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 Hiding the Bodies

42 or Thereabouts

42 answer

In response to the recent BMJ editorial on serotonin and depression, there were seventeen letters of which three were published, along with my response.  These are copied below along with the best letter – by Barney Carroll – which wasn’t published.  Make your own mind up as to why.

Another piece of minor intrigue is that this editorial, originally entitled So Long and Thanks for all the Serotonin, a title BMJ felt uncomfortable with, registered well on Altmetric – an index that tracks how much Buzz an article is generating.  When I started looking at this, the article was rated at 43 on Altmetric and then moved down to 40 passing through 42 en route.  It will presumably pass back through 42 at some point as it gets displaced by Buzzier pieces.  Amusing given the Hitch-Hiker link.

serotonin and depression

 

Healy States the Obvious

As a matter of clinical science, the notion of a simple serotonin deficiency in depression ended 45 years ago, when the proposed therapeutic utility of monoamine neurotransmitter precursors was disconfirmed.1 There has been little incisive progress since then, owing to major missteps in the intervening years – for starters, the foolish introduction of generic major depression in lieu of clinically differentiated types of depression as the focus of investigations;2 the displacement of disinterested clinical science by corporate experimercials;3 the corruption of journals and of educational forums by key opinion leaders who promoted corporate marketing narratives;4 and the capture of research funding agencies and regulatory agencies by commercial forces. The discomfort that David Healy’s editorial has caused in some quarters reflects a general embarrassment at the emptiness of current research in mood disorders. The yield has not been commensurate with the billions of dollars thrown at the problem – to the point where most corporations have exited the field out of a healthy self-interest. Little wonder, then, that those who have reason to be embarrassed are now throwing the book at Dr. Healy for stating the obvious.

REFERENCES
1. Carroll B.J. Monoamine precursors in the treatment of depression, in «Clinical Pharmacology and Therapeutics» 12, 743-76 (1971).
2. Carroll B.J. Bringing back melancholia, in «Bipolar Disorders» 14, 1-5 (2012).
3. Carroll B.J. Sertraline and the Cheshire cat in geriatric depression, in «American Journal of Psychiatry» 161, 1145-1146 (2004).
4. Carroll B.J., Rubin R.T. The high cost of non-disclosure, in «Clinical Psychiatry News» 34(10), 27 (2006).

Bernard Carroll

Serotonin and depression Healy does a disservice to psychiatrists

Alexander E Langford,  South London and the Maudsley NHS Foundation Trust

David Healy does a great disservice to jobbing psychiatrists with this editorial. By portraying them as ‘co-opted into a myth’ about low levels of serotonin being the sole cause of depression he paints them as gullible, and by stating that the same theory is ‘an easy shorthand for communication with patients’ he paints us as lazy and reductionist in our appraisal of the complex and diverse causes of depression.

In reality, good psychiatrists are and always have been only too ready to admit that they are unsure how antidepressants work. Serotonin does play an important role – likely via factors like neurogenesis and gene expression downstream from synapses – but modern psychiatry is way ahead of where Healy seems to think it is. The picture is far more complex. The fact that ketamine has been shown to be useful in depression does not ‘cast doubt on the link between serotonin and depression’, it rather confirms that the neurobiological underpinnings are as multifaceted as we think.

In any case, whatever their mode of action, SSRIs do work. Even the most stringent of analyses (i.e. Kirsch) support this. There is no good evidence that SSRIs work any less well than TCAs for depression , and the SSRIs have not become so commonplace in clinical practice due to some form of pharma-doctor conspiracy, as Healy would suggest, but because the older TCAs have a far less admirable side-effect profile and were also lethal in overdose. The safety of our patients should always come first, and they are far less safe without treatment for their depression.

Healy D. Serotonin and depression. BMJ 2015;350:h1771. (21 April.)

Serotonin and depression: myth or legend?

Philip J Cowen, Professor of Psychopharmacology, University of Oxford,

David Healy’s observations on serotonin and depression make interesting , if familiar, reading [1]. However, I was struck by the remarkable claim that the focus on serotonin has led to the ‘eclipse of cortisol’ in mood disorder research. A quick search in Scopus with ‘cortisol’ and ‘depression’ revealed a rapidly increasing number of published articles from the late 1990s, continuing unabated to the present time. Only last year saw the completion in the UK of a large placebo-controlled study which examined the effects of inhibiting cortisol synthesis in patients with depression refractory to SSRIs[2]. David also manages to suggest that ketamine has been shown superior to SSRIs in melancholic depression whereas no such comparison has been carried out. He further implies that the work of Andrews and colleagues is based on the intellectually paralysing notion that low serotonin causes depression whereas in fact these authors argue exactly the opposite [3].

Should one confront myths by constructing different ones? As an avid BMJ reader I find myself increasingly confused by this question. For if scientific narratives are manifestations of competing power claims and vested interests perhaps there isn’t really a ‘fact of the matter’- the important thing is to be on the right side. I agree with David.

  1. Lacasse JR, Leo J. Serotonin and depression: A disconnect between the advertisements and the scientific literature. PLoS Med 2005; 2: e392 DOI: 10.1371/journal.pmed.0020392 (http://medicine.plosjournals.org).
  2. Watson S, Anderson IM, Apekey TA, et al. Antiglucocorticoid augmentation of antidepressants in depression: The ADD study. J Psychopharmacology 2014; 28 (suppl): A38.
  3. Andrews PW, Bharwani A, Lee K R, et al. Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response. Neurosci Biobehavior Rev 2015; 51: 164-188.

Serotonin and depression  Personalized pharmacotherapy: An interim solution?

Adam M Chekroud. Yale University, USA

Prof. Healy offers an engaging historical perspective on the rise of serotonergic antidepressants that questions their efficacy and biological plausibility. However, this focus on low serotonin levels is a distraction that is basically irrelevant to whether serotonergic antidepressants are effective treatments for depression. It is important to note that response to serotonergic antidepressants appears to be heterogeneous rather than universally poor.  Unbiased trajectory-based analysis of over 2500 patients treated with SSRI antidepressants or placebo indicated that the majority of patients (over 75%) showed a superior response to patients treated with placebo.  However, nearly one quarter of patients treated with SSRIs showed a poorer response than patients treated with placebo. This suggests that in these patients, SSRI treatment actually interferes with their capacity to mount a placebo response, or perhaps even their capacity for resilience to depression [1]. This raises the critical issue of whether there are ways to identify those patients who would seem to be better off avoiding SSRIs and to divert these individuals to other treatments for their depression.

One factor reducing the effectiveness of antidepressants treatment is our inability to personalize pharmacotherapy, i.e., clinicians have no mechanism for predicting whether a particular patient will respond to a specific antidepressant. Instead, the process of matching patients and treatments requires a prolonged period of trial and error, delaying clinical improvement and increasing the risks and costs associated with treatment. Despite important progress in trying to identify depressed patients at high risk of treatment resistance [2], Psychiatry continues to lag behind other specialties like Cardiology and Oncology in which personalized treatment selection is far better established [3,4].

Developing more generally effective treatments and more rapidly effective treatments would be extremely important advances for public health.  However, in the absence of any such silver bullet, we advocate the development and implementation of innovative statistical methods to get the best available drug to each patient, as an interim solution. Personalized pharmacotherapy may still enable us to “save lives and restore function”. Giving up on these patients is not an option.

1          Gueorguieva R, Mallinckrodt C, Krystal JH. Trajectories of Depression Severity in Clinical Trials of Duloxetine: Insights Into Antidepressant and Placebo Responses. Arch. Gen. Psychiatry. 2011;68:1227–37. doi:10.1001/archgenpsychiatry.2011.132

2          Perlis RH. A clinical risk stratification tool for predicting treatment resistance in major depressive disorder. Biol Psychiatry 2013;74:7–14. doi:10.1016/j.biopsych.2012.12.007

3          Kumbhani DJ, Wells BJ, Lincoff AM, et al. Predictive models for short- and long-term adverse outcomes following discharge in a contemporary population with acute coronary syndromes. Am J Cardiovasc Dis 2013;3:39–52.http://www.ncbi.nlm.nih.gov/pubmed/23467552

4          Roobol MJ, Carlsson S V. Risk stratification in prostate cancer screening. Nat Rev Urol 2013;10:38–48. doi:10.1038/nrurol.2012.225

A Pleasing Look of Truth

I wrote an almost identical editorial as this in 1991 (1). Covering the marketing of serotonin in 1997 (2), I cited Jerome Gaub’s 1767 opinion of Leibniz’ views on the relations of the mind to the body – it is a “fable whose novelty has recommended it, whose recommendation has spread it, whose spread has polished it, refined and adorned it with.. a pleasing look of truth” (3)

I use SSRIs.  Nevertheless I believe the SSRI era will soon stand as one of the most shameful in the history of medicine.  The shame does not stem from what pharmaceutical companies have done, which is just as might have been expected.  The shame will be seen to have arisen from the failure of doctors to know as much as they should have done about medicines they dish out so liberally.  A recent study showing how a dollop of neuroscience dressing can disguise otherwise meaningless material should be compulsory reading for doctors who are after all the true consumers of these drugs (4).

