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

Magic is from Venus

This the final instalment of a series that began with Being Black, and went through I Can’t Breathe, I Can’t Breathe II, I Can’t Breathe III, To the Last Breath, and Algorithms are from Mars.  There was a delay as the series has spun off a lot of other ideas that will hopefully bear fruit in time.  In mid-series, George Floyd got justice but this is clearly just a beginning.  The tens of thousands yearly killed by medicines given by their doctors need recognition and justice also – people like Stephen O’Neill, and Sam Morgan.

Algorithms and procedures risk being authoritarian rather than democratic.  They call on us to follow rules. When these work as in cars or computers they can be good for each of us, even conveying a degree of freedom, but the extension of this If X then Y thinking into every nook and cranny of our lives leaves us in systems that inevitably end up managed by someone other than us – managed essentially by bureaucrats.

At one point, Rulers stood in contrast to democracies. The democracies that replaced them became representative democracies rather than the androcracies for which Athens was famous. Thanks to science, these representative democracies have now been captured by technocrats and related special interests. We are told we have no option but to do as we are told because our leaders are following the science when in fact science opens up doubts rather than provides rules we should blindly follow.

Ultimately robots and 3-D printers and A.I. could take care of everything that is If X then Y-able leaving us free to explore the universe, be artistic, pursue scientific questions that will overturn the answers we are told to follow today, focus on things that are not programmable or perhaps engage in the question of ruling ourselves through something more like citizens’ assemblies where each of us has a vote.

Medicine stands as one domain where a great deal, all the important things, are not If X then Y-able or should not be handled as though they were. At its heart lies an element of magic – bringing good out of the use of a poison or a mutilation.  Mention the word poison now and liberals – progressives hiss. They buy into a sacramental vision of the drugs we use.  Sacraments are something that can only do good and cannot harm (although the Catholic Church had a recent oops moment and removed gluten from the Eucharist).

The idea of bringing good out of the use of a poison or mutilation does not compute for health insurers or managers of health services.

A consumer ‘right’ to access poisons doesn’t compute either.

The magic is not about correcting some blood levels of something – it lies in bringing a person out of the mix, enabling someone to live the life they want to live.

This cannot be done without a relationship. No one can help someone live the life they want to live if they don’t engage with that person and find out what it is they want. They may not be bothered about living an extra few months compared with having enough mental clarity to ensure a child, or grandchild, or friend gets the input now that only they can give.

Relationships stand beyond procedure.  They offer a matrix in which the rules can be made to work for a person rather than having the person bent to fit the rules. They create trust without which no procedure can ultimately work – a trust that for millennia has been known to give a brother supported by a brother the strength of a walled city.

Is it economic to spend time getting to know people?  It is.  It’s the difference between having a doctor handle 100 what are often called heartsink patients or having 100 free research assistants. People with problems or conditions or a problem from some drug have skin in the game and this gives them a motivation worth at least as much as expertise.

Anne Marie who discovered the role of SSRIs in causing alcoholism is a great example of this as are the many people with enduring sexual dysfunctions like PSSD, PFS, PRSD or PGAD who have done so much testing of treatment options and so much pushing against doors to get these conditions recognitions and who should get recognition by whoever wins a Nobel Prize for work in this area when an answer comes as it surely will.

At some point in the not too distant future it looks like robots will let us produce pretty well all If X then Y-able goods for free.  There will at least be no labour costs.  Money will lose a lot of its relevance.

The focus will turn to the production of the most valuable asset we have – other persons. While we can be nudged and surveilled and often controlled far more than we might like to think, ultimately each of us retains a spark of something that is not If X then Y-able. Whether you call it the divine or just the human, it is a spark of something that is not one dimensional.

If there is to be money, and perhaps even power, in this new world, it makes the most sense that it should lie with those who produce people. Whether literally those who labor to produce people.  Or those who work on transforming infants into people initially at home but later in schools and then ensuring the survival of the person when faced by illness – this doesn’t mean ensuring they live as long as possible it means ensuring they have a chance to bring something out of the situation they are in and that they remain seen and heard as persons in the midst of it.

This applies in spades to the elderly.  These are the people with the most experience and often wisdom who should be enabled to live as full a life as possible and contribute as much as possible rather than be warehoused.  When they complain about being tired, this should not be put down to old age, if they have for instance recently been put on some medicine for osteoporosis or hypertension.

Perhaps not exclusively, but largely, in this new world women would hold the power and the money. As things stand, the whistleblowers to everything from corporate misdeeds to drug wrecks are more likely to be women. When it comes to drug wrecks, it’s not women standing up for their own rights but women as the daughters of parents, mothers of children, and occasionally the partners of men or possibly more often other women.

Too used to being overlooked, they often don’t stand up for themselves.  But, perhaps because they are more used to being gaslighted than men, and having to distinguish gaslighting from the genuine thing, they aren’t as easy to palm off when others in their care are affected.

