what they’re for…

Posted on Saturday 30 August 2014

Ever since I ran across this graph of the rates of institutionalization, I’ve been mulling over the plight of the severely mentally ill during my time in psychiatry [that faint line above the abscissa marks when I was directly involved]. Writing about it a week or so ago [functional improvement…], I called it Transinstitutionalization – a term from those days predicting that this is what would happen. It does seem naive in retrospect to think that one could Deinstitutionalize the patients in our massive State Hospital system simply by shutting it down. The planned Community Mental Health system was never fully realized, and this graph suggests that the patients essentially moved next door into our prisons:

Looking around to find the magnitude of the problem, I ended up on the National Institute of Corrections web site where I found this:

Mentally Ill Persons in Corrections

Mentally ill persons increasingly receive care provided by corrections agencies. In 1959, nearly 559,000 mentally ill patients were housed in state mental hospitals. A shift to "deinstitutionalize" mentally ill persons had, by the late 1990s, dropped the number of persons housed in public psychiatric hospitals to approximately 70,000. As a result, mentally ill persons are more likely to live in local communities. Some come into contact with the criminal justice system.

In a 2006 Special Report, the Bureau of Justice Statistics estimated that 705,600 mentally ill adults were incarcerated in State prisons, 78,800 in Federal prisons and 479,900 in local jails. In addition, research suggests that "people with mental illnesses are overrepresented in probation and parole populations at estimated rates ranging from two to four time the general population. Growing numbers of mentally ill offenders have strained correctional systems.

There are so many ways to think about this, most of them suffused with cynicism. When I’m in a cynical mood, I can look at these numbers and cast blame in all directions, but then I come up short, because I’m not really sure what to do about it either. If there is ever a place where the parable of the blind men and the elephant fits like a glove, this is it:

Everyone’s looking at the part that effects them, and the big picture gets lost in the shuffle. Like most mental health types, I tend to accept the MAD vs BAD distinction and want to separate out the mental patients and get them out of the prisons and into the community – the battle cry of my era and the Community Mental Health Movement. Allen Frances and DJ Joffe have an excellent post up that somewhat takes that perspective [see The Hall of Shame - Who Is Failing the Severely Ill?]. I agree with their every word, but always worry that it will fall on deaf ears like it has for such a long time. I was actually impressed with some of the information and policy discussions on the National Institute of Corrections web site as well as a report I found there [Improving Outcomes for People with Mental Illnesses under Community Corrections Supervision:] focused on the parole system. They’re much more mental illness savvy than I realized.

Again, like most mental health types, I look at that pie graph up there and after I get over the magnitude of the problem, I begin to wonder about diagnosis. How many have psychotic illnesses? Are these the homeless chronic patients who have been picked up for minor crimes? How many are primarily substance abusers? I haven’t been able to find those numbers yet, but I’m still looking.

Looking at that graph at the top, I have to remind myself that it is not populations in jail or mental hospitals, it’s rate of institutionalization. They aren’t the patients from the days of Denstitutionalization, they’re a new generation. And it looks to me as if we have a surprisingly fixed rate of removing people from our society for one reason or another. The graph itself is from a study of violent crime – homicide [An Institutionalization Effect: The Impact of Mental Hospitalization and Imprisonment on Homicide in the United States, 1934–2001]. And what it shows is that there was a dramatic increase in the homicide rate in the 1970s and 1980s when Institutionalization had its big dip. It’s a complex legal article, and you’ll have to read it yourself to figure out what they make of their findings:

