Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Archive for November 2012

Access to RxISK Data: Conflicts of Interest

Won’t get fooled again outlined a stunning propaganda coup by GSK. On the back of a campaign for open access to clinical trial data that has drawn its inspiration from efforts by the Cochrane Tamiflu reviewers to get access to Roche’s clinical trial data, Andrew Witty came out and proclaimed that GSK were all in favor of access to clinical trial data. The BMJ threw its hat in the air and said whoopee.

In fact GSK had only issued a press release. They don’t have a policy. They have at best an aspiration or perhaps more ominously a strategy. Getting such great publicity out of a press release shows considerable tactical skills at the very least.

The GSK press release came a week before a key European Medicines’ Agency meeting on access to clinical trial data. It was aimed at shutting an open door – EMA have granted access, industry want to close it down. Industry representatives at the EMA Access to Data meeting on November 22nd sang from the same song sheet as GSK – of course we are in favor of access and transparency but we have to respect patient privacy and we have to have good governance. Access should be restricted to serious scientists. (These are red herrings – see the next post Access to data: privacy issues).

RxISK has data that GSK should want

At the end of Won’t get fooled again, I said the post had been written against the background of a serious undeclared conflict of interest. Since then, coincidentally probably, I’ve been critiqued by Arthur Schafer on Biojest for an overly casual approach to conflict of interest. This makes it of even greater importance to spell out the conflict (see Medical Partisans).

Here it is. We on Rxisk.org have data GSK should want, should need. We have raised the issue of accessing the data with them. They don’t seem to want access. They do not seem keen to have the issue raised. Interests seem to be conflicting.

Data on hazards – the key to good medical care

So let’s back up a minute. The campaign for access to clinical trial data is about getting a proper picture of the effects of a drug, both the possible therapeutic effects and the hazards. Restricting access is in fact more about restricting access to information about the hazards than about the relative inefficacy of treatment.

Clinical trials are not the correct way to establish the hazards of a drug – the diseases in which they are conducted commonly mask the hazards of treatment (The Spin that no Data can Overcome, Cri de CoeurOnce is Never, The Unbearable Lightness of Being.)

The best approach to hazards is to do what RxISK is trying to do. That is harness the real world experience of people taking a medication to get best quality descriptions of events as well as applying standard approaches to causality such as checking for dose response, challenge-dechallenge-rechallenge and other related methods. The best way to determine risk-benefit ratios is to ask doctors and patients what they think of the possible trade-offs between the effects of a drug – as RxISK asks but clinical trials don’t. We get both doctors and patients to look at the wider impact of an event in a person’s life in addition to reporting on just the event.

There is an industry out there almost it seems aimed at ensuring that we get the most degraded possible descriptions of events with no accompanying details (American Woman, American Woman 2). An industry that has succeeded in building a culture in which even good descriptions of the effects of drugs are dismissed as anecdotes – except of course for patients reporting stunning benefits on treatment. Those who unwittingly repeat the mantra of RCTs offering gold standard evidence on the effects of drugs play straight into industry’s hand in this regard. Words come before numbers – without the right words, the numbers are meaningless.

Andrew Witty eavesdropping on the train

The second consideration is this. If Andrew Witty was to take a train tomorrow and I was sitting in the seat behind him and he overheard me mention a side effect I was having on one of GSK’s drugs he is legally bound to report this to the regulator. Here is Leigh Thompson then the Chief Scientific Officer of Eli Lilly being deposed by Paul Smith on this issue in 1994 for the Fentress trial in Louisville Kentucky after Joseph Wesbecker, shortly after going on Prozac, had shot dead 8 of his co-workers and seriously injured 12 more before killing himself.

Q. The other day you said something that I have a question about. You said something about… employees calling adverse event reports in?

A. I can’t recall that. The rules under the DEN system that I put in place, I think it was ’83 or maybe ’84 — no, it was ’83 we began it, was that any Lilly employee anywhere in the world that learns of any adverse event through any source, and I’ve done it from cocktail parties
and overhearing conversations, should in fact report by telecommunications to DEN within
twenty-four or seventy-two hours, depending on where they are in the world. So, yes, we got a lot of adverse events, including ones I report because I’ve literally called up DEN and said, you know, that I overheard a conversation in the hallway just now that somebody’s wife was taking Ceclor and had an allergic reaction.

Q. Do you usually stop and ask for more information about that adverse event or do you just report what you overheard in a conversation in the hallway?

A. Depending on who the individual is, but, for example, you remember you showed me the document about that meeting of the expert opinion leaders that I had gone to wherever it was, I had another Lilly employee come to that meeting and follow me around so that that
person could in fact report all the adverse events that I was hearing, so that I wouldn’t have to do it myself.

A. I think it fulfills a regulatory requirement… if you right now told me that you had heard of a patient who had taken one of our drugs and who had their hair turn blue, I will guarantee you that I would call DEN up within two days and that would be in the DEN database. And I may or may not ask you for more information, but I would identify you.

Q. What if their hair turned loose?

A. You’re the lawyer, but if you read the law and the regulations, I think that’s exactly what it requires. The NDA, for example, requires all information…

Q. So let me make sure I understand. You feel it is your absolute duty to report a conversation that you have overheard in the hallway, but you don’t necessarily feel it’s your duty to report an issue raised by another regulatory agency and the analyses that were done
by the drug company in response to that issue being raised?

A. Under the FDA laws and regulations, I think you’ve stated it correctly.

Writing to GSK about access to data

Against this background it seemed appropriate to alert Andrew Witty last March to the fact that we expected RxISK to start generating data on GSK’s and other drugs – mentioning that despite everything many still considered GSK to be among the more responsible pharmaceutical companies. GSK’s response was to misattribute the remark that they were a responsible company to me and to thank me for this recognition, but to turn down a possible collaboration while in a follow up letter stating their full commitment to their regulatory obligations.

The growing data set

It is now November and RxISK.org has been up and functioning for two months. It is getting on average 10 treatment effects reported per day directly from the public. In two months it has had more patients report effects to it than the Irish Medicine’s Board has had since opening up for patient adverse event reporting in 2009. RxISK has had more treatment effects reported to it by Germans than Germany has ever had – reporting by the public is still not facilitated in Germany. Within a year we expect to have more treatment effect reports from the public than anyone except FDA.

RxISK & free appetizers?

FDA have 4.1 million adverse event reports from around the world collected since 2004. A number of companies have set up businesses, selling these reports to doctors, patients or anyone else for $200 for basic information on a drug and a possible problem linked to it – we make this information available for free to anyone who accesses RxISK.

We are on our way to having a substantial amount of RxISK data. We will make the key components of this available for free from the get-go. We are particularly keen not just to give people the number of reports of Leigh Thompson’s side effect – Hair turning blue on Prozac – but want to make the data local in the belief that if people in Baltimore, Brisbane, Birmingham or Bordeaux find its happening there and not in Calgary, Cologne, Chicago or Chenai, they may be able to bring local knowledge to bear on the issue and help work out what is going on.

We also want to bring the stories to life so that people can identify their own stories with those of others. These collected stories can help us all understanding the real story about these drugs. We think everyone can play a part in understanding and interpreting the stories – that access should not be restricted to just a few people who want to “guide” the narrative.

Leigh Thompson is now dead. But from his testimony above it seems like he would probably have been delighted to know we have a Hair Zone opening up soon, to complement the Violence and Suicide Zones already on RxISK, and the Skin and Sex and Relationships Zones still to come.

