2. when n=many

Posted on Thursday 25 August 2011

Dr. Patrick McGorry had convinced the Australian government to fund a $400 M Program – Early Psychosis Prevention and Intervention Centres [EPPIC] which provoked a brisk reaction – a lot of it negative. One of his critics was Dr. Allen Frances, former Chairman of Psychiatry at Duke, and Chair of the DSM-IV committee who has been writing a blog in Psychology Today [DSM5 in Distress] criticizing the closed process of the DSM5 Committee and many of their proposed changes, including the possible addition of the Prodromal Risk Syndrome [Psychosis Risk Syndrome, Attenuated Psychosis Syndrome] to the manual. It was, in fact, this diagnosis that prompted Dr. Frances to speak out against the DSM-5 process in the first place [Psychosis Risk Syndrome: Just As Risky With A New Name]. In March 2011, Dr. Frances wrote a very critical blog post [Australia’s Reckless Experiment In Early Intervention] about the EPPIC Project and Dr. McGorry:
McGorry’s goal is certainly great. But its current achievement is simply impossible and Australia’s plans are patently premature. Early intervention to prevent psychosis requires first that there be an accurate tool to identify who will later become psychotic and who will not. Unfortunately, no such accurate tool exists. The false positive rate in selecting prepsychosis is at least about 60-70% in the very best of hands and may be as high as 90% in general practice. That’s right, folks, nine misidentified non patients for one accurately identified truly prepsychotic patient. Those are totally unacceptable odds.

What are the costs? McGorry does not recommend antipsychotic medications as a routine part of his prevention regimen. But experience teaches us that they will be overused despite having no proven efficacy and posing the risk of massive weight gain [and its consequent array of serious complications]. The false positives will also suffer unnecessary stigma and worry and will undergo unnecessary and misdirected treatment. And surely there are many more productive ways to spend $400 million doing a better job of managing the mental health needs of those who have real and treatable psychiatric disorders.

Unfortunately, McGorry is a false prophet who’s visions are offered at least a few decades before their time. Australia, led astray by his impractical hopes, is about to embark on a vast and untried public health experiment that will almost surely cause more harm to its children than it prevents. Before embarking on this headlong and reckless rush, the following research steps need to be accomplished:

    1. Developing a proven and reliable definition of "Psychosis Risk"
    2. Learning how to use it in a way that reduces current outrageously high false positive rates to levels that are tolerable.
    3. Demonstrating that the interventions chosen are indeed effective in preventing psychosis.
    4. Determining the likely rate of antipsychotic use and how this influences the overall risk/benefit balance sheet of early intervention.
    5. Studying the beneficial and harmful impacts of early diagnosis on stigma and self perception.
    6. Comparing the marginal utility of a dollar spent trying to prevent an alleged future disorder vs a dollar spent treating an already clearly established one.
This is a research enterprise that will take many groups around the world many decades to complete. But it is an absolutely necessary precondition before spending $400 million on what is likely to be a failure. The Australian experiment will be flying blind on an airplane that is not at all ready to leave the ground. Doing prevention prematurely and poorly will give a good idea an unnecessary bad name. McGorry’s intentions are clearly noble, but so were Don Quixote’s.
Dr. McGorry had actually submitted a Clinical Trial to the Australian New Zealand Clinical Trials Registry in 2010, planning to study antipsychotic treatment of his Ultra-High-Risk [for psychosis] group:
To investigate the effect of quetiapine, in addition to CBCM (cognitive behavioural case management) on the incidence of first episode psychosis… The primary outcome variable is the rate of transition to psychotic disorder in the two treatment groups at 6 months post study entry.
This was to be an AstraZeneca-funded drug trial of Seroquel, used not to treat psychosis, but to prevent it. Previous trials with Risperdal and Zyprexa in this group haven’t been promising [or remain unreported]. In the Preventive Medicine terms from the last post, this would be a trial aiming at Primary Prevention.

Getting confused? Don’t be alarmed. It is confusing. This story mirrors the whole tangle of modern psychiatry, not just a piece of the puzzle. It involves fundamental things, like for example our diagnostic system which is controlled by expert opinion from behind closed doors. In this case, a research category is being considered for premature elevation to a "disorder." The story includes the pharmaceutical industry financing a clinical trial of major medication in an unproven preventive strategy in a symptom complex that may sometimes predict a disease of unknown etiology. Like TMAP, it’s murkily connected to a massive government program of questionable value [at least, uproven value] promoted by a charismatic key opinion leader. Solid science drifts in and out of this story, but more like wind blowing through open windows than mortar in the foundation. The whole narrative might have a few really good questions, but they seem overwhelmed by the noisiness of speculative answers and expensive programs.

As this story progressed, many things happened: Dr. Frances continued to complain about McGorry’s  EPPIC program [Continuing Controversy On Australia’s Mental Health Experiment], as did a number of blogging sites [Psychiatrist Patrick McGorry Slams His Critics [Diddums], US expert slams Patrick McGorry’s psychosis model] and reports in the Australian Press [McGorry accused of conflict of interest]. Many of those complaints were about the "drugging" of children, but some questioed the whole enterprise. The next definitive thing was a letter from a group of concerned scientists a month ago [McGorry Letter] protesting the Seroquel Clinical Trial and asking for an investigation along ethical grounds. It’s a strong letter. Their summary:

    In summary, the NEURAPRO-Q trial will use the atypical antipsychotic quetiapine, which has well documented harms, for ‘treatment’ of people at high risk of psychosis, despite evidence of the ineffectiveness of antipsychotics for this purpose (misrepresented in the trial description), and despite much more promising evidence for a safer alternative treatment, omega-3 fatty acids. Furthermore, in the absence of a predictive marker for psychosis, the high false positive rate means that most of the people treated with quetiapine would not have become psychotic in the absence of treatment. Not only is the use of atypical antipsychotics such as quetiapine potentially dangerous, it is also costly, and its use is at the expense of other interventions that on the current evidence are both safer and more effective.