Right now, Law Enforcement is having to carry the ball for the most important mental problems in our country. While they seem to be doing a credible job under the circunstances, it’s not what their system was designed to do. Here’s what Dr. Frances and DJ Jaffe have to say:
Dr Jaffe writes:
The bipartisan Helping Families in Mental Health Crisis Act (HR3717) has wide support among those who advocate for the 5 percent of the population with the most serious mental illnesses. But there are parts of the mental health industry that ignore the seriously ill. Over 500,000 of the most seriously ill are incarcerated or homeless, largely because the mental health industry focuses on all others.
  • Substance Abuse and Mental Health Services Administration: SAMHSA distributes over $400 million in mental health block grants to states and tells them how to spend it. But as Representative Tim Murphy noted, "SAMHSA has not made the treatment of the seriously mentally ill a priority… It’s as if SAMHSA doesn’t believe serious mental illness exists." SAMHSA encourages states to spend block grants on the highest functioning. It wants to replace the scientific medical model with their internally invented recovery model, and creates it’s own "illnesses" — bullying and trauma being the most recent.
  • Consumer Groups: The National Coalition for Mental Health Recovery (NCMHR) is the umbrella organization for SAMHSA-funded consumer groups like the National Empowerment Center and National Mental Health Consumers Self Help Clearinghouse. Rather than advocating for the seriously ill, they advocate for anyone with "lived experience." They believe everyone should self-direct their own care, thereby ignoring those too sick to do so.
  • Mental Health Lawyers: The Bazelon Law Center, ACLU, the National Disability Rights Network (NDRN) and State Disability Rights organizations not only ignore the most seriously ill, their actions cause harm. These non-profit law centers fight against Assisted Outpatient Treatment and creation of hospital beds for the most seriously ill thereby making incarceration inevitable for many.
  • Mental Health America: Mental Health America is a trade association for service providers. Rather than serious mental illness, MHA is "dedicated to helping all Americans achieve wellness." MHA of Essex County New Jersey is one of the few chapters that does try to help the most seriously ill.
  • National Council for Community Behavioral Health: This organization represents behavioral healthcare conglomerates. They mainly lobby for funding Mental Health First Aid (MHFA) classes they sell. MHFA is based on the false premise that the mentally ill are so asymptomatic special training is needed to identify them and that once identified services are available to refer to. MHFA is not proven to help the seriously mentally ill.
  • National Alliance on Mental Illness: Historically, NAMI did focus on serious mental illness because it was founded by families of the very seriously ill. In 1993, NAMI argued for parity for people with severe mental illness. In 1995, NAMI endorsed various forms of involuntary treatment when needed. Cut to today. Instead of the 14 million who are most seriously ill, NAMI National now claims to represent 60 million people with any mental health issue. Some brave state and local chapters like NAMI/NYS have refused to follow their lead and they still focus on helping people with serious mental illness.
  • American Psychiatric Association: The APA represents psychiatrists and publishes the Diagnostic and Statistical Manual that determines what is and isn’t a mental health problem and therefore gets a billing code. It is in the APAs interest to have everyday problems declared a disorder so members can be reimbursed for treating them. A subset of psychiatrists do treat the seriously ill and immediate past president, Dr. Jeffrey A. Lieberman has gone out of his way to increase the visibility of serious mental illness, but serious mental illness is still only a small part of APAs focus.
  • American Psychological Association: This APA represents "130,000 researchers, educators, clinicians, consultants and students." The most popular subjects for their members are addiction, bullying, marriage and divorce, personality, sexual abuse, and depression, not serious mental illness.
  • Celebrity Centric Advocacy Organizations: None of the 29 events sponsored by The Rosalynn Carter Symposium on Mental Health Policy focused on serious mental illness. Patrick Kennedy’s One Mind for Research is primarily involved in post-traumatic stress disorder, traumatic brain injury, and stigma education, not schizophrenia and bipolar. He has used The Kennedy Forum on Mental Health to call for an end to the IMD Exclusion, but has not spoken out on important initiatives like implementing Assisted Outpatient Treatment or criticized the CMHCs created by his uncle for refusing to serve the most seriously ill.
  • Law Enforcement: Ironically, this is the one bright spot. Law enforcement organizations like The National Sheriffs Association, the New York State Association of Chiefs of Police  have stepped in to fill the void left by the mental health industry’s abandonment of the most seriously ill. They’ve become powerful advocates for increasing hospital beds for the seriously ill and are working to force the mental health system to stop ignoring them. Law enforcement is vigorously supporting Rep. Tim Murphy’s Helping Families in Mental Health Crisis Act and working with families of the seriously ill helped it gain 95 cosponsors from both parties. Those who want to help people with serious mental illness should ask their Representative to support this bill.
From Dr. Frances:
And I would add one more name to DJ’s shame list. The National Institute Of Mental Health devotes almost all of its enormous research budget to glamorous, but very long shot, biological research that over the last four decades has contributed exactly nothing to the treatment and lives of the severely ill. Surely, biological progress will eventually be made, but at best it will take decades to have any impact on the current real world problems of the mentally ill.
The only things I would add at this point to their synopsis is that the time for decrying, blaming, or ignoring this has passed. It’s time for the mental health agencies and the professional organizations to turn their attention to where our most-in-need patients actually live – our jails and prisons. And I would amplify Dr. Frances’ point. This effort should be lead by the National Institute of Mental Health and the Substance Abuse and Mental Health Services Administration. That’s what they’re for. Psychiatry came into being to care for these specific patients and we’ve abandoned them…
Mickey @ 10:15 PM
Filed under: politics