One hundred and fifty years ago, in Venus in Furs, Leopold von Sacher Masoch made the case that for relations between the sexes to be on a sound footing there needed to be equality of education, income and power. Power has been the most elusive element in the mix. But in algorithmythising so much and putting so much weight on algorithms, men may have painted themselves into a corner. The most worthwhile thing to do – making people – will become almost the only thing to do and they are way behind when it comes to being able to do this.

Making people requires affection or perhaps love or care.  The correct word should connote something tough and muscular. It involves standing up with someone else for what looks like its happening when Dalek-like the algorithms are saying Does Not Compute, Does Not Compute.

There is more in heaven and earth, more in the world of people, than was ever dreamt of by your algorithms Horatio.

This is not just a matter of Mercy.  In the final analysis this applies to Justice also which relies on collective judgement calls by groups of women and men who are given a chance to weigh the testimony of others in front of them.

I shop therefore I am needs to become Decernimus ergo Summus – it is in making judgement calls together that we are.

This is the message of Shipwreck of the Singular.

 

To The Last Breath

This photo is of Terence MacSwiney, in 1920 Lord Mayor of Cork in Ireland. The featured photograph on the blog front page is also of MacSwiney in October 1920.

The plan was to end this series of posts starting with Being Black and Janet’s email to me I can’t Breathe with a final post Drawing Breath. The series with its promised completely unrealistic but only possible denouement will now run on to one more post – Agorithms are from Mars, Magic from Venus.

Sarah

One of the most telling comments on any post in this blog since it began in 2012 or so was from Sarah under I Can’t Breathe II . The full comment is worth reading, the punch line is here:

What is the point if the perpetrator of our distress is at home in a blister pack on the bedside table?

A perpetrator who is commonly white – definitely not black.  A perpetrator who must be male as everyone is obsessed with his potency, which is viewed with awe and is allowed to sweep aside all other considerations

Annie

This was followed up with a comment by Annie after I Can’t Breathe III who noted Emma Walmsley, CEO of GlaxoSmithKline – a company that began making baby milk:

“Since February, the highest levels of our company have been working to understand and address what happened,” GSK CEO Emma Walmsley wrote in a note to employees. “Protecting the woman who came forward and her privacy has been a critical priority throughout this time. This will continue. I respect and admire her courage and strength. I’ve spent many nights lately putting myself in her shoes. More than anything, this simply should not have happened.”

We are in an age of progress with a female CEO, growing ranks of female leaders, new commitments to diverse representation, and a culture that values speaking up,”

On a personal level, I am shocked and angry about all of this, but I’m resolute,” Walmsley added. “I want to be clear that sexual harassment is strictly prohibited and will not be tolerated.”

Walmsley added that GSK will rename its Slaoui Center for Vaccines Research in Rockville, Md.  See Silverman report in Stat on a senior GSK employee who had abused women.

It would have been wonderful if Witty, the former CEO, and then Walmsley spent the occasional night putting themselves in the shoes of all the people who have committed suicide on their drugs – bupropion, paroxetine and lamotrigine – or the shoes of those whose lives have been destroyed by voracious sexual promiscuity caused by ropinirole marketed for restless legs.  Perhaps they figure they’ve evened the risk-benefit balance by wiping out sexual function completely for so many with paroxetine.

As Micky Nardo put it in Sex, Lies and Videotape:

The most obscene version was GSK settling a $3B suit and signing this agreement – then writing a response in a letter to the Chronicle of Higher Education that denies admission of guilt [see the only enduring contract…]. The way this China-gate story is going, it doesn’t at this point look like that’s going to be an option. This is just plain old crime, and one that has the Chinese up in arms [as it should].

Crazy Shrink

Being Black asked is there a way to end this lunacy and imagined one of the scenarios facing a black man, arbitrarily picked on by the police as so many are.

The very best therapy for the homicidal thoughts that would result would be to go down to a police station, walk in, tell them you have been left feeling homicidal by what they have done but thanks for this chance to get it off your chest.  Almost no-one who knows about these things, black, white, male, female figures that doing something like this is a recipe for anything other than disaster.  The system just will not work for a black man.

The most sensible comment I got was there might be mileage to be made from someone going to the police-station and getting themselves videoed and explaining at the door its just too dangerous to go inside and outlining what would be likely to happen before trying to leave and walk home. This might bring some relief.

Would a video like this trigger a useful response – by which I mean help change anything more than marching up and down behind a Black Lives Matter banner?

The system doesn’t work for women either.  I’m not in a position to tell if its worse for Black men or for White women.

The trick for both is knowing what to do that might make a difference.

This is the same problem faced by those who are Drug Wrecked – who may be the most unfortunate group.

People with Enduring Sexual Dysfunctions get openly sneered at by healthcare professionals.

Grieving parents seeking to bring some good out of the death of a child at the hands of a drug destroying the mind of their own child, or someone else’s child leading to a manic killing spree, find themselves up against what can only laughingly be called ‘due process’.

They find their obvious truth pitted against a ghostwritten and fraudulent literature that Courts psychotically designate as science.  See There is no Sanity Claus.