    In addition, the timeframe of the trial is too short to adequately assess the primary outcome, incidence of first episode psychosis, and too short for some of the adverse effects to emerge and/or peak. Furthermore, because quetiapine suppresses symptoms of psychosis, and it will be administered throughout the six-month trial, the trial will not be able to detect the emergence of many cases of emergent psychosis in the quetiapine group, which will strongly bias the results in favour of quetiapine. There is a strongly arguable case that this poorly designed trial represents a valuable marketing strategy for AstraZeneca, the manufacturer of quetiapine and the sponsor of the trial. We note that AstraZeneca has not provided support for a comparative study of essential fatty acids [the NEURAPRO-E trial]. There is a danger that this short duration trial may be used to justify the prescription of quetiapine to individuals who are not psychotic, for more extended periods, with the risk of serious harms such as weight gain and diabetes. This cannot be justified when there is evidence that safer and more effective treatments may be available. The main benefit would accrue to AstraZeneca in expanding the market for their drug; the harms would be borne not only by trial participants, but also by a much larger number of people prescribed quetiapine for a broad spectrum of symptoms.

    On the basis of these serious ethical and methodological problems, we request that the NEURAPRO-Q trial be denied ethical approval. The claimed benefits do not stand up to analysis, but the risks are considerable. Therefore, the trial does not meet the NHMRC ethical guidelines in relation to an appropriate balance between potential risks and benefits and it should not proceed.

So there have been complaints at several levels – the clinical trial of Seroquel [above], the massive funding of such a large program based on hypotheses that are enthusiastically presented but are largely unproven, and questions about the program itself [other than medications]. I’ll have to play dumb on this last point. The EPPIC web site is "epic" in and of itself – filled with initialed subprograms [C.O.P.E., S.T.O.P.P., etc.]. They call their intervention "Cognitive Behavioral Case Management" and there are training manuals and videos that explain what that is. While I’m curious about it, it’ll have to wait for a more thorough look [because it’s sure not apparent at first glance]. And then there’s the question of Dr. McGorry’s influential support to the addition of this category to the DSM-5 Manual.

Before proceeding with this narrative, I’d like to react a bit. This is the centennial of the publication of Eugen Bleuler’s Dementia Praecox or the Group of Schizophrenias, a classic in a time of classics. This whole idea of a pre-schizophrenic personality type was his – a grouping he called the Schizoid Personality. While not in vogue right now, psychoanalysts and others have long studied this particular group of people – and it is anything but a uniform grouping. Bleuler pointed that out 100 years ago. Dr. McGorry reports that he can parse among this group those more likely headed for psychosis by including other criteria that define an "Ultra High Risk" group. That would be a significant advance in what we’ve known. It’s exciting to imagine that such early detection might at some point give us an opportunity to alter the course of this potentially devastating manifest illness. It might even offer new clues to the nature or even cause of Schizophrenia. But that’s as far as I can get with this story. After that, I find myself getting that "here we go again" feeling that has plagued psychiatry throughout its history – the race to treatment. We don’t even have a satisfying treatment for Schizophrenia when we know a person has the disorder. While much maligned, the antipsychotics are effective with certain psychotic symptoms, and when used carefully, have moved many of these patients from the chronically institutionalized to those living among us with variable levels of adaptation. In chronic cases, most would agree that the case management model has been effective tool – using case managers who have a "knack" and intuition for the difficulties that the afflicted encounter in life. But I don’t know of a proven cognitive-behavioral approach that’s generally effective in any kind of Schizophrenia. In fact, the idea that preventing, supressing, or prolonging the onset of the first psychotic break might change the course of things is speculative. It sounds good, but it’s at best a hypothesis only. So Dr. McGorry may be a little beyond Bleuler’s starting gate, but I agree with Dr. Francis – it feels like he’s broken into a full gallop way too early in this race.

In case you don’t already know how this is playing out, I’ll get there soon…
    Evelyn Pringle
    August 25, 2011 | 8:50 PM

    I continue to be amazed every time I see Allen Frances quoted as the great protector against the over prescribing of atypical antipsychotics, being we now know he was a on J&J’s payroll and was the original creator of the template for TMAP, the off-label marketing scheme that led to the rampant over prescribing of the drugs all over this country to begin with. That’s in addition to being chairman of the DSM-IV that he admits led to the massive increase in the misdiagnosis of bipolar disorder and the epidemic in prescribing of the drugs for it.

    Also, why isn’t Frances, or anybody else, reporting on the Robert Wood Johnson Foundation funded programs in the US that are definitely drugging children as young as 12, who have never been psychotic? J&J’s been feeding Risperdal to kids via the PIER program for about a decade. In 2010, the NIMH was offering grants for similar programs by listing it as an example of the kind of “evidence-based” program that would qualify for a grant.

    I have nothing but disgust for all the paid quacks identified as being involved in these drug peddling schemes, but quite frankly I don’t understand why McGorry isn’t hammering Frances on these points.

    In fact, considering how long this tale has dragged on all over the internet and how many stories are filled with the quotes of Saint Frances, I find it very strange that he hasn’t by now. I really don’t know what to make of it.

Sorry, the comment form is closed at this time.