learned, and I almost always came away from those talks having learned something myself. It was kind of like this blog – a way of collecting my thoughts. Nothing makes you think about things so much as the possibility of saying it out loud to others. I wouldn’t necessarily push that approach on anyone else. It just is what worked for me.