But perhaps an even greater shame will be seen to lie with the fact that this has been an era in which the bulk of publications on on-patent drugs in our best journals were ghostwritten, an era in which the journals refused to demand access to trial data as the price of publication – nowhere more clearly demonstrated than in the area of antidepressant studies on children.  It has been an era when industry has controlled journals, by spending money on some of them and by intimidating others into self-control.

  1. Healy D. The Marketing of 5HT.  British J of Psychiatry, 1991; 158, 737‑742.
  2. Healy D. The Antidepressant Era. Harvard University Press, Cambridge Ma 1997.
  3. Rather LJ. Mind and Body in 18th Century Medicine. Wellcome Historical Medical Library, London, P 17. 1965
  4. Weisberg DS, Keil FC, Goodstein J, Rawson E, Gray JR The Seductive Allure of Neuroscience Explanations. J Cogn Neurosci. 2008; 20, 470–477.

 

Meanwhile the patient information leaflets for pretty well all antidepressants and wannabe antidepressants like quetiapine as of today continue to promote versions of the Low Serotonin Hypothesis (thanks to Julie P for pointing this out).

Citalopram-low-serotonin

This should incense a lot of people.

 

Sense about Science: Follow the Lawsuit

Editorial Note:  This is a third in a series of posts about Sense about Science and Access to Clinical Trial Data that began with Follow the Rhetoric and followed up with First Admit no Harm.

There are some facts in the last few posts. There are also some extrapolations that may not be right.

Tracey Brown has gone on the Parliamentary Record to make clear what AllTrials are asking for – its not the data and not even full Clinical Study Reports.  If This is the AllTrials position, it is easy see why GSK felt they could sign up.  Even ghostwriting companies have signed up. But perhaps AllTrials have moved on.

It may be that the GSK periscope is an invention of subversives within GSK who saw a way to persuade AW1 that this would block access to the data for ever – all the time intending to gradually make it more and more user friendly and accessible.  Perhaps AW1 is the mastermind trying to leverage things forward.

Partnering Pharma

I’ve been a consultant to pharma and an expert for both plaintiffs and pharmaceutical companies in lawsuits.  These contacts definitely bias me – as much by virtue of the people you meet as the money you might be paid.  Under oath when asked if I’m biased I have always said yes – absolutely.

But I’ve never thought when it comes to science that it matters whether I or anyone linked to RxISK are moral or even nice people.  Science might be better served if I’ve got some strange biases or am being paid to try and find the flaws in an argument.  The key thing is access to the data, and given access to the data the more biases the better. Sometimes it takes a true weirdo to see how the data hangs together.

Being motivated whether because you have suffered an adverse event or because you’re being paid makes a difference to the effort you put in to solving problems.  But at the end of the day, if you aren’t free to access the data it’s not science.  If you’re a doctor and accept not being given access to the data – such as all doctors and statins –  that’s quackery not medicine.

Science moves ahead, when people with different biases have their views challenged by the data.  This is the very definition of science as opposed to philosophy or the humanities or business.

Medicine moves ahead when things happen to patients and when doctors and patients work to understand what has happened.

Business would likely do better in the long run if it built on this framework of doctors and patients working together to generate new knowledge. But instead at the moment business is not open for business on this issue. Why?

Study 329 & The Lawsuit that Didn’t Bark

Linked to Peter Doshi’s RIAT initiative, a group of us are working on re-authoring Study 329 – close to the most famous RCT of all time.  In this study GSK’s paroxetine (Paxil) was compared to imipramine and placebo in a group of children.

Those of us taking on this re-authoring job were among the first to be introduced to the GSMA-ESK scope – a periscope for looking at the data on which the GSK seagull regularly sits blocking the view.

The periscope gives the outside world the illusion GSK are offering transparency but it’s not meaningful transparency.

But periscopes are not the crux of the matter.

Damaging Children

Children became suicidal on paroxetine in Study 329.

Before they had the results of Study 329, GSK had seen patients in clinical practice and clinical trials become suicidal and homicidal on paroxetine where the company had coded the event as caused by their drug.  They knew the profile of what happens when an SSRI causes a problem.  In their adult trials from the late 1980s, there was a doubling of the rate of suicidal acts on paroxetine compared to placebo.

They have run clinical trials that use the fact that paroxetine caused people to become suicidal to hide the fact that paroxetine caused people to become suicidal.

In breach of FDA regulations they had moved wash-out suicidal acts into the placebo column in clinical trials to hide the problem.

But in public, they have consistently denied there is a problem.

In Study 329, paroxetine didn’t work and wasn’t safe.  Sally Laden ghostwrote the 329 paper and made paroxetine safe and effective.  There were 22 authors on the authorship line, possibly none of which barring company personnel had seen the full dataset.

Informed Consent? 

The consent form says that in this trial you will be treated in just the same way as you would in normal clinical practice.  Even from the protocol it was clear this was a lie.

The children taking imipramine were to be force titrated to 300mg where possible – this is just not normal clinical practice.  This is double the standard dose for adults.  It’s dangerous and seems designed to make imipramine look worse than paroxetine.

Even so imipramine wasn’t worse than paroxetine.  There was a statistically significant elevation in the number of children on paroxetine who had a suicidal event in this trial alone compared to placebo.

In normal clinical practice if someone becomes suicidal on an SSRI it would be usual to make the link for them and tell them that in future they should try an antidepressant from another group.  They are much more likely than the average person to become suicidal if exposed to another SSRI.

If the drug has caused the problem, it’s very important to their self-image that they know this.  They are being done a further injury, in this case an unnecessary one, if this information is withheld from them.

Have any of the children who became suicidal on paroxetine been told that paroxetine may have caused their problem?

No.

Whose Baby is it?

GSK say it’s the doctors – the non-authors of the paper – who know these children, whose responsibility it is to say whatever needs to be said to any of these children.

These are doctors who refuse to retract a paper that has been deemed fraudulent by New York State Attorney General Elliott Spitzer’s office.  (Elliott Spitzer of Good Wife fame).

To come full circle, this is the paper that led to the data access story we have today.  In response to a fraud charge in 2004, GSK agreed to post the CSRs on the company website in downloadable (non-periscope form).

Without Study 329 and the subsequent fraud charge and later $3 billion fine, GSK would likely never have felt the need to sign on to AllTrials.

Tomorrow and Tomorrow and Tomorrow

This is not a piece of history.  This is our future.

Right now today GSK are refusing to tell the children who have been injured by their drug in Study 329 that they were injured by their drug.  Tomorrow GSK will do the same and tomorrow and tomorrow.

Their drugs never injure people.

The reason GSK, Pfizer, Lilly and AbbVie don’t want anyone to get access to the data is so that no-one can access the damage.  No-one can find out about the Dan Markingsons who die or are injured in company trials.

They are not doing this out of a concern for Dan Markingson’s confidentiality.  They are doing it in order to avoid being sued.

This, Ben and Iain, is why I think GSK are playing the confidentiality card.

What do you think?  And what should we do about it?

The Cowardice of a Pampered Society

Tracey Brown and Dick Taverne of Sense about Science (SAS) have a publication:

Over-precautionary Tales: The precautionary principle represents the cowardice of a pampered society.

Is this Sense about Science?

What would the real SAS – the Short Arm Squad – say?

See SAS to Lisbeth

Sense about Science: Follow the Rhetoric

Editorial Note: This is the first of four posts about the link between Sense about Science and AllTrials triggered by the post Fucked and comments afterward by Ben Goldacre, Tracey Brown and others which raised these links.

My first contact with Sense about Science was linked to the Simon Singh affair.  Singh had made some relatively innocuous statements about chiropractic and been sued for libel as a result. The case became a cause celebre – there was widespread support for his position among the scientific community and widespread concern about an inappropriate deployment of British Libel Law.

I supported him.  I ended up on the mailing list for Libel Reform.  As both of us had been on the receiving end of efforts to shut us up on academic issues, I met him when we were both invited to a workshop on academic freedom in 2011 in Cambridge.

It made sense that Singh’s efforts to change the libel laws was linked to an organization called Sense about Science, and by association Sense about Science seemed a good thing.  It didn’t seem unreasonable to me either to have Sense about Science linked to AllTrials when AllTrials took shape.

The Cowardice of a Pampered Society

Long, long before I had ever heard of Sense about Science I’d read Living Marxism and thought it a breath of fresh air. Marxism like this felt like it might even stand a chance in the marketplace.

Looking at the Sense about Science website now, I realise I know some of its trustees and even have stayed in one of their houses.  The people I know are reasonable people.  Others must think they are reasonable too as these trustees have ended up as Presidents of Royal Colleges for instance – very much part of the establishment as Dick Taverne the founder of Sense about Science is.  I’d imagine Tracey Brown is engaging and interesting also.

