where I came in…

Posted on Sunday 13 July 2014

I work in a fairly unusual charity clinic, one that only has one paid employee – a Director. The place is teeming with volunteers, most of us with grey [or little] hair – many living in retirement communities nearby. The doctors who started the clinic had an amazing vision, so we have a pharmacy stocked with donated samples and some purchased medications. And there’s a group that is skilled in getting patients with individual medical needs their medications through the indigent programs of the drug companies. In addition, this group helps patients seen elsewhere [mental health centers] get in-patent medication. Another group arranges for patients with specialty needs to be seen by doctors in the community where possible [by begging], or set up tests that we can’t do [like EEGs or MRIs] elsewhere [also by begging]. Their skills in getting people taken care of are remarkable. Some of the local docs volunteer too [eg a diabetic clinic].

I saw a woman Friday who has been followed in a State contracted Mental Health Clinic in a nearby town. She developed a psychotic illness in her mid-fifties with agitation and persecutory delusions. She was hospitalized with a diagnosis of "Schizophrenia" and treated with Geodon® [Ziprasidone], an Atypical Antipsychotic, which she has taken continuously for six years. She saw me at the request of our pharmacy staff for an "administrative" matter. Our pharmacy has been able to supply her with the medication through an indigent program, but is no longer going to be able to do that. She has a nine month’s supply, but they can get no more. So she came to see me to find an alternative. She’d thought about Risperdal®. In the original hospitalization, they had tried Seroquel® [she made an it-made-me-sick face as she said it]. She had taken 60 mg daily since being hospitalized, but the dose had recently been lowered [at her request] to 40 mg. She still had some "60’s," and was "taking them up" before going to "40s." She said she could never afford to buy it herself at "$300/a month" at the pharmacy. Her husband had died in the recent past and she lives alone. She said with a grin that if I picked "too high a dose," she’d know it ["I’ve got the Internet"] and wouldn’t take it. I admired her spirit [putting me in my place, not knowing I was already there].

 

If it were just an "administrative" matter, it wouldn’t be a big problem. The local pharmacies are as helpful as the local doctors and our volunteers. The reason we can’t get it for her anymore is that the patent on Geodon® ran out, and along with it, the indigent program shut down. The Generics are now available and with the discounts and the good will of our local druggists deferring their profit, it could be purchased for $55/month. It is likely that I could get the pharmacy at our clinic to get it for her with discretionary funds at that price. But it’s not just an "administrative matter." First, "Schizophrenia" with a first episode in her mid-fifties? Sounds odd to me. And she’s had no symptoms since that hospitalization. So was the diagnosis "Schizophrenia?" I don’t know that but have my doubts. When I saw her, the focus was on her meager finances, as well as staying on a lowest possible dose. She also mentioned that she had tried going off of it altogether, but couldn’t sleep without it. She seems to have been followed as if lifelong-medication were the standard treatment, and we’re not thinking that anymore – at least I’m not. But that’s not the whole story.

She has early Tardive Dyskinesia [TD]. It’s subtle, but it’s noticable if you know what it is – fingers, a little in the face. So from my point of view, the imperative at this point is to begin to taper her off of the medication altogether. She was the last patient of the busy day and the clinic and pharmacy staff had all left. So I encouraged her to go ahead and go down to the 40 mg dose, reassuring her that we would take care of all the administrative matters. There are domain issues as she’s not really our patient and if we’re going to taper her, I’ll need to get some lower dose capsules. But those kind of "administrative" matters are do-able. I’m obviously mentioning the case here in relation to the recent discussions of the treatment of psychosis and the medications used.


In my first medical life, I was a Clinical Immunologist, which meant treating diseases of unknown etiology [like Rheumatoid Arthritis, Systemic Lupus Erythematosis, etc] and it was the early days of organ transplants. We used some mighty toxic drugs in those days – steroids, anti-inflammatories, immunosupressives, antineoplastics – poisons. The consequences were potentially dire, but the alternatives were even worse. Getting people off the medications was always part of starting them. Toxic drugs like those could often be used safely short term, but were long term nightmares. Every case was a rock and a hard place. That’s just how it was. That’s still kind of true in that field, though they have a lot wider [and safer] range of drugs to choose from these days – but the risk/benefit ratio remains a constant watchword [just listen to those mumbled warnings at the end of the t.v. ads].

I think that mentality came with me when I came to psychiatry. In Rheumatology, I’d learned the concept that every single pill was a therapeutic trial, and we saw people frequently to see how the endless trials were going. Coming to psychiatry and encountering the neuroleptics of the 1970s was no different to me. Acute psychosis was a show-stopper and antipsychotics "worked," but the medications long-term were toxic [as in Tardive Dyskinesia as one example]. It felt familiar to me – just another rock and a hard place as a part of a medical life [those double binds I was talking about in part one: the bind…]. I was fortunate in having teachers who taught that these were symptomatic medications and they were in the lowest-effective-dose-drug-holiday-when-possible mindset of the day. Most of the people who pushed the notion that our job was insuring endless medication compliance or using depot injections were not psychiatrists, but rather administrative types trying to keep people out of harms way [and out of the hospitals]. By temperment, I might have fallen into the no medication set, but by experience following some of these patients long term, I am planted in judicious-use-of-medications-and-supportive-psychotherapy where I will likely stay. Like in Rheumatology, I use the medications when I have to, and aim for less or none when I can – another rock and a hard place as a part of a medical life.

So I agree with Robert Whitaker’s campaign against medications-for-life, though the anti-medication-altogether meme seems ill-informed to me. When the Atypical Antipsychotics were introduced, it was hoped that they were not going to cause the long-term neurological problems, but that turned out to be untrue as in this case. I personally think this patient has been ill-advised in that the medicine has been continued for six years – an older patient [more prone to Tardive Dyskinesia] with no apparent attempt to get her off [even though she is asymptomatic]. I’ve seen patients like this who have tried to stop it themselves, but had symptoms that interfered [like insomnia] and so they continued it. I would suspect in this case that those symptoms may well have been from withdrawal and might’ve been managed by a slow tapering and help with safer medications for sleep if needed, but that’s not what happened. In addition, TD can sometime worsen when the medication is withdrawn [another rock and a hard place]. Sometimes it goes away with stopping the medications – sometimes it doesn’t.

There are a number of forces perpetuating the medications-for-life idea. Our KOLs certainly haven’t been much of a help in alerting people to the adverse events. The drug companies made money from the number of pills sold so medications-for-life is not something they would discourage. Rather, they’ve actively minimized adverse events. Families, doctors, law enforcement officers, and staff who live in the revolving door world get very burned out by the patients who stop their medications on discharge and keep showing up every few months with recurrent psychosis. Insurance companies, families, and public mental health centers aren’t keen on the costs of repeated hospitalizations so they tend to advocate for staying on medications. Back in the day, when one or another of the psychiatry residents was showing signs of that kind of frustration, getting angry when patients stopped their medications, I often suggested that they try a dose themselves one free weekend. Some took me up on that, and slept the weekend away. One said he felt like "a tree." The point is that the patients are between a rock and a hard place too. Antipsychotics are no fun to take.


This is the first case of Tardive Dyskinesia I’ve seen in a long time. I’ve not practiced in a situation where I would see it a lot, but I’m still surprised at how little I’ve seen. The case reminded me that that this is where I came in forty years ago. The drugs were different then [first generation], more toxic, but the music was the same – the same rocks and hard places, the same impossibilities. Then, we worried about the mental patients confined to State Hospitals. Now, we worry about those in State Prisons. The opinions about neuroleptics was similarly polarized though the divisions cut along somewhat different lines – more within specialty groups in 1974 rather than between them now.

More to the point, what are the differences between 1974 and 2014? the differences between those first generation antipsychotics and the Atypical Antipsychotics of the modern era? Well, underneath all the drug company propaganda, there’s some actual data:


[C.A.T.I.E.]


[European Schizophrenia Study]

And also this from that European Schizophrenia Study:

 

At least in the area of neurologic Adverse Effects, there’s been some demonstrable progress.

