1 Boring Old Man

It’s unlikely that anyone reading this blog or following the peculiar trajectory of academic and organized psychiatry doesn’t know a lot about Charlie Nemeroff and his fall from "Boss 0f Bosses" as Chairman at Emory. He’s become a paradigm for so many things – ghost writing, conflicts of interest, speaker’s bureaus, advisory boards, wheelings-and-dealings, etc. After the fall in 2008, he landed on his feet as Chairman in Miami by 2009 and by 2012 he got himself back on the Grand Rounds Circuit with the topic, The Neurobiology of Child Abuse: Treatment Implications and as an NIMH grantee with PROSPECTIVE DETERMINATION OF PSYCHOBIOLOGICAL RISK FACTORS FOR PTSD [speechless…].

During Dr. Nemeroff’s time as Chairman at Emory, I had already left the Department there as a full time faculty person during the revolution in psychiatry in the 1980s, remaining on the clinical faculty. One interest was PTSD, the psychological part, but I didn’t even know that the chairman of my department was following this other path, one he still follows. I don’t personally believe PTSD has anything to do do with neurobiology or psychobiology, but what I think is not what this post is about. It’s about something known as grantsmanship and wasted research dollars.

I’m not the only person that follows the Travels with Charlie. Carl Elliot of Fear and Loathing in Bioethics points us to Dr. Nemeroff’s coming visit to the Department of Psychiatry at his University of Minnesota.

Grand Rounds – 2014-2015
September 3, 2014	Grand Rounds: TBD Presenter: Charles B. Nemeroff, MD, Professor and Chair, Dept. of Psychiatry and Behavioral Sciences and Director, Center on Aging, University of Miami

I don’t know if the topic will be The Neurobiology of Child Abuse: Treatment Implications like it was at NYU or in London. The video of the NYU version has unfortunately been taken down, but here’s a synopsis of his closing slides:

I don’t happen to believe any of the speculative parts of that [3, 4, & 5]are known or even likely, but like I said, what I think is not what this post is about. Here’s a piece of that grant write-up for orientation:

I don’t happen to believe there is"already considerable evidence that the likelihood of developing PTSD after trauma exposure is due to a combination of genetic and environmental factors" either, but…

So to the grant itself. So far, we’re into it for a bit over a million NIMH dollars. This is the second time around for this project. Last time, they recruited subjects from hospital waiting rooms and ads on rapid transit [MARTA]. How did they get funded to do it again? I’m not sure, but I think it’s that they’re taking different measurements and using different analyses [?], but what I really think is that Dr. Nemeroff is a master of grantsmanship…

We were all mystified that he got an NIMH grant at all with his track record [speechless…], and particularly with this topic – a tired remnant from the days when the biology-is-everything mantra was king. I doubt that anyone much thinks that anything will come from this study. So why would he be so quickly rehired after being definitively discredited and how did he get a grant for this of all topics? That is what this post is about. Back in the day, Dr. Nemeroff became the paradigmatic insider. He knew all the people in power [some of whom he’d helped to get there]. And he was an expert in parlaying his influence in raising money from the pharmaceutical companies and the NIMH. He got away with some outrageous antics because he brought home the money to his university and department, so people looked the other way. Even in disgrace, he was still an effective power broke – thus landing on his feet. And what’s the point? He’s still bringing home the bread. And, oh look, three fifths of the way through this grant life, what has been charged to it?

It’s pretty easy to see that these articles don’t have anything to do with the PROSPECTIVE DETERMINATION OF PSYCHOBIOLOGICAL RISK FACTORS FOR PTSD. But that’s not to say that the study isn’t going on. I expect at the end we’ll be treated to slides of findings added to those from the other time around. But it’s highly unlikely that the results will add anything to our understanding of biology or PTSD. At best, they will become references for a further grant application. Over the course of the years, Dr. Nemeroff has been PI on ~$45M worth of NIMH Grants. To my knowledge, none have produced anything that is a lasting addition to the scientific record [note the Senator Grassley Gap 2008-2011]:

When I hear the criticisms of the modern bio-bio-bio psychiatry, while I often agree, I add something else in my mind – motives. The upper layer of academic psychiatry is populated predominantly by people selected by their medical schools because they can do some version of what’s described in this post – bring home the bacon from the NIMH, industry, foundations, et cetera. And for thirty plus years, they’ve talked about little other than biological research and pharmaceutical studies, selecting their future academic colleagues from the like-minded pool [that got us where we are today]. Dr. Nemeroff isn’t an exception, he’s just bolder, more reckless – reckless enough to have been busted for a time. And that’s just the NIMH story. The financing from pharmaceutical companies was probably even more impressive, and flexed the same muscles as the NIMH grantsmanship. He’s just one among many. I recently described a $50M version from UT Southwestern [retire the side…] – equally expensive, with equally non-memorable results. And there are too many more examples.