Being a consultant to a pharmaceutical or tobacco company or the military is no bar to being engaging.  I have several friends who have been consultants for all three and the greatest help in terms of adverse events has come from people employed within Pharma.

I’m sure Andrew Witty (AW 1) is also engaging and interesting.  Guido Rasi of the European Medicines’ Agency is handsome, charming, engaging, sophisticated, dresses in great suits and had me believing him after a meeting at EMA eighteen months ago on data access that he wanted me to keep in touch.

And many of the views that Sense about Science espouse are ones that should be heard.  They think the precautionary principle is over-precautionary – “Over-precautionary Tales: The precautionary principle represents the cowardice of a pampered society”.  That people who smoke should be responsible for their own behaviour.  That we need GM foods.  That climate change has been overplayed.

The problem arises with views that aim to capture or pre-empt debate and rather than being views for debate are part of an agenda that is being implemented.  Not that being part of an agenda to be implemented is wrong either, but a political program deserves more scrutiny and anyone engaging with such views deserves to know that the person opposite them is not holding incidental views.  It’s good to know when you’re dealing with a believer.

Risk Management

The common focus in Sense about Science views is on risk – the risk to corporations and other interested parties such as governments of things being perceived by the public as risky rather than the risk to you and me from treatments or climate change.

Within the pharmaceutical domain, the luckiest break for the Sensible Scientists was Andrew Wakefield (AW 2).  Wakefield’s paper on the risks of the MMR vaccine gave the British and other governments a wonderful example of how a scientific paper can cause a huge scare that threatens lives and corporate profits.  Managing the fall-off in vaccination uptake was a significant national event.

While many people fought shy of the MMR vaccine, perhaps even Tony Blair himself, this was an event that the public – me included – could readily understand and we were quite prepared to turn on Wakefield as the perpetrator, the bogeyman, the visible manifestation of why we needed sense about science.

In the UK, the most potent weapon on the lips of the academic puppets sitting on corporate hands ever since has been that Godlee or Jefferson is another Wakefield. In the fuss about the BMJ’s article about the hazards of statins a few weeks ago, Rory Collins, one of the industry associated statin supporters, accused Fiona Godlee, the editor of BMJ, of potentially being far worse than Andrew Wakefield.

Elsewhere in the world, where AW is not a household name, the accusation is one of being an anti-vaccinationist or being someone who pays heed to the TV actress Jenny McCarthy.

Many of the people I know who seem to have been approached to be a Trustee of Sense about Science would have readily signed up to an organization offering to bring sense to bear on scientific issues like this.  I might have signed up myself if approached and unaware of its background.

Ben Goldacre began life taking on health fads and health scares like MMR (AW 2) for which he got a GSK sponsored prize (AW 1).

Fighting Fire with Fire

But something else has happened over the last decade since Sense about Science has been set up.

Doctors in general like a quiet life.  Not unreasonably, they assume that what the regulators and their professional bodies say on issues are likely to be right.  Doctors are also horribly vulnerable to complaints from patients or colleagues should they speak out about something.  In addition for the last two decades, many of them are likely aware that they increasingly face a world where if they speak up about some treatment related problem – to do with Vioxx, Avandia, or SSRIs – they will be subject to vituperative rhetoric and be branded as being in league with the forces of darkness – in a way that would never have happened twenty years ago.

The rhetoric gets at doctors where it hurts.  It’s been designed by people who understand doctors better than they understand themselves, and know just what to say to make them feel uncomfortable.

Some of the Sense about Science trustees that I know who have been subject to death threats from people unhappy with their scientific views could be forgiven for thinking its maybe no bad thing to fight fire with a little bit of fire.

Before coming to AllTrials, two housekeeping points.  Another important and increasing criticism is that critics are anti-capitalist. We’ll tackle this in a third SaS post.

Yet another defence has been that raising questions linked to Sense about Science is just a smear tactic.  This will be tackled in a fourth SaS post.

The AllTrials Coalition

AllTrials is a coalition between the BMJ, PLoS, the Cochrane Collaboration, Sense about Science, the Centre for Evidence Based Medicine (Carl Heneghan), the Dartmouth Institute for Health Policy and Clinical Practice, the James Lind Library (Iain Chalmers) and Ben Goldacre.

It called for the registration of all trials and their results to be shared as open data.  It probably took off so well because this ask was simple and vague.  Even GSK could sign up.

In embryo this looked like a great thing.  The idea that getting only the appearances of greater access might be harmful is too subtle a point for most people.  And we don’t like to think that good intentions can be hazardous.

From outside it’s hard to know what might be going on in the AllTrials bedroom.  The BMJ, and PLoS can be expected to go along with proposals that ask for the registration of trials and it’s hard to argue against greater access to the data from trials.   Their editors, Fiona Godlee and Virginia Barbour, working within constraints have taken their journals to places no man would ever dare.

I know nothing about Dartmouth or the CEBM.

Cochrane is a mixed bag – Peter Gotzsche, Tom Jefferson and Peter Doshi have done more to drive this debate forward than anyone else.

The Sense about Science website is a masterpiece of non-direction but their track record suggests a clear focus even if all their trustees don’t realise it.  GSK, one of the major signatories to AllTrials, have an even more focussed agenda.

When the Music Stops

Iain Chalmers and Ben Goldacre are the two who are hardest to read. It came as a huge surprise to many to see Iain co-author an editorial with Patrick Vaillance a sneior figure within GSK, accepting the view that patient level data was out of bounds.

Ben has eloquently told Pharma on many occasions that people will simply not accept the sequestration of data. But what is data?

For AllTrials and EMA it now looks like Clinical Study Reports (CSRs) are data. This is likely not what most people understand by data.  It’s certainly not my understanding.

CSRs are a company’s first edited report on what the underlying data looks like – the point at which they begin to mislead themselves.  If companies know these and only these are going to be made public they will very rapidly become tools designed to mislead the rest of us.  These are the documents that even when the company didn’t think they might become public have already coded suicidal events as episodes of emotional lability.  Without access to the data its impossible to know what is reliable and what isn’t.

The data are contained in what are called Clinical Record Forms (CRFs).

After a study is finished, a company will ghostwrite an article like the infamous Keller et al article in Study 329.  For every page of this article there will be roughly 100 pages to the CSR from which it is drawn – or 500 pages if the company is being fully transparent.   Behind this lie the CRFs.  For every published page in a standard article there are between 5000 – 10,000 pages of CRFs.  This is as close to the data – the patients – as we are ever likely to get.  In some cases the real data never exist.

Here and here are EMA’s proposals about how CSRs will be redacted, and here is Ben’s acceptance of this redaction and apparent buying the line that CSRs contain commercially confidential information.

At the moment with the music stopped Iain and Ben look like they are in bed with Tracy, Guido and Andrew.  Are they in bed just to stay in the game, still hoping to make the right call at the right time?

The time is now.

Fucked

Editorial Note: Apologies for the Language

A year and a half ago this blog ran a series of posts about access to clinical trial data – reporting on how industry were going to engineer the appearances of transparency.  See Won’t get Fooled Again, Access to Clinical Trial Data, and  The Data Access Wars.

Do Academics have Wild Dreams?

Several months later, soon after being fined $3 Billion, GSK trumpeted their endorsement of transparency by signing up to the AllTrials campaign and declaring their intention to put in place a method to allow researchers access to clinical trial data that would go beyond the wildest dreams of researchers.  See April Fool in Harlow, and GSK’s Journey.

Its all to easy to imagine a marketing department figuring that academics don’t have very wild dreams.

When GSK signed up to AllTrials Ben Goldacre rolled over and purred.  The BMJ featured Andrew Witty on their front cover as the candidate of hope.

Rain on the Parade

In contrast, on this blog, 1boringoldman and on RxISK a small group have warned consistently that this was not good news.  That what would be put in place was a mechanism that gave the appearances of transparency but in fact would lock academics into agreeing with GSK and other companies as to what the outcomes of their trials have been.

No one wanted to rain on the AllTrials parade – it never seems like a good idea to fracture a coalition. RxISK put the AllTrials logo on its front page.

Not content with a few academic ghost authors, GSK’s maneuver has put industry well on the way to making Academia a ghost, a glove puppet manipulated by company marketing departments.

Meanwhile Iain Chalmers co-wrote an editorial with GSK endorsing the GSK approach (The Attitude of Chicks to Trojans and Horses) and the British Government produced a document on clinical trial data access that could have been written in GSK central.

The GSMA-ESK Model

The great hope for those dismayed at all this lay with EMA who following Peter Gotzsche’s initiative and a European Ombudsman’s ruling looked like a beacon of hope.  But this week EMA has come out and said it is going to put in place the GSK model of data access.

Everyone is in a spin.  AllTrials are asking for more donations to continue their successful campaign.