I’ve always thought it ironic that many KOLs [specifically Dr. Lieberman] stick to the line that medication compliance is a key, even using the term "neuroprotection" [see Neuroprotection: A New Strategy in the Treatment of Schizophrenia] [for the record, I don’t believe that Lilly-funded CME roundtable]. The irony is apparent in the discontinuation rate in Dr. Lieberman’s own NIMH C.A.T.I.E. study above, and in other studies like this one from the VA hospitals:

The medication-for-life [or at least for a long time] recommendation has been repeatedly voted down by the patients themselves. I have been unable to find any studies to the contrary. Back in 2011 when I was collecting these graphs, Dr. Carroll made an observation that relates to some of our more recent discussions:
    Upon eyeballing the attrition curves you displayed above, it looks like the median time to discontinuation [50% attrition] was 3-5 months in this Veterans population receiving usual clinical care. In CATIE, it was 3-6 months except for olanzapine. In the European study it was 14 months for one drug and the other agents never reached 50% attrition. What might be the magic ingredient that the Europeans possess? Was it more intensive case management?

That’s certainly what I think, and hope for with the coming changes in parity, or the RAISE program, or its SAMHSA extensions – that it will allow these patients more face time. In the patients I’ve followed over the years, case management has been much more than about medication compliance. It has been about using the least amount of medication possible and learning with the patient how to live with the illness as it is manifested in their specific case. As I said, by temperment, I’d love to be in a medication free world and I read all the Open Dialog studies with great interest. But the lives of the patients trump my temperment, and so I live with the rocks and hard places and the double binds along with them – I worry when they’re on medications and I worry when they’re not. Such is my lot just like it was in Rheumatology. I personally think that if there’s something -for-life, it’s not meds, it’s periodic contact no matter how infrequent with someone who knows the case and can jump into action when it’s needed [In a crisis, I can do a hell of a lot better job with patients I already know than otherwise].

So what is different for me from those ancient times? I now have no qualms about tapering or stopping medication and seeing what happens. I am aware of the frequency of withdrawal symptoms, something I didn’t even know about back then – so I plan for them. I realize that a lot of patients like this lady I saw Friday continue to take the neuroleptic medications for symptoms better dealt with with other, safer drugs [like Benzodiazepines for sleep or anxiety]. And I’ve learned to have an eagle eye for TD and the metabolic syndromes. And with cases like the lady that started this ramble, I question the diagnosis of a chronic illness based on one discrete episode in middle age. But the main difference for me now is a comfort with these patients and what are called "negative symptoms." I see them as primary – a relative cognitive impairment that makes for certain difficulties in living – things that one can actually help with over time in ways other than medications.
Mickey @ 1:58 PM

the manual…

Posted on Friday 11 July 2014

Back in early May, I was looking into the NIMH ARA funded RAISE study [Recovery After an Initial Schizophrenia Episode], an as yet incompleted program being used as a template for a Congressionally mandated SAMHSA block grant allocation of funds to treat these patients:
One component of this RAISE program was something called Individualized Resiliency Training [IRT], basically designed to teach these patients adaptive skills – to be "resilient": 
I got a bit diverted by a comment by Sandra Steingard who brought up a fascinating program from the days right after Thorazine was introduced for the treatment of Schizophrenia in the mid 1950s called The Vermont Longitudinal Study of Persons With Severe Mental Illness done by Dr. George Brooks and his staff. The patients who were unable to leave the State Hospital after being treated with the newly introduced Thorazine then underwent an extensive psychosocial rehab program – something along the lines of the therapeutic community model. The combination of medication and this additional treatment was successful in getting these medication-only-treatment-failure cases out of the hospital, and had good results for the long haul. That’s the subject of these three posts:
I’m still wandering around with this topic. This post adds a 1963 paper to the mix written by two prominent psychiatrists of the time – one British [as in Max Hamilton of the Hamilton Depression Rating Scale] and the other from Australia, Anthony Hordern. As you recall. 1963 was the year of the Community Mental Health Act that established public mental health centers in the US as a part of the "deinstitutionalization" process already underway. Enthusiasm for the neuroleptics was high in the US in 1963. These authors had a somewhat different take on things [I included my purloined not-very-good OCR copy because I think it’s worth a read if you have any interest in this topic]:
by ANTHONY HORDERN and MAX HAMILTON
The British Journal of Psychiatry. 1963 109:500-509.

The advent of the phenothiazines as a treatment for chronic schizophrenics has been enthusiastically hailed as a great advance, but the history of medicine teaches that the enthusiasm with which a new treatment is greeted is not necessarily a measure of its efficacy, and this is as true of psychiatry as of other branches of medicine. In general, the results obtained with the phenothiazines have not bettered the results of those pioneers who introduced "moral treatment" over a century ago. The present-day equivalent of "moral treatment" has also achieved good results, and its supporters are not over-enthusiastic about the value of the phenothiazines. This review has attempted to bring some sort of order in the conflicting reports and an examination of the work done to combine these two forms of treatment has shown that their role is not yet established. Many more investigations will have to be made to establish the value, indications, and inter-relationship of the various treatments available for the mental hospital chronic patient.
By the time I came along [1974], "deinstitutionalization" was something of a done deal. The megalithics State Hospitals had emptied out and closed their doors. Central State was replaced by a Regional Hospital System in Georgia, but beds were disappearing at what seemed like an alarming rate. So it was the Era of the Revolving Door. Patients were admitted to the hospital and back out in a matter of days. It was called "Stabilization" which essentially relied on neuroleptic medications. The hospitals were brief custodial medication units. There were an increasing number of "street people" – many with chronic psychotic illness – and there was a migration of these patients to the urban centers, often given a bus ticket by the rural sheriffs to get them out of the small towns. The system that relied essentially on medication and brief custodial hospitalization sure didn’t look very effective to me. It wasn’t pretty, and was a striking contrast to the formal lectures about community treatment given to students in training. I personally never saw an effort like that described in the Vermont study, or like some of those "moral treatments" mentioned in the Hordern and Hamilton Drugs and "Moral Treatment" article. I just saw Drugs and More Drugs.

While the RAISE study and the recent plan to implement something like it in the States through dedicated Block Grants even before the RAISE results are in seems more rushed and driven by the availability of funding than one might like, that’s the way things work in the real world. The ARA stimulus money becomes available – jump on it. The SAMHSA Block Grant money comes along – grab it. In this world, you take advantage of any breaks that come your way. The thing that worries me isn’t that, it’s specific – it’s the Individualized Resiliency Training [IRT] aspect of the program. I had my say about that earlier [from on IRT, some comments…]:
    Speaking of honesty, again  with this, of all groups, "honesty is the  best  only policy." For example, on page 181 under Summary Points for – What is psychosis?, the manual includes:

    • Scientists believe psychosis is caused by a chemical imbalance in the brain.
    • Both stress and biology contribute to psychotic symptoms.
    • Biological factors contribute to this chemical imbalance in the brain.
    I doubt the authors really know that, or even believe it. I expect the motive in putting it there is to simplify things for the patient. But there’s nothing we know about Schizophrenia that’s "dumb." The Manual is filled with pseudo-expertise and, as Dr. Bracken rightly says, "It is much better to start with doubt, with questions, with openness." And when he says "questions," he means the explorative kind.

    I won’t go on and on here. I expect I’ve really already said what I wanted to say in another IRT prequel…. I think the reason this doesn’t feel like something new is that it’s about training the patients, yet it’s not informed by the patients themselves or what we know about them. What would be new would be to organize this around learning together rather than how to train them. I agree with Dr. Steingard that these clinicians need something to go on, but I think we’d be much more effective if we tried to train the clinicians in the ways of these specific patients. The manual may offer a road-map to some of the areas in need of exploration [and some of the examples are useful]. But if the point is to teach the clinicians to do their jobs ["many well meaning and caring people will use the manual but end up not following it to the T"] and the hope is that "some of them are bound to look up and see the human being sitting in the room," why not start there in the first place?