Posted on Tuesday 26 August 2014

My last post [and wasted research dollars…] lead me to Dr. Nemeroff’s 1984 paper announcing that Cortictrophin-Releasing Factor [CRF] is significantly elevated in the CSF [cerebrospinal fluid] of patients with Major Depressive Disorder – a thirty year old observation that has figured heavily in his research since then – culminating in the clinical trial listed in the last post. It’s a short paper in Science and it’s been open on my desktop for several days. The graph haunts me when I look at it. Here’s the abstract and that one figure from the paper, followed by a description of the analytic methods from the paper:
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.

"The results (see Fig. 1) were statistically analyzed by both parametric [analysis of variance (ANOVA) and Student-Newman-Keuls test] and nonparametric (Mann-Whitney U test) methods."

One of the most frustrating things about papers like this is that the raw data isn’t available, even if one has the time to go over it in detail. Once again, I find myself looking at a graph that I’m told is meaningful, significant, has something to say important about a major psychiatric syndrome. And what I see looks like a trivial difference that is probably meaningless, and I even doubt significant. So I did something that I’ve been tempted to do many times. I opened it in a graphics program and reconstituted the data by measuring the pixel count to the center of each data point and using that table, the baseline, and the ordinate scale to reproduce the data. I wouldn’t recommend this on a Nobel Prize application or even in a paper, but I thought I’d give it a shot because I don’t believe the analysis is correct, or correctly done [the next paragraphs is only for the hardy].

So armed with my little made-up table, I proceeded to the analysis. It says that they used an ANOVA. That means considering the numbers as a continuous variable. In an ANOVA with four groups, first you check the whole dataset to see if there is any significance to the grouping. If there is, then you test the groups against each other to locate the significant difference. But with a small dataset like this where the assumptions of ANOVA [normal distribution] are questionable, it is more accurate to use a non-parametric statistic that only considers the ranking of each value, not its magnitude. With four groups, the drill is the same. First one tests the whole dataset to see if the grouping in significant [Kruskal-Wallis]. If it is, you test the groups against each other to find the significant differences [Mann-Whitney]. If you read their paragraph [in italics], it’s hard to figure out exactly what they did but it looks like some steps were skipped. Here’s my version using the R statistical package.

The top green value [p = 0.007656] says that the ANOVA is significant [p<0.05]. But in the table of pairwise comparisons, it’s not the difference between NORMAL and MDD that achieves significance [p = 0.10858]. In the non-parametric test, the overall Kruskal-Wallis test of the table is not significant [0.1485]. There’s nothing there. Whether my crude method is valid or not, it sure doesn’t say this:
The CSF concentration of CRF-LI was significantly increased (by both methods of statistical analysis) in patients with major depression compared to either the normal controls or the patients with schizophrenia or senile dementia."
My point in playing this little game is that we deserve the access to raw data for this very reason. This 30 year old study has been rehashed and discussed for years and has been nuclear to several grant requests, including the Clinical Trial in the previous post. It looks like a thorough vetting thirty years ago might well have put it to rest. I can’t find further studies to confirm this finding and nothing that suggests that this compound has any solid connection with PTSD. If you haven’t figured it out yet. I think this whole line of research is based on unsubstantiated speculations.