As someone who has been working the GSK system, I can say with confidence that this is a disaster.

The key thing that companies are trying to hide are the data on adverse events.  To get to grips with the adverse events in a clinical trial is a bit like playing the children’s game Memory – where you have a bunch of cards with faces turned face down and you get to pick up two and then have to remember where in the mixture those two were when you later turn up a possible match.

Patterns of Deception

In the same way, picking up adverse events is about recognizing patterns – patterns of events, and patterns of deception.

To do this you have to be able to spread maybe a hundred documents out over a big area and dip back into them if something in one document reminds you of something in another.  The new GSMA-ESK remote access system simply won’t allow this.

Not only will it not allow this but it is about to make things far far worse than they are at present.

At the moment when it comes to studies like Study 329, GSK have been stuck by a Court order with putting the Company’s Study Reports up on the web where they can be downloaded and pored over – all 5,500 pages of them for Study 329.  They have refused to do the same for the 77,000 pages of raw data from Study 329, making it available to a small group of us through a remote desktop system.

For all other trials – future and past – investigators won’t even be able to get the Company Study Reports in usable form.  They too will only be accessed remotely.

For anyone who wants to look at the efficacy of a drug this might just about work for outcomes that involve rating scale scores or lipid levels.   The efficacy of drugs is pretty well all that most Cochrane groups, Iain Chalmers and Ben Goldacre are interested in.  The Cochrane exceptions have been Tom Jefferson, Peter Doshi and the Tamiflu group.

But this system is a bust when it comes to adverse events and it won’t work if the efficacy outcomes are in any way complex.

What can be done?

The first point to make is this.  Clinical trials are not all they are cracked up to be.  Even if well designed, not using surrogate outcomes, of sufficient duration, done on patients who actually exist, and not written up by ghostwriters, clinical trials systematically get the wrong answer, especially on adverse events.  Clinical trials are the gold standard way to hide adverse events.

One of the risks of the data access wars is that it will put an unwarranted premium on clinical trials and their data – and in this way play straight into pharma’s hands. This is what led “Crusoe” to warn Peter Gotzsche a year ago that his data access crusade might backfire – See Marilyn’s Curse.

Let’s make no mistake here – it’s morally indefensible that there is not full access to the data from scientific experiments.  In this sense Peter is right and his outrage is well-placed and close to magnificent.

But, ceteribus paribus, it would be better for mankind if all clinical trial data were sunk to the bottom of the sea rather than being made visible to academics stuck in a submarine and only able to view things through a periscope, which is what the GSMA-ESK system offers.

It might have been better if AbbVie had won their legal action.  Instead EMA’s accomodation with them has fucked us all.

Rape is a loaded word these days but in so far as what is happening is an abuse of consent and will primarily do harm to women and children it perhaps come close to being the best word.  Consent processes in clinical trials were about telling you you were on a new drug that might be dangerous or might be involved in a marketing trial.  Instead they have become a way for companies to justify hiding your data on the basis of a confidentiality clause they have slipped into the forms. See When Does Yes Mean No.   Iain Chalmers, Ben Goldacre and AllTrials appear to have signed up to this.

Whether raped or fucked, the Dan Markingson case is a stunning example of what has gone wrong – the Markingson petition is probably a much better petition to sign if you really want to save yourself and others you know and love than the AllTrials one.

Let’s Do the AbbVie Again

Second the data companies are really hiding is their adverse event data.  There are other ways to collect adverse event data.

We invited you 18 months ago to join an AbbVie – Let’s Do The AbbVie Again.  This Irish invention is the reverse of a boycott – another Irish invention.

A boycott of a company’s drug would mean you don’t get the benefit.  If you decide to AbbVie a company’s drug, you – we – can all make these drugs better by reporting on the effects they have.

Company efforts are geared more than anything else to ensuring that doctors and patients don’t report adverse events or ensuring that these events don’t register.  If you really want to get up their nose, if you really want to send the marketing departments into a spin, if you really want a company CEO to blow a fuse, this is what you need to do.

Companies want to transform adverse events into non-information.  You can stop this happening. If an event happens to you on a drug, you are in possession of the missing information.  It’s our tolerance of the patients who have Disappeared in clinical trials that is killing medicine as we have known it.

AbbVie with us and then sit back and take pleasure in a marketer who says “Thank you for helping us make our drugs better – without you we couldn’t do it“.

Now there is of course a huge conflict of interest here.  RxISK.org was set up precisely for this purpose – to register adverse events. But we will hand all events on to FDA or MHRA or whoever you want us to.  What we will also do though, and we invite any doctors or others out there with backbone to help us do it, is to decide when a drug is causing an event – this is something no regulator will ever do for you or for anyone.

Boycott

The other option is a Boycott.  Doctors could refuse to prescribe drugs for which the information was not fully available.  The Panalba and Thalidomide cases have shown that this is the one thing industry is scared of – Report to the President.

If I made claims about a drug to my colleagues but refused to show them the data, they’d have no problem telling me to get lost. I’d be boycotted from here to kingdom come.  But when it comes to industry, 99% of doctors lack balls

Doctors have been given a license to degrade us by treating us like addicts – the origins of prescription-only status.  They have been given a license to print money – we can only get our drugs through them.  The very least they could do in return is show some backbone.

But this is a decadent situation and decadence rarely breeds courage.

Emily’s Balls

The boycott was likely invented by Irish women.  The Abbvie was too.  There is one bulwark still standing in the way of GSMA-ESK.  It’s the European Ombudsman, an Irish woman – Emily o’Reilly.

 

 

Lullaby

childrens books

Editorial Note: Another study published this week suggests that the issue of birth defects on antidepressants rather than suicide or homicide may yet end up as the Mark of Cain by which these drugs are remembered. This post appeared on RxISK.org first.

Hush, little baby, don’t say a word,
Mama’s gonna buy you a mockingbird.
If that mockingbird won’t sing,
Mama’s gonna buy you a diamond ring
If that diamond ring turns brass,
Mama’s gonna buy you a looking glass.
If that looking glass falls down,
All the better for the sweet little babies in town.

In The Beginning 

The first report of antidepressants causing birth defects goes back to 1972.

In the 1980s the companies making SSRIs undertook animal studies to look at the behavioral effects of antidepressants on the offspring of animals given the drugs during pregnancy. These were difficult studies to do because the companies at the same time had to avoid generating evidence of major birth defects, when there was good reason to think the drugs might cause birth defects. The studies that were done gave evidence of both developmental delay and birth defects. This evidence never saw the light of day.

Then a strange study appeared from Motherisk in Toronto claiming there were no behavioral problems in children borne to mothers on SSRIs. The methods used were just what you might have used if you didn’t want to find a problem. This was such an unconvincing study it almost came labeled with Smell a Rat.

In the last five years several decently done studies have been published all pointing to problems such as increased rates of Autistic Spectrum Disorder (ASD) or Developmental Delay (DD) in children born to mothers who have been on antidepressants, primarily serotonin reuptake inhibitors through pregnancy. Aside from the Motherisk study, there is no study saying there is no problem.

A New Study and New Concerns

On Monday a new study by Harrington and colleagues was published with the finding that there is a three to four-fold increase in the rates of Autistic Spectrum Disorder and Developmental Delay in children, especially boys born to mothers who have been on antidepressants through pregnancy. This has already had considerable media coverage.

There are further studies with comparable findings in the offing.

Added to all the evidence from animal studies and epidemiology studies that SSRIs double the rate of major birth defects, double the rate of miscarriages, and increase rates of voluntary terminations, this extra evidence really suggests that these drugs should all be pregnancy category D if not category X.

Not only this but it looks as though the SSRIs may redefine what it means to be a teratogen. Other teratogens produce their effects in the first trimester of pregnancy when organs are first being formed. But it looks like antidepressants used in the third trimester can lead to autistic spectrum disorder and developmental delay.

Pregnancy Category D

Pregnancy drug category C which is what most antidepressants currently are means ‘Use with Caution’. Category D means ‘Do Not Use’. Here’s what a Category D warning would look like:

Category D: (See WARNINGS sectionPregnancy Teratogenic Effects: Pregnancy).

SSRIs can potentially cause fetal harm when administered to pregnant women. If LEXAPRO-PRISTIQ-CYMBALTA  is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the SSRI class, LEXAPRO-PRISTIQ-CYMBALTA is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.

When these issues have come up before on RxISK we have tried to engage Mumsnet and anyone else who thinks that putting material like this into the public domain is just scare mongering. We should be much more responsible. (See I’m not Pre-Pregnant, I just have a Womb, and linked posts – The Dark is for Mushrooms, not for Women, and Preventing Precaution and Mumsnet). 

A warning like this does indeed look off-putting and scary. There has been almost no response from women.

Why Benzos and not SSRIs?

But the extraordinary thing about it is that this is the warning that’s on benzodiazepines in the USA. Substitute benzodiazepine for SSRI and XANAX for LEXAPRO-PRISTIQ-CYMBALTA and you have the XANAX warning.