If any family members ever participated in a clinical trial, they may now realise that in so doing they put their family, friends and communities in a state of legal jeopardy.  They did so when they signed a consent form that lets some company claim it has a duty never to show their data to anyone.

A Reverse Boycott

When grappling with the English, the Irish invented a few things such as the boycott. A few posts from 2013 put the idea of a Reverse Boycott on the map – see Let’s do the Abbvie again.

A reverse boycott means as many people as possible writing to companies with names attached and indicating a willingness to come into court and testify that there was no other way to explain this death.

There is no point sending a report on a drug or vaccine to regulators (anyone sending any Covid vaccine reports to CDC or EMA or MHRA – forget it its pointless).  The regulator will simply file all reports away in cabinets or on hard drives but will never make a judgement about cause and effect.

As Stephen O’Neill’s case and others documented extraordinarily on AntiDepAware show, there is no point having coroners assess a death that involves a drug at an inquest. They do not routinely note the drugs a person is on at the time of death and are too scared to make the obvious call themselves.

Much better to send any report to the company, who have a legal duty to assess and make a judgement of cause and effect.  See American Woman 1 and American Woman II.

Over a decade ago, some corporate lawyers began telling some company personnel never to make a judgement of cause and effect. But the law hasn’t changed, so instead companies now try to get you to report to regulators like FDA or EMA rather than to them – and, stupidly, we have been falling for this in ever greater numbers. These seemingly enlightened companies know exactly what they are doing when they encourage us to report to regulators rather than to them –  avoid the conflict of interest of sending it to us.  This is getting us to pour water into sand rather than leading to a determinations of cause and effect that might end up in the drug label.

Half-truths are more dangerous than lies

Illustration: Humira: Half-Truths, © 2013 created by Billiam James .

Hunger Strike

The Irish also invented the hunger strike.  Whether reverse boycotts or hunger strikes, the drug wrecked among us and our families need some very public gestures like these now.

There are countless families like the O’Neill’s where a family member has clearly died a horrific death as a result of an SSRI, doxycycline or one of over 100 other drugs given to her or him a short while before that can cause suicide. See The Death of Stephen O’Neill and The Perfect Killing Machine.

In all cases, there is a doctor who fails to step up to the plate and support the family in forcing regulators and politicians to acknowledge that drugs are poisons out of which good can come if used with great care. Someone who has the guts to say unfortunately in this case there has been a poisoning and I feel obliged to tell my colleagues, other prescribers of poisons like me, they need to know about this.  See High Noon and Do not Forsake me Oh my Doctor.

Instead, the efforts of regulators, and politicians, geared to letting companies hide the fact that the blister-pack contains a poison within, can continue unhampered by doctors and coroners. Not surprisingly, an ever increasing number of people are getting poisoned, including more and more young people.

It needs something like a hunger strike.

Terence MacSwiney pictured above, was the Lord Mayor of Cork in 1920, when Ireland were trying to pull away from England. He was sentenced to two years in prison in Brixton, London, for having Irish Republican articles in his possession. He went on hunger-strike. The British State became catatonic. Shamed by world opinion from Australia to South America, with a boycott of British goods by America, the Brits were petrified to let him go and unable to do anything. He died after 74 days on hunger strike, giving rise to a new mantra of Irish nationalism as he did:

It is not those who can inflict the most, but those who can suffer the most who will prevail

MacSwiney’s assumption here is that suffering in silence at home is worthless as the following quote brings out and as the people of Myanmar understand.

I am confident that my death will do more to smash the British Empire than my release

Ireland became a Free State seventeen months after his death.

George Floyd didn’t go out of his way to suffer but owing to his family’s efforts on his behalf and the quick wittedness of 17-year old Darnella who turned on her video camera, perhaps in death he too will prevail.

MacSwiney influenced many people. Among them was Ho Chi Minh, who went on against extraordinary odds to liberate Vietnam.

Another was Gandhi, who liberated India.

Another Hunger Strike made Michelle O’Neill deputy first minister of Northern Ireland – maybe the O’Neill’s need to think about this if Stephen O’Neill’s death is to smash the conspiracy of silence that surrounds the number of deaths from drug wrecks each year which is vastly greater than, multiples of, the numbers of women murdered each year by men.

Or do politicians end up like Lilly CEO Randall Tobias whose wife Marilyn committed suicide four weeks after going on Prozac didn’t stop him continuing to act as the sales front for Prozac.  Kathryn Taurel, the wife of Lilly’s subsequent CEO also appears to have committed suicide.  (Randall lost a later senior Washington job in the Bush administration for his involvement with an escort service).

It doesn’t have to be a Hunger Strike but we do have to have something that will reach the doctors who are currently failing us to at least as great an extent as the police are failing black people.

It should be win-win because if doctors don’t step up this plate, they are likely to go out of business pretty soon.  Any doctor sitting comfortably, who doesn’t spot why they are all but certain to go out business if they keep going on the way they are, should read Shipwreck.

