3. when n=many

Posted on Thursday 25 August 2011

McGorry aborts teen drug trial
Sydney Morning Herald
by Jill Stark
August 21, 2011

THE FORMER Australian of the year Patrick McGorry has aborted a controversial trial of anti-psychotic drugs on children as young as 15 who are ”at risk” of psychosis, amid complaints the study was unethical. The Sun-Herald can reveal 13 international health experts lodged a formal complaint calling for the trial not to go ahead. They were concerned children who had not yet been diagnosed with a psychotic illness would be unnecessarily given drugs with potentially dangerous side effects.

Quetiapine, sold as Seroquel, has been linked to weight gain and its manufacturer AstraZeneca, which was to fund the trial, last month paid US$647 million [$622 million] to settle a lawsuit in the US, alleging there was insufficient warning the drug may cause diabetes. Professor McGorry, one of the Prime Minister’s key mental health advisers, planned the trial at Orygen Youth Health in Melbourne, listing it on the Australian New Zealand Clinical Trials Registry last March. It was to investigate whether the drug would decrease or delay the risk of people aged between 15 and 40 with early signs of mental illness, developing a psychotic disorder such as schizophrenia.

Last month, psychiatrists, psychologists and researchers from Australia, New Zealand, Canada, Britain and the US lodged a complaint with the ethics committee of Melbourne Health, the umbrella service which includes Orygen. They argued there was little evidence the onset of psychosis can be prevented and it was potentially dangerous to use anti-psychotics on those who merely had risk factors such as a family history or deterioration in mental health, with evidence showing up to 80 per cent will never develop a disorder.

Professor McGorry insists the decision to scrap the trial was made in June and is unrelated to the complaint, which he said he was only alerted to just over a week ago. He said Orygen had to choose between the drug trial or pursuing another trial using fish oil – which had proven useful as an early intervention treatment for schizophrenia in a smaller study. It opted for fish oil because it had less potential for side effects. Melbourne Health’s research ethics committee will still consider the complaint in September.

The Sun-Herald recently revealed a growing backlash against the government’s mental health reforms, with Professor McGorry’s peers claiming his youth early intervention model had been "massively oversold"…
Seven Questions For Professor Patrick McGorry
Psychiatry cannot promise more than it can deliver
Psychology Today

by Allen Frances M.D.
August 18, 2011

The great news is that Professor McGorry has recently renounced the relevance of psychosis risk syndrome in the current practice of clinical psychiatry. He has done so in two separate and dramatic ways: 1: by withdrawing his support for the inclusion of psychosis risk in DSM 5; and 2: by promising not to include it as a target in Australia’s massive new experiment in early intervention. Psychosis risk syndrome is an extremely promising topic for ongoing research, but it is not nearly ready for current clinical application and if introduced prematurely could cause disastrous unintended consequences…

But a dark cloud surrounds the silver lining of having one psychiatrist in a position of almost unopposed influence. Professor McGorry has developed the messianic blind spot that is so common in visionary prophets. His zeal has made him an unreliable evaluator of scientific evidence, allowing him to defend absolutely indefensible positions with the convincing, but inaccurate, force of a true believer…

Below are seven questions that beg for Dr McGorry’s immediate public response. No evasion or questioning of my motivation is called for- just straight answers to simple questions. It will be useful for Professor McGorry to respond for the record now, before Australia’s makes final the terms of its much needed and awaited investment in mental health.
    Question 1: Please spell out on what scientific basis you have dismissed the findings of the Cochrane report and indicate why Australia should base policy decisions on your personal interpretation of these data rather than on Cochrane’s more objective and systematic approach
    Question 2: What will be your role in establishing the goals and in directing the implementation of Australia’s early intervention programs and what protections are in place to ensure that opposing voices and interpretations get a fair hearing? Who else will be involved in the governance of these programs and how will they be selected?’
    Question 3: Can you now state with certainty that the newly funded early psychosis intervention programs will be restricted exclusively to those who are already diagnosed with definite psychosis and will definitely not include individuals deemed to be only at some increased risk for future psychosis?
    Question 4: Do you now agree that it is inappropriate to prescribe antipsychotic medication for psychosis risk except under the close supervision of an approved research protocol?
    Question 5: What protections will be in place to avoid the premature and incorrect differential diagnosis of psychosis? The distinction between prepsychotic and psychotic is much clearer on paper than in practice and psychotic symptoms in teenagers are often transient, caused by substance abuse or mood disorder. Will strict diagnostic requirements, careful differential diagnosis, and quality control guard against incorrect, premature, and stigmatizing diagnoses and also against unnecessary and potentially harmful treatments?
    Question 6: Why not roll out the EPPIC programs in gradual steps? This would ensure that the model translates well from the research environment to day to day practice and would provide an opportunity to demonstrate its efficacy and cost effectiveness before disproportionate investments are made in it.
    Question 7: How do you justify the funding shortfalls for other necessary continuity of care programs that will likely be caused by the front ending of expenditures for EPPIC [especially given lack of convincing evidence that EPPIC confers enduring benefits or any reduction in future need for, or cost of, services]? Is it worth staking such a large proportion of the mental health budget on such an uncertain roll of the dice?
His track record makes clear that Professor McGorry can not be relied upon as a neutral reviewer of scientific evidence or a neutral advisor on the question of which mental health investments will bring to Australians the highest and safest returns. His countrymen should be very grateful to Professor McGorry for having obtained desperately needed funding for mental health, but should also be cautious in following his lead in determining how to best to allocate it. The mental health situation in Australia is without historic precedent. Never before has the future direction of an entire country’s mental health program depended almost solely on the unopposed opinions and actions of one charismatic psychiatrist and his band of loyal followers. His inordinate power places a huge responsibility on Professor McGorry to exercise responsible and responsive leadership. Direct answers to the questions raised above are needed to ensure that public policy will follow the scientific evidence and not be unduly influenced by the blinkered zeal of one man, however well meaning and highly respected he may be.
So Dr. McGorry backed down on his Seroquel trial. That was a good decision. And it remains to be seen what will come of EPPIC, Australia’s grand plan for early intervention in Schizophrenia. In the full version of his commentary, Dr. Frances talks about Dr. McGorry’s ad hominem responses to his critics along the way. I have nothing much to add to Dr. Frances’ excellent comments on future directions – his questions are sound. I wish Dr. Frances had expressed a similar wisdom back when he was in the "guidelines" business a decade ago [detestable…, gpp?…, a long awaited corner…, a connection…]. Likewise, at this point, I have nothing to say about whether Dr. McGorry belongs in the category of shady characters like Drs. Nemeroff, Schatzberg, and Biederman, or if he’s simply on a misguided path – falling prey to the shoals of therapeutic zeal. I just don’t know enough yet to speculate on that point, but I expect this story is far from over and we’ll know more in due time.