    This RAISE program is a good idea. It gives these patients some time to work with clinicians who can get to know them. The clinicians aren’t "dumb" either. We need to support them not as trainers with a training manual, but as people who have been given the tools [and the opportunity] to engage their patients, and learn with them what might move things along a helpful path…
As I gave this manual a second chance and read it again, it became clearer to me what bothers me about it. It’s strategic. People with paranoid trends [these patents] see through strategies and are suspicious of their indirectness independent of the content. If implemented as it is, they will feel "talked at" rather than helped. So I hope Dr. Steingard is right, "many well meaning and caring people will use the manual but end up not following it to the T." The principles in the Vermont Study and the Drugs and "Moral Treatment" article would be a useful guide to its rewriting…

An Aside: Discussions of this topic this often deteriorate into Either/Or ["Moral Treatment" vs Drugs] and tend to become contentious. The "Moral Treatment" advocates are characterized as trying to love people into health and in turn become self-righteous accusers. Those advocating Drug treatment are seen as controlling and ignoring the patient’s humanity while seeing their opponents as naive. I tend to see window-shades coming down when such arguments get going and become uncontrollably sleepy. I think that’s a developed somnabulism after twenty-five or thirty years of hearing those arguments go nowhere. I’m a Both person. Without the neuroleptics, we had huge "snake pits." Without "Moral Treatment," we had a different kind of chronic problem with mental patients living under bridges and in prisons. So I’m a careful-and-wary-use-of-existing-medications person and also a moral-treatment-is-the-way-to-go person who is in that dualistic position for life and will likely ignore invitations to change my mind. And while the below [from Drugs and "Moral Treatment"] was written in 1963 about a previous era, it could’ve equally been written in the present about the contemporary past:
    Moral Treatment in Decline: The Rise of Custodialism

    Many authors have discussed the slow attrition of "moral treatment", attributing its decline to such general factors as increasing urbanization, mass immigration, increase in the size of mental hospitals and, in psychiatry itself, to a mechanistic approach patterned on the discoveries in cellular pathology made by Virchow and Van Gicson. In addition, towards the end of the nineteenth century, the development of Kraepelin’s comprehensive nosological system led to a preoccupation with patterns of disease or constellations of pathological entities while mental hospital inmates were regarded as of little interest and of only minor importance as individuals. Whatever the reason, the mentally ill were regarded as suffering from incurable degenerative diseases and were locked away in huge human warehouses which, of necessity, began to be organized on custodial lines. Conditions worsened towards the end of the nineteenth century, and as late as Meyer’s early days at Kankakee, a vigorous search for specific causative agents or noxae, adequate to account for the various manifestations of mental illness, was stall in progress. In the general climate of enthusiasm which surrounded this quest for specific etiological factors the lessons of the past were forgotten or ignored, and only painfully and slowly did academic psychiatry, through Bleuler, Freud and Meyer, return to consider the claims of individual patients.
Mickey @ 8:00 AM

a long hot summer…

Posted on Wednesday 9 July 2014

Further discussion required on wording and practical arrangements
European Medicines Agency
Press Release
09/07/2014

The Management Board of the European Medicines Agency [EMA] has postponed formal adoption of the policy on publication of clinical trial data to its 2 October 2014 meeting. Further clarifications on wording and practical arrangements will be discussed by Board members, who have confirmed their general support to the overall aims and objectives of the policy, including the more user-friendly amendments proposed by EMA Executive Director Guido Rasi that would allow data to be downloaded, saved or printed for academic and non-commercial research purposes.

Further to the agreement reached with the European Commission in accordance with Article 80 of Regulation [EC] No 726/2004, the Board was not able to conclude on the final wording of the policy through a written procedure. Members of the Board have offered additional valuable contributions which will now be considered and addressed in the next few weeks, with a view to reaching final agreement at the next Management Board meeting in October.

The Agency welcomes this additional round of joint reflections and respects all opinions, as well as the views expressed by several Member States, which largely reproduce the complexity of the debate on both political and technical aspects which have emerged during the previous general and more targeted consultation phases. In the last 12 months the Agency has attempted to strike a balance between proactive data disclosure, the absolute need to protect personal data and the concerns relating to the protection of commercially confidential information.

The Agency management remains committed to introducing this additional measure towards transparency as soon as possible, so as to enhance citizens’ awareness and confidence in the EU authorisation system for medicinal products. The Agency has also underlined several times that the new policy, if approved, will be without prejudice to the provisions of Regulation [EC] No 1049/2001 on access to documents and the new clinical trial Regulation [EC] No 536/2014, which will become applicable in 2016 at the earliest and, as also noted during the debate, will apply to clinical trials conducted in the European Union.

The Agency management is conscious that any delay prevents citizens, and in particular academics and non-commercial researchers, from enjoying the benefits of proactive publication of clinical trial data for a further period. The Agency will continue to work with the Management Board and the European Commission ahead of the 2 October meeting to ensure that members receive the clarifications requested and to facilitate the adoption of the policy.
Pharmalot
By Ed Silverman
July 9. 2014

Drug makers and academic researchers will have to wait a little longer for the new policy on disclosing clinical trial data from the European Medicines Agency. The regulator has postponed formal adoption of the policy until its next board meeting on October 2, according to a statement issued today. Why? The EMA did not offer many specifics, other than to say its board was unable to reach agreement on final wording, although board members have “confirmed their general support to the overall aims and objectives of the policy.”

This is the second time that approval has been delayed in two months and one source indicated there may be disagreement among member states. The continual delays come amid controversy over the direction the EMA has taken in finalizing its stance toward the disclosure of clinical trial data, a hot-button issue for the pharmaceutical industry. Disclosure has been a contentious topic following scandals over safety or effectiveness data that was not publicly shared. The EMA had publicly committed itself to ensuring trial data is accessible and easily analyzed. And its public statements suggested the pharmaceutical industry would be required to release significant amounts of data, including clinical study reports, which collect and summarize trial data.

For their part, however, drug makers maintained that the EMA sought to go too far in releasing data that could contain trade secrets or compromise patient privacy. In fact, two drug makers – AbbVie and InterMune – went to court in hopes of preventing the agency from releasing data about some of their drugs. Those cases were recently settled. Last month, though, the EMA began circulating its draft policy and was accused by some academics and policy makers of doing an about face in the wake of the settlements. European Ombudsman Emily O’Reilly claimed the agency revised its policy to adhere to the “wishes” of the pharmaceutical industry and she is now reviewing redacted records from those court cases for clues to the EMA change in policy. Despite such impressions, the EMA attempted yesterday to reassure its critics that the policy will lead to greater transparency and, in particular, noted that access to documents will be permitted under freedom of information requests in keeping with European Commission regulations. The EMA also reiterated its willingness to allow data to be downloaded, saved or printed, a restriction that was unexpectedly included in the draft policy, but removed last month amid the burst of criticism.
I’m actually neither surprised nor disheartened. Literally Billions of Dollars, Pounds, and Euros are riding on this decision, and we would be naive indeed to think that this could happen without a fight. Had there been true data transparency, the last twenty-five years might have been very different, particularly in psychiatry. The Clinical Trials of the SSRIs and Atypical Antipsychotics might have looked very different if we had the opportunity to thoroughly evaluate them. And that’s also true of many of the general medicine "blockbusters" [> $1B/year]. So I wouldn’t be terribly surprised if another suit popped up along the way. And I wonder how solid that 2 October deadline will turn out to be. We can almost be guaranteed that some PhRMA/EFPIA workgroup is very busy at work even as I write this, jockeying for position. Remember this [a closing argument…]. A long hot summer up ahead…
Mickey @ 5:27 PM

antipsychiatry sentiment…

Posted on Wednesday 9 July 2014

As with benzodiazepines in the 1980s, the UK is prescribing SSRI antidepressants at a staggering rate – and to no good effect
The Guardian
by Peter Gøtzsche
30 April 2014

We appear to be in the midst of a psychiatric drug epidemic, just as we were when benzodiazepines [tranquilisers] were at their height in the late 1980s. The decline in their use after warnings about addiction led to a big increase in the use of the newer antidepressants, the SSRIs [selective serotonin re-uptake inhibitors]. Figures released by the Council for Evidence-based Psychiatry, which was set up to challenge many of the assumptions commonly made about modern psychiatry, show that more than 53m prescriptions for antidepressants were issued in 2013 in England alone. This is almost the equivalent of one for every man, woman and child and constitutes a 92% increase since 2003.

The problem is that many of these drugs simply do not work as people suppose. The main effect of antidepressants is not the reduction of depressive symptoms. They are no better than placebo for mild depression, only slightly better for moderate depression, and benefit only one out of 10 with severe depression. In around half of all patients, they cause sexual disturbances. The symptoms include decreased libido, delayed orgasm or ejaculation, no orgasm or ejaculation and erectile dysfunction. Studies in both humans and animals suggest that these effects may persist long after the drug has been discontinued. The US Food and Drug Administration has shown that antidepressants increase suicidal behaviour up to the age of 40, and many suicides have been reported even in healthy people who took the drugs for other reasons [for example, for stress or pain]. Another report also said that, among people over 65, antidepressants are believed to kill one out of every 28 people treated for one year, because they lead to falls and hip fractures. Indeed, it is not clear whether antidepressants are safe at any age.