But then again maybe not. There are endless ways to adhere to the letter of a regulation but not its spirit. This is why you hire lawyers. Or perhaps GSK thought we were at the press release before the policy stage. Or perhaps they don’t have a policy on access to data yet.

How does RxISK move forward?

The issues for anyone reading this blog from Arthur Schafer to Andrew Witty, to Aetna Insurance, to lawyers like Andy Vickery, to Anne-Marie and all the people who have reported on RxISK stories and our still anonymous American Woman are:

  • what interests conflict,
  • where exactly do the conflicts arise, and
  • what should RxISK be doing with its data?

We welcome your ideas and will respond.

Won’t Get Fooled Again? GlaxoSmithKline and Access to Data

On November 22nd the European Medicines’ Agency (EMA) is holding a workshop on access to the data from clinical trials.

While there have been many efforts by many people over the years to make the clinical trial process more transparent, the EMA workshop has come about primarily following the efforts of Peter Goetsche of the Danish Cochrane Group and Peter Doshi and Tom Jefferson from another Cochrane group.

Peter Goetsche

In 2007, Goetsche began the ball rolling by asking EMA to provide access to study reports on the weight loss drugs rimonabant and sibutramine – both since withdrawn because of suicide risks among other issues. EMA refused citing commercial confidentiality. Goetsche argued EMA were in breach of EU treaties. He appealed to Nikiforous Diamandouros, the European Ombudsman, and also applied to the Danish Medicine’s Agency for comparable data. In August 2009, he got some of the data from the Danish Agency. Diamandouros then required the EMA to provide access to all the data, and in February 2011 the data finally came. Goetsche wrote up the saga and has made the entire correspondence available online.

Peter Doshi & Tom Jefferson

The other driving force came from Peter Doshi and Tom Jefferson’s efforts to conduct a Cochrane review on Roche’s antiviral for influenza – Tamiflu. With recent scares about Avian and later Swine Flu, and other potential pandemics, governments around the world stockpiled billions of dollars worth of this under the impression it saved lives by reducing transmission, kept people out of hospital and got them back to work faster. The first publications from Doshi and Jefferson’s efforts to review the evidence began to appear in 2009 in the BMJ. Doshi and Jefferson asked Roche for access to the data – they agreed – but never delivered. They have since told the story in many places (Op-Ed New York Times), outlining the billions of dollars lack of access has cost us. The BMJ have picked the issue up as the most clear cut case on which to campaign for data access. Roche’s resistance have been a gift that keeps giving for those in favor of data access.

Andrew Witty?

Meanwhile GlaxoSmithKline have been winning kudos after their CEO Andrew Witty promised to make the data from their clinical trials available. This offer has been welcomed glowingly by the BMJ, who civilly steered clear of mentioning the fraud action for withholding trial data that led to a $3 Billion fine for GSK.

Over a decade ago before merging with SmithKline, Glaxo-Wellcome made a comparable offer of transparency. Perhaps good Glaxo has got the upperhand on the more worldly SmithKline – lawyers sometimes put GSK’s aberrations down to legacy issues. But there are wrinkles – this is not unfettered access. A panel set up by the company will vet applications to access the data. The BMJ slid over this.

Maybe good Glaxo has got the upper hand but perhaps the BMJ should have resisted the temptation to gush. Even if they were just being civil, the gush factor will lead many who don’t understand the way the “English” read between lines to think that industry have undergone a Damascene conversion. GSK’s “gift” is a far more effective form of resistance than Roche’s.

Robert Gibbons?

The best way to explain what GSK may be up to is perhaps to repeat the wonderful story of Robert Gibbons – modest hero.

On May 1 this year, The Scientist ran an article, Data Diving, on the benefits of data access. It said what every article on this subject says – in the presence of full and unfettered access to scientific data the truth will out, while without access, companies can claim their trials show whatever the company wants them to show, get to charge whatever they want for their products and can hide what they know about any harms.

Data Diving opens with the struggles of Doshi, Jefferson and colleagues to get access to the data on Roche’s Tamiflu. It then portrays Robert Gibbons as a member of the same club as Goetsche, Doshi and Jefferson, a pioneer in favor of unfettered access to data, who with access to patient level data denied to others has been able to turn myths on their head.

The truth is infinitely more intriguing. Gibbons, a professor at the University of Illinois and regular expert witness for pharmaceutical companies, published two articles in Archives of General Psychiatry in early 2012 claiming that patient level data from trials of Lilly’s Prozac and Wyeth’s Effexor (see Coincidence a fine thing & May Fool’s Day) showed that in contrast to media hype antidepressants in fact work very well and don’t cause suicide. It was, it turns out, lack of access to the data that led us to these mistaken beliefs. Companies don’t engage in conspiracies, they are masters of the cock-up, and if given a choice of feet to shoot themselves in will opt for both feet. It needs independent academics like Robert Gibbons to wade in and put a stop to their self-injurious behavior, and show the world how good these drugs truly are.

Fooling the journals

The writers of The Scientist, the Lancet and BMJ were fooled by superficial similarities into classifying the Fool’s Gold of Gibbons with the real gold of Goetsche, Doshi and Jefferson. They managed this despite the fact that very few articles in recent years in the psychiatric or any other literature have received such withering critique as Gibbons’ articles – see boringoldman, and madinamerica by Bob Whitaker. Medscape, National Public Radio, the Los Angeles Times and other outlets from Canada to Australia gave Gibbons airtime and print space in what at one point looked to me like a campaign to roll back the Black Box warnings of suicidality on antidepressants.

Gibbons in fact didn’t have access to anything the original authors of the Prozac papers hadn’t already had access to. The original authors were all Lilly personnel with presumably even fuller access than Gibbons was later given. Gibbons also managed to steer clear of other data in the public domain that could be readily accessed that show incontrovertibly that Prozac and Effexor can not only trigger suicide but that the clinical trial data shows that on balance there are more lives lost on these drugs than saved.

Perverting science

By ignoring relevant accessible data in favor of data no-one else can access, Gibbons has turned the standard access to data argument on its head and made access to data that comes through companies a potential liability for all of us. It’s hard to call the Gibbons version of data access anything less than a perversion.

Last May (May Fool’s Day) I joked that the only explanation for The Scientist getting things so badly wrong seemed to be that they were trying to perpetrate a hoax. The best response of course was to carry on in joke mode and in this vein I suggested Dr. Gibbons should be invited to chair an interview panel to recruit academics to whom companies would be prepared to make data available in the manner Lilly and Wyeth had done.

The joke has turned extremely black. This is almost exactly the mechanism Andrew Witty has just proposed for GSK’s data – to warm applause from the BMJ.

Perverting journals

What happened next in the Gibbons story is a cautionary tale. Several sets of academics – Glen Spielman and colleagues, Barney Carroll, Mickey Nardo, and Matthew Miller and colleagues all wrote to Archives pointing out the lethal flaws in the Gibbons papers that ranged from inappropriate data inclusion to incompetent mathematical calculations to biased interpretations. Letters like this would once have been published in a good journal – science depends on robust debate about the data shows. Without debate of this kind error is propagated and the self-correcting function of science is disabled.

But Archives refused to print. They offered to consign the letters to an online limbo where they would be untraceable for anyone interested to chase the issues.

Why publish when on the face of it, Gibbons was claiming access to data that his critics didn’t have? Science does not depend on publishing the rants of people who are unhappy about something but have not analyzed the data. From an editor’s point of view allowing letters that were not based on the data seems to be tackling the man rather than the issue.