Evaluation of a corticotropin releasing hormone type 1 receptor antagonist in women with posttraumatic stress disorder: study protocol for a randomized controlled trial

by Boadie W Dunlop,corresponding author1 Barbara O Rothbaum,1 Elisabeth B Binder,1,2 Erica Duncan, Philip D Harvey, Tanja Jovanovic,1 Mary E Kelley,5 Becky Kinkead, Michael Kutner,5 Dan V Iosifescu, Sanjay J Mathew,7 Thomas C Neylan,8 Clinton D Kilts, Charles B Nemeroff, and Helen S Mayberg

Trials. 2014; 15: 240.

http://clinicaltrials.gov/show/NCT01018992

[full text online]

Acknowledgements
Funding for the study is provided from a grant from the National Institute of Mental Health, U19 MH069056 (BWD, HM). Additional support was received from K23 MH086690 (BWD) and VA CSRD Project ID 09S-NIMH-002 (TCN). GlaxoSmithKline contributed the study medication and matching placebo, as well as funds to support subject recruitment and laboratory testing. GSK is uninvolved in the data collection, data analysis (excepting some pharmacokinetic analysis), or interpretation of findings. The GSK561679 compound is currently licensed by Neurocrine Biosciences, which will also perform pharmacokinetic analyses.

Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients.

by Nemeroff CB, Widerlöv E, Bissette G, Walléus H, Karlsson I, Eklund K, Kilts CD, Loosen PT, Vale W.

Science. 1984 Dec 14;226(4680):1342-4.

The possibility that hypersecretion of corticotropin-releasing factor (CRF) contributes to the hyperactivity of the hypothalamo-pituitary-adrenal axis observed in patients with major depression was investigated by measuring the concentration of this peptide in cerebrospinal fluid of normal healthy volunteers and in drug-free patients with DSM-III diagnoses of major depression, schizophrenia, or dementia. When compared to the controls and the other diagnostic groups, the patients with major depression showed significantly increased cerebrospinal fluid concentrations of CRF-like immunoreactivity; in 11 of the 23 depressed patients this immunoreactivity was greater than the highest value in the normal controls. These findings are concordant with the hypothesis that CRF hypersecretion is, at least in part, responsible for the hyperactivity of the hypothalamo-pituitary-adrenal axis characteristic of major depression.

hat-tip to James O’Brien…

This graph is from a legal article about something else, but the data seems solid. There’s a faint line above the abscissa which marks the period when I was in training and then full time on an academic faculty, daily involved with the treatment of psychotic patients. It was towards the end of the massive deinstitutionalization of mental patients. As Dickens said, "it was the best of times, it was the worst of times."

"it was the worst of times"
Deinstitutionalization was a massive happening. People like to think of it as something the antipsychotics were responsible for. True enough that it couldn’t have happened without them, but they came into the picture in the mid-1950s and other pieces were needed. In 1963, the Community Mental Health Act poured enormous resources into Community Treatment [for a short while]. But there were two other pieces – SSI [disability income] and a ruling that patients had to be paid for their labors [Souder v. Brennan] taking vital revenue away from the hospitals. This is not meant to be a definitive history, just a picture from the time I came into consciousness – meaning that when I showed up, the resources were disappearing like the tide returning to the sea [except it just kept going out]. So by then, the lectures and articles were about the wonders of Community Treatment and the evils of institutionalization, but the days and nights in the ER were filled with the chaos of too many psychotic people who couldn’t go home, and there was no place else to go. The overcrowded and shrinking hospitals became "revolving doors" with very short stays. It was a time when medication was becoming king and the terror about long term consequences was ever-present, but undealt with…

In those days, we talked about TransInstututionalism as a coming possibility – the net movement from Mental Hospitals to other institutions [like prison]. That graph up there is rate of institutionalization, not absolute populations – so it doesn’t do total justice to the extent of the problem we now have – the huge problem of mental patients living in our jails. TransInstututionalism happened. And don’t think for a minute that they are medication free. To my mind, it’s a tragic irony that so many of the liberated mental patients have moved from the frying pan into the fire.

"it was the best of times"
In spite of all the negative things one can say about the past and the present, that period of my line on the graph, it was a time when people with psychotic illness were seen, and saw the light of day. For the century before, they just went away. Looking at the charts of older patients in my time, one could read "Agitated, Psychotic. To CSH." and the next entry might be decades later, parentheses on their life in Central State Hospital – out of sight and out of mind. In my day, we actually saw the patients and had the idea that they could improve. We saw a lot of them able to live among us, and saw some get a whole lot better. Society was more tolerant than we might have thought, sometimes even kinder than we expected, and some of the most obviously impaired chronic patients found ways to survive.

I didn’t change to psychiatry to treat chronic psychosis, but once I arrived, I found it fascinating [and still do]. For one thing, psychotic people teach us all about the workings of the mind because it’s all right out there. And one quickly learns that with a bit of ongoing help their lot can be dramatically improved – that they are more persons than Schizophrenic. Another super-pertinent thing that every discontinuation study ever done confirms, no matter what the experts recommend they do about medication, the majority of patients regularly discontinue antipsychotics on their own anyway.

Wunderink et al…
What’s different about the Wunderink et al study reported in the last post [well worth reading…] and other recent studies is not just that they confirm a minority recommendation from the past. It’s they show with evidence that there’s another big reason to try for the minimal effective dose or to aim for eliminating medication altogether at some point. The patients treated in this way have a dramatically better chance of recovery – a functional recovery. That they will have more relapses, or that some who will require long term maintenance will have more relapses along the way is a given. But the possibility of long term functional improvement is worth the problems if it pans out in further studies.