Even more amazing is the fact that there is not a fraction of the animal studies or epidemiological data pointing to pregnancy risks on benzodiazepines comparable to the data there is for the antidepressants.

The MHRA is Britain’s FDA equivalent. Asking them about the pregnancy risk of benzodiazepines turns up no evidence in the last 20 years that they are aware of indicating a risk from benzodiazepines. According to MHRA, they have been advising women not to take benzodiazepines from the get-go and the warnings were strengthened when the marketing of SSRIs got into full swing in the 1990s and SSRI companies were doing a great deal to blacken the name of the benzodiazepines.

There is nothing about the UK warnings that looks half as scary as the FDA warning, but FDA provide no link to the evidence base for this warning.

The best explanation for this warning is that its a hang-over from efforts twenty years ago by SSRI companies to elimination benzos and replace them with a group of drugs that cause as many if not more problems. This was a supremely successful marketing campaign to make Valium seem darker and scarier than Prozac. On the street Valium sounds almost as dangerous as Heroin – while within mental health care if forced to take Valium or Prozac for life, nine out of ten staff would take Valium. Prozac – and other SSRIs – are by far the darker drugs.

Meanwhile Back in Denmark

Meanwhile Back in Denmark, as elsewhere, there is a drive to screen all pregnant women for depression and get them on antidepressants.  Women are being bullied and harassed into treatment by unfounded claims that leaving a depression untreated will cause birth defects and developmental delay.

Peter Gotzsche, one of Denmark’s leading epidemiologists, a longtime skeptic about many screening programs,  and more recently someone who has been publicly wondering whether  psychiatry needs to be compulsorily detained because of the risk it poses to people in general (Psychiatry Gone Astray), gave a lecture 6 months ago to Danish doctors on the insanity of screening for depression in pregnancy.

A video of his lecture can be found here.  The Transcript of the screening part is here.  The section on screening is almost at the start.  The horror on the video wonderfully transcends translation and perhaps is all the better because of Peter’s lack of training as a stand-up comedian.

Hush little baby don’t you Cry
Momma’s gonna buy you an SSRI.

Get Real: Peter Gøtzsche Responds

Editorial Note: Two weeks ago we ran Peter Gøtzsche’s Psychiatry Gone Astray. There was a context – a Danish  doctor had been found responsible for the suicide of a young man put on antidepressants. This and Peter’s article stirred up debate in Denmark drawing a hard to credit defensive response from senior Danish Psychiatrists.

Peter’s blog was critiqued by George Dawson on Real Psychiatry. An anonymous tweeter @psycrit said “a post about @DrDavidHealy‘s nuttiness turns into an amazing discussion, with unbelievably high-quality comments”. Apparently my nuttiness lies in having anything by Peter G on the site. 

There should be new word for this kind of ad hominem attack – which also flavor’s Dr Dawson’s post. It’s ad hominem by association or ad parahominem.

A number of colleagues such as Barney Carroll thought Peter’s piece was over the top. There are major differences between Peter and I – he locates the problem within industry in a way that I don’t. But the correct analysis is not always what carries the day. People like Peter, Ben Goldacre and Bob Whitaker can be effective – the worry then is whether the change they deliver is the right one – are GSK really one of us now?

History will recognize Peter as the man who, among other achievements, prised open the question of access to RCT data, forcing the European Medicines’ Agency to open up their files. His motivation to do this came in part from a discovery of how appallingly bad the state of affairs in psychiatry IS. How almost all trials on which the field depends are ghostwritten, all data withheld and all dissent suppressed. Whatever it is this is not science and there has to be a good chance it’s killing and disabling more people prematurely than it helps.

What you hear from Peter is a howl of horror. The rest of us have got so inured to the situation we can no longer see how bad it is. The Allied troops arriving at concentration camps must have reacted the same way, where many inmates had gotten used to the situation.

It’s quite possible as George Dawson says that psychiatrists could make equivalent comments about other concentration camps in internal medicine. That doesn’t excuse what’s happening in either psychiatry or the rest of medicine. It’s time to Get Real or at least recognize how an outsider from the media or elsewhere would react if they found out what is really going on.

Peter’s response to George Dawson is here.

Unwarranted criticism of “Psychiatry Gone Astray
Peter C. Gøtzsche Copenhagen

On 6 January 2014, I published the article “Psychiatry Gone Astray” in a major Danish newspaper (Politiken), which started an important debate about the use and abuse of psychiatric drugs. Numerous articles followed, some written by psychiatrists who agreed with my views. For more than a month, there wasn’t a single day without discussion of these issues on radio, TV or in newspapers, and there were also debates at departments of psychiatry. People in Norway and Sweden have thanked me for having started the discussion, saying that it’s impossible to have such public debates about psychiatry in their country, and I have received hundreds of emails from patients that have confirmed with their own stories that what I wrote in my article is true.

Three months earlier, I gave a one-hour lecture about these issues in Danish, which was filmed and put on You Tube with English subtitles: http://www.youtube.com/watch?v=i1LQiow_ZIQ. After only two weeks, it had been seen by over 10,000 people from over 100 countries.

What this tells me is that I must have hit something that is highly relevant to discuss. I therefore translated my article and David Healy uploaded it on his website: http://davidhealy.org/psychiatry-gone-astray/. It also came up on www.madinamerica.com, the website of the science journalist Robert Whitaker, who gives many lectures for psychiatrists and whose recent book, “Anatomy of an epidemic,” was an eyeopener to me, as was David Healy’s “Let them eat Prozac.”

On 8 February 2014, psychiatrist George Dawson wrote “An Obvious Response to ‘Psychiatry Gone Astray“‘ on his blog. Having read Dawson’s blog, I feel the final sentence in my article, which was not translated into English, becomes relevant: It will be difficult when the leaders in psychiatry are so blind to the facts that they will not see that their specialty is in deep crisis. It is also relevant to quote the opening sentences in my acticle:

“At the Nordic Cochrane Centre, we have researched antidepressants for several years and I have long wondered why leading professors of psychiatry base their practice on a number of erroneous myths. These myths are harmful to patients. Many psychiatrists are well aware that the myths do not hold and have told me so, but they don’t dare deviate from the official positions because of career concerns. Being a specialist in internal medicine, I don’t risk ruining my career by incurring the professors’ wrath and I shall try here to come to the rescue of the many conscientious but oppressed psychiatrists and patients by listing the worst myths and explain why they are harmful.”

I listed 10 myths in my article, which I shall repeat here, and will now rebut Dawson’s criticism of them. Dawson says that the myths I describe “are mythical in that they are from the mind of the author – I know of no psychiatrist who thinks this way.” As I have just indicated, there is no person as blind as he who will not see and no psychiatrist as deaf as he who will not listen. Everything I wrote in my article has been documented, most of it in my book “Deadly Medicines and Organised Crime,” and many responses on his own blog shows Dawson to be wrong.

Myth 1: Your disease is caused by a chemical imbalance in the brain

Dawson: “This is a red herring that is frequently marched out in the media and often connected with a conspiracy theory that psychiatrists are tools of pharmaceutical companies who probably originated this idea. What are the facts?”

The facts are abundant. Many papers written by psychiatrists have stated this, and it is also what most patients say that their psychiatrists tell them. I have lectured for patients and asked them, and every time most patients say they have been told exactly this hoax about a chemical imbalance. The drugs don’t cure a chemical imbalance; they create one, which is why it is difficult to get off them again.

Myth 2: It’s no problem to stop treatment with antidepressants 

Dawson: “Another red herring.”

Dawson agrees that there may be “difficulty discontinuing antidepressants” but then tries to get off the hook by noting that this can also be seen with other drugs than psychiatric ones. Allow me to say that one illegal parking doesn’t make the next one legal. Dawson agrees with me but tries to say he doesn’t. Pretty weird.

Myth 3: Psychotropic drugs for mental illness are like insulin for diabetes

Dawson invents strawmen here, e.g. by saying “Am I getting prednisone for my asthma because I am deficient in prednisone?”

That’s totally off the point, as no asthma specialist would be as silly as many psychiatrists are. Again, most patients have told me that this is what their psychiatrists tell them, and professors of psychiatry have also propagated the myth publicly, e.g. in numerous interviews and in articles written by themselves.

Myth 4: Psychotropic drugs reduce the number of chronically ill patients 

Dawson: “I don’t know of anyone who has actually suggested this.”

Pardon me, but Dawson must be both blind and deaf to have escaped this, which psychiatrists say and write all the time. Dawson finds the argument “demeaning to anyone with a severe psychiatric disorder who is interested in staying out of hospitals and being able to function or trying to avoid a suicide attempt. Being able to adhere to that kind of plan depends on multiple variables including taking medications,” and he furthermore says that, “It is reckless to suggest otherwise and any psychiatrist knows about severe adverse outcomes that have occurred as a result of stopping a medication.” Whitaker has documented at length in his book that the increased use of psychotropic drugs has led to an explosion in the number of chronically ill patients on lifelong disability pension and he has also explained and documented the mechanisms behind this.