As you may recall, when we looked at Dr. Nemeroff’s NYU Grand Rounds and London lecture to the Institute of Psychiatry, we were alerted to a study reported as positive that Dr. Nemeroff, himself, had reported as based on an error so the significance disappeared, yet he presented it as a valid study in those presentations [see has to stop…]. So the best predictor of future behavior is past behavior. Now we have GSK, the VAH, and the NIMH chasing some new drug as a treatment for PTSD based on the very shakiest of speculations. Shame on him. Shame on them. And shame on journals that don’t vet questionable studies like this.

Maybe we ought to say shame on me too for using a pixel count to get my numbers. But instead of that – why not support Data Transparency so I don’t have to resort to extreme measures to confirm my reaction to that graph. Like I said, this kind of silliness has to stop…

Whoops: [for the even more hardy] I left out this plot from the R package. The upper and lower borders of the "boxes" represent 25% and 75% of the points. The fact that the Means [bold horizontal lines] aren’t centered in the box points to a skewing of the data [not normally distributed], suggesting that the ANOVA is not the best choice of statistics, and that the non-parametric test is a more appropriate choice [Kruskal-Wallis]. My method of data capture is also more likely to be accurate using only the rank order.

Mickey @ 8:12 PM
Filed under: politics
and wasted research dollars…

Posted on Saturday 23 August 2014

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:

Although the majority of trauma victims experience the cardinal symptoms of re-experiencing, avoidance and hyperarousal, for the large majority of such individuals, these symptoms do not become chronic nor do they develop syndromal PTSD. It is important to identify the large minority of trauma victims with a high likelihood of developing PTSD because of the very significant medical and psychiatric morbidity and mortality associated with this disorder. There is already considerable evidence that the likelihood of developing PTSD after trauma exposure is due to a combination of genetic and environmental factors. This two-site, linked R-01 application seeks to utilize state-of-the art advances in genomics, transcriptomics and epigenetics, coupled with comprehensive clinical and psychological measures, to address this seminal unanswered question in PTSD clinical service and research…

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

To achieve this goal, 500 trauma-exposed subjects will be recruited at the University of Miami Ryder Trauma Center and the Emory University affiliated Grady Memorial Hospital and followed at regular intervals for one year. This focused, hypothesis-driven study will scrutinize previously identified psychological and biological risk factors. Genetic risk factors include polymorphisms of the ADCYAP1R1, FKBP5, DAT, BDNF, COMT, CRFR1, 5HTTLPR, RGS2, GABA2 and 5HT3R genes, novel genetic and epigenetic risk factors and most importantly, the primary downstream effects of these genomic and epigenetic findings by the use of conventional and newer statistical modeling methods.

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.

Update: Oh yeah. This seems related – an example of using both the NIMH and industry…
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.

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.
Going back thirty years!
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
Some things never change…
Mickey @ 6:40 PM
Filed under: politics
functional improvement…

Posted on Thursday 21 August 2014

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.

since I was there
I feel comfortable saying that the injunction to keep people on medication indefinitely is partly a legacy from those days, preventing relapse requiring hospitalization [in the face of no hospitals being available]. Even the most recent Cochrane Systematic Review concludes that maintenance neuroleptics are better than placebo in preventing relapse as if that’s the major question:
The results clearly demonstrate the superiority of antipsychotic drugs compared to placebo in preventing relapse. This effect must be weighed against the side effects of antipsychotic drugs. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality associated with these drugs.
That’s true – as true as it was in 1974. We knew it then as we do now. In those times, many of us were still taught to go for the lowest possible maintenance doses [or none] because of the fear of causing Tardive Dyskinesia. But the official recommendation was maintenance medication, even though compliance was very low. A look at today’s APA Guidelines shows essentially the same recommendation today for stable patients – still heavily focused on relapse prevention.

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.