I can’t breathe III

This post follows on Being Black, I can’t breathe and I can’t breathe II and will be followed by Drawing Breath (I and maybe II).  Patsy Stephenson has managed to wriggle her way in again, see comments on I can’t breathe II.  Whether she managed to stage this photo or not, as a red-head Patsy has had to live with a terrible stigma – although perhaps not as bad for a woman.

Another Game in Town

I can’t breathe II features women and antidepressants.  Why the mass consumption of numbing agents?  With benzos, it was men handing them out.  With SSRIs its other women handing them out.  (While more likely to get headline abuse from their fathers, daughters are more likely to be trapped in an ongoing struggle with their mothers).

Women and ADHD is another game in town.  This used to be a disorder of young boys until Lilly started to market Adult ADHD.  Adult ADHD is not the same condition as hyperactivity in young boys.  People with childhood ADHD do not become Adult ADHD. See NZ ADHD.

Over 80% of childhood cases are boys, easily recognisable by their bee in a jam-jar activity level.  But over 60% of cases in adults are women.  Adult ADHD is not a disease – there is no disease in medicine that changes sex ratio like this, never mind so dramatically.

There is no disease in medicine where it was possible to run a simple back of an envelope experiment in 2010 in North Wales, a part of the world that had no Adult ADHD then, where doctors responded saying they didn’t believe there was such a thing, but at the same time indicating they expected that in five years from then they would be diagnosing this condition and prescribing for it. And they are.  See Adult ADHD.

There are other ways to frame things like ADHD. It can be seen as extraversion, something to cherish, an indicator of creativity.  Why would women not want to be creative?  Success in life is about finding the right relationship and work niches to make the gifts we have work for us and others rather than Stepfordizing ourselves.

It seems many of us view being damaged as the way to go. Especially women. Granted there is the possibility of weight loss on stimulants and society puts tremendous pressure on women to be svelte.

Whether extraverted or introverted, women are supposed to be able to multi-task.  Having a stimulant induced increase in focus, an increase in stereotyped looping, sounds like giving up on a birth-right.  Unless being a woman has lost its appeal.

Rapid Onset Gender Dysphoria

One of the most striking phenomena of recent times is Rapid Onset Gender Dysphoria.

Transgender states have been around for a long time. Men, mostly older men, have figured that being a woman, or something like a woman, was very appealing. And for some men, the switch seems to work well.

There are profound poorly understood issues here.

What is novel and unprecedented is a surge in the last decade of teenage girls who want to be…  It’s not even want to be boys. It seems more just don’t want to be girls.  Teenage girls are now transitioning in ever increasing numbers, unchecked by anyone – their parents, the culture, medicine, anyone.

See Transgender Meds and Snakes in a Love Drug 2.

They are also detransitioning in ever increasing numbers, leaving both themselves and the transgender community pretty confused.

Rapid Onset Death Wish

The most confusing of all is the young women seeking medically assisted dying in Belgium and the Netherlands supposedly for Treatment Resistant Depression (TRD) and soon in Canada and elsewhere.  TRD is not a real illness – See MAiD in Canada and M.A.D. Treatment Resistant Depression.  TRD is primarily caused by the psychotropic treatments these young women have been previously given.

Antidepressants are now the second most commonly taken drugs by adolescent women, who migrate into their early twenties on them – with heading toward 25% of women in their twenties on them.

The clinical trials of antidepressant drugs for ‘depressed’ adolescents are the greatest concentration of negative trials for anything ever in human history.  Essentially 30 out of 30 trials done are negative, including the two trials that got Prozac (fluoxetine) licensed.  Prozac has more negative trials in this age group than any other drug.  See Adolescent Antidepressant Trials.

In the Treatment of Adolescent Depression Study (TADS), a supposedly independent study of fluoxetine compared to placebo, there were 34 suicidal events on Prozac compared to 3 on placebo in the trial.  All written out of the script – saved in an obscure hiding place by Goran Hogberg. It appears that the data for this trial, sold as an independent, supposed National Institute of Health trial (conducted on Lilly forms and paper) has now been destroyed.  A euphemistic way of saying….

Young women given antidepressants for the last twenty years in ever increasing amounts stood very little chance of being helped.  Not being helped these days is not a recipe for your drug being stopped at some point.  Instead, mood stabilisers and stimulants get added into the mix.  The upshot of this is Treatment Resistant Depression and Medically Assisted Death.

Young White women go along with this while Black and Muslim women have so far been more cautious but are now coming under pressure, from members of their own communities sent to medical school, to drop their stone-age attitudes. Black and Muslim women are now doing it to Black and Muslim women.

Consumerism?

We have moved into a world of Medical Consumerism. MAiD, medical assistance in dying, is an ultimate expression of this.