But in a bizarre twist six months later Glen Spielmans got a voice mail from someone named Debbie at the behest of the Archives editor (J Coyle) stating “Dr. Coyle has sent you an accept letter for your letter regarding the Gibbons papers…”. Why?

The plot to capture data access?

So what’s going on? Are GSK making an offer aimed at frustrating the EMA process? Offering to give access to their data through an academic body is the kind of move that would appeal to politicians and might lead them to step back from granting the kind of unfettered access to the data that EMA have been offering in recent months. For politicians, what’s not to like about the GSK offer? It would come wrapped in company commitments to ensure good research governance, panels of experts, and boxes to tick. And joy of joys it would produce a succession of Robert Gibbons rather than the Tom Jeffersons, who embarrass governments as well as companies.

The long march

Before asking the tantalizing question as to why Archives suddenly backed down, there’s a twist to the Gibbons’ Legacy to explore.

In June 2009, Gibbons had chaired an Institute of Medicine public workshop that brought together experts from industry, academia, government, and advocacy groups to discuss the issue of managing perceptions of suicidality on psychotropic drugs. The participants were asked to examine and discuss currently available data, data analysis, and the future of potential partnerships in the area of clinical trials involving the nervous system.

The Planning committee included

WILLIAM POTTER (Co-chair), Merck Research Laboratories, an NIMH based defender of Prozac in 1991 who soon after joined Lilly
ROBERT GIBBONS (Co-chair), University of Illinois at Chicago
CHARLES BEASLEY, JR., Eli Lilly and Company
DAVID BRENT, University of Pittsburgh School of Medicine – an outspoken critic of the Black Box.
YEATES CONWELL, U of Rochester School of Medicine – colleague of Eric Caine below, networked to Tom Laughren
WALTER KOROSHETZ, Nat Inst of Neurological Disorders & Stroke
THOMAS LAUGHREN, Food and Drug Administration – the FDA official who likely has hidden evidence of harm over a longer period than any other
HUSSEINI MANJI, Johnson & Johnson Pharmaceutical
DAVID MICHELSON, Merck & Co.
ATUL PANDE, GlaxoSmithKline, Inc.
PHILIP WANG, National Institutes of Health – expert witness for GSK and voter against the Black Box Warning

This was billed as a consensus conference. Consensus conferences are supposed to bring proponents of differing viewpoints together in an attempt to find common ground but it would be close to impossible to have found differences between these participants before the meeting began. Calling this a consensus conference is a wonderful irony.

The project was supported by the National Academy of Sciences, the National Science Foundation, the Alzheimer’s Association, Astra-Zeneca, CeNeRx Biopharma, the Department of Health and Human Services, National Institutes of Health (including the Nat Inst on Aging, Nat Inst on Alcohol Abuse and Alcoholism, Nat Inst on Drug Abuse, Nat Eye Inst, the NIH Blueprint for Neuroscience Research, NIMH, Nat Inst of Neurological Disorders & Stroke), Eli Lilly, GE Healthcare, GSK, Johnson & Johnson, Merck Research Laboratories, the Society for Neuroscience and Wyeth. So it was clearly very important to a lot of people.

At it Gibbons recommended examining the item-3 of the weekly Hamilton Depression Rating Scale, the suicide item, and the degree of suicidal ideation and planning according to four levels of severity— plus overall Hamilton weekly ratings to determine treatment responsiveness and suicide attempts. He and Charles Beasley of Eli Lilly, he said, were conducting a reanalysis of the RCT data to determine whether this approach improves suicidal ideation as a predictor of suicidality. This he suggested was better than the approach taken by FDA in 2004-2006.

This was the exact same approach taken by Beasley and Lilly in 1991. It had been rejected by FDA in 2004 and 2006. It was this “new” research that gave rise to the papers he published in 2012 – without Beasley’s name on them.

A report came out of the meeting. “This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC’s report review committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence and responsiveness to the study charge.”

The reviewers included Charles Beasley, Eric Caine (See Y Conwell above), J Greenhouse and R Temple (T Laughren’s boss at FDA). This was a very closed circle. What were they up to?

The 2009 watershed

There was another “consensus conference” in March 2009 that featured many of the same participants, notably Charles Beasley, along with Herb Meltzer and other academics in collaboration with FDA and industry on the topic of suicidality. This was written up in the Journal of Clinical Psychiatry.

These groups appeared to be all desperately grappling with a need to find some way to stop people – patients or doctors – believing the evidence of their own eyes. When someone becomes suicidal on an antidepressant and it clears up when the drug is stopped and reappears when the drug is started again, this is conclusive evidence the drug causes suicide. But over the last 20 years companies have deployed rating scale data, arcane classification systems for suicidal events, miscoding of events, statistical significance and lack of access to the clinical trial data as ways to obscure the problem.

There was a lot more happening in 2009. To me all this activity looked like a concerted effort to roll back the Black Box. The only reason to think not, was that it didn’t make any sense that people would want to roll back the Black Box – which had had almost no effect on clinical practice or the sales of drugs. But whatever this effort might have started out as, the real fruit of the exercise may well have been the Gibbons experiment. It’s hard to see any reason for rolling out a set of publications than repeated a 20 year old discredited article other than as an experiment to see what might happen if companies stood the data access argument on its head.

Why did Archives suddenly back down? Having tested the model and found it works beautifully, putting GSK in a wonderful position to make their offer, secure in the knowledge that this was a close to perfect way to control the scientific process – why draw attention to what’s going on?

Why would Archives play ball? For journals, there is the tempting prospect on the one hand of a series of apparently data-driven Gibbons-type papers that have all been through a strict research governance process that will win the journal huge amounts of money in reprint fees, rather than on the other hand a series of articles a la Doshi, Goetsche and Jefferson, that will get them nothing in reprint fees, will risk tying them up in legal knots and might even put them out of business.

Too paranoid? Not paranoid enough.

Too English? Far too English.

[Conflict of Interest:  I have a serious conflict of interest with this piece that will be laid out in the next post].

The St Bartholomew’s Day Massacre: Protestant Patients, Catholic Drugs

Margot’s lover in La Reine Margot was one of the Huguenots who survived the massacre set in train by her brother Charles IX on St Bartholomew’s Day in Paris in 1572.

There are many politicians, bureaucrats, doctors and others, the Royalists, in a position to make a difference who know that psychotropic drugs can cause suicide or other serious problems but who instead attempt to close down any discussion of these issues. The Huguenots (patients) must not be alerted to what is going on. How it works is this – someone like me gets told by a Professor of Psychiatry you can’t say this to non-academic psychiatrists, or gets told by a psychiatrist you can’t say this to primary care doctors, or gets told by primary care doctors you can’t say this to patients.  Its a control thing.

It can get very personal. Nearly 10 years ago the question of suicide on antidepressants came up in Ireland. I volunteered to debate with anyone on the topic. A number of senior figures declined. Finally two Irish academics accepted – with apparently extensive ad hominem backup from pharmaceutical companies for one of them in particular. They lost the debate. But to this day the Irish Psychiatric Association (IPA) goes out of its way to deny a link even though companies are legally obliged to state their drugs can cause suicide.

The driving force behind the creation of the IPA and its first President was a close friend over three decades. He is someone who knows that psychotropic drugs can cause suicide but faced with the Shane Clancy homicide-suicide was part of the public face of Irish psychiatry’s dismissal of a possible link to treatment – see Professional Suicide – The Clancy Case. Here was the perfect opportunity to open up a back channel conversation but all I got was a dead phone and since then nothing. Recently members of the IPA seem likely to have been involved in an extraordinary attempt to get the Clancy inquest re-opened. The request was turned down by the attorney-general.