My studies of the research literature in this whole area lead me to a very uncomfortable conclusion: the way we currently use psychiatric drugs is causing more harm than good. We should therefore use them much less, for shorter periods of time, and always with a plan for tapering off, to prevent people from being medicated for the rest of their lives.
The Lancet
by David J Nutt, Guy M Goodwin, Dinesh Bhuqra, Seena Fazel, and Stephen Lawrie
May 27, 2014

Psychiatry is used to being attacked by external parties with antidiagnosis and antitreatment agendas. However, the recent disclosure that a doctor [Professor Peter Getzsche] had joined a new group, the Council for Evidence-based Psychiatry, whose launch was accompanied by newspaper headlines such as "Antidepressants do more harm than good, research says" and "Psychiatric drugs are doing us more harm than good" in The Times and The Guardian plumbs a new nadir in irrational polemic. What is especially worrying is that this doctor is a co-founder of the Nordic Cochrane collaboration, an initiative set up to provide the best evidence for clinical practitioners. What is the truth about antidepressant efficacy and adverse effects, and why would Professor Getzsche apparently suspend his training in evidence analysis for popular polemic?

Of course, all active drugs have adverse effects, but for the new antidepressants these are rarely severe or life-threatening, even in overdose situations. Indeed, the new antidepressants, especially the selective serotonin reuptake inhibitors, are some of the safest drugs ever made. In our experience, the vast majority of patients who choose to stay on them do so because they improve their mood and well·being rather than because they cannot cope with withdrawal symptoms when they stop. Many of the extreme examples of adverse effects given by the opponents of antidepressants are both rare and sometimes sufficiently bizarre as to warrant the description of an unexplained medical symptom. To attribute extremely unusual or severe experiences to drugs that appear largely innocuous in double-blind clinical trials is to prefer anecdote to evidence. The incentive of litigation might also distort the presentation of some of the claims.

Whatever the reasons, extreme assertions such as those made by Prof Gøtzsche are insulting to the discipline of psychiatry and at some level express and reinforce stigma against mental illnesses and the people who have them. The medical profession must challenge these poorly thought-out negative claims by one of its own very vigorously.
I picked these two articles because at first reading they seem like antipodes – two diametrically opposed takes on the same thing. Dr. Peter Gøtzsche has become a lightning rod for criticism since writing Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare, a book whose very title makes his position clear to all. And yet his conclusion doesn’t strike me as particularly radical – more like good advice:
    …the way we currently use psychiatric drugs is causing more harm than good. We should therefore use them much less, for shorter periods of time, and always with a plan for tapering off, to prevent people from being medicated for the rest of their lives.
He doesn’t argue that the drugs shouldn’t be used. He says that they are overused, and reaffirms that depressions are time limited, so the use of the medication should be time limited. His recommendation for tapering is rooted in clinical observation. Withdrawal symptoms are common and are frequently misinterpreted as returning depression. We regularly see people who have been on antidepressants for years, afraid to stop as if some underlying depressive something-or-another will raise its ugly head. So in spite of Dr. Gøtzsche’s confrontational style, his actual recommendations seem "evidence-based" to me.

Dr. Nutt’s reply to Dr. Gøtzsche is pretty much standard fare for him – forever championing the notion that there’s too much attention paid to adverse effects of the psychopharmacologic drugs. Three years ago, he made a similar speech to the Royal College of Psychiatry, No Psychiatry Without Psychopharmacology, that vilified Dr. David Healy as a "scaremonger" in an opening slide:

I had decided to skip Dr. Nutt’s article [Attacks on antidepressants: signs of deep-seated stigma?], but yet I kept it around. I looked at it periodically and was never quite able to close it. So here it is over a month after it was published. These are the phrases that linger:
    Psychiatry is used to being attacked by external parties with antidiagnosis and antitreatment agendas. However, the recent disclosure that a doctor [Professor Peter Gøtzsche] had joined a new group, the Council for Evidence-based Psychiatry, whose launch was accompanied by newspaper headlines such as "Antidepressants do more harm than good, research says" and "Psychiatric drugs are doing us more harm than good" in The Times and The Guardian plumbs a new nadir in irrational polemic..

    … and at some level express and reinforce stigma against mental illnesses and the people who have them. The medical profession must challenge these poorly thought-out negative claims by one of its own very vigorously.
Several things. I don’t much mind Peter Gøtzsche’s style. He goes after mammography with the same passion [see the video in a major force…]. His conclusions seem right as rain to me, so he can rant all he wants. The antidepressants are unquestionably overused; people are on them too long [and hard to get off]; and I’ve come to believe that they should always be tapered. Solid points. And as for Dr. Nutt’s implication that it represents an attack on psychiatry, I didn’t think of that when I read what Gøtzsche had to say. He says, "the way we currently use psychiatric drugs," and I take him literally as meaning "we doctors." And he’s right from where I sit. Most of the overuse of antidepressants I see is by primary care physicians [though there aren’t  many psychiatrists around here in rural Georgia]. So I guess I see Dr. Gøtzsche as an acquired taste – not for everyone. But I don’t particularly think of him as attacking psychiatry as a medical discipline.

On the other hand, there are some things about this piece by Dr. Nutt that do bother me. In fact, most of what he writes bothers me. I think it dredges up my memories of the conflicts of the late 1970s. Dr. Szazs monotonous definitions of disease requiring some biological marker [the Myth of Mental Illness] and the neoKraepelinians going him even one step further by saying "The focus of psychiatric physicians should be on the biological aspects of illness" and then sliding over the years to Tom Insel’s "Psychiatry is a Clinical Neuroscience Discipline" version. I guess they all feel like dogmatic pronouncements or injunctions – but they’re really just opinions. I was personally comfortable with the more traditional Doctors take care of sick people. That’s who came to my office, and that’s what I did. Sickness came long before any biological understanding was around. We started with just "Do no Harm" and that’s where we’re still supposed to be. So my complaint is that besides Dr. Nutt’s pharmaphillia, and his neoKraepelinian bio-dogma, I think he perpetuates what seems to me a false dichotomy, one that goes back into the dawn of our history.

But if that were all, I would’ve probably just sent this article to cyberspace. It’s this part that kept it around:
    … and at some level express and reinforce stigma against mental illnesses and the people who have them. The medical profession must challenge these poorly thought-out negative claims by one of its own very vigorously.
I recalled something similar from Dr. Lieberman [Psychiatry: Nothing to Be Defensive About]:
    I recently wrote an article for the Scientific American blog that explores how stigma and antipsychiatry sentiments fuel prejudice against our field and our patients. But I think it’s also important to note how the unwillingness of the public and pundits to accept psychiatry as a scientific discipline and full-fledged medical specialty perpetuates the false dualism of the mind and the brain — attempting to transport psychiatry back to the Cartesian philosophy of the 17th century…
I don’t question that there is still a stigma with mental illness, though less than there used to be. And I don’t question that there are anti-psychiatrists or people who question psychiatry as a medical specialty. But I think that in this case, Dr. Nutt and Dr. Lieberman are misappropriating those things to keep from looking in the mirror. If Peter Gøtzsche is making his complaints as a veiled attack on psychiatry as a medical specialty, I sure can’t see it. And I read him as a patient advocate. I frequently make the same comments about not overprescribing antidepressants, using antidepressants in a more time limited way, warning about the dangers, and tapering these drugs. And I’m neither an antipsychiatrist nor prejudiced against mental patients. I’m saying those things because the antidepressants are used too often, too long, too casually, and stopped too abruptly. I resent him imputing other fantasied motives to people that disagree with him. And his maximizing efficacy and minimizing adverse effects is no different from people who do the opposite. There’s a rational place in the middle. I would propose that the Dr. Nutts and Dr. Liebermans of the world do no one any favors by making these defensive and externalizing kind of comments. They actually cause a lot of the antipsychiatry sentiment they seem to think they’re fighting against. That’s not Peter Gøtzsche’s doing…
Mickey @ 1:47 PM

part four: the answers?…

Posted on Tuesday 8 July 2014

Families that communicate with Double Binds create children who often spend an inordinate amount of time in their lives trying to find solutions to problems that really have no solution [part one: the bind…]. To review the elements of a Double Bind: [1 & 2] Two mutually exclusive commands ["lose weight" and "clean your plate"]; [3] the injunction that you have to act; [4] the prohibition against addressing the impossibility of the situation. What does a "healthy" person do in that circumstance? In the words of the ancients, they "go between the horns." Said in other ways, they deny that [1 & 2] are the only possibilities; they break rules [3] and [4] by talking about the impossibility of the task, that neither action is correct [in this case, "silence is not golden"]. In the real world, the problem needs to be reframed in a more realistic way to look for solutions.