While we await the coming or not coming of future wonder drugs, this is the time to give this a real test. There’s money in the SAMHSA Block grants [see out of the loop…]; there’s decent evidence; and there’s the long held intuition of a lot of us that medication is necessary for acute psychosis, but that chronic use dulls the mind and may well interfere with moving forward for those who can. There’s sure enough to justify more decent trials in First Episode Psychosis, maybe in more chronic cases as well. Who knows, maybe we could even make a dent in that Jails & Prisons graph that we could be proud of…
Mickey @ 8:01 PM
Filed under: politics
well worth reading…

Posted on Wednesday 20 August 2014

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]:
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.
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…
At the time of publication, there were two commentaries, one in Medscape and a blog post by Tom Insel MD, Director of the National Institute of Mental Health [The remainder of these references are available online]:
Sandra Steingard MD, Medical Director at the Howard Center in Burlington Vermont and blogger on Robert Whitaker’s Mad in America, wrote a piece in the Washington Post later last year that discussed the findings of Wunderlink et al and some of her experience in her clinic.
The first response article came from E. Fuller Torrey MD, founder of the Treatment Advocacy Center and Associate Director of the Stanley Medical Research Institute. [To read some of the articles cited below, you will need to register on the Psychiatric Times site. It's free and in-so-far as I can see, painless].
And was followed by one from Joseph M. Pierre, M.D., Co-Chief of the Schizophrenia Treatment Unit at the VA Greater Los Angeles Healthcare Center and Clinical Professor of Psychiatry at UCLA.
While I have thoughts of my own about some of the issues mentioned in these articles, I’ll save them for later. I thought this was a conversation that needed to be collected in a single place. There is no disagreement that it is desirable to use the lowest effective dose of medications. In my day in this particular arena, that was what I was taught and practiced. The "medication for life" injunction certainly has its proponents, but is hardly a specialty-wide injunction. But previously, the central reason was preventing harm – avoiding the specter of Tardive Dyskinesia. The study by Wunderlink et al and some others suggests something further, that patients who can be maintained on either low dose or no medications are able to achieve a better functional recovery. Many of us have felt that intuitively, but this study adds the weight of a controlled trial. While there’s no clear consensus in this discussion, this is a high level dialog of pros and cons among experts of the hands-on variety, well worth reading…

Update: Here’s a critical analysis of the Wunderlink et al study written by George Dawson shortly after it was published:
Mickey @ 5:06 PM
Filed under: politics
intent to mislead…

Posted on Tuesday 19 August 2014

I never thought of myself as a "learned intermediary" – someone who is a go-between between patients and the pharmaceutical industry. I think of myself as someone who needs to know a lot about the drugs I prescribe – gathered from the literature, colleagues, and patients. In fact, I resent being seen that way by industry. No matter how hard they push this point, I’m not their "vendor," I’m a doctor who sees sick people. But I could rant on about that topic for hours, and there are other points to be made. So how did I get this designation – learned intermediary?
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
For example, we just learned that Roche just won the appeal of a judgement against Accutane® based on such an argument. The appeal court ruled that Roche had informed the doctor of the possible adverse effect and that ended their obligation. It’s now an essential piece in the lawsuits against Eli Lilly in Cymbalta® withdrawal cases [see Antidepressant discontinuation syndrome] where it was rejected in an attempt to have the suit dismissed:
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
The number of suits around this issue of the Discontinuation Syndrome with Cymbalta® are definitely on the rise [they prefer the term Discontinuation Syndrome rather than Withdrawal because the patients aren't drug-seeking]:
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…  
ProzacWhen 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.

… but even moreso when I saw that it says essentially the exact same thing in the original label at the time of FDA Approval on 08/03/2004 [except that it says "2% or greater" instead of "1% or greater" - go figure]. Here’s the 2005 study referred to above:
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.

CymbaltaThis 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.

ZyprexaIn 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…
Mickey @ 2:06 PM
Filed under: politics
only that – tools…

Posted on Sunday 17 August 2014

I was in a Clinical Trial frame of mind after my last post, and I happened to run across a CD that I had gotten with a FOIA [Freedom of Information Act] request a few years ago when I was looking at Paxil Study 329. It’s the data from the original Paxil NDA [New Drug Application] in 1992. I’d never looked at it because it wouldn’t load. But that was several computers ago, and when I put it in the drive this time, it loaded just fine. It’s 500+ pages, but as I scanned through it, I thought I’d post some of its contents, mainly to illustrate some of the quirks in an actual Clinical Trial. They submitted 17 trials in their application. 11 were single site, 6 week, RCTs with placebo controls. Of these, 6 were identical trials that also had an Active Comparator [Imipramine]. The HAM-D scores for the placebo controlled trials are summarized in the figure below.
These are all the ITT [Intent to Treat] populations with a LOCF [Last Observation Carried Forward] correction for drop-outs and missing values. The outcomes are expressed as Cohen’s d [Effect Size] which is the Difference in the Means divided by the Group Standard Deviation – to allow comparison across studies. As a rough gauge, 0.25 is a slight effect, 0.50 is a moderate effect, and 0.75 is a strong effect. Studies with a 95% CI bar that does not cross zero are significant at p < 0.05.