Myth 5: Happy pills do not cause suicide in children and adolescents

Dawson believes that I reveal my “antipathy to medication used by psychiatrists” by referring to antidepressants as “happy pills.”

Dawson plays the antipsychiatry card here, which is the ultimate trump card psychiatrists use when they have no valid arguments. I consider the term happy pill extremely misleading, as, for example, half of those treated get their sex life disturbed, which has led me to call them unhappy pills whose main action is to ruin your sex life. However, since everybody uses the term (instead of the cumbersome “selective serotonin reuptake inhibitors”), including many psychiatrists, I also use it. Dawson says he has never met a psychiatrist who calls antidepressants “happy pills,” but what can you expect of a man who seems to be both blind and deaf? Dawson claims that “saying that happy pills are a cause of suicide is the equivalent of saying that “sugar medicine” (insulin) is a cause of hypoglycemia that harms children and therefore it should not be prescribed.” What exactly does Dawson mean by this smoke and mirrors? It is a fact, which the FDA has demonstrated, that SSRIs increase suicidal behaviour up to age 40, and package inserts warn about the risk of suicide and recommend not using SSRIs in children and adolescents. Then why do psychiatrists use them in this age group? To use Dawson’s allegory, we wouldn’t use insulin if it increased blood glucose and the risk of dying in a diabetic coma.

Myth 6: Happy pills have no side effects

Dawson’s naivity with respect to the drug industry is heartbreaking. About the incidence of sexual problems caused by SSRIs, he refers to FDA data. But what is buried in FDA archives is not what the companies tell doctors. It is true when I write that companies have said that only 5 % get sexual problems. The true rate of sexual problems is above 50%, and there are reports that these disturbances might become permanent, which agree with rat studies where the rats showed less interest in sex long after they had come off the drugs.

Myth 7: Happy pills are not addictive

Dawson’s says that ‘antidepressants aren’t addictive’.

They surely are, as half of the patients have difficulty coming off them again even with slow tapering and experience similar symptoms as patients who try to come off benzodiazepines.

Dawson claims that SSRIs have no street value and will not make you high, and that my comparison with amphetamine is completely off the mark and consistent with my general lack of knowledge of addiction. Allow me to say that there are striking similarities between the effects of amphetamine and SSRIs and also to quote a few sentences from my book:

“In 2004, the FDA issued a warning that antidepressants can cause a cluster of activating or stimulating symptoms such as agitation, panic attacks, insomnia and aggressiveness. Such effects were expected, as fluoxetine is similar to cocaine in its effects on serotonin (73). Interestingly, however, when the EMA in 2000 continued to deny that the use of SSRIs leads to dependence, it nonetheless stated that SSRIs ‘have been shown to reduce intake of addictive substances like cocaine and ethanol. The interpretation of this aspect is difficult’(77). The interpretation is only difficult for those who are so blind that they will not see.”

“Until 2003, the UK drug regulator propagated the falsehood that SSRIs are not addictive, but the same year, the World Health Organization published a report that noted that three SSRIs (fluoxetine, paroxetine and sertraline) were among the top 30 highest-ranking drugs for which drug dependence had ever been reported (62).”

Myth 8: The prevalence of depression has increased a lot

Dawson and I seem to agree that there is hardly any true increase in the prevalence of depression. The apparent increase is caused by lowering the criteria for what is considered a depression. I also agree with his argument that since 80% of antidepressants are prescribed by primary care physicians we might call this “Primary care gone astray.”

Myth 9: The main problem is not overtreatment, but undertreatment

Dawson’s main argument is that we should not blame psychiatrists for the overtreatment but the primary care prescribers. Well, they are certainly to blame but so are the psychiatrists. Although the Danish National Board of Health recommends that only one antipsychotic should be used at a time, this is not the case. According to a report by the Board of Health, only half of patients with schizophrenia received one antipsychotic drug, one third got two drugs, and the rest got three, four or even more drugs.

Myth 10: Antipsychotics prevent brain damage

Dawson calls my arguments “More rhetoric.”

They are not. Leading psychiatrists have written this and tell their patients that they need to take the drugs in order to prevent brain damage, although it has been documented that antipsychotics cause brain damage in a dose-dependent manner. Dawson continues his futile attempts at killing the messenger: “He also talks about antipsychotic medication with the arrogance of a person who does not have to treat acutely psychotic people and incredibly talks about these drugs killing people.” These drugs do kill people. Doesn’t Dawson know this? I have estimated that Eli Lilly has killed 200,000 people with Zyprexa, and that is just one of the many antipsychotic drugs.

Dawson ends by saying: “At the end of this refutation what have we learned? I am more skeptical than ever of David Healy and his web site.” Dawson is very much against that Healy put my article on his website and he seems to suggest again that one illegal parking makes the next one legal: “It is well known in the US that the 20 year CDC initiative to control antibiotic overprescribing is a failure.” So what? That doesn’t let the psychiatrists off the hook, does it? I think a dose of self-criticism would help not only Dawson, but many other psychiatrists, and their patients.

Dawson finally says that:

“internists have enough to focus on in their own specialty before criticizing an area that they obviously know so little about. The author here also states that he is affiliated with the Nordic Cochrane Center and I think that anyone who considers the output of that Institute should consider what he has written here and the relevant conflict of interest issues.”

These are the words of a desperate man. Short of good arguments, Dawson shoots in all directions. I have done research on SSRIs for several years; had a PhD student who defended her thesis on SSRIs in 2013; have access to unpublished clinical study reports on SSRIs from the European Medicines Agency that no one else outside the agency have access to, and which tells a completely different story to that in published trial reports; and I therefore know more about these drugs than most psychiatrists do. I don’t have a clue what my relevant conflict of interest should be about. I have none! Finally, the Nordic Cochrane Centre, which I established 20 years ago when I co-founded the Cochrane Collaboration and whose director I have been ever since, is highly respected for its research. As an example, I have published more than 50 papers in the big five (BMJ, Lancet, JAMA, NEJM, Annals), which very few people in the world have done. So I think my credentials and my centre are okay.

Psychiatry Gone Astray

Editorial note: We follow up the Guilty post last week with a piece written by Peter Gotzsche that has caused a stir in Denmark and provoked some of the Danish professors he critiques to respond.  

Peter C. Gøtzsche

At the Nordic Cochrane Centre, we have researched antidepressants for several years and I have long wondered why leading professors of psychiatry base their practice on a number of erroneous myths. These myths are harmful to patients. Many psychiatrists are well aware that the myths do not hold and have told me so, but they don’t dare deviate from the official positions because of career concerns.

Being a specialist in internal medicince, I don’t risk ruining my career by incurring the professors’ wrath and I shall try here to come to the rescue of the many conscientious but oppressed psychiatrists and patients by listing the worst myths and explain why they are harmful.

 Myth 1: Your disease is caused by a chemical imbalance in the brain

Most patients are told this but it is completely wrong. We have no idea about which interplay of psychosocial conditions, biochemical processes, receptors and neural pathways that lead to mental disorders and the theories that patients with depression lack serotonin and that patients with schizophrenia have too much dopamine have long been refuted. The truth is just the opposite. There is no chemical imbalance to begin with, but when treating mental illness with drugs, we create a chemical imbalance, an artificial condition that the brain tries to counteract.

This means that you get worse when you try to stop the medication. An alcoholic also gets worse when there is no more alcohol but this doesn’t mean that he lacked alcohol in the brain when he started drinking.

The vast majority of doctors harm their patients further by telling them that the withdrawal symptoms mean that they are still sick and still need the mediciation. In this way, the doctors turn people into chronic patients, including those who would have been fine even without any treatment at all. This is one of the main reasons that the number of patients with mental disorders is increasing, and that the number of patients who never come back into the labour market also increases. This is largely due to the drugs and not the disease.

Myth 2: It’s no problem to stop treatment with antidepressants

A Danish professor of psychiatry said this at a recent meeting for psychiatrists, just after I had explained that it was difficult for patients to quit. Fortunately, he was contradicted by two foreign professors also at the meeting. One of them had done a trial with patients suffering from panic disorder and agoraphobia and half of them found it difficult to stop even though they were slowly tapering off. It cannot be because the depression came back, as the patients were not depressed to begin with. The withdrawal symptoms are primarily due to the antidepressants and not the disease.

Myth 3: Psychotropic Drugs for Mental Illness are like Insulin for Diabetes

Most patients with depression or schizophrenia have heard this falsehood over and over again, almost like a mantra, in TV, radio and newspapers. When you give insulin to a patient with diabetes, you give something the patient lacks, namely insulin. Since we’ve never been able to demonstrate that a patient with a mental disorder lacks something that people who are not sick don’t lack, it is wrong to use this analogy.