This is not really a blog post – more like a library of selected readings. Over the last year, there has been a dialog about the use of maintenance antipsychotic medication in the long term treatment of schizophrenic patients scattered around in various publications that hinges on an article published in JAMA Psychiatry last summer. It’s a Dutch Study that followed patients with First Episode Schizophrenic illness for 7 years. First the abstract of the article and an excerpt from the accompanying editorial [both behind a paywall]:

Recovery in Remitted First-Episode Psychosis at 7 Years of Follow-up of an Early Dose Reduction/Discontinuation or Maintenance Treatment Strategy

Long-term Follow-up of a 2-Year Randomized Clinical Trial

by Lex Wunderink, MD, PhD; Roeline M. Nieboer, MA; Durk Wiersma, PhD; Sjoerd Sytema, PhD; and Fokko J. Nienhuis, MA

JAMA Psychiatry. 2013 70[9]:913-920.

Importance: Short-term outcome studies of antipsychotic dose reduction discontinuation strategies in patients with remitted first-episode psychosis [FEP] showed higher relapse rates but no other disadvantages compared with maintenance treatment; however, long-term effects on recovery have not been studied before.

Objective: To compare rates of recovery in patients with remitted FEP after 7 years of follow-up of a dose reduction discontinuation [DR] vs maintenance treatment [MT] trial.

Design: Seven-year follow-up of a 2-year open randomized clinical trial comparing MT and DR.

Setting: One hundred twenty-eight patients participating in the original trial were recruited from 257 patients with FEP referred from October 2001 to December 2002 to 7 mental health care services in a 3.2 million–population catchment area. Of these, 111 patients refused to participate and 18 patients did not experience remission.

Participants: After 7 years, 103 patients [80.5%] of 128 patients who were included in the original trial were located and consented to follow-up assessment.

Intervention: After 6 months of remission, patients were randomly assigned to DR strategy or MT for 18 months. After the trial, treatment was at the discretion of the clinician.

Main Outcomes and Measures: Primary outcome was rate of recovery, defined as meeting the criteria of symptomatic and functional remission. Determinants of recovery were examined using logistic regression analysis; the treatment strategy [MT or DR] was controlled for baseline parameters.

Results: The DR patients experienced twice the recovery rate of the MT patients [40.4% vs 17.6%]. Logistic regression showed an odds ratio of 3.49 [P = .01]. Better DR recovery rates were related to higher functional remission rates in the DR group but were not related to symptomatic remission rates.

Conclusions and Relevance: Dose reduction/discontinuation of antipsychotics during the early stages of remitted FEP shows superior long-term recovery rates compared with the rates achieved with MT. To our knowledge, this is the first study showing long-term gains of an early-course DR strategy in patients with remitted FEP. Additional studies are necessary before these results are incorporated into general practice.

Antipsychotic Medication During the Critical Period Following Remission From First-Episode Psychosis: Less Is More

By Patrick McGorry; Mario Alvarez-Jimenez; and Eoin Killackey

JAMA Psychiatry. 2013 70[9]:898-899.

…It now seems probable for patients who achieve clinical remission from FEP that as many as 40% can achieve a good longterm recovery with use of no or low-dose antipsychotic medication. It is important to identify these patients at an early stage. Combining DR strategies with proactive psychosocial recovery interventions maximizing early functional recovery, delivered in specialized, optimistic systems of early psychosis care, is likely to further increase the percentage of full functional recovery. Physical health would also be expected to improve through reduction of antipsychotic load and greater levels of social inclusion and employment.

The crude use of antipsychotic medications, the delay in building evidence to guide their use, the ideological storms that continue to distort the discussion, and the tendency of human beings to seek either/or solutions to problems have combined to cause us to pose the wrong questions. In moving to a more personalized or stratified medicine,we first need to identify the probably very small number of patients who may be able to recover from FEP with intensive psychosocial interventions alone.  For everyone else, we need to determine which medication, for how long, in what minimal dose, and what range of intensive psychosocial interventions will be needed to help them get well, stay well, and lead fulfilling and productive lives. These factors have rarely been the goal in the real world of clinical psychiatry — something we must finally address now that we are armed with stronger evidence to counter poor practice. Antipsychotic load is a key concept that takes us beyond polarized views stoked by alarmists on the one hand and hard neurobiological reductionists on the other…

• Antipsychotics in First-Episode Psychosis: Less Is More
  Medscape Medical News
  By Nancy A. Melville
  July 16, 2013
• Antipsychotics: Taking the Long View
  Director’s Blog: NIMH
  By Thomas Insel MD
  August 28, 2013

• A psychiatrist thinks some patients are better off without antipsychotic drugs
  Washington Post
  by Sandra Steingard MD
  Dec 9, 2013

• Better Off Without Antipsychotic Drugs?
  Psychiatric Times
  By E. Fuller Torrey MD
  June 18, 2014
• Response to “Better Off Without Antipsychotic Drugs?”
  Psychiatric Times
  by Sandra Steingard MD
  August 15, 2014
• Response to “Better Off Without Antipsychotic Drugs?”
  Psychiatric Times
  By E. Fuller Torrey MD
  August 15, 2014