Gender dysphoria seems like another. Medical advances appear to make it possible for the health industries to do anything to us and our bodies.  Change sex?  Sure, step this way.  Become invulnerable like Achilles?  No problem

There has always been some degree of medical consumerism, albeit against a background of things that were more readily distinguishable from current fashions. The Treatment Resistant Depression that now leads to MAiD, which according to industry is close to epidemic, is not a fashion.  It is caused by meds and before MAiD used to lead to ECT and still does.  Some services turned requests for ECT for these patients down on the basis they were unlikely to respond but this becomes more difficult if both doctor and patient are signed up to the idea. And its women mainly. If we are willing to fry the brains of people unlikely to benefit from ECT, if they insist on it, are we going to say no to MAiD?  Maybe a few times, until we get used to it.

This scenario portrays women as helpless – consumed by Vampires. Is this all there is to it?

Young women have also been ignored visionaries from Cassandra in Troy, to the young women in Fatima who put sexual abuse on the radar for the Catholic Church and didn’t back down where Freud did, and the young women who seem to have prophesied the Rwandan massacres.

Greta Thunberg now looks more like a leader for our times than pretty well anyone in political office at the moment.

While some young women lead, others are left choking on the air they breathe, or perhaps today its their pills, inhaled on the cultural air they breathe.  What would have to happen for them all – Black, Muslim, Asian, and White – to breathe more freely?

 

I can’t breathe II

This post continues a sequence that began with Being Black and I can’t breathe. and will be continued with I can’t breathe III and Drawing Breath. 

The picture features Patsy Stephenson, one of a well-heeled group of women, including Kate Middleton – likely there for the photo-op – protesting the death of Sarah Everard in London, killed for walking down a suburban street at the wrong time. Whether they are black or white, young or old, Muslim, Christian, Jew or nothing, women like Sarah Everard are in a similar position to George Floyd.  Patsy isn’t in this position but the photo is eye-catching. 

If someone in a group said they had AIDs, others would likely get nervous.  If they add, they are on Triple Therapy everyone relaxes.

If someone said they have epilepsy but manage it without anticonvulsants, everyone would get nervous. If they say ‘only joking, I’m taking an anticonvulsant’, everyone relaxes.  (Even though lots of epilepsy can be managed without meds and the meds double the risk of suicidal or homicidal outbursts).

If a woman says she is taking an SSRI, everyone relaxes.

As though this demonstrates her competence and reduces the threat to everyone else – the men anyway, perhaps other women. In the case of other women, the reassurance may lie in ‘she’s one of us, she’s on the pills.’

It was a woman explained this to me, a psychiatrist, who was taking meds.

Forty years ago, saying you were on Valium was an admission of weakness. Feminists fought against the subjugation of women by drugs.  Ironically the benzodiazepines were more likely to lead women to rebel against the patriarchy than any SSRI does.

SSRIs are Stepford drugs blunting awkward emotions – all emotions that is.

But saying you take an SSRI, if you are a woman, is a statement of competence.

Among a younger generation of white women taking an SSRI has moved beyond being a statement of competence.  Good for you if along with eating the right foods, spending hours in the gym, you not just admit but declare you are taking Zoloft, Lexapro or whatever.  Their 800,000 followers cheer Influencers on Instagram who make declarations like this.

The word depression may slip in somewhere, but SSRIs don’t treat depressive illness. As Joe Davis in Chemically Imbalanced explains, really what is being said is I am treating a glitch – just like I wear glasses – that is holding me back from seeing and being seen properly. Holding me back from being my true self.

SSRIs numb us, ease the pain. They make us more authentically us in the way alcohol does.  At the moment, non-white and non-Christian groups are less likely to buy into this, just as they are less likely to buy into alcohol.  You are supposed to have a community for times like this when you need support.

SSRIs though give lots of people the impression they treat an illness.  They do treat an illness – it’s called dependence.  Miss your pills for a few days, and we feel desperately ill, which getting back on our pills magically relieves.  The extreme form of this illness is called Treatment Resistant Depression.

Because so many figure the pills are saving their lives (by relieving withdrawal), if anyone questions these pills, without any bidding from pharma or their doctors, millions of defenders will march out to say these pills saved their lives.  Close to 15% of the population at the latest estimate.

The Dark is for Mushrooms

Close to 25% of the population of women of child-bearing years are defenders. The last group you’d expect to insist on access to meds they might not be able to get off. Meds that double the rate of miscarriages, and double the rate of birth defects. They also drastically lower libido and make love-making a chore, so maybe miscarriage and birth defects are not an issue.

The defenders of the meds, decent progressive women, portray comments like this is an attack on a woman’s right, duty, to look after herself.  Women are too quick to sacrifice themselves for others and this has to stop.  Calls for women to think twice before taking drugs that will make them feel better are now a touch twentieth century, second millennium even, we are told.  Time to move on.

This is today’s equivalent of Edward Bernays organizing for women to march down the street smoking – as a sign of liberation, equality and access to opportunity.  See

The Dark is for Mushrooms

Preventing Precaution 

Mumsnet

Herding Women

Looking after themselves conflicts with the instincts of many women (instincts put there just by the patriarchy?) to take themselves off drugs when they find out they are pregnant, even when male ObGyns are telling them its fine to stay on treatment and an untreated illness can harm their baby more than the meds.