In the case of the challenging/disruptive intellectually impaired child, the Hamlet question, "to prescribe antipsychotics, or not to prescribe antipsychotics" is hardly the right way to formulate the clinical problem. Probably the first order of business is to explore the situation of the specific patient and the specific caregiver and the specific living situation to see if one can figure out what’s so upsetting, what’s wrong? Sometimes it’s something you can’t do anything about, but often it is amenable to change. Mentally retarded people are just like the rest of us – just less able to figure out and communicate what needs to be dealt with. Trying to control behavior with medication if there is ongoing conflict is a dubious enterprise. You end up with a sleepy conflicted person.

The next thing that comes to mind is that such things are rarely acute problems that need to be solved in a single visit. The challenging/disruptive behavior is usually chronic and deserves more than a one-shot decision – so there really is no requirement to act immediately – prescription or otherwise. And as for medication, we really don’t know the answer as to whether psychoactive medications like antipsychotics or anxiolytics are helpful in these situations [part two: the dogma…, part three: the questions…] – when or if to use them. We do know that the Dogma that they are helpful is not based in science.

But we also need to consider the situation I described earlier [part one: the bind…]:
    So you’re a doctor and a parent/caregiver brings a mentally retarded child to see you who is oppositional/challenging/disruptive in the waiting room and in your office. Then you look at the child’s parent/caregiver and you see a person hanging on by a thread, on the edge of tears, spent from dealing with this child. Maybe it’s a Foster Parent, one you already know to be a real trooper, about to give up return the child to DFCS…
This situation is one of the consequences of what’s been wrong in psychiatry and mental health care in general as it has evolved in recent decades. It’s a common problem and what people do has been heavily influenced by the short-session ways of managed care or the pill for every ill meme of the pharmaceutical industry. We ought to be ashamed of ourselves for going along with this superficial approach to something that can be a compelling 24/7 problem for both the patient and the parent/caregivers. In my opinion, this is actually an example of a major failing of our National Mental Health Institute – taking on the real world problems of mental health workers and families with impaired children. A few well designed retrospective and prospective, unbiased studies could provide all the answers needed to give our Double Bound doctor and his patient[s] a path to follow that actually goes somewhere. And this is not just a problem for the biomedical among us. It’s time for the behaviorist or the social worker to get into the act too. Tyrer et al say:
    "Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population."
While I agree with them, they are still constrained by too limited a question, "to prescribe antipsychotics, or not to prescribe antipsychotics." What is the right thing to do in this situation? Where can the caregiver/parent turn to best approach the problem? What’s wrong with medication? What are the alternatives? I’m no fan of guidelines because they are so vulnerable to bias, but this may well be a situation where a well thought out white paper might really help.

We’re still in the midst of a climate that has been pervasive for much too long – the fantasy that we’re going to knock the ball out of the park, crack the great riddles of the causation of mental illness, figure out the brain. Our National Institute of Mental Health is currently obsessed with discovering new treatments to make up for the deficiencies of the ones we currently have. The solutions remain in the as-yet-unrealized future. Dr. Insel’s NIMH is now saying that future NIMH Clinical Trials will need to contain probes that look for etiological clues – "a focus on learning more about the disorders, as well as the mechanisms of intervention" [time for a sabbatical…].

But what about the treatments we’re currently using? One would have to have been in a prolonged coma state not to know that many of our current practices and beliefs about psychoactive medications have been heavily shaped by influences that don’t have to do with patient care – the profit motives of PHARMA, the cost-cutting motives of third party carriers. Medical science has been clearly twisted to serve both masters. It seems to me that the onus falls on the National Institute of Mental Health [and our professional organizations] to investigate problems like the one addressed in Tyrer et al’s editorial. It’s time to stop simply decrying over-prescribing, and provide some solid evidence-based science to the practitioners who sit in their offices seeing patients.

Writing a prescription may well be the solution to the physician’s discomfort at being in a Double Bind in a given session. In fact it probably will solve the problem of that moment. But a frank discussion of the downside of that option, at least long term, might be a much more effective use of the time and open the door to a more productive approach. It may well turn out that there are situations where the use of medication may be medically sound rather than just a momentary solution, but that’s the kind of thing that requires solid research with follow-up, and right now it’s just not available. The pharmaceutical companies can’t be expected to do this kind of study. That’s why we have a publicly funded NIMH, to help us answer this kind of everyday question. The answers? Not yet…
Mickey @ 6:00 AM

part three: the questions…

Posted on Monday 7 July 2014

As for efficacy, Tyrer et al say [see part one: the bind…]:
    What is the evidence for the benefits of these drugs in the treatment of challenging behaviour? Virtually none. Almost all the evidence in favour comes from small trials conducted by drug companies. Yet it would be perverse if doctors continued to prescribe these drugs, knowing about their adverse effects, if they were entirely without efficacy, and many claim that they cannot care adequately for their patients without the option of drug treatment…
In 2012, a Cochrane Systematic Review [not limited to children with mental retardation] found only eight studies of a quality to include – seven with Risperdal® and one with Seroquel®:
by Loy JH, Merry SN, Hetrick SE, and Stasiak K.
Cochrane Database of Systematic Reviews. 2012 9:CD008559 .