Patients with depression don’t lack serotonin, and there are actually drugs that work for depression although they lower serotonin. Moreover, in contrast to insulin, which just replaces what the patient is short of, and does nothing else, psychotropic drugs have a very wide range of effects throughout the body, many of which are harmful. So, also for this reason, the insulin analogy is extremely misleading.

Myth 4: Psychotropic drugs reduce the number of chronically ill patients

This is probably the worst myth of them all. US science journalist Robert Whitaker demonstrates convincingly in “Anatomy of an Epidemic” that the increasing use of drugs not only keeps patients stuck in the sick role, but also turns many problems that would have been transient into chronic diseases.

If there had been any truth in the insulin myth, we would have expected to see fewer patients who could not fend for themselves. However, the reverse has happened. The clearest evidence of this is also the most tragic, namely the fate of our children after we started treating them with drugs. In the United States, psychiatrists collect more money from drug makers than doctors in any other specialty and those who take most money tend to prescribe antipsychotics to children most often. This raises a suspicion of corruption of the academic judgement.

The consequences are damning. In 1987, just before the newer antidepressants (SSRIs or happy pills) came on the market, very few children in the United States were mentally disabled. Twenty years later it was over 500,000, which represents a 35-fold increase. The number of disabled mentally ill has exploded in all Western countries. One of the worst consequences is that the treatment with ADHD medications and happy pills has created an entirely new disease in about 10% of those treated – namely bipolar disorder – which we previously called manic depressive illness.

Leading psychiatrist have claimed that it is “very rare” that patients on antidepressants become bipolar. That’s not true. The number of children with bipolar increased 35-fold in the United States, which is a serious development, as we use antipsychotic drugs for this disorder. Antipsychotic drugs are very dangerous and one of the main reasons why patients with schizophrenia live 20 years shorter than others. I have estimated in my book, ‘Deadly Medicine and Organized Crime’, that just one of the many preparations, Zyprexa (olanzapine), has killed 200,000 patients worldwide.

Myth 5: Happy pills do not cause suicide in children and adolescents

Some professors are willing to admit that happy pills increase the incidence of suicidal behavior while denying that this necessarily leads to more suicides, although it is well documented that the two are closely related. Lundbeck’s CEO, Ulf Wiinberg, went even further in a radio programme in 2011 where he claimed that happy pills reduce the rate of suicide in children and adolescents. When the stunned reporter asked him why there then was a warning against this in the package inserts, he replied that he expected the leaflets would be changed by the authorities!

Suicides in healthy people, triggered by happy pills, have also been reported. The companies and the psychiatrists have consistently blamed the disease when patients commit suicide. It is true that depression increases the risk of suicide, but happy pills increase it even more, at least up to about age 40, according to a meta-analysis of 100,000 patients in randomized trials performed by the US Food and Drug Administration.

Myth 6: Happy pills have no side effects

At an international meeting on psychiatry in 2008, I criticized psychiatrists for wanting to screen many healthy people for depression. The recommended screening tests are so poor that one in three healthy people will be wrongly diagnosed as depressed. A professor replied that it didn’t matter that healthy people were treated as happy pills have no side effects!

Happy pills have many side effects. They remove both the top and the bottom of the emotions, which, according to some patients, feels like living under a cheese-dish cover. Patients care less about the consequences of their actions, lose empathy towards others, and can become very aggressive. In school shootings in the United States and elsewhere a striking number of people have been on antidepressants.

The companies tell us that only 5% get sexual problems with happy pills, but that’s not true. In a study designed to look at this problem, sexual disturbances developed in 59% of 1,022 patients who all had a normal sex life before they started an antidepressant. The symptoms include decreased libido, delayed or no orgasm or ejaculation, and erectile dysfunction, all at a high rate, and with a low tolerance among 40% of the patients. Happy pills should therefore not have been marketed for depression where the effect is rather small, but as pills that destroy your sex life.

 Myth 7: Happy pills are not addictive

They surely are and it is no wonder because they are chemically related to and act like amphetamine. Happy pills are a kind of narcotic on prescription. The worst argument I have heard about the pills not causing dependency is that patients do not require higher doses. Shall we then also believe that cigarettes are not addictive? The vast majority of smokers consume the same number of cigarettes for years.

 Myth 8: The prevalence of depression has increased a lot

A professor argued in a TV debate that the large consumption of happy pills wasn’t a problem because the incidence of depression had increased greatly in the last 50 years. I replied it was impossible to say much about this because the criteria for making the diagnosis had been lowered markedly during this period. If you wish to count elephants in Africa, you don’t lower the criteria for what constitutes an elephant and count all the wildebeest, too.

Myth 9: The main problem is not overtreatment, but undertreatment

Again, leading psychiatrists are completely out of touch with reality. In a 2007 survey, 51% of the 108 psychiatrists said that they used too much medicine and only 4 % said they used too little. In 2001–2003, 20% of the US population aged 18–54 years received treatment for emotional problems, and sales of happy pills are so high in Denmark that every one of us could be in treatment for 6 years of our lives. That is sick.

 Myth 10: Antipsychotics prevent brain damage

Some professors say that schizophrenia causes brain damage and that it is therefore important to use antipsychotics. However, antipsychotics lead to shrinkage of the brain, and this effect is directly related to the dose and duration of the treatment. There is other good evidence to suggest that one should use antipsychotics as little as possible, as the patients then fare better in the long term. Indeed, one may completely avoid using antipsychotics in most patients with schizophrenia, which would significantly increase the chances that they will become healthy, and also increase life expectancy, as antipsychotics kill many patients.

How should we use psychotropic drugs?

I am not against using drugs, provided we know what we are doing and only use them in situations where they do more good than harm. Psychiatric drugs can be useful sometimes for some patients, especially in short-term treatment, in acute situations. But my studies in this area lead me to a very uncomfortable conclusion:

Our citizens would be far better off if we removed all the psychotropic drugs from the market, as doctors are unable to handle them. It is inescapable that their availability creates more harm than good. Psychiatrists should therefore do everything they can to treat as little as possible, in as short time as possible, or not at all, with psychotropic drugs.

Drug Traffic Accidents: ADHD

Editorial Note: In an End of Year post on RxISK, the concept of a Drug Traffic Accident was introduced. This can refer to being run over by a drug, sometimes called side effects, or adverse events, or adverse drug reactions or it can refer to the trafficking of drugs. This post covers both types. The first part is written by David Antonuccio and the second by the Editorial Board of the New York Times.

ADHD on a chalkboard

David Antonuccio:
Schopenhauer and ADHD

You are a decorated researcher, with multiple peer reviewed nationally funded research grants on the prevalence and treatment of ADHD. These have shown that the rate of diagnosis of ADHD seems to be rising inexorably. You have developed a model behavioral program that is relatively inexpensive and can be implemented in any classroom in America. 

Industry funded critics come out of the woodwork to call you a fringe scientist, an attempt to marginalize that appears to be standard operating procedure when new developments threaten industry profits and firmly entrenched beliefs. You are accused of inflating the prevalence of ADHD in order to further your “anti-medication agenda”, despite the fact that you are open to medication treatment for patients with severe problems who have been properly evaluated. 

You decide that you must stand up for the data, no matter whose ox is gored. You warn that there are at least some communities in the United States where the rate of ADHD and related drug treatment exceed all reasonable estimates of the disorder. You gladly participate in public debate with your critics because you see it as a way to advance the science and participate in important academic discourse. 

Then, out of nowhere, an anonymous typewritten complaint, that you are not permitted to see, launches a series of investigations into your research. Academics from all over the world rally to your defense by signing a petition supporting you. You are absolved of any wrongdoing in three subsequent investigations, recommended for promotion and granted the honor of a sabbatical. But ultimately your research is suspended and the data buried forever apparently because the university where you work is worried about the political fallout from the controversy. To make matters worse, since your position is not protected by tenure, your contract is not renewed the next year.  So much for academic freedom! 

About a decade later the data you produced are replicated and your work is essentially vindicated. In fact, new national studies suggest that ADHD is being diagnosed and medicated at rates that are higher than what your research indicated.

This may sound too far fetched to be true but it is what happened to Dr. Gretchen Lefever, a leading epidemiologist and ADHD researcher from Virginia. The details of her story are compelling and can be found in the peer reviewed journal article entitled “Shooting the Messenger”, published in Contemporary Psychotherapy.

Her story is reflected in the famous Arthur Schopenhauer quote, “All truth passes through three stages. First, it is ridiculed. Second, it is violently opposed. Third, it is accepted as being self-evident.”

 

An Epidemic of Attention Deficit Disorder

By THE EDITORIAL BOARD, New York Times, Dec 18th 

The hard-sell campaign by drug companies to drive up diagnoses of attention deficit hyperactivity disorder, or A.D.H.D., and sales of drugs to treat it is disturbing. The campaign focused initially on children but is now turning toward adults, who provide a potentially larger market.