The ObGyns are offering quintessential neo-Medicalism (aka neo-Liberalism) as outlined in Shipwreck of the Singular. There cannot be any clearer divide between how we once thought and the neo-Medical/Liberal way of thinking than the question of taking drugs in pregnancy.  It runs smack into Margaret Thatcher’s ‘there is no such thing as society’.

A pregnancy is either an embryonic society or a weird and inexplicable weight gain that happens to some chromosomally compromised individuals.

That progressive women in particular should buy into the no such thing as society mantra shows how much the Left or progressivism has lost its way.

There is a lot going on in between the lines here.  Sure there are women who have to insist they are diseased and need treatment, maybe never taking the drugs, in order to get benefits.  Telling them they are not depressed is like whipping a lifebelt away from them.  And it’s not sin to trumpet a disorder which you are now treating in order to maintain some self-respect.  And there are times when the termination of a pregnancy may be the best option.

But there is very little sign of the women’s movement saying to women – sure play the game but remember it is a game. The women’s movement now buys into Evidence Based Medicine and believes the Fake literature (entirely ghost-written literature on drugs with zero access to clinical trial data) is the best evidence we have. Our Bodies Ourselves is now an outsourced marketing arm of Pharma. The movement is petrified of being branded Anti-Vaxx or Anti-Science. Settle for anything other than the full scientific deal – Us? No Way!

A Seat at the Table

The medical model emerged around the same time, or just before capitalism – a movement that figured on making money out of producing goods. Capitalism was and is different to mercantilism or Free Trade and has nothing to do with neo-Liberalism. See Shipwreck of the Singular.

Capitalism was novel and successful – leading to great increases in wealth and goods so much so that, while some of us rejected capitalists, most of us who weren’t capitalists figured it was worth having a seat at this table.  All could benefit from this engine which did seem to driving us ‘forward in an acceptable direction’.

Socialism (including trade unionism) was all about having a seat at the table. The communists in contrast figured we needed a completely new set up.  Socialists figured there was absolutely no point in not being at the table – so much so they executed communists like Rosa Luxembourg.

The medical model was the Table within health.  It produced solid advances in our understanding putting us in a position to correct things and able to choose whether to take a poison or undergo a mutilation in order to correct something that would otherwise kill and disable us.  It gave us new abilities to investigate things and intervene so that for most of us having a seat at this table was a no brainer.

Through to 1980 – 1990, medicine and capitalism increased health and wealth.  Within medicine the AIDs pandemic is the best example of what could be done.  An intense mobilization by activists (lay people with the disease who mostly believed in the medical model) led in remarkably short time to a life-saver if not a complete cure. The activists split into two groups – those looking for a seat at the table (mostly male) who went into FDA and got clinical trial rules and FDA culture changed and those who rejected the entire way medicine was going and called for a totally new set-up (many more women in the mix).

AIDs activism was the final flourish of medicine as was.  The vast majority of people now taking poisons have nothing wrong with them – something inconceivable in medical model terms.

Medicine has given way to a neo-Medicalism just as Capitalism has given way to neo-Liberalism.  Now financialization leads to money chasing money while poverty rises, and pharmaceuticalization has led to drugs chasing drugs while life expectancies fall.

Socialists hung around at the table too long and embraced the operationalism that made neo-Liberalism, figuring as Maggie said ‘there is no alternative’.

The Vanished

Now that the table has vanished – neither wealth nor health is increasing – socialists have no idea what do.  Their ongoing defence of the once very reasonable idea that it is important to have a seat at the table now validates a system that is causing increasing harm.

The idea of a medical model that underpins the giving of a poison or performance of a mutilation within a relationship that is at least semi-genuine still offers a glimmer of what a table we could all get around might look like.

As things stand women seem among the most likely to get cut by the cutting edge of the operationalism that underpins both neo-Medicalism and neo-Liberalism. Their music, art and science vanishes as though written on water. They too can vanish and no-one much is bothered.

Women though may be better placed than men to work out what needs to happen next. For centuries, they have been forced to figure its better have a seat at the table the men are seated around than not. Even when the cost is getting abused, or vanishing while walking down suburban streets in daylight

We can’t go back to the 1980s.  We have to go forward.  We need to redefine what a seat at the table should look like and unless the table and seating works for women, black, white and brown, rich and poor, old and young, its not likely to be a table worth sitting at.

Drawing Breath in two posts time will offer what seems to me a crazily idealistic proposal about what the table might look like – but the only viable proposal.

 

Medically Assisted Death in Canada

Policy Options, a Canadian forum, published the piece below by Jocelyn Downie, David Wright and Mona Gupta, all of whom I know, as a contribution to a wider debate on the Medical Assistance in Dying (MAiD) legislation currently under review in Canada, and especially the question of where does mental illness fit into this mix.  The Downie and colleagues published piece is HERE.