• Do Antipsychotics Worsen Schizophrenia in the Long-run?
  Psychology Today
  by Joseph M. Pierre MD
  August 8, 2014
• Comments on "Do Antipsychotics Worsen Schizophrenia in the Long-run?"
  Psychology Today

• First Episode Psychosis
  Real Psychiatry
  by George Dawson MD
  September 2, 2013

Learned intermediary is a defense doctrine used in the legal system of the United States. This doctrine states that a manufacturer of a product has fulfilled his duty of care when he provides all of the necessary information to a "learned intermediary" who then interacts with the consumer of a product. This doctrine is primarily used by pharmaceutical and medical device manufacturers in defense of tort suits. In a clear majority of states, the courts have accepted this as a liability shield for pharmaceutical companies. Wikipedia

2013 class action lawsuit

In 2013, a proposed class action lawsuit, Jennifer L Saavedra v. Eli Lilly and Company, was brought against Eli Lilly claiming that the Cymbalta label omitted important information about "brain zaps" and other symptoms upon cessation. Eli Lilly moved for dismissal per the "learned intermediary doctrine" as the doctors prescribing the drug were warned of the potential problems and are an intermediary medical judgement between Lilly and patients; in December 2013 Lilly’s motion to dismiss was denied. Wikipedia

Lawsuits charge Eli Lilly with misleading consumers about Cymbalta withdrawal effects

Salient News

by Stoff

August 15, 2014

Pharmaceutical giant Eli Lilly and Company is facing a growing number of lawsuits charging the company with misleading patients about the risk and severity of the withdrawal effects of its antidepressant, Cymbalta.  Cymbalta, which lost its patent protection last year, was Lilly’s top selling drug in 2013, earning $5 billion, according to the website FiercePharma.

In an August 14 press release, the law firm Baum, Hedlund, Aristei & Goldman reports that nearly two dozen Cymbalta withdrawal lawsuits were recently filed in federal courts across the nation, adding to 7 suits filed in 2013, and a class action lawsuit filed in 2012. Plaintiffs in those suits claim they endured serious withdrawal symptoms, lasting in many cases for months, when they tried to stop taking the drug, and allege that Eli Lilly failed to warn them even though it knew, from its own published research, that severe withdrawal effects were commonplace and lasting.

Central to the charges is the Cymbalta drug label itself, which states that the risk of withdrawal effects is “greater than or equal to 1%.” In 2005, a study designed, conducted and funded by Lilly, and published in the Journal of Affective Disorders, found that up to 51% of users experienced discontinuation symptoms, which were severe in 10 – 17% of cases. In over 50% of the patients, withdrawal reactions had not resolved by the end of the study’s two week withdrawal period.

Cymbalta’s withdrawal effects include severe nausea, vomiting, dizziness, headaches, vertigo, nightmares, and electric-shock-like sensations in the brain. In a declaration filed in, Harvard Medical School psychiatrist Joseph Glenmullen, author of two books on antidepressant side effects, says that the true incidence of withdrawal reactions may be as high as 78%.

Plaintiffs in the lawsuits allege that Cymbalta’s label misled them by suggesting that the risk of withdrawal effects was in the range of 1% and that the effects were generally short-term. The Cymbalta label makes no reference to the findings of Lilly’s study, instead referring to “spontaneous reports of adverse events” that are “generally self-limiting.”

hat tip to Bob Fiddaman…  

When I read this, I had a déjà vu moment. I was reminded of the early days of Prozac® [also from Eli Lilly]. Package inserts aren’t my primary resource when a new drug shows up, but I’ve always read the PDR [Physician’s Desk Reference] which is essentially a book of package labels for all of our drugs. Over my fifty years in medicine, the PDR has gotten much thicker and the print has gotten much smaller, so I have one of those plastic wallet card magnifiers as an always-around book-mark stuck in my copy. Whenever I learn of a new drug I might prescribe, I always check the PDR [package label] for adverse events and drug interactions. I can’t find the original Prozac® label, but I remember reading about the sexual side effects back in the day. And what it said and what turned out to be true weren’t even in the same state, much less the same county. I sure was no "learned intermediary" in that instance. It’s the first time I can recall feeling like I was being gamed about a drug. I feel the same thing reading this final label for Cymbalta® before it went off-patent this year…

5.6 Discontinuation of Treatment with Cvmbalta

Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, nausea, headache, paresthesia, fatigue, vomiting, irritability, insomnia, diarrhea, anxiety, and hyperhidrosis.

During marketing of other SSRIs and SNRIs [serotonin and norepinephrine reuptake inhibitors], there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances [e.g., paresthesias such as electric shock sensations], anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with Cvmbalta. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Symptoms following abrupt discontinuation of duloxetine treatment in patients with major depressive disorder

by Perahia DG1¹, Kajdasz DK¹, Desaiah D¹, Haddad PM².

[all either Lilly employees¹ or on their paid  advisory board²]

Journal of Affective Disorders. 2005 89[1-3]:207-212.

[submitted 01/10/2005]

BACKGROUND: Discontinuation symptoms are common following antidepressant treatment. This report characterizes symptoms following duloxetine discontinuation.

METHODS: Data were obtained from 9 clinical trials assessing the efficacy and safety of duloxetine in the treatment of major depressive disorder [MDD].