It is against this background that the PLoS Medicine exchanges below around this Mortality in Schizophrenia article need to be interpreted. The review process in PLoS is typically open – when I review for this journal the authors know my name. But in this case I have no idea who the reviewers are or even which editor is commenting anonymously at the end. The first submission was turned down; let us pick up the story with the appeal. For first readers of this blog, the rules outlined in La Reine Margot for academic conversations apply. The other point to note is that there may be off the record comments to the editor that have not been forwarded to us – and these can be ad hominem in any kind of way – as may be reflected in the comments of the anonymous editor. If someone like Herb Meltzer (see La Reine Margot) was the reviewer (an obvious choice of reviewer)  its easy to imagine what the comments might have been and there is no way for me to find out what might be happening.

Healy et al appeal PMEDICINE-D-11-03195 R1 decision

Dear Editors

We wish to appeal the decision in the case of this article. The basis for the appeal is that almost all the points raised by the reviewers, particularly the methodological ones, have been taken care of in the revised draft. The only other points are ones on which the reviewers have speculated rather than offered data or knowledge – viz there is no early intervention or outreach service here that might have contributed to the data we report, and there were no restrictions on the liberty of patients 100 years ago that might have led to the results then, and no reason to believe the illness was less severe then than now.

The methodological issues raised by the reviewers have greatly enhanced the paper and given that the findings are so striking and could contribute significantly to public health we still believe that publication in a high impact journal is called for.

Our responses to each point raised by each reviewer are given in bold below. We also include a tracked copy of all changes (Healy et al… Tracked) and a clean copy of the revised article (Healy et al … Clean).

Yours sincerely

David Healy

Reviews

Reviewer #2

Mortality in Schizophrenia and Related Psychoses: Two Cohorts, 1875-1924 & 1994-2010, Compared

The strengths of this paper are:

  • It compares two quite distant time periods
  • The paper produces interesting findings re comparable mortality rates over two time periods separated by over a century
  • The lack of recorded suicides in the historic sample is indeed odd and the authors are correct to exercise caution here

This paper can be improved by:

  • More discussion of the limitations of using hospital admission as an admission criteria at both times points when many first episode cases these days are not admitted to hospital
  • The authors may also wish to discuss bias introduced into their data from this source

This is discussed briefly in the text – but is not a factor in our data.  We have no early intervention service and no reason to believe first episodes are not being admitted here.

  • A more full discussion about the completeness of the records of mortality for both cohorts and the validity of cause of death determinations

We have discussed this and in particular the validity of suicide diagnoses in both historical and contemporary cohorts in more detail

  • More information about the basis on which the schizophrenia diagnosis was applied to the 19th century cohort

We have written an entire paper on this – it doesn’t seem appropriate to go into too much detail

  • The procedure for calculating inferred deaths on p5 of the manuscript for the historic cohort is not clearly described

We agree and have attempted to make this clearer.  This problem is overcome in the survival analysis that has also been added to the current paper.

Reviewer #3

This paper addresses an important question for public health – whether there have been changes in standardized mortality ratios (SMRs) in patients with schizophrenia compared with the general population. This particular study examines case records of two cohorts from Wales, and concludes that there was been an increase in the SMR in the newer cohort, which can be mostly attributed to high SMRs for suicide.

There appear to be three main problems with the analyses and conclusions. First, as it is likely that more severe cases of schizophrenia were hospitalized in the newer cohort, the patients groups are not really comparable in this way. There is a 70 year gap between the last patients admitted in the older cohort and those admitted in the newer cohort – and over this time, the threshold criteria for hospitalization will have dramatically changed.

We have discussed this in detail and offered three reasons in the text as to why this is unlikely to be the case – the cases superficially were more severe historically, patients had relief from distress with medication today, and more patients were admitted voluntarily today.

Second, absolute numbers particularly in the newer cohort are very small, and to base the main conclusions of this paper on 13 deaths (for the diagnoses F20/25) in the newer cohort seems problematic. Hence, the CIs actually overlap for the main outcomes, so the authors are overstating their findings. So the average 5 year SMR for schizophrenia for both genders in the historical cohort was 4.0 (3.5-5.0) and 4.5 (3.7-5.6) in the newer one.

We have introduced more confidence intervals and modified out discussion in the abstract and discussion sections accordingly. The sample size is of lesser importance given that our findings are consistent with all other data in the field – the merit our study adds is its cohort nature makes it easier to see where risks arise

Finally, the authors attribute some of the high SMR to antipsychotic medication. This seems overly simplistic – many other possible reasons could explain the high SMR (to increasing stigma, lack of family support, untreated comorbid depression). Schizophrenia is a heterogeneous disease, and therefore the potential problems with diagnosis, changes in etiology, and treatment over the 70+ time periods between these two cohorts mean that in my view these data are at most hypothesis generating, but cannot be presented as definitive findings.

We have discussed this in detail in the revision.  We offer reasons why medication is the most likely option – but have made this suggestion more tentative.

Two methodological queries – it is unclear from the text how SMRs were calculated for the newer cohort. Ideally, SMRs for each cause of death for every year by age band should be calculated. The text reads as if the authors took average SMRs for each cause of death over 1994-2010. I don’t think this is correct as there have been changes to suicide SMRs over this period, and the limited power of this study would argue against using averages in this way.

We have calculated SMRs as suggested standardized by age, sex and year for suicide.  There are too few deaths from other causes to make the exercise reasonable

In addition, I was unclear about the extent of missing data. The authors state that 359 died in the community. How many of these did not have PM data on?

We have clarified this in the text. 

Reviewer #5

This is very interesting and well written report. I have only few comments and suggestions.

Major
page 5. Paragraph starting “All deaths in hospital (N=513) were recorded in…”. I suggest considering to move this  this paragraph to “Results” section.

We have revamped this section completely

page 6. “When computing standardized mortality rates for years 2, 3, 4 and 5″, Does this mean “years after first admission”?

Yes.  Again this is clarified

page 7. “There is a clear difference in age of death in those dying from suicide compared…” How was censoring treated? Instead of reporting mean age of death authors should apply survival analysis (Poisson regression or Cox’s PH model) and report RR or similar measures when comparing populations. ANOVA is not suitable for this kind of data.

We agree ANOVA is not suitable.  As regards Table 3, we have given this issue a great deal of thought and have reorganized the material by age and diagnosis in Tables 3A and 3B
We have taken up the proposed survival analysis and this has added greatly to the paper.  This has led to additions to the methods, results and discussion sections.

page 12. Paragraph starting “In the Tiihonen study, the best outcomes were found for patients on…”. This part of the discussion is not based on any results given in this MS, because authors used no medication data. This is more speculation than discussion based on facts.

Agree – have removed entirely

Tables 1, 2, and 3. These tables contain not much information. Authors should consider replacing them with results of survival analysis. E.g. Table 3 could be replaced with Age-Period type Poisson regression analyses. ( http://bendixcarstensen.com/APC/ )

As outlined we have replaced Table 3 and introduced Figure 1 – giving the survival analysis.

Reviewer #6

General comments

This is a well designed trial though there are potential avenues that could have improved the standard of the study. I am very worried by the censoring of individuals in the contemporary cohort. In particular the all column indicates 355 psychoses, with 33 causes of death however how many of these had 10 year follow-up data is not indicated by the authors.