BACKGROUND: Disruptive behaviour disorders include conduct disorder, oppositional defiant disorder and disruptive behaviour not otherwise specified. Attention deficit hyperactivity disorder [ADHD] is frequently associated with disruptive behaviour disorders. The difficulties associated with disruptive behaviour disorders are demonstrated through aggression and severe behavioural problems. These often result in presentation to psychiatric services and may be treated with medications such as atypical antipsychotics. There is increasing evidence of a significant rise in the use of atypical antipsychotics for treating disruptive behaviour disorders in child and adolescent populations.
OBJECTIVES: To evaluate the effect and safety of atypical antipsychotics, compared to placebo, for treating disruptive behaviour disorders in children and youths.
SEARCH METHODS: We searched the following databases in August 2011: CENTRAL… MEDLINE… EMBASE… PsycINFO… CINAHL… ClinicalTrials.gov… Australian New Zealand Clinical Trials Registry… CenterWatch… and ICTRP…
SELECTION CRITERIA: We included randomised controlled trials with children and youths up to and including the age of 18, in any setting, with a diagnosis of a disruptive behaviour disorder. We included trials where participants had a comorbid diagnosis of attention deficit hyperactivity disorder, major depression or an anxiety disorder…
MAIN RESULTS: We included eight randomised controlled trials, spanning 2000 to 2008. Seven assessed risperidone and one assessed quetiapine. Three of the studies were multicentre. Seven trials assessed acute efficacy and one assessed time to symptom recurrence over a six-month maintenance period.We performed meta-analyses for the primary outcomes of aggression, conduct problems and weight changes but these were limited by the available data as different trials reported either mean change scores [average difference] or final/post-intervention raw scores and used different outcome measures. We also evaluated each individual trial’s treatment effect size where possible, using Hedges’ g.For aggression, we conducted two meta-analyses. The first included three trials [combined n = 238] using mean difference [MD] on the Aberrant Behaviour Checklist [ABC] Irritability subscale. Results yielded a final mean score with treatment that was 6.49 points lower than the post-intervention mean score with placebo [95% confidence interval [CI] -8.79 to -4.19]. The second meta-analysis on aggression included two trials [combined n = 57] that employed two different outcome measures [Overt Aggression Scale [modified] [OAS-M] and OAS, respectively] and thus we used a standardised mean difference. Results yielded an effect estimate of -0.18 [95% CI -0.70 to 0.34], which was statistically non-significant.We also performed two meta-analyses for conduct problems. The first included two trials [combined n = 225], both of which employed the Nisonger Child Behaviour Rating Form – Conduct Problem subscale [NCBRF-CP]. The results yielded a final mean score with treatment that was 8.61 points lower than that with placebo [95% CI -11.49 to -5.74]. The second meta-analysis on conduct problems included two trials [combined n = 36], which used the Conners’ Parent Rating Scale – Conduct Problem subscale [CPRS-CP]. Results yielded a mean score with treatment of 12.67 lower than with placebo [95% CI -37.45 to 12.11], which was a statistically non-significant result.With respect to the side effect of weight gain, a meta-analysis of two studies [combined n = 138] showed that participants on risperidone gained on average 2.37 kilograms more than those in the placebo group over the treatment period [MD 2.37; 95% CI 0.26 to 4.49].For individual trials, there was a range of effect sizes [ranging from small to large] for risperidone reducing aggression and conduct problems. The precision of the estimate of the effect size varied between trials.
AUTHORS’ CONCLUSIONS: There is some limited evidence of efficacy of risperidone reducing aggression and conduct problems in children aged 5 to 18 with disruptive behaviour disorders in the short term. For aggression, the difference in scores of 6.49 points on the ABC Irritability subscale [range 0 to 45] may be clinically significant. For conduct problems, the difference in scores of 8.61 points on the NCBRF-CP [range 0 to 48] is likely to be clinically significant. Caution is required due to the limitations of the evidence and the small number of relevant high-quality studies. The findings from the one study assessing impact in the longer term suggest that the effects are maintained to some extent [small effect size] for up to six months. Inadequately powered studies produced non-significant results. The evidence is restricted by heterogeneity of the population [including below average and borderline IQ], and methodological issues in some studies, such as use of enriched designs and risk of selection bias… Further high-quality research is required with large samples of clinically representative youths and long-term follow-up to replicate current findings.
Nothing much to write home about there – confirming Tyrer et al’s point that although the use of antipsychotics in intellectually impaired kids with challenging/disruptive behavior is near "Dogma," it’s not "evidence-based Dogma." It’s just what "doctors-habitually-think-Dogma." So all the questions remain unanswered:
  • Are [Atypical] Antipsychotics effective in managing challenging/disruptive behavior in intellectually impaired children? or for that matter, children with other non-psychotic diagnoses? Short term? Long term?
  • What is the incidence of various Adverse Effects using [Atypical] Antipsychotics in intellectually impaired children? or again, children with other non-psychotic diagnoses? Short term? Long term? Are these drugs actually harmful?
  • What are alternative recommendations for managing challenging/disruptive behavior in retarded children? or children with other non-psychotic diagnoses? Short term? Long term?
The ubiquitous influence of the pharmaceutical industry and the cost-cutting restrictions of managed care have had an enormous influence on the way we approach issues like this over the last fifty years. The editorial by Tyrer points out that the use of antipsychotics [I would add particularly Atypical Antipsychotics, particularly Risperdal®] is based on a belief that has achieved the level of Dogma, but the basis for that belief is hardly confirmed by the available scientific record. The problem their editorial addresses – the use of antipsychotics in mentally retarded children – seems to me to encompass an even greater domain than they mention i.e. Autism, primary behavioral problems, whatever-the-Biederman-Bipolar-kids represented, other non-psychotic conditions. And the answer to the question "What is the best practice response, if any, to challenging/disruptive behavior in children with intellectual impairment?" is actually unknown, as is specifically "What is the place of antipsychotics, if any?"

Parenthetically, I marvel at how a study like Aman et al’s [Risperidone Disruptive Behavior Study Group] Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Disruptive Behaviors in Children With Subaverage Intelligence can have such a large effect over the years. It was a small industry run study that was part of a failed attempt early on get approval for the behavioral management of mentally retarded children. It was reincarnated as a justification for using antipsychotics in kids with "super angry/grouchy/cranky irritability" that came to be called Bipolar, at least for a time. And here fifteen years later, it remains as 1/7th of the literature suitable for the Cochrane meta-analysis.

I’m aware that I put more emphasis on the impact of PHARMA on this prescribing practice than Tyrer et al. I don’t think that’s because I’m some kind of wild-eyed activist. I think it’s because I heard it in person with my own ears when I went to the J&J/TMAP trial in Austin in January 2012 [State of Texas and Allen Jones v. Janssen et al]. If you find yourself doubting that influence, I’ve posted the transcripts of that trial. I would recommend reading the testimony of sales rep Tiffany Moake and particularly sales manager Tone Jones [here and here]. I can pretty much guarantee that you will come around to my view before you are halfway through.
Mickey @ 11:56 AM

part two: the dogma…

Posted on Monday 7 July 2014

Even though we know the long term consequences of using antipsychotics, most psychiatrists think that antipsychotics are helpful in controlling challenging/disruptive/oppositional behavior in intellectually impaired or autistic kids. Tyrer et al call it "Dogma," and that seems right [part one: the bind…]. Why do we think that? For one thing, we’ve seen antipsychotics used in out of control patients – mania, psychosis, the mentally impaired, agitated people of all kinds. It works in those circumstances if you give enough. But we’ve also been told repeatedly that it works in these circumstances with kids. When the first Atypical Antipsychotic [after Clozaril], Risperdal®, was approved, Janssen quickly began a Clinical Trial of the drug in Mental Retardation done by their Risperidone Disruptive Behavior Study Group:
They went for FDA Approval and were turned down. The study was published in 2002:
Here’s the Janssen business plan for 2002 lest you think the didn’t get mileage from that study [trial 93: a very bad penny…]:
    The clinical development program for RISPERDAL has yielded important new efficacy and safety data in the child and adolescent area. These efforts have previously been focused in the area of Disruptive Behavior Disorders and Subaverage IQ. Several trials, RI5-U5A-93 and RI5-CAN- 19 (as well as the open label 48 week follow up trials, USA-97 and CAN-20), initially designed to support filing for an FDA indication, have been completed and have yielded an impressive volume of new efficacy and safety data. Unfortunately, the FDA determined that Disruptive Behavior Disorder lacks the diagnostic specificity necessary to receive an approved indication. Nevertheless, these studies have contributed significantly to the clinical knowledge of RISPERDAL in the child and adolescent population, and provide a basis for ongoing medical education activities… It is expected that the request will include the following requirements:
      • Pediatric PK trial;
      • Adolescent schizophrenia trial; and
      • Pediatric bipolar trial.
    … the child and adolescent market is not driven by diagnosis, but rather by treatment of symptoms such as aggression, agitation, self-injurious behavior, and explosive rage. This lack of consistent diagnosis stems from a reluctance to "label" children at an early age, as well as a fundamental lack of consensus regarding the actual underlying disease states causing this symptomatic behavior. As a result, multiple diagnoses and comorbidities are the rule, rather than the exception in this area. These issues have influenced the clinical development process and limited the ability to achieve an FDA approved indication for RISPERDAL in children…
As it turned out, this focus on symptoms became an industry-wide meme and formed the nidus for the message from the sales reps who visited individual physicians. In the TMAP trial. we heard example after example of the detailing of clinicians who saw a lot of foster children. focusing on symptoms, not diagnosis. But then along came Dr. Joseph Biederman and the Bipolar Child craze. His notion that "super angry/grouchy/cranky irritability" was a symptom of Bipolar Disorder in Children gave broad license to prescribing antipsychotics to a whole new cohort of kids. In a move that seems almost too bizarre for words, that same study mentioned above was repurposed by Excerpta Medica and published under Dr. Biederman’s name as a study about treating these supposed affective symptoms in the newly created unofficial category of the Bipolar Child with Risperdal®:
The point here is that the pharmaceutical industry and particularly Janssen were vigorously detailing the Atypical Antipsychotics as a treatment for disruptive children including the mentally retarded, autistic, Bipolar, and psychotic groups without making much of a diagnostic distinction [bipolar kids: biedermania and super angry/grouchy/cranky irritability…]. They were essentially pushing treating the symptom of being a difficult child with antipsychotics.