RESULTS: In a pooled analysis of 6 short-term treatment trials, in which treatment was stopped abruptly, discontinuation-emergent adverse events [DEAEs] were reported by 44.3% and 22.9% of duloxetine- and placebo-treated patients, respectively [p<0.05]. Among duloxetine-treated patients reporting at least 1 DEAE, the mean number of symptoms was 2.4. DEAEs reported significantly more frequently on abrupt discontinuation of duloxetine compared with placebo were dizziness [12.4%], nausea [5.9%], headache [5.3%], paresthesia [2.9%], vomiting [2.4%], irritability [2.4%], and nightmares [2.0%]. Dizziness was also the most frequently reported DEAE in the analyses of 3 long-term duloxetine studies. Across the short- and long-term data sets, 45.1% of DEAEs had resolved in the duloxetine-treated populations by the end of the respective studies, and the majority of these [65.0%] resolved within 7 days. Most patients rated the severity of their symptoms as mild or moderate. A higher proportion of patients reporting DEAEs were seen with 120 mg/day duloxetine compared with lower doses. For doses between 40 and 120 mg/day duloxetine the proportion of patients reporting at least one DEAE differed significantly from placebo. Extended treatment with duloxetine beyond 8-9 weeks did not appear to be associated with an increased incidence or severity of DEAEs.

CONCLUSIONS: Abrupt discontinuation of duloxetine is associated with a DEAE profile similar to that seen with other selective serotonin reuptake inhibitor [SSRI] and selective serotonin and norepinephrine reuptake inhibitor [SNRI] antidepressants. It is recommended that, whenever possible, clinicians gradually reduce the dose no less than 2 weeks before discontinuation of duloxetine treatment.

LIMITATIONS: The main limitation is the use of spontaneously reported DEAEs.

There were only 5 months between the FDA Approval of Cymbalta® and the submission of this Lilly-funded article. So they had to know about the frequency of discontinuation symptoms back then. After all, it was their own trials being reviewed. And this study is not mentioned in any of the label revisions along the ten years of patent protection. Surely they weren’t counting on all doctors to be subscribers to the Journal of Affective Disorders. And I hardly think that the blurb in that package insert comes close to alerting us "learned intermediaries" to the true incidence of discontinuation symptoms. Cymbalta® appeared after I retired and it’s not available in the charity clinic where I work, so I’ve never prescribed it or even looked it up in the PDR. It has only just gone off-patent. But it’s easy to see why the motion to dismiss the class action suit was denied. I had no idea that the withdrawal symptoms were so frequent until I started writing this post.

This learned intermediary thing is yet another loophole the drug companies use to increase their sales, like so many others. They minimize or even hide the adverse events that might put a damper on their enthusiastic ad campaigns. That labeling commentary for Cymbalta® seems to me to be written with intent to mislead doctors by not highlighting the frequency. It’s certainly not something planned to make me a more learned intermediary. I expect them to accentuate the positive but I’m surprised that they eliminate the negative so regularly. I used to think that the idea that they just figure losing suits after the fact for withholding adverse events into the "cost of doing business" was perhaps an over-blown charge. But it now seems inescapable that it’s regular and by design. Their losses don’t come close to equaling the gain of a true blockbuster. And thinking back on things, I used to learn a lot about the efficacy and liability of drugs from the review articles that pepper our literature. But in modern times, review articles, at least in psychiatry, seem more often  infomercial-like than comprehensive discussions.

In the case of Eli Lilly’s Prozac®, the incidence of sexual side effects was minimized. With Lilly’s Zyprexa®, the tendency for significant weight gain and Diabetes was downplayed. Comes now Lilly’s Cymbalta®, and we find yet another inconvenient [secret] truth, a regular Withdrawal Syndrome now increasingly moving into the light of day as the drug goes off-patent. What has this learned intermediary gleaned from Eli Lilly? They specialize in deceit when it comes to reporting the adverse effects of their psychiatric drugs. That’s what…

Just scanning the figure, it looks okay. 7/11 of the Paroxetine trials are in the moderate range and are statistically significant. By FDA standards, this passes the efficacy requirements with flying colors. It looks to leave Imipramine in the dust with only 2/6 studies in the moderate range and statistically significant. However, the Paroxetine/Imipramine difference is an illusion. The only statistically significant differences in those 6 identical studies are the two marked with asterisks, one favoring each drug. And the weighted composites [in red] are likewise not significantly different. The unmentioned 6 trials were either uncontrolled or failed trials with recruitment/drop-out problems. The values shown above for the 5/6 of the trials against Imipramine are from only 4 weeks because by the time the planned 6 week period came around, there had been too many drop-outs to make valid calculations. The overall dropout rate by 6 weeks for the 11 trials was ~50%.

Finally, if you look at the breadth of the 95% Confidence Intervals in the figure, there was a lot of variability and many subjects that would fall out of the clinically effective therapeutic range.

These problems of drop-outs, missing data, wide variability among the subjects in a given study or between separate studies, not really knowing if the patients are help-seeking or paid recruits, etc. are part and parcel of most clinical trials whether run in an academic center, by a large Clinical Research Organization, or by a small center like those in Carl Elliot’s recent piece [under some of the rocks…]. Human beings don’t have uniform illnesses, don’t have the genetic uniformity of cloned white mice, aren’t confined to wire cages on a strictly controlled diet. So even in the most pristine and unbiased of trials there’s an intrinsic heterogeneity that transcends the clean demographic tables found in the published articles. And in psychiatry, the subjectivity of the symptoms just adds to the confusion.