We have clarified this issue and taken it into account  A very large proportion had 5 year follow-up data.

Specific comments

1.  In England and Wales there has been a full death registration system for some time. Individuals that left the asylum back to the community would have been registered as the deaths in the national system. The exact date and cause of death could have been obtained for all these individuals.

This is not reasonable. Because of the Welsh nature of the sample, we have 67 John Jones in our records. There is no way to get reasonable certainty as to time and cause of death in the missing sample. Our approach offers a safe over-estimate for likely mortality.

2.  The historical cohort is obviously complete in terms of death, however the contemporary cohort has not yet reached the 5 year mark. Therefore the authors need to detail the size of the cohort by first admission year so that the reader can understand how many people are censored. It doesn’t affect the person years analysis, but the reader needs to know where the information is coming from. However the contemporary cohort is poorly explained with 1994-2010 in the drawing of the database, but 2008 for the mortality and then an indication of 10 year mortality which clearly has only been seen for a minority.

We have done this. Owing to the marked drop in incidence of schizophrenia from 2005, it will be seen in the data that fewer patients than might be expected are lost to follow up.

3.  This leads to a more important comment about the analysis, not using person years has strong assumptions for the individuals for whom deaths were not observed. I’m afraid I couldn’t understand what the authors had actually done from their methods section. As far as I can tell they took just a count of the total number who were alive at the time of risk but excluded all those who died some unknown time in the future and then counted deaths that year. How is this count then adjusted for incomplete person years by the deaths?

We have now supplied a person years analysis. As regards adjustment for incomplete person years we have done a sensitivity analysis and refer to this in both results and discussion.

4.  I am uncertain why the suicide deaths being uneven is a problem as there is not distributional assumption within a simple person-years analysis. Other analyses of rates do require distributions of deaths, but the current analysis doesn’t appear to.

We have done a person years analysis as suggested

5.  The incidence data is not well explained as there is little information about the relative size of the general population that was used to calculate this information. The publication does go into this, but the aspect of severity gets lost between the two publications.

We have picked up the issue of severity in the discussion in response to the point made here and by reviewer #2

6.  The severity of the mental health problems may well be very different in the two time periods therefore reflecting a different mortality risk.

We have discussed this further in detail in the discussion section – it seems most unlikely that patients in the modern period are more severely ill than the historical period

7.  Was 2008 used for deaths in 2009-2010? When was you last death that was included?

The last death comes from 2009.  We have managed the issue of loss to follow up by including a survival analysis.

8.  The tables should have the condition not the ICD10 code as the heading.

They do now

9.  The contemporary cohort is not well enough matured to analyse the data in this way. When the majority of your age groups have <5 deaths it is unlikely that any of the results are particularly well estimated. This is reflected within the confidence intervals.

ONS have rebanded the age-groupings and we have followed suit.  It gives > 5 deaths in most age groups.

10. The authors have provided very few confidence intervals. This would clearly have shown such a large error rate.

We originally provided the confidence intervals for all key figures. We have now provided confidence intervals for all

11. The authors can actually calculate the years of life lost from their data which would aid their conclusions.

We have taken up this suggestion. This seems appropriate for the history cohort but less appropriate for the contemporary cohort for reasons outlined in the text.

12. The authors need to make sure that the conclusions take into account the size of the confidence interval in the discussion.

We have now done so

13. The risk of suicide is complicated by the issue that to have suicide as a cause of death you need to have opportunity to commit suicide. It may well be that registration of suicidal tendencies in the historic cohort meant that suicide opportunities were completely withdrawn using methods we would find unacceptable now and there is a benefit/harm balance to be had.

We have specifically dealt with this issue in the discussion. There was not an unacceptable deprivation of liberty in the historical period

14. The confidence interval for the SMR in the discussion appears to go to 0.0 this is highly unusual and seems at odds with the properties of the SMR. Is this correct?

We made a mistake here and this point has been taken care of

15. It is interesting that after removing suicides there is relative little excess risk of death. This needs more discussion.

We agree – this is the key point in the paper. We have discussed but don’t want to speculate too much

16. It is unlikely that short term mortality from cancer is related to a recent admission in either cohort as the majority of the cancers mentioned here have a much longer natural history.

We don’t relate cancer to recent admission. The discussion now makes this far more clear. But in addition we have used this issue to raise questions about estimates about loss of years of life

We got nowhere with these responses. The final put down came as an anonymous editors’ comments.

Editors’ comments

I have read through the comments and the manuscript, but echoing the previous comments I have serious concerns about the manuscript. The first issue, raised in the comments several times, is the hazard of making a diagnosis from chart review and comparing it with more recent criteria. There are many historical instances of patients being labeled as mentally ill when they did not fit in with societal norms (even a article in a psychiatry journal in the 1960s that described “angry young black man syndrome” during the beginning of the civil rights movement; young black men were hospitalized for months and placed on antipsychotics for this “psychotic condition”). The charts would have reflected the biases of the persons recording. It likely would be possible to make a diagnosis of schizophrenia in a classic case, but there are many more gray areas where it can be difficult to make a diagnosis even today with DSM criteria so the authors are likely not comparing apples with apples.

Second, the issue of looking at suicide rates within an institution vs in free-living patients is also highly problematic. Suicide requires means, and much of the point of the institutionalization then and now was to remove the means for a patient to commit suicide. The authors claim to have addressed this issue, saying “In addition, the monitoring of patients in the asylum was by the same methods used today. There was not an undue or unacceptable restriction of liberty by today’s standards.” I can’t imagine how they can say this categorically; before medications were available to constrain patients, physical restraints like straightjackets were used and these would hardly be acceptable by today’s standards. Regardless, a patient in an institution would have a much harder time getting access to the means to commit suicide than a person on the outside.

Third, the issue of selection bias because only the most severely ill patients are hospitalized now is a substantial one. I also am concerned about competing mortality risks given that TB was so frequent in the earlier population.

Finally, as raised in the reviewers’ comments, “the absolute numbers particularly in the newer cohort are very small, and to base the main conclusions of this paper on 13 deaths (for the diagnoses F20/25) in the newer cohort seems problematic. Hence, the CIs actually overlap for the main outcomes, so the authors are overstating their findings. So the average 5 year SMR for schizophrenia for both genders in the historical cohort was 4.0 (3.5-5.0) and 4.5 (3.7-5.6) in the newer one.” to which the authors replied: “We have introduced more confidence intervals and modified out discussion in the abstract and discussion sections accordingly. The sample size is of lesser importance given that our findings are consistent with all other data in the field – the merit our study adds is its cohort nature makes it easier to see.” The fact that their data are consistent (if they are) with previous studies doesn’t negate the fact that this study is based on extremely small numbers, and given all the above limitations the current data seem hard to support.

Why anonymous?

I emailed querying the anonymity of the editor and got a reply telling me that’s just the way it was.

From: “David Healy”
Date: 10 July 2012 19:43
Subject: Re: PMEDICINE-D-11-03195R2 Decision
To: PLoS Medicine

Emma

I am not raising these points to re-open the argument. I will take the paper elsewhere.

But I have already written a piece for History of Psychiatry on some of the issues raised by historical epidemiology of this type and the first point raised under Editor’s comments is one to add to the paper before it goes off. It would be better to attribute it to a person rather than to Editors PLoS Medicine and I wonder if you can help with this.