The focus in this debate so far has been on the individual seeking MAiD which the Downie piece brings out.  Mental Illness does bring individual irrationality into the frame.  But is it just the person with a so-called mental illness.  What about their doctors?  While there are many great people in Healthcare, the experience of people with ‘mental disorders’ is often that those ‘caring’ for us can be far more murderous – in practice if not by intention – than anyone imagines.  Those caring for us are not always angels – a series of posts on RxISK tagged Medical Kidnap bring this point out.

Policy Options invite submissions but never acknowledged this submission.  I contacted them directly nearly a week later and they said they would pass on this one.  Which left little option but to post here.

What’s the Relationship between Suicide & MAiD?

Jocelyn Downie, David Wright, Mona Gupta

Should people with mental illness as their sole underlying medical condition be allowed to have access to medical assistance in dying (MAiD)? That’s a question in front of Parliament right now. The House of Commons has passed a Bill that excludes MAiD for persons suffering from mental illness as their sole underlying medical condition. The Senate amended that Bill to put a sunset clause on the exclusion (it will cease to have any force and effect 18 months from the coming into force of the Bill). Soon the amended Bill will be back before the House, which will have to decide whether to accept the amendment.

Notably, in its report on Bill C-7, the Senate standing committee on legal and constitutional affairs wrote that some witnesses “underscored that an exclusion and strong safeguards are needed to protect Canadians with mental illness under a MAiD regime, especially given that suicidality may often be a symptom of certain mental illnesses.” Unfortunately, this way of thinking about the relationship between suicide and MAiD confuses more than it clarifies.

Suicidality is associated with certain psychiatric diagnoses, but by no means all or even most of them. Furthermore, not all persons who are suicidal have a mental illness. Rational suicide – the desire for individuals not suffering from a mental illness to end their own lives – has always existed. Indeed, the entire project of MAiD is premised on the idea that there are individuals who under certain circumstances have justifiable reasons to end their own lives. In addition, Parliament has already taken the position that the presence of a mental illness itself does not exclude the possibility of a rational desire to die, as there are people who have already legally accessed MAiD who suffer from both mental illness and physical conditions concurrently. (See the Feb. 2 testimony of Dr. Derryck Smith at the Senate standing committee, at the18:02:40 mark.)

From a clinical point of view, decisions to try to prevent someone from dying are not motivated by the mere presence or absence of a diagnosable mental illness. Rather, we intervene in order to try to modify their specific circumstances, such as a personal crisis, or the acute symptoms of their illness. Our actions also depend on whether the person is able to act in their own interests. We are likely to intervene to prevent the death of a person who is considering suicide when they lack decision-making capacity, for instance when they are severely intoxicated, even if they have no psychiatric history.

By contrast, we do not necessarily intervene to prevent the death of a person who wants to refuse life-sustaining treatment or to access MAiD due to a physical condition even if this person has a concurrent serious, and chronic, psychiatric condition. The answer to the question –does this person have a mental illness? – does not tell us whether we should prevent or assist the person ending their life.

When it comes to mental illness and MAiD, therefore, we must determine whether an individual seeking to bring an end to their life should be prevented from doing so, or not. Trying to decide whether the person is “suicidal” is simply shorthand for talking about the kinds of circumstances previously mentioned – personal crisis, acute episode of illness, incapacity, among others – where collectively, we have already determined that we should intervene to prevent a person from acting. The possibility of permitting some individuals with mental illness to make a request for MAiD does not impede suicide prevention efforts in these kinds of circumstances.

Thus, the statement “suicidal behaviour can often be a symptom of mental illness” is at once too broad and too narrow. It misuses the idea ofa symptom as a proxy for situations in which we want to act to prevent death. And by focusing on only those circumstances in which suicidality is a symptom of a mental illness, it simultaneously ignores the fact that there may also be situations in which we want to prevent death amongst those with no diagnosed mental illness at all.

By legalizing MAiD, Canadian Parliament has already decided that, in certain circumstances, it is acceptable to assist someone to die. Instead of excluding mental illness through a reflexive association between mental illness and suicide, we propose reframing the debate about MAiD and mental illness by asking: In which circumstances do we, as a society, wish to prevent death? In which circumstances, and under what safeguards, are we prepared to assist its arrival? By avoiding the shortcuts of medical terms, we can clarify what’s at stake and focus the debate on what criteria and safeguards will prevent those deaths that we should prevent.

Assisting Consumerism in Dying (ACiD)

Downie, Wright and Gupta’s points about MAiD centre on issues of capacity and consumerism.

Opting to end a life can indeed be quite rational. The role of medicine in their model is primarily to decide whether the person deciding to end their life has the capacity to do so.  The focus is on the consumer of a medical service.

This neglects physicians. Medicine is the perfect place for a murderer to hide and medicine may have or have had more doctors who murder their patients than the Catholic Church has had paedophile priests.  See Robert Kaplan’s Medical Murder – the image above is Harold Shipman, one of the cases he deals with.  For these doctors, MAiD will be a godsend. There have always been physicians who find the removal of a healthy limb in someone with apotemnophilia technically satisfying. For the technician in some doctors, MAiD will be also satisfying.