The main charge of the FDA is safety, adverse events, and I didn’t look at that part of this NDA [maybe another time]. Proof of efficacy was added in 1962 by the Kefauver-Harris Amendment to keep the ineffective patent medicines out of our pharmacopoeia. The efficacy criteria are minimal – two well conducted studies demonstrated efficacy. This Paroxetine submission easily achieves that requirement. It seems that the drug, Paroxetine, does have antidepressant properties, but that’s all it means. Leaving aside the crucial issue of harms for the moment, that’s what the FDA is for – certifying that the drug does what its sponsor says it does, that it’s not snake oil or some inert substance of no therapeutic value. How well it does it or how often or in whom or when indicated are another matter.

When I found this disc, I was initially curious because it came from several decades ago. It would be surprising to find single site trials these days. It’s hard to recruit the number of subjects needed to show differences [called power] at a single site. Nowadays, the trials use multiple sites to achieve the necessary power [and they’re a lot faster]. This study is from a time before the meteoric rise of the Clinical Research Organizations, so these trials were at the smaller clinical research centers of the time or academic institutions. I expected [and found] that the NDA would show why Clinical Trials are really not some bottom line knowledge [beyond…], just a piece of data among the many other things that go into a clinical recommendation. Talking about them, people like to use the word confounders. and RTCs always have confounders like in this study.

When David Healy critiques “the notion that clinical trials provide a higher form of knowledge than knowledge borne in a clinical encounter – the realm of the experiential and the singular…” he draws from the distinction between disease and illness. Clinical trials deal with operationally defined diseases, whereas treating clinicians deal with singular illnesses. As you say, relevant factors that operate in the singular illness may not be considered in the clinical trials – age; co-morbidity; concurrently required medications; insight; capacity for a treatment alliance; duration of required treatment; family stress; economic stress; and many others. So, the knowledge gained in clinical trials is needed but is not necessarily generalizable to or determinative in the management of an individual patient. So, it’s not a question of a higher form of knowledge so much as it is addressing a different question…

There are two always-available criticisms of physicians’ decisions: "That’s just what you think! What’s your evidence base?" and "You’re just following a guideline by rote and not seeing the person in front of you!" At one time or another, each of those negative epithets might well be accurate – sometimes both apply. But somewhere in recent times, the battle cry of evidence based medicine has shifted the balance and fostered the notion that the guidelines derived from groups dictate the best course for an individual case – implying a uniformity among people and a strict objectivity to medical care that is illusory. Randomized Clinical Trials, Rating Scales, Statistical Significance, FDA Approval, Expert Opinions, and all the other ways we try to extract objective markers from subjective phenomena are vital tools in the medical toolbox, but only that – tools…

Finally wading through my emails for the 10 days I was gone, I ran across this:

Having had some experience with the screen-only interface proposed for the EMA Data Transparency, we were among the throng that complained about their proposed use of such a system. We had written:

As you may recall, the promise of the EMA [European Medicines Agency] to release all of the data for clinical trials hit a snag with add-on restrictions [see also Welcome to Troy, Ombudsman concerned about change of policy at Medicines Agency as regards clinical trial data transparency, EMA policy on publication of and access to clinical-trial data, the U-Turn…]. There was much wailing and gnashing of teeth [the end game…, to be continued…, a decision to reconsider…, a crushing setback…, oh how we’ve missed our Pharmalot!…]. And then they recanted! [awaiting further information…, some further information…, out of the shadows…]. And then, as they say above, they put off their decision until October 2, 2014.

• the leaked memo [in the shadows…]
• their Trade Commission letter [see an ill-gotten fortune…]
• the AbbVie/InterMune suit
• the PhRMA/EFPIA conference in Brussels [see a deal-breaker?…]
• the article [Intellectual Property Protections Are Vital to Continuing Innovation in the Biopharmaceutical Industry]

I sincerely doubt that there will come a time when some pill will come along that will quickly whisk away the kind of profound depression that Robin Williams was apparently suffering. He was no stranger to feel better pills, and chose not to take them – to his credit.  There were a myriad of risk factors we know about: waning celebrity; financial problems; a cancelled tv series; the diagnosis of Parkinson’s Disease [which can be associated with Depression over and above as a stressor]. He was sleeping 18 hours a day and had no appetite. In his last picture, his weight loss is obvious.

I don’t want to pile on with after the fact analysis. There’s plenty enough of that coming from everywhere. But there is one thing that needs saying. A mainstay of treatment for patients with this kind of profound depression is hospitalization. And one of the reasons is protection from suicide. This is the kind of depressive illness that got lost in the 1980 DSM-III Revision that lumped it in with the more usual depressive illnesses – once called neurotic depression. Independent of one’s theories about the etiology or nosological preferences, impulsive suicide is a constant risk in such severe depressions, so protective hospitalization is a big part of any rational treatment plan – or at least it was. Managed Care and the psychopharmacological revolution have essentially eliminated the kind of mental hospitalization such patients need. It’s a paradox that with all the modern talk about depression, this kind of depression with delusional hopelessness and unbearable pain has gotten lost in the shuffle.