My point in this post is that while I’m sure that Tyrer et al’s comment that "Drug treatment has been a mainstay for managing a common syndrome subsumed under the label ‘aggressive challenging behaviour’ since chlorpromazine was first introduced for its treatment over 40 years ago" is true, it was also actively amplified and reinforced during the period of aggressive marketing of the Atypical Antipsychotics. That these antipsychotic drugs are for treating disruptive challenging kids was oozing from every pore of the pharmaceutical companies that manufactured them, and that surely had something to do with that usage becoming "Dogma" – even though it was mostly an off label campaign. And the problem Tyrer et al addresses in their editorial spills over into any disruptive behavior in children – not just in mental retardation.
Mickey @ 8:00 AM

part one: the bind…

Posted on Sunday 6 July 2014


by Peter Tyrer, Sally-Ann Cooper, and Angela Hassiotis
British Medical Journal. 2014 348:g4323.

Time to rethink?

Do we still need to be reminded that the drug treatment of people with intellectual disability is often prolonged and not without dangers? We probably do. Drug treatment has been a mainstay for managing a common syndrome subsumed under the label “aggressive challenging behaviour” since chlorpromazine was first introduced for its treatment over 40 years ago… Challenging behaviour is the most common disturbance requiring intervention in intellectual disability services, but it does not have proper diagnostic status in standard psychiatric classifications.

Yet this does not inhibit the wholesale import of adult psychopharmacology into its management. Psychotropic medication in its many forms mainly antipsychotics, sedatives and tranquillisers, antidepressants, and mood stabilisers — has seen extensive off-label prescribing for the past 50 years. Thus, a recent population based cohort study of 1023 adults with intellectual disabilities showed that 49.5% were taking some form of psychotropic drug, with 23.2% taking an antipsychotic despite only 4.4% having a psychotic disorder…

This prescribing would not be a concern if adverse effects were few and easily corrected, but neither of these is true. The high levels of obesity, metabolic syndrome, and diabetes in this population are largely due to these drugs and predispose to premature mortality. National audits such as those carried out by the Prescribing Observatory for Mental Health suggest that more people with intellectual disability are being regularly checked for known and established side effects of antipsychotic medication in secondary care. But there is a lack of primary care data on whether people with intellectual disability prescribed psychotropic drugs receive similar care and are targeted as a higher risk group. Once these drugs are prescribed they far too often become part of long term management, reinforced by the nervousness of care staff with limited knowledge of psychopharmacology and reluctance of practitioners and carers to alter a treatment when it may be wrongly perceived as effective. Attempts to stop these drugs after people have been taking them for many months or years have had only limited success.

What is the evidence for the benefits of these drugs in the treatment of challenging behaviour? Virtually none. Almost all the evidence in favour comes from small trials conducted by drug companies. Yet it would be perverse if doctors continued to prescribe these drugs, knowing about their adverse effects, if they were entirely without efficacy, and many claim that they cannot care adequately for their patients without the option of drug treatment. We therefore need clear indications for drug treatment, as well as to develop a range of more effective psychosocial treatments, for which there is now increasing evidence, but there is still ground to cover. In the interim, a key element is education of prescribers… Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population..

Drug treatment of challenging behaviour in people with intellectual disability should no longer be on the sidelines of evidence based medicine. If we are going to achieve parity of esteem for people with mental illness, we can no longer tolerate our ignorance on this subject. Quite apart from the deficiencies in evidence allowing dogma and opinion to rule, the cost of prescribing these drugs is enormous. If they truly are unnecessary, clinicians, pharmacists, service managers, and those who fund services for people with intellectual disability need to know, and soon.
The belief that one can control or at least dampen the disruptive [challenging, aggressive, etc] behavior in impaired children with antipsychotics really is in the range of Dogma as this editorial implies. I think I even believe it, though I wish I didn’t. So they’re absolutely correct in saying, "Good randomised trials, preferably not funded by the drug industry, are needed to show efficacy. At present there are no randomised trials with adequate numbers that can give definitive advice on the value of any drug group in this population." Absent that, the belief will persist along with Papal Infallibility and Transubstantiation throughout the ages – Dogma endlessly debated but unresolved. And even if it turns out to be true that these medications are somewhat effective, the problem remains in the form of adverse effects – metabolic syndrome, weight gain [often dramatic], diabetes, neurological symptoms, tardive dyskinesia – because the disruptive [challenging, aggressive, etc] behavior doesn’t just evaporate on its own. It comes with the package and leads to long term use once started, again as this editorial implies.

Which brings me to Hamlet and company, the tragic figures in Shakespeare’s immortal play. Thirty plus years ago, my kid sister [now a retired academic] wrote a paper about that play, Hamlet, "A Man to Double Business Bound", out of her usual genre [Milton]. She analyzed the play using Double Bind theory, and did a mighty fine job of it, if I do say so myself [ignoring my obvious COI]. I knew Double Bind theory, but her paper etched it on my brain, and I thank her for that. It was an invaluable tool in understanding the narratives of the patients I saw over the years, and it was no small factor in working out my own dilemmas – as the life of a physician is filled with Double Binds that never stop coming. A Double Bind, oddly enough, has four commands: Two injunctions that are diametric opposites [thus the synonym – an impossible situation] – one overtly stated and the other usually covert. Then there’s a third injunction – that you have to act, to do something [even though there’s nothing right to do]. And the final rule caps the nightmare, you can’t address the obvious impossibility of this complex of commands. All you can think to do is pick one or the other side and surely fail; or give endless soliloquies about a paralysis of mind; or go crazy. Most psychotherapists can think of endless examples in a heartbeat. I sure can [see postscript…].

So you’re a doctor and a parent/caregiver brings a mentally retarded child to see you who is oppositional/challenging/disruptive in the waiting room and in your office. Then you look at the child’s parent/caregiver and you see a person hanging on by a thread, on the edge of tears, spent from dealing with this child. Maybe it’s a Foster Parent, one you already know to be a real trooper, about to give up return the child to DFCS. And you think hope that an antipsychotic might possibly help [or you can’t think of anything else to do], knowing full well the long term side effect profile of the drugs. That’s when the prescriptions often get written, even by the most principled doctor in the clinic. If you do nothing, you’ve done nothing, reinforcing the hopelessness the parent/caregiver already feels. If it doesn’t work, you’re in trouble because you’ve implied that medication is the way to go and what’s next? If it does work, you’re committing to a road you might really not want to be on sooner than you think. That’s what a Double Bind feels like – absolutely nothing right to do, and a pressure to act [yesterday].

Tyrer et al have written an excellent editorial. They obviously don’t think these kids should be on antipsychotics or at least not like they are now, but they don’t preach, rant, or moralize like many ["those damn doctors think everybody needs to be on medications!"]. They simply present an all too common clinical problem, one that’s often handled by the gestalt of the moment with no clear evidence-based guidance. And their heading ["Time to rethink?"] is a confrontation of sorts, because they’re implying that this is a topic doctors don’t want to think about [I would add "don’t want to think about because it doesn’t have any apparent solution"]. And the definition of a confrontation is simple – telling someone something they don’t want to hear.

If you’re not on to my ways, you haven’t figured out that this is the first of several posts [hints: "part one" in the title; this is the last paragraph and I’m not close to an ending]. The take home point for this post is that this is not necessarily a moral problem having to do with the ethical commitment of the doctor. It’s a clinical problem that’s often handled as if it’s acute [as in my scenario], but is actually chronic and needs to be approached as such with the long haul in mind. We obviously need some real data to formulate rational interventions – not quick decisions made in the fog of the moment…
Mickey @ 8:00 PM

still watching…

Posted on Sunday 6 July 2014

It has been eight months since this apology was published in JAMA Psychiatry. After over a decade of Dr. Kupfer self-righteously swatting away accusations that his DSM-5 Task Force was riddled with members who had conflicts of interest, he was forced to acknowledge that he had a whopper of a conflict of his own – a company poised to capitalize on his wished-for "dimensional diagnoses" as a screening device:
by Robert D. Gibbons, PhD, David J.Weiss, PhD, Paul A. Pilkonis, PhD, Ellen Frank, PhD, and David J. Kupfer,MD.
JAMA Psychiatry. Published Online: November 20, 2013. doi:10.1001/jamapsychiatry.2013.3888