Here’s why its wrong. The paragraph refers to the incarceration of black men in the 1960s (there is a recent book on this topic which may have led to the mistake being made here).

The reason we know these black men were not schizophrenic is we have case notes extending over the entire time of their incarceration which retrospectively make it clear they did not have schizophrenia. Without the benefit of these records we would have no way of knowing.

But all the diagnoses made in N Wales in both historical and contemporary cases were made with this benefit – often with the benefit of 30-40 years worth of records.

Your reviewer/ editor has completely misunderstood the basis for diagnosis or is reading their own worries or prejudices into what is here rather than reading the paper.

Similarly with point 2, psychotic patients in North Wales a century ago spent the vast majority of their time on farms or in knitting rooms even when actively psychotic. The idea that they were straitjacketed is “lunatic”. We have the records to show this is wrong.

At least one of your reviewers/ editors appears to have a One Flew Over the Cuckoo’s Nest image drawn from US institutions in the 1950s as to the clinical population we are describing here.

Despite making it clear in my responses that today’s patients in North Wales are less severely ill than patients 100 years ago, the third comment reiterates a point – that may be true for the US today but is emphatically not true for North Wales.

I’m used to reviewers getting our data wrong. But 4 different journals have published our papers now and I’ve presented this at academic meetings involving epidemiologists and historians worldwide without significant criticism of the methods involved.

This is why its so disheartening to see PLoS get some of the key issues so badly wrong.

David

On St Bartholomew’s Day

The issues here are largely about control. A lot of people in the system want to remain in control (they are Royalists). They do not want publication of data, they do not want the Bible put into the hands of the common people, who “would not understand”. Who would not see things the way we do.

By generating our own data RxISK.org will pose an interesting challenge to the Royalists.

La Reine Margot: Data access, ghostwriting, suicide and mad reviewers

Another study giving a first hint of the findings in our 2012 Mortality in Schizophrenia paper (See The Madness of Psychiatry) was published in the British Journal of Psychiatry in 2006 – Lifetime Rates of Suicide in Schizophrenia. It took several years and some smuggling to get it into print. In the course of exploring the issues, it seemed useful to touch base with Herb Meltzer who had links to the InterSePT study, a widely marketed study which looked at suicide on clozapine and olanzapine.

Failing to get the InterSePT data

From: David Healy [mailto:[email protected]]
Sent: Wed 1/22/2003 3:51 AM
To: Meltzer, Herbert; Tom Ban; tom ban
Subject: InterSePT

Dear Herb

Along with I suspect many others, I’ve been poring over the InterSePT results published in Archives. This is a study that will almost certainly open up the question of suicide in schizophrenia as a live issue for years to come.  Congratulations.

The Archives paper suggests that you should have the number of patient exposure years to both clozapine and olanzapine, but this is not actually presented. I wonder whether I could ask you for these details? I have access to other FDA data and a further unpublished dataset on suicide in schizophrenia and these details would enable comparability between datasets.

Regards

David Healy

22/01/03
Dear David:

Thanks for the congratulations. I will try to obtain the exposure information for you from Novartis. The drop out rate was the same in percentage and I believe in time so there  probably will be no significant difference. Forty percent was the approximate rate for both. This is given in the paper.

Should you find any significant issues with regard to the study, I would encourage you to bring them to light.

If I can be of further help to you in your interest in suicide in schizophrenia, please do not hesitate to write. It remains a keen interest of mine.

With best regards

Herb
Herbert Y. Meltzer, MD

From: David Healy [mailto:[email protected]]
Sent: Wed 2/5/2003 7:37 AM
To: Meltzer, Herbert; Tom Ban; tom ban
Subject: Suicides in Schizophrenia

Dear Herb and Tom

Please find attached a draft M/s on suicide in schizophrenia. This has gone nowhere at this point. I would greatly appreciate any comments on methodology, or conclusions or on the overall characterisation of these sensitive clinical issues.

The InterSePT paper offers sufficient detail to include the probably correct patient exposure years for the whole group. Clearly a confirmation of the figures would be great. There is no way to distinguish between clozapine and olanzapine without specific figures for each drug.

If there are no insuperable methodological or conceptual issues here I would envisage presenting some of the figures in Geneva in April, so a relatively rapid response would be appreciated.

David

2/6/03
David:

I have looked over the draft you sent me. In my judgement, it is very, very premature for you to think of presenting or sending it anywhere. You get yourself into all kinds of problems by trying to do too much and not concentrating on the good ideas. (Now where have I said that before?).

The data from Wales is interesting in its own right. Stick to it. Explore it. Ask the tough questions about that data set in as rigorous a way as you can. Don’t try, in this paper, at least, to use it as the platform to launch the idea that antipsychotics increase the risk of suicide attempts and completions. If you take a step back, you will realize that differences in time, place, diagnosis, psychosocial support (family structure in particular), substance abuse, longevity, availability of hospitalization or its equivalent, to name the most obvious, make this an extremely weak way to explore your hypothesis about antipsychotic drugs increasing the rate of suicide.

You could do a real service to the field and your reputation by a solid bit of historical epidemiology here. From there, take on the Khan data. Your interpretation of what it says about suicide and antipsychotic drugs should be confined to what you can glean from the paper itself, not this historical comparison which in no way can be used as the reference point for the effect of drugs in the Khan study. The reference point is the placebo group in that study, and there is no hint that the drugs increased the rate as I recall. In discussing the Khan study in InterSept and talks, we have been cautious in making comparisons in the rates between the two studies because there are so many differences between them. After taking the Khan paper on, take on InterSept and have a go at its methodology, conclusions, whatever. Or go after it first, if that is your wont. You have, in trying to do much, produced a very weak argument so your good points get overlooked, a repetition of the strategic error in your last book, in my judgement.

I wish I had the time to be of more help to you but I really don’t. There are very many, many pressing things I have to do. My advice is to find a colleague who you respect and plead with him to deconstruct your logic and approach, to make you justify every line, every inference. You really need that. You do not need the adulation of an unusually beneficient Max Fink whose affection for you is equalled only by your affection for him. You are a gifted person. I have thought of you as the person who could someday write a splendid history of some particular aspect of psychopharmacology. Don’t squander those gifts. Don’t worry about tilting at windmills. Build the edifice first.

One last thing. I just read Amos Elon’s The PIty of It All. It is a recently published story of the German Jews from the 18th century to 1933. It is the most magnificent piece of history I have ever read. It is filled with intimate details gleaned from years of scholarship. When he reaches a conclusion, you feel its inevitability given what he has presented you with. You finish the book and you feel great lessons have been learned. You get inside the people he has written about.

I hope someday to see writing from you of that quality. Tom Ban knows how much I revere good history. That is why my response to your recent book was so strong. You can do so much better than you are doing. Why rush to present something before its time? If you have gotten yourself into a situation where every time you give a talk you have to have some very provocative view point that causes your audience to get their adrenals and pituitaries secreting at full blast, you are in deep trouble. Forgive me for being so blunt and harsh here. I come at this out of genuine desire to be of help. If you interpret this that I have any desire to suppress evidence that antipsychotic drugs increase the risk of suicide, you could not be more wrong.

I asked the Novartis people to send you the data when you first asked me. I am not sure they are willing to.

I will try again.

Herb

Reading Herb

First even Herb appears to agree that antipsychotics “cause” suicide. But his line, like that of so many others, is that patients can’t be told this – the media can’t be told – no-one can be told.