In June, Robin Williams checked in to the Hazelden Rehabilitation facility. not because of a relapse, but for a "tune up" of his sobriety. Maybe people do that, but I’ve never heard of such a thing. My guess is that he was looking for help in the only way he knew how, but that’s not what he needed. This kind of Depression is uncommon, but in a modern world, the "diagnosis, treatment, care, and support"  that Dr. Summergrad mentions are rarely, if ever, available for these particular patients…

UK Recommends Covering Sovaldi Hepatitis Pill

Pharmalot: WSJ

By Ed Silverman

Aug 14, 2014

The U.K. agency that evaluates the cost effectiveness of prescription drugs has recommended the government pay for the controversial Sovaldi hepatitis C treatment, although not for all patients. The move, which still requires a final endorsement, comes as the medicine causes a ruckus in the U.S. The price tag – $84,000 for a 12-week regimen – has insurers and state Medicaid directors worried that the Gilead Sciences medication will become a budget buster and helped to fuel a national debate over the rising cost of prescription drugs.

Generally, the U.K.’s National Institute for Health and Care Excellence causes a ruckus of its own by declining to recommend coverage for medications. Consequently, the agency has often butted heads with drug makers and patient groups over its decisions. Last week, for instance, NICE and Roche battled over the cost of a cancer drug, although in a rare development, patient groups sided with the agency. NICE, in fact, sent mixed signals two months ago about its Sovaldi decision. The agency asked Gilead to supply additional data about certain patient populations and maintained there were “substantial uncertainties in the evidence” that the drug maker provided to win a coverage recommendation. The request for more data prompted speculation that NICE may not recommend coverage.

After reviewing the data, though, NICE agrees that Sovaldi is an effective improvement over existing treatments. The Gilead drug, by the way, can cure nine of 10 patients. The decision was likely helped by the lower price tag in the U.K. Gilead is selling its drug for about $56,000, according to a NICE spokesman. “It’s a lot cheaper here,” he tells us. The agency is recommending Sovaldi, plus interferon and ribavirin, for adults with genotype 1, which is the most common form of hepatitis C, and accounts for 46% of all cases in the U.K., a NICE spokesman says. The recommendation also extends to patients with genotype 3, which accounts for 43% of hepatitis C sufferers…

How Much? Gilead Will Charge $900 for Sovaldi in India

Pharmalot: WSJ

By Ed Silverman

Aug 7, 2014

“We have set three basic pricing tiers [based on a country’s per capita income and hepatitis C prevalence] that serve as the starting point for negotiations with national governments. The tiers are low-income, low middle-income and upper-middle income,” Gregg Alton, a Gilead executive vice president for corporate and medical affairs, tells the paper. Such decisions, however, have further fed a controversy in the U.S., where Sovaldi costs $84,000 for the same 12-week regimen and has become a proxy for a growing national debate over the rising cost of prescription drugs…

^{Boston Tea Party, 1773}

Desperate, Vulnerable Research Subjects, Cost-Cutting Contract Research Organizations and Threats to the Integrity of Clinical Research

Healthcare Renewal

by Roy Poses

August 13, 2014

Dr Carl Elliott seems to be one of the few people willing to investigate how modern medical research may threaten vulnerable research subjects.  His book, White Coat, Black Hat, opened with a chapter on vulnerable "guinea pigs," people willing to be clinical research subjects for money.  Such people may be desperate for money, and further may be homeless, and have psychiatric problems, including psychosis or drug or alcohol problems.  Dr Elliott just wrote another important article on the plight of vulnerable research subjects…

Say goodbye to the Clozaril King

Fear and Loathing in Bioethics

by Carl Elliot

August 11, 2014

Illinois has suspended the medical license of Dr. Michael Reinstein, aka The Clozaril King.  Reinstein "received ‘illegal direct and indirect remuneration’ from the maker of generic clozapine; did not consider alternative treatments for his patients; and disregarded patients’ well-being because of potentially life-threatening side effects of the drug."  

In 2009, ProPublica and the Chicago Tribune detailed how he had prescribed more of the antipsychotic clozapine to patients in Medicaid’s Illinois program in 2007 than all doctors in the Medicaid programs of Texas, Florida and North Carolina combined. Autopsy and court records showed that, by 2009, at least three patients under Reinstein’s care had died of clozapine intoxication.

Illinois Suspends Medical License of Leading Prescriber of Antipsychotic Drugs

ProPublica

by Charles Ornstein

Aug 11, 2014

Illinois medical regulators have indefinitely suspended the medical license of psychiatrist Michael Reinstein, who prescribed more of the most powerful and riskiest antipsychotic drug clozapine than any other doctor in the country. The decision by Illinois’ Department of Financial and Professional Regulation, signed Friday, suspends Reinstein’s license for a minimum of three years, at which time he can apply to have it reinstated.

The state’s medical disciplinary board recommended the sanction in May after determining that Reinstein, 71, received "illegal direct and indirect remuneration" from the maker of generic clozapine; did not consider alternative treatments for his patients; and disregarded patients’ well-being because of potentially life-threatening side effects of the drug. Reinstein’s motion for a rehearing was denied Friday, making the matter public.