Some physicians opt to do labioplasties and sculpt breasts rather than repair perforated duodenal ulcers but most distinguish between plastic and cosmetic surgery. The wider public view it as in the public interest to financially support the restoration of someone disfigured, perhaps while working on our behalf as a firefighter for instance, to something more like their normal self.  We hope that in so doing s/he will be better able to contribute to the greater good. We sense, in contrast, that individuals seeking cosmesis should pay for themselves.

MAiD in the case of someone with terminal Motor Neurone Disease is something many doctors and a wider public would quietly support, but can we avoid paving way to cosmetic or romantic deaths?

For some decades, bioethicists have been concerned that doctors exercise ever less discretion in their dealings with us. Pharmaceutical corporations certainly believe that few doctors have a thought in their minds not put there by them or their competitors.

Company control has extended from the primary consumer, the doctor, to us who go to doctors having diagnosed ourselves with ADHD, ASD (autistic spectrum disorder) or other conditions, based on marketing materials put in our way by pharmaceutical companies. These diagnoses are fashionable and can suck people in, young people in particular, in the way cults do. While some doctors will try to persuade us that consumerism and poisons (medicines) or mutilations (surgery) are not natural bedfellows, and some of us can be persuaded, an increasing number of us complain if we are not given what we want. We have the rating scale score, where’s our drug?

We are now in a world of medical neo-liberalism. Health services have replaced Healthcare.  We face Margaret Thatcher’s phrase of the 1980s – there is no alternative to the logic of the market. While clearly every case must be dealt with on its merits, are we saying anything goes? If anything goes, the strongest players in the game will give us as many disorders as they can and hook us into as many medical services as possible, even assisted dying.

In the case of patients with significant disabilities induced by treatment such as Enduring Sexual Dysfunction or Treatment Resistant Depression, who seek MAiD, will the panels see it as their brief to do anything about this? It’s difficult to imagine MAiD panels raising concerns about companies in the case of patients with lung or other cancers caused by tobacco or other carcinogens. Who benefits from viewing the administration of lethal agents in these circumstances as just a technical operation without entailing wider obligations?

MAiD as a health service contrasts with Healthcare which traditionally has been about relationships that enable people to endure and ‘heal’ – even when the condition is terminal. This is not something technicians or panels can deliver.

It has seemed appropriate to reserve the extreme form of caring that MAiD involves to illnesses rather than distress and extreme illnesses rather than just any disorder.

It has seemed appropriate to have a sanction of murder in place when a doctor supports a patient in this way requiring others to decide if this constituted care. It makes sense not to drag all doctors caring in this way through a murder trial, but by exactly how much do we want to loosen this sanction? Do we want doctors to simply carry out a technical procedure without engaging in the wider issues on behalf of their patient?

Coda

This is where the submission to Policy Options ends.  The original submission had Robert Kaplan’s book in mind but did not mention it.

MAiD can be an act of caring – it can also be the ultimate symbol of the Medical Consumerism whose rise and growing force Shipwreck of the Singular charts and attempts to tackle

Having walked across Sydney Harbour Bridge yoked to Jocelyn Downie I have a permanent attachment to Jocelyn and I know both David and Mona from 20 years ago when I was having difficulties in Toronto – so this comment is not aimed at them in any way.  It reflects my surprise at what seems to be a blind spot in the debate so far.

Finally one of the main driving force behind the debate in Canada – or perhaps that should be braking force is Trudo Lemmens who has been raising concerns for several years about these issues – see Here for his latest.  I know Trudo from 20 years ago also – when Jocelyn, David, Mona and both he and I were all on the same side as I’m sure most people in these debates actually are.  The trick is to avoid one more instance of good intentions leading to a nightmare.

 

Sex, Drugs and a Leap Year Proposal

See Sex, Drugs and Bureaucrats for the start of this correspondence. You will need both posts to understand next weeks Suicide, Drugs and Bureaucrats.

February 26 Rasi to Healy

Thank you for your letter of 31st January 2020 regarding SSRIs and PRACs latest recommendation on the risk of persistent sexual dysfunction after treatment with serotonin and noradrenaline reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs). I am sorry to hear about the suffering of your patients and would like to reiterate EMA’s commitment to public health and that it does everything it can to ensure that medicines are as safe as possible.

You are dissatisfied with the outcome of the assessment and state that patients with Post SSRI Sexual Dysfunction (PSSD) “had hoped for more than the very minimal set of words”. We are sorry that you feel this way. Please note that the wording of the product information reflects the outcome of the assessment. The issue will of course remain under review and the wording of the product information will be updated as necessary to accurately reflect any new knowledge of this risk.

We would like to clarify that sexual dysfunction is a well-known side effect described in the product information of SSRIs. For example, for the antidepressant Cymbalta, sexual dysfunction was highlighted in the product information when it was first authorised in 2004 and was extensively discussed in the initial assessment (report available here:

https://www.ema.europa.eu/en/medicines/human/EPAR/cymbalta).

Please also