To the Editor: We apologize to the editors and readers of JAMA Psychiatry for our failure to fully disclose our financial interests in an article1 that reported a diagnostic tool, the Computerized Adaptive Test for Depression [CAT-DI]. Following acceptance of the paper, we disclosed that “The CAT-DI will ultimately be made available for routine administration, and its development as a commercial product is under consideration.” The company that owns the rights to CAT-DI and several related tests is Psychiatric Assessments, Inc [PAI], which uses the trade name of Adaptive Testing Technologies [ATT] on a website describing these tests. Lead author Robert D. Gibbons, PhD, is the president and founder of PAI,which was incorporated in Delaware in late 2011, then registered to do business in Illinois in January 2012. Dr Gibbons awarded “founder’s shares in PAI” to us, yet all 5 of us failed to report our financial interests in connection with our article and again in a Reply to Letters to the Editor regarding the article. Neither PAI nor ATT has released the CAT-DI test [or any other test] for commercial or professional use, but our ownership interests were relevant to the research article and Reply we submitted and should have been disclosed to the editors. Our submitted disclosure lacked transparency, and we regret our omission.
The APA investigated and said everything was fine. You may or may not have noticed that my letter to the APA and Timeline went unacknowledged [open letter to the APA…]. Since then, we’ve heard little to nothing from Dr. Kupfer, Dr. Gibbons, or their other partners in Adaptive Testing Technologies. This post is just a marker to remind them that we’re still watching…
Mickey @ 8:00 AM

no commercial interruptions…

Posted on Saturday 5 July 2014

Why have I reproduced this entire Perspective piece even though it’s available full text on-line? It’s because it’s in the New England Journal of Medicine – that’s why. I want to emphasize its existence in a top flight American Journal. As much as I’ve appreciated all the play Data Transparency has gotten in Europe, it’s time for some official noise like this on this side of the pond. It has been a long time coming. So here it is [with no commercial interruptions]:
by Kevin Outterson, J.D., LL.M.
New England Journal of Medicine. 2014 371:1-3.

This year promises to be an auspicious period for some long-running battles over the dissemination of biomedical research. Some companies seeking more freedom to promote their products have bristled at recent guidance documents from the Food and Drug Administration [FDA] regarding promotion of drugs and devices for off-label uses, claiming that they violate the First Amendment. Simultaneously, industry is divided over calls for increased transparency of clinical trial results. But as the FDA’s regulatory authority is weakened by First Amendment challenges, the need for clinical trial transparency becomes more urgent.

In the recent guidance documents, the FDA recommended that scientific articles used for off-label promotion be scientifically sound, come from peer-reviewed journals, and be distributed in unabridged form with the approved labeling and a comprehensive bibliography. Clinical practice guidelines used for marketing should be based on a systematic review of the evidence and "be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups." The FDA also recognized the growing importance of social media, describing the situations in which a company is responsible for comments on Facebook and patient advocacy websites focusing on specific diseases and treatments. In early June, the FDA expanded this guidance process to include communications about new risk data for existing drugs. The FDA is concerned that companies might use incomplete new information to weaken the impact of warnings on the approved drug label.

Some companies have complained that these rules overly constrain their marketing practices and impermissibly infringe on commercial speech. These claims find some support in recent cases that have undermined the FDA’s regulatory authority over drug marketing. The First Amendment has emerged as a potent deregulatory weapon for corporations. Governments increasingly face First Amendment challenges to rules related to the marketing of regulated products, not only from the drug industry but also from companies selling tobacco, alcohol, and processed foods. These industries claim that the government violates a core principle of liberty — freedom of speech — by regulating how food, drugs, alcohol, and tobacco are sold. The FDA issued the new guidance documents with these concerns in view.

In recent years, drug companies have paid billions of dollars in fines related to off-label promotion. Whether the First Amendment protects this activity remains an open question. The FDA’s position is nuanced. Under the law, a drug is viewed as "mislabeled" unless "its labeling bears adequate directions for use." The FDA does not require labels to discuss all possible uses, which would be burdensome to the companies, but only those actually intended by the company. One way to prove this intention is to examine company statements about the drug, including promotional activity. Companies can make any truthful and nonmisleading statement about their drugs, but when they choose to speak about any particular use, the label must bear adequate directions for that use. Speech is frequently used to prove elements of other crimes; examples include perjury, premeditated murder, and conspiracy.

Seen in this light, the recent draft guidance documents do not constrain First Amendment values. They provide safe harbors, listing circumstances in which the FDA will not consider actions to be evidence of intent to sell a drug for a particular use. And the guidance is quite lenient: a company can sponsor biomedical research for an off-label use, refuse to submit that research to the FDA for an expanded label, but nevertheless widely distribute reprints of relevant journal articles to physicians and chat about them on Facebook and other social media. The FDA is keeping a respectful distance from the First Amendment, while gentry reinforcing better practices, including peer review and disclosure of conflicts of interest.

If the Supreme Court’s interpretation of the First Amendment continues to constrain FDA influence over the dissemination of research, then even greater importance must be placed on improving research quality and providing the support independent research teams need to reanalyze clinical trial data. Studies have highlighted strategic weaknesses in the research enterprise, including failures in peer review, publication bias, bias introduced by sponsors or investigators, and extensive financial relationships.

Transparency is an important tool for addressing these issues, and many stakeholders are working to improve transparency in biomedical research. The International Committee of Medical Journal Editors has adopted standards to improve the quality of the peer-review process, require registration of clinical trials before patient enrollment, and improve disclosure of conflicts of interest The United States requires advance registration of many clinical trials; since 2007, summary results must also be published. Similar initiatives have been implemented in Europe and beyond, including a global clinical trial registry maintained by the World Health Organization. Advance registration and summary publication are important tools for reducing opportunities for publication bias and making it harder to hide negative studies.

Pressure is now building for two additional data-transparency goals: giving responsible independent researchers access to patient-level data to enable them to replicate studies and perform meta-analyses; and requiring public release of clinical study reports submitted to governments for marketing approval, which have substantial informational value.* Companies have traditionally protected these data as trade secrets,* but maior changes are under way. In the United States, the FDA requested comments in 2013 on a proposal supporting a limited level of transparency for product-masked patient data. Product masking protects the identity of both the drug and the patient, which limits the data’s clinical utility for research. Currently, this effort appears to be on ho!d, awaiting results from a review by the Institute of Medicine. Meanwhile, transparency initiatives by some companies and legislative action in Europe may have reached the tipping point, with momentum growing for transparency that goes well beyond product-masked data.

Limited patient-level data are now being made available to independent researchers. In May 2013, GlaxoSmithKline opened some of its patient-!evel data to responsible researchers, with an independent review pane! acting as the gatekeeper.4 Johnson & Johnson followed suit in January 2014, partnering with a group at Yale. These programs are welcome improvements and should expand across the industry.

I believe that transparency should also extend to the clinical study reports submitted to the FDA and other drug-regulatory authorities. On April 2, 2014, the European Parliament adopted reforms to its rules governing human clinical trials, including a key provision requiring delayed release of clinical study reports submitted to the European Medicines Agency. The next day, AbbVie dropped its lawsuit against the agency, which had sought the release of clinical study reports on two AbbVie drugs. Other litigation remains pending, and the European Union may yet weaken these rules, but these events suggest that disclosure of clinical study reports may soon be the norm in Europe.

In public comments on the European reforms, the drug industry raised objections to the release of clinical study reports. Although companies have no trade-secrecy right to hide safety data on medicines, they make a reasonable point regarding the danger of substantial competitive harm from full transparency. Governments offer non-patent-based incentives for special categories of drugs, such as orphan drugs and biologics. These incentives have frequently rested on data exclusivity, prohibiting other companies from using data for regulatory approval purposes. To the extent that transparency disrupts data-exclusivity incentives and the timing of generic entry, both domestically and internationally, the law will need to be adjusted in order to restore the competitive position of the companies. The alternative is to delay data releases until many years after a drug is approved, but neither the progress of science nor public safety should wait for full transparency. The companies will also retain the full force of patent law to block premature generic entry. If this issue is resolved, the onus will be on the industry to articulate why clinica! study reports should not be immediately released when a drug is approved.

After decades of criticism about bias in the clinical trial enterprise, new norms are being established that promote transparency. Additional transparency is particularly welcome in the United States, since the Supreme Court has increasingly constrained the FDA’s ability to regulate off-label marketing activities. In the deregulatory environment fostered by First Amendment challenges. clinical trial transparency is perhaps the best remaining option for informing physicians and protecting patients.
One Perspective piece in the New England Journal of Medicine doesn’t mean this issue is resolved, but it’s damn sure better than none…
Mickey @ 10:02 PM