There is no doubt that a small percentage of children, perhaps 5 percent, have the disorder and that medication can alleviate the symptoms, such as inability to concentrate, that can impede success in school or in life. Some studies have shown that medications helped elementary schoolchildren who had been carefully evaluated for A.D.H.D. improve their concentration and their scores on reading and math tests.

Recent data from the Centers for Disease Control and Prevention showed that 15 percent of high-school-age children had been diagnosed with the disorder and that the number of children taking medication for it had soared to 3.5 million, up from 600,000 in 1990. Many of these children, it appears, had been diagnosed by unskilled doctors based on dubious symptoms.

A two-decade campaign by pharmaceutical companies promoting the pills to doctors, educators and parents was described by Alan Schwarz in The Times on Sunday. The tactics were brazen, often misleading and sometimes deceitful. Shire, an Irish company that makes Adderall and other A.D.H.D. medications, recently subsidized 50,000 copies of a comic book in which superheroes tell children that “Medicines may make it easier to pay attention and control your behavior!” Advertising on television and in popular magazines has sought to persuade mothers that Adderall cannot only unleash a child’s innate intelligence but make the child more amenable to chores like taking out the garbage.

The potential dangers should not be ignored. The drugs can lead to addiction, and, in rare cases, psychosis, suicidal thoughts and hallucinations, as well as anxiety, difficulty sleeping and loss of appetite. On Tuesday, the Food and Drug Administration warned that some A.D.H.D. medications, including Ritalin, Concerta, and Strattera, may, in rare instances, cause prolonged and sometimes painful erections known as priapism in males of any age, including children, teens and adults.

So many medical professionals benefit from overprescribing that it is difficult to find a neutral source of information. Prominent doctors get paid by drug companies to deliver upbeat messages to their colleagues at forums where they typically exaggerate the effectiveness of the drugs and downplay their side effects. Organizations that advocate on behalf of patients often do so with money supplied by drug companies, including the makers of A.D.H.D. stimulants. Medical researchers paid by drug companies have published studies on the benefits of the drugs, and medical journals in a position to question their findings profit greatly from advertising of A.D.H.D. drugs.

The F.D.A. has cited every major A.D.H.D. drug, including the stimulants Adderall, Concerta, Focalin and Vyvanse, for false and misleading advertising since 2000, some of them multiple times. The companies, when challenged, typically stop those misleading claims, but the overall impact appears marginal. The number of prescriptions for A.D.H.D. drugs for adults ages 20 to 39 nearly tripled between 2007 and 2012, and sales of stimulant medications in 2012 were more than five times higher than a decade earlier.

Curbing the upsurge in diagnoses and unwarranted drug treatments will require more aggressive action by the F.D.A. and the Federal Trade Commission, which share duties in this area. It will also require that doctors and patients recognize that the pills have downsides and should not be prescribed or used routinely to alleviate every case of carelessness, poor grades in school or impulsive behavior.

 

Editorial Footnote:

  • The true rate of hyperactivity in children that could unequivocally benefit from ADHD medication is unlikely to be more than 1%.
  • Shire is not an Irish company any more than Forest Laboratories is.  Both have a base there for tax reasons.

 

A Black Box Warning for Clinical Trials?

Controlled trials are universally touted as providing gold standard information on drugs. Doctors are routinely taught to disbelieve the evidence of their own eyes and trust in controlled trials instead. Governments in North America and Europe are forcing patients to participate in controlled trials — saying that you get better care in a controlled trial — and claiming that participation is also good for the health of the economy.

This belief that controlled trials are the only legitimate way to evaluate drugs is damaging healthcare and poses an increasing risk to everyone on medicines.

There is a tragic story behind this — the story of Louis Lasagna — the man responsible for the current glorification of controlled trials. Before he died he attempted to undo what he started. No one was listening. Will anyone listen now?

This lecture was delivered in Varese, Italy in June 2013. There is a lengthy question and answer session at the end.

AbbVie: Humira Timeline

Editorial Note: An article in Forbes this week suggested Humira is set to become the biggest selling drug of all time. The timeline below, found by Harriet Rosenberg on the JusticeSeekers’ website, covers the timeline of its elevation to the blockbuster Hall of Fame.

This post and several to come are part of a sequence outlining how we can all help make Humira a better medicine by use of an AbbVie.

Humira Timeline

December 2002
Humira is approved by FDA. (link to FDA)

May 2006
The Journal of the American Medical Association (JAMA) reports 3-fold increased risk of cancer in people taking TNF-blockers such as Humira. (JAMA Article)

February 2007
Humira introduces a new label design as ordered by the FDA for the benefit of physicians that identifies the current changes to the label. (February 2007 Label)

February 2008
Humira introduces a Patient Medication Guide – separate from the label and for the benefit of the patients. (Patient Medication Guide)

June 2008
The FDA releases an Early Communication letter regarding the possible association between the use of Humira and the development of lymphoma and other cancers in children and young adults. (link to FDA)

September 2008
The FDA orders stronger warnings for Humira and the risk of opportunistic infections, including histoplasmosis. Included in their requirement that the Black Box be changed to include these warnings, Abbott Labs was ordered to comply with a Risk Evaluation Mitigation Strategy (REMS) due to the seriousness of the risk. (link to FDA)

December 2008
The FDA reprimands Abbott Labs for airing a misleading advertisement for treatment of plaque psoriasis with Humira. Abbott is accused of misbranding Humira and misleadingly minimizing the serious risks associated with Humira. (link to FDA)

August 2009
The FDA orders a Black Box warning for the increased risk of lymphoma and other cancers in children and young adults. (link to FDA)

November 2009
November 2009 marked some of the most serious changes in the Humira label.

– Black Box of the label was strengthened to include a serious risk of opportunistic infections including histoplasmosis and bacterial sepsis, and the risk of lymphoma and other cancers in children and young adults. (Nov 2009 Label)

– In the Warnings Section under Full Prescribing Information, after years of stating that taking Humira concomitantly with Methotrexate and other immunosuppressants was just fine, the increased risk of infection leading to hospitalization and even death in those that do so is added. (Nov 2009 – Methotrexate & Histoplasmosis Warning)

– Also in the Warnings Section under Full Prescribing Information, the seriousness and difficulty in diagnosing histoplasmosis and other opportunistic infections is highlighted, as well as the recommended treatment.(Nov 2009 – Methotrexate & Histoplasmosis Warning)

– The risk of acute or chronic leukemia is added to Section 5.2 Malignancies.(Nov 2009 – Leukemia Warning)

– Under Adverse Events, incidences of patients reporting new onset or worsening psoriasis is added to Section 6.2 Postmarketing Experience. (Nov 2009 – Psoriasis)

April 2010
Abbott implements the REMS requirement for Humira, as ordered by the FDA for a drug that poses a potential serious safety risk. (link to REMS)

May 2010
Abbott releases the Dear Healthcare Provider letter (6 months after adding the risk to the Black Box) outlining the serious risk of histoplasmosis and other opportunistic infections.(Dear Doctor Letter)

July 2010
Under Section 5.5 Neurological Reactions, the risk of demyelinating disease is expanded to include multiple sclerosis, peripheral demyelinating disease, and Gullain-Barre syndrome.(July 2010 Label) (July 2010 – Section 5.5)

March 2011

A number of updates took place during March 2011.

– Abbott updates the REMS and the Invasive Fungal Infection Educational Pamphlet. (March 2011 Label – REMS)

– The risk of hepatosplenic T-cell lymphoma (HSTCL), an extremely rare cancer, is added to the Black Box.(March 2011 Label – Black Box)

– Section 2.5 Monitoring And Assessing Safety was added, advising that patients should be tested for TB before and during treatment with Humira. (March 2011 Label – Section 2.5)

– Sections 5.1 and 5.11 were strengthened to include the risk of increased serious infection when taking Humira concomitantly with Abatacept in patients with RA. (March 2011 Label – Section 5.1)

– The statement that had been included in all previous labels, “the role of TNF and cancer is not know,” is removed in Section 5.2 Malignancies. The malignancy risk is now outlined to include lymphoma, non-melanoma skin cancer, and cancer risk in children and young adults. (March 2011 Label – Section 5.2)

– The risk of acute liver failure is added to Section 6.1 Adverse Reactions – Clinical Studies Experience. (March 2011 Label – Section 6.1)

April 2011
The FDA issues a Drug Safety Communication Letter warning of the serious risks of Humira and the development of the rare T-cell lymphoma, HSTCL. (link to FDA)

September 2011
The risks of Legionella and Listeria are added to the Black Box. (link to FDA) (September 2011 Label) (September 2011 Label – Legionella)

November 2011
The FDA issues a Drug Safety Update and the announcement of enhanced surveillance regarding the risks of Humira and people under 30 years of age. (link to FDA)

December 2011
The risk of optic neuritis is added to the Neurological warnings in the label. (December 2011 Label) (December 2011 Label – Optic Neuritis)