This particular story has an uncanny déjà vu feel to me. I came into psychiatry on the waning cusp of two paradigms – psychoanalysis and the community mental health movement. Both have survived, but have been eclipsed in the intervening years by the emphasis on psychopharmacology and neuroscience. At the time I started, the rhetoric of community health was alive and strong. Institutionalization of mental patients was detrimental. They needed to be treated in the community with an army of mental health workers and social support staff. The old hospitals were emptying [closing]. Hospitals were for short term stabilization only. While the rhetoric was put in terms of a social reform movement, the motor driving it was the coming of the neuroleptic medication – the antipsychotics – which made the change a possibility. By the time I arrived, the funding and the availability of even acute beds had fallen below the critical point, and we struggled to maintain chronic patients with limited staff and ever-falling resources. That struggle is ongoing. The "street people" [chronic mental patients] were beginning to appear in our cities on the streets and living under bridges.

When I read that the coming of the neuroleptics  in the late 1950s heralded the dawn of a new age of neuroscience and psychopharmacology, I recall to other side of that coin as the director of a public crisis intervention service with a community support team overwhelmed by the task at hand. So I’ve always found that time being touted as the beginning of a golden age to be a dramatic rewriting of the history as I saw it on the streets of Atlanta Georgia. The neuroleptics may have been the driver, but they weren’t holding things in the road. And the side effects of the drugs were as apparent on Peachtree Street as they were in the Halls of Grady Hospital. That experience undoubtedly colors how I hear the story of Dr. McGorry’s EPPIC program and its massive government funding. Back then, the watchword was Preventive Medicine too – rapid treatment [Secondary Prevention] and Community Services that prevented deterioration [Tertiary Prevention]. The Community Mental Health Movement was easy to sell when it was young with high hopes for the future, but moved to the ranks of an albatross when it came to long term funding. So now, some places have somewhat functioning versions – but most don’t. Governments, like the most dedicated of Mental Health Professionals, burn out when success is measured by slowing the rate of decline rather than something like cure or at least regular improvement.

But there’s one point in this story that is undebatable from my perspective. It’s typified by the oft-used NIMH phrase "Translational Science."  It refers to the push to move research findings quickly from the "bench to the bedside." There’s nothing wrong with the idea itself. Of course we’d want effective medical discovery made available to patients quickly – provided its safety and efficacy is assured. But I’m afraid that it has all too often been used when a better term would be "the race to market." With appropriate warnings and safeguards, all of the neo-psychiatric drugs have a place in our armamentarium of therapeutic tools [neuroleptics, SSRIs, mood stabilizers, even atypical antipsychotics]. But that is certainly a much smaller place than in current practice, with a lot more monitoring for true efficacy, and a great deal more attention to the toxicity of the drugs – particularly long term. Even if Dr. McGorry does assure us that his program is not a conduit for medicating people with toxic drugs on the 30% chance that they might develop an illness that the medication might help, his plan still only reaches the level of a "pilot project," not a national mental health initiative. He’s coming off the bench way too fast.

If you read my earlier n=1 musings, you probably guessed that I actually don’t think he’s on the right track. My opinion rises no higher than just that, an opinion, but it’s actually based on a lot more ns than just the single case I mentioned. It’s based on ten years in the trenches of the chronic care of Schizophrenic patients during the nova of the Community Health Movement. In my view, psychosis is a cataclysmic complication of what we call Schizophrenia, but there’s a more basic problem in processing internal and external experience that antedates the first psychotic episode, even the trema, and is untouched by antipsychotic medication. Active psychosis isn’t good for people sure enough, and warrants prompt attention, but I don’t think psychosis is the only long term problem and I doubt that premedication will make a difference. I’d like to see Dr. McGorry and his EPPIC Project focus some attention on further refining our understanding of that underlying process in his "Ultra High Risk" group by looking carefully at how the patients who don’t develop psychosis and the ones that do differ. And in his ongoing treatment of the psychotic patients, I’d like to see him hone in systematically on what actually helps and what doesn’t – what "treatment" means. We’re still not sure about that. Schizophrenia is at the same time one of the most fascinating and the most tragic of human fates and it deserves all the attention we can give it, but Schizophrenic people have historically done their time as experimental subjects. Such programs need to be well thought out, genuinely "evidence-based," and move in careful baby steps

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