Herb refers to his hostile review of one of my books The Creation of Psychopharmacology which had appeared in 2002 – in contrast to a positive review of it by Max Fink. It is now widely accepted that second generation antipsychotics are no better than first generation drugs. Creation stated this clearly in 2002, and stated that the field was being fooled by marketing. The ability to make a call like this shows that you don’t need clinical trials to tell when something is evident – there is evident based medicine that tells anyone looking that the second generation drugs weren’t all that good. Then there is evidence based medicine like InterSePT, and doctors are keen to be fooled by evidence-based medicine. (See False Friends)

Creation was written in 2000. It was the book behind the talk – Psychopharmacology & the Government of the Self – at which Charlie Nemeroff was present and after which he put pressure on the University of Toronto to let Healy go.

Second, it is clear Herb doesn’t have the InterSePT data, and possibly never had. The paper was probably “ghostwritten”.

Herb is linked to the reintroduction of clozapine and second generation antipsychotics to the US market. InterSePT did a great deal to boost the sales of clozapine – with its PR message that patients are much more likely to die from suicide than from the effects of clozapine on their white blood counts – and the marketing material produced by Novartis exhorting doctors to give clozapine early the only drug shown to reduce the risk of suicide.

But in InterSePT there were in fact more suicides on clozapine than on olanzapine – the drug with the highest suicide and suicidal act rate in clinical trial history. A convenient choice of comparator for clozapine.

Queen Margot

This email to Herb came relatively soon after his hostile review of Creation, and after the email sequence between Herb and Bruce Chartton below. So what’s with the friendly tone?

In Alexandre Dumas’ novel La Reine Margot, made into an extraordinary movie by Patrice Chéreau, Margot returns to a Ball in the Palace being held by the King her brother. She is returning from the morgue where she has just kissed the head of her lover guillotined by the King. A drop of his blood has ended up on her sleeve. The King comments on the blood. What matter she says provided we all keep smiling.

What’s up Herb?

A colleague Bruce Charlton was surprised by HM’s review of Creation and tackled him on some issues leading the following email sequence.

From: Self <Single-user mode>
To: “Meltzer, Herbert”
Subject: Science Healy review
Date: Mon, 26 Aug 2002 13:41:39

Dear Dr Meltzer,

I am writing about your Science review of David Healy’s ‘The creation of psychopharmacology’. While I appreciate that you did your best to provide a balanced evaluation of a book with whose perspective you apparently fundamentally disagree, I was nonetheless puzzled by the fact that you focused and framed the review with statements about Healy having advocated free availability of drugs – eg:

‘What many will find most provocative about this book and its predecessor, The Antidepressant Era (2), is the recommendation that powerful psychotropic drugs, including neuroleptics such as chlorpromazine, could or should be available without prescription.’

and

‘he believes  that people should be allowed to purchase these drugs without medical supervision’

Having read the book with some care, I don’t recall Healy having made such statements, at least not explicitly – could you direct me to the places where he does so? Or were you perhaps drawing upon other background information concerning the author’s views?

Sincerely yours, Bruce Charlton

Bruce G Charlton  MD

Subject: RE: Science Healy review
Date sent: Mon, 26 Aug 2002 11:25:51 -0500
From: “Meltzer, Herbert”

Ask yourself why you think what he has written is not so straight forward and read on. In the next few pages, he makes his case against requiring prescription for psychotropic drugs in general very clear. On  p 264 he writes,

“Should the conspiracy against the public that is prescribing rights be extended to nonmedical health professionals such as clinical psychologists.”

You will find many, many passages in the book I reviewed where his intent is very clear but he writes to give himself some “wriggle room” if he is called to justify his position. I believe he is attempting to convince the uninformed but to give himself “an out” with people like me.

I have high regard for David Healy as an interviewer.

Are you a colleague of his?

Herb Meltzer

From: Self <Single-user mode>
To: “Meltzer, Herbert”
Subject: RE: Science Healy review
Date: Mon, 26 Aug 2002 16:48:29

Thanks for this clarification – I see the passage you mean. However, I wouldn’t really call this straightforward advocacy, especially since the section is clearly framed as a ‘thought experiment’. Rather, I think the passage makes a specific argument concerning  the way the neuroleptics have been used (especially in terms of dosage), compared with how they might have been used.

Anyway, thanks again.

Sincerely yours, Bruce Charlton

Subject: RE: Science Healy review
Date sent: Mon, 26 Aug 2002 09:47:42 -0500
From: “Meltzer, Herbert”
To: “Charlton, Bruce”

Dr Charlton:

David Healy makes the case that chlorpromazine should have been an over the counter drug from the start and that medical use of the drug produced adverse events that might not have occurred if it was over the counter  in “the Antidepressants” on pgs 258-259.  As you indicate, he did not reiterate this in the book I reviewed. I assume that if he had changed his view on such an important matter he would have stated so. You will have to ask him why he made such an important point in a book mainly on depression and makes no mention of it in a book that deals with chlorpromazine.

Herb Meltzer

From: Charlton, Bruce”
Sent: Wed 8/28/2002 9:40 AM
To: Meltzer, Herbert
Subject: Science Review

Dear Dr Meltzer,

I know David Healy (although I am not a colleague) and rate his work very highly. As you suggested, I checked with him, and he says that he has never advocated OTC availability of chlorpromazine etc. in print, and that the examples you cited from the Antidepressant Era were indeed intended as a thought experiment, as I had assumed.

I don’t actually know what his private views are on the topic, but – whatever they are – it seems rather strange that Healy’s assumed but unstated opinions should have formed the main thrust and focus of your Science review.

Anyway, thank for clarifying this point for me.

Sincerely yours, Bruce Charlton

Subject: RE: Science Review
Date sent: Wed, 28 Aug 2002 10:58:06 -0500
From: “Meltzer, Herbert”
To: ” Charlton, Bruce”

Whatever you and Healy mean by a thought experiment, there is a clear advocacy that this is what Healy believes would have been in the best interest of people who need chlorpromazine. I take that as advocacy for changes in public policy which he then goes on to explicitly ask for. His statement, in the second book,  that ‘any future Rousseau’s should be able to try the interventions of twenty-first century psychiatry in a setting that will enable him to decide freely whether they have anything to offer him” and the continued attack on the concept of having to receive a prescription for psychotropic drugs from physicians is advocacy.

If he is just venting spleen for all the attention he devotes to the issue, that is rather pathetic in my view. I and others read his views as a call for a change in policy. Read again the last two pages of the postscript of the Antidepressants, which followed the section on chlorpromazine. He is clearly advocating the end of prescription medicine. Whatever ambiguity there is is more likely deliberate than accidental.

Space limitation really prevented me from describing many of the things in the book, which profoundly disturbed me. Sentences like; “The current thinking is that there is little or no scientific knowledge about the latest generation of compounds other than what is provided by pharmaceutical companies.” offend me deeply. Firstly, they are untrue. I and my colleagues have done extensive research with no support from industry, studies which have had a big impact on the field. Secondly, even if there has been industry support, I have NEVER changed my views one iota on what I wrote or said to please any of them. Thirdly, this type of exaggerated prose,  is very misleading to the lay leader who does not know better.

I believe the review covered much more than that single issue.

Herb Meltzer

Patients as cannon-fodder

For the record, my position about prescription only is that it confers an extraordinary privilege on the prescriber but brings an extraordinary responsibility – to go way beyond the extra mile to keep the person in your care safe.