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.

As Dr. Carroll said in a recent comment:
    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…
Mickey @ 10:00 PM
Filed under: politics
the beginning of an end…

Posted on Friday 15 August 2014

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

August 8, 2014

Thank you for your email of 20 May 2014 and the EMA request for information (reference number 3644) of 10 June 2014 concerning the draft policy on proactive publication of and access to clinical trial data. Your email and your request for information have been received and your comm

Yours sincerely

Guido Rasi
Executive Director
European Medicines Agency

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:

… In writing about your proposal [the U-Turn…], I made the analogy, "It’s like going to sea to see the world in a submarine looking through a periscope." If anything, that’s an understatement. Trying to review the CRFs in the single window interface is beyond difficult. In our case, there are 275 subjects with the CRFs averaging over 200 pages each [more than 55,000 pages]. The data tables are equally voluminous making computation and extraction of data very difficult. I don’t know what process suggested that you change your policy, but it makes data analysis extremely awkward. I would suggest you have one of your own scientists try it out to see how really obstructionistic this policy is going to be. Please consider going back to the plan of access originally described…

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.

Is there something that brings this to mind other than getting a belated response from Dr. Rasi? It’s my ongoing suspicion that the tenacles of PHARMA are never still. We may be waiting expectantly, but you can count on the fact that the PhRMA/EFPIA lawyers are burning the candle at both ends in this lull:
In the illusion of evidence… and beyond…, I was echoing Dr. Healy’s point that Clinical Trial Data Transparency is just a starting place, not a destination. The escalation of Clinical Trials, Algorithms, and Treatment Guidelines to the level of Dogma is also a big problem – perpetuating somebody’s silly fantasy that a group mean in a controlled trial can direct treatment for individual patients. That said, insisting that the data from Clinical Trials is freely available for independent analysis is of vital importance to insure accurate baseline efficacy and adverse event data as a drug enters the real arena of clinical medicine. This coming EMA policy is going to be the linchpin for establishing integrity in Clinical Trials if properly implemented – the beginning of an end to the untenable notion that patient data is the proprietary property of trial sponsors…
Mickey @ 8:54 PM
Filed under: OPINION
rarely, if ever, available…

Posted on Friday 15 August 2014

But our discussions of mental illness rarely focus on this inconvenient truth: these illnesses are currently just as fatal as the “big killers.” We must continue to invest in research to develop new and more effective treatments for people with depression and other mental illnesses. The goal must be a future in which no lives are lost as a result of suicide.

“It’s very important that we stop seeing these illnesses as false and stop blaming patients and see them for what they are — which are medical conditions, genetic conditions, brain disorders that require appropriate diagnosis, treatment, care, and support,”
APA President Paul Summergrad, M.D., on NBC Nightly News

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…

"…the pain of severe depression is quite unimaginable to those who have not suffered it, and it kills in many instances because its anguish can no longer be borne. The prevention of many suicides will continue to be hindered until there is a general awareness of the nature of this pain. Through the healing process of time — and through medical intervention or hospitalization in many cases — most people survive depression, which may be its only blessing; but to the tragic legion who are compelled to destroy themselves there should be no more reproof attached than to the victims of terminal cancer."
Mickey @ 9:08 AM
Filed under: politics
into the Boston Harbor…

Posted on Friday 15 August 2014

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…
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…
In the US, Sovaldi® costs $1000/day [total $84,000/patient]. Now we learn that in the UK, it will cost $56,000/patient [~$667/day]. And in India and Egypt, it’s being offered at $900/patient [~$11/day].  We once knew what to do about situations like this one:

Boston Tea Party, 1773
Mickey @ 6:36 AM
Filed under: politics