Clozapine is approved to treat patients who don’t respond to other medications. But it can have dangerous side effects, including seizures, inflammation of the heart muscle, and a drop in white blood cells. The drug is considered particularly dangerous for elderly patients…

In 2009, ProPublica and the Chicago Tribune detailed how he had prescribed more of the antipsychotic clozapine to patients in Medicaid’s Illinois program in 2007 than all doctors in the Medicaid programs of Texas, Florida and North Carolina combined. Autopsy and court records showed that, by 2009, at least three patients under Reinstein’s care had died of clozapine intoxication. At that time, Reinstein defended his prescription record, arguing that clozapine is effective and underprescribed.

Last year, as part of an investigation into Medicare’s failure to monitor problem prescribers, ProPublica reported that Reinstein prescribed even more clozapine in Medicare’s prescription drug program for seniors and the disabled. We found that the program continued to let him prescribe even after the U.S. Department of Justice accused him of fraud and Illinois’ Medicaid program suspended payments to him…

I came back Monday from a vacation trip with friends where I spent little time thinking about contemporary matters medical. When I got back Monday night, I was out of the rhythm of keeping up with the things I usually follow. What I always find when I’ve taken a break is that I feel anew the same kind of outrage I felt five or six years ago when I first began to understand how the pharmaceutical-academic psychiatry alliance had become so widely corrupting. Obviously it’s a much bigger problem than simply psychiatry, but it appears my specialty was especially vulnerable [and had some people in high places who dove in head first]. It always takes me a few days to recover my composure and get back into the state of play, rather than this just rant on and on about the myriad of absurdities like those mentioned above.

I remain awed by the tenacity of the people who have dogged this problem for years – people like Drs. Bernard Carroll and Bob Rubin, Jon Juriedini and Healthy Skepticism, David Healy and Rxisk, Stephany of Soulful Sepulcher, Danny Carlat, Dr. Poses of Healthcare Renewal, Ed Silverman of Pharmalot, Joe Friday at Pharmagossip, Carl Elliot of Fear and Loathing in Bioethics, Ben Goldacre of AllTrials, the volunteers of the Cochrane Collaboration – and the growing number of others who’ve taken up the task of shining spotlights into the dark corners of the medical industries. What’s missing, by my read, are strong stands by the various medical professional organizations and particularly their sponsored academic journals. Dr. Fiona Godlee of the British Medical Journal stands tall as an exception to the laissez–faire attitude of journal editorial staffs elsewhere.

On my trip, I returned to the Museum of Civil War Medicine in Frederick Maryland that I mentioned last Fall [in the museum…], this time with four other doctors and our wives – people we were stationed with in the early 1970s that we spend a week with every summer. In the Fall, I was impressed with the advances in medicine in the Civil War – triage, ambulances, hospitals, nursing care, anesthesia and early amputation to prevent gangrene. This time through, I found myself thinking about what was missing. About the only medication in the displayed pharmacy kits that would pass muster was opium. Everything else was either in the toxic poison or inert patent medicine category. Those were the days before Pasteur and Lister so antiseptic techniques were unknown, much less antibiotics. The real killers in the Civil War were the infectious diseases that swept through the camps in waves, killing many more than the enemy’s bullets. On the nearby battlefield at Antietam where 23,000 soldiers became military casualties in a single day, there was an unfinished stone with a small embedded brick cross among the cannons and heroic granite sculptures of soldiers. It marked the spot where Clara Barton [later founder of the American Red Cross] narrowly escaped a miniball that killed the fallen soldier she was tending to. The chief of nursing there was Dorthea Dix, the crusader for moral treatment of the mentally ill.

How Much? Gilead Will Charge $900 for Sovaldi in India

Pharmalot: WSJ

By Ed Silverman

Aug 7, 2014

India has become the latest country where the Sovaldi hepatitis C treatment will be offered for $900 per patient. The move, which was reported by The Times of India, comes a few weeks after the manufacturer, Gilead Sciences GILD +0.66%, is making the medication available for the same price in Egypt. The pricing reflects an effort by Gilead to forestall the sort of criticism the pharmaceutical industry has often encountered when selling life-saving medicines in poorer countries, which have often complained bitterly that many of its citizens have been unable to afford some treatments. An advocacy group last year formally opposed a patent for Sovaldi in India, claiming the treatment is based on “old science” and, therefore, does not deserve patent protection. An Indian generic drug maker made a similar point recently in asking Indian officials to deny the patent. If they prevail, generic alternatives could become available at low prices.

“We have set three basic pricing tiers [based on a country’s per capita income and hepatitis C prevalence] that serve as the starting point for negotiations with national governments. The tiers are low-income, low middle-income and upper-middle income,” Gregg Alton, a Gilead executive vice president for corporate and medical affairs, tells the paper. Such decisions, however, have further fed a controversy in the U.S., where Sovaldi costs $84,000 for the same 12-week regimen and has become a proxy for a growing national debate over the rising cost of prescription drugs.

The U.S. price tag has prompted objections from insurers, state Medicaid programs and politicians, among others, who complain the cost for Sovaldi will bust budgets as more hepatitis C sufferers are diagnosed and seek treatment. Gilead and its supporters say this argument is, effectively, short sighted by noting that Sovaldi can cure nine of 10 patients, many of whom would require more expensive treatment over a protracted period. In other words, society saves money in the long run…