All too often prescription only privileges puts doctors in the position of the generals in the Crimea or Great War who sent the troops over the top in a doomed Charge of the Light Brigade. We want generals that we the infantry can trust, generals with a proven track record of keeping their troops safe to fight another day – Chiefs like Joseph of the Nez Perce, perhaps.

Benefit Risk Madness: Antipsychotics and Suicide

Following the posting of The Madness of Psychiatry, there has been a flurry of activity in the twittersphere with Louis Appleby, the UK’s suicide czar posting:

What makes adolescents act on suicidal thoughts? New paper shows psychotic symptoms increase risk 20-fold. archpsyc.jamanetwork.com/article.aspx?a…
You might get the impression from this that all patients have to do is stay on treatment and all will be well, when in fact the patients in this case weren’t psychotic (psychotic symptoms is not the same thing) and the risks of drug-induced suicidality were not systematically taken into account.

Others have berated me claiming while I have said we should be aiming at having people on the right treatment for them I am also saying we should have them on treatment rather than not, when in fact what I have advocated for is a recognition of the risks of treatment – be it drugs or ECT or whatever. The right treatment in these circumstances might not involve any physical treatments – a doctor who can’t doctor without drugs is not much of a doctor.

Batman takes on the public health machine

But does treatment come with risks? DSM IV, for all it is castigated, recognizes that antipsychotics cause akathisia and that akathisia can lead to suicide. Is there data rather than just the opinions of a DSM committee? Some of the data has already been posted. The following is from What would Batman do now posted just before James Holmes turned up at the cinema in Aurora (See The Hidden Gorilla).

In the 1950s, the VA hospital system commissioned Norman Farberow to look at rising rates of suicides among veterans. He studied veterans hospitalized for either medical or psychiatric conditions during the periods 1950 through to the mid 1970s. The 3 figures below bring out the findings.

Figure 1 shows a set of fluctuating suicide rates year on year for veterans admitted to medical beds. The rates are higher than national suicide rates but these rates and their fluctuations are in keeping with what might have been expected in a set of younger men. The increases in the late 1950s and early 1970s may mirror the effects of the Korean and Vietnam wars, or perhaps other social factors or they may be entirely random.

Figure 1

Figure-1

Figures 2 and 3 are strikingly different to Figure 1. Figure 2 does not show the expected fluctuations linked to social factors or any randomness. It shows a steady rise in suicide rates in those who have been hospitalized for a mental condition. Until 1955 the rates are identical to the rates found in those hospitalized for a general medical condition.

But as of 1955, they start climbing in an uninterrupted fashion. The rises and falls we see in Figure 1 that might or might not be linked to social factors such as the Korean war are not there. This can be seen clearly in Figure 2 when the two sets of figures are superimposed and again in Figure 3 which show admissions to psychiatric beds on their own.

Figure 2

Figure-2

Figure 3

Figure-3

Why the bifurcation in 1955? This was the year of the introduction of chlorpromazine. Year on year after 1955 a greater number of tranquilizers (antipsychotics / neuroleptics) like chlorpromazine were consumed by veterans with mental health problems as an ever greater number of these drugs were marketed. These drugs were given to veterans who were depressed, anxious or psychotic – they were not as might be thought now restricted to veterans who were schizophrenic.

The question for Batman in the face of rising suicides in the US military, what would he do now.

What’s with the question marks?

In 2001, Khan et al had an article in the American Journal of Psychiatry which showed the figures for Risperdal, Zyprexa and Seroquel below. Intrigued by the high rates of suicide on Zyprexa, but even more so by the question marks where the missing data should be, I checked the FDA reviews for this drug and found unlike other reviews for other drugs the data was indeed missing. I have added extra data for Sertindole, and Geodon.

Suicidal-Acts-in-AntiP-trials

What if we tell him we didn’t collect the data on suicides?

I wrote to Lilly asking for the data and had the following response:

Dear Dr Healy

Thank-you for your letter concerning suicide attempts in clinical trials with olanzapine, which was forwarded to us by Harry Owens. I am sorry you did not find our previous letter on this subject helpful.

Your question was referred to our parent company in the USA, but unfortunately the specific data you requested are not available.

Yours sincerely – Dr A Simpson, Medical Director

The previous letter had intimated the data didn’t exist, which was scarcely credible. This was a time when the company according to documents later obtained under FOI were doing everything they could to get me or my junior doctor to prescribe Zyprexa, not showing me the data made it impossible to prescribe their drug.

Informed consent and Zyprexa

I wrote to the then Minister for Health Alan Milburn to see if he could help as he had responsibility for clinical trials in the UK, which could not both involve Zyprexa and informed consent if these data were not available. I never got a reply. Not even an acknowledgement. This was a time when Lilly it is rumored were threatening to pull out of the UK if Zyprexa were not written prominently into the Guideline for Schizophrenia, which was the very first NICE Guideline.

I later got to see the data. The number of suicidal acts on Zyprexa was higher than the number on Risperdal.

These data do not include suicides and suicidal acts that might have been triggered by withdrawal. In a 1993 FDA approval review of Risperdal, Andrew Mosholder, one of the agencies reviewers, notes that:

“The sponsor reports no instance of risperidone abuse or dependence. Withdrawal phenomena were not formally assessed after patients discontinued risperidone. Several patients committed suicide within one month of discontinuing risperidone, however, it does not seem reasonable to attribute this to withdrawal, given the absence of other indications of a risperidone withdrawal syndrome and the fact that schizophrenia is known to be a risk factor for suicide”.

The Madness of Psychiatry shows this is a totally unwarranted assumption.  There is a compelling case antipsychotics cause dependence and withdrawal (See Tranter and Healy 1998).

The data

These clinical trial data are ambiguous. They are not good quality data. There is no adjustment for patient exposure, and in this case some adjustment is called for but there is no way to undertake it. There should also be data for suicidal acts during the withdrawal period but these data are not included.

As they stand the data show a statistically significant increase in risk. This doesn’t mean antipsychotics cause suicide, it means that in these trials they caused a significantly greater number of suicides and suicidal acts than happened on placebo.

Although the data are poor, you might have thought journals would be interested. Far from it. They are not prepared to publish, even though this is the best we have and there is not a journal editor who does not trumpet clinical trial data as the gold standard.

In fact clinical trials are close to useless when it comes to suicide. It is easy to design a study of a drug known to cause suicide that would show a reduced rate of suicide compared to placebo (See Healy 2012). Clinical trials function instead for public health officials and journal editors as a bureaucrat’s tool to avoid exercising judgement. When they pose problems like the data here do – better they remain unpublished.

The bureaucrat will see you now

Louis Appleby and other officials take a public health or vaccination perspective. This is essentially anti-medical when it comes to drugs. It accepts casualties without attempting to mitigate the risks. There is not supposed to be any questioning of drugs any more than there might be of vaccines. When officials like this talk about benefit risk ratios, they mean benefit on a public scale that includes job creation or the relocation of a company like Lilly out of the UK rather than the good of patients. The benefit is moreover ambigous – Zyprexa would in fact have an effect for GPI – dementia paralytica – tertiary syphilis, but using it might get in the way of us discovering that in fact penicillin would be a real benefit. The language has been perverted – an effect that suits some interest groups has been termed a benefit when it may well not be for many.

If bureaucrats of this type had run the automobile industry from the start they would never have allowed brakes in cars – and it would be close to impossible to persuade them that good drivers can in fact drive quicker if they have brakes than if they don’t. If you want a good driver or a good doctor these days, well now that’s getting harder and harder to find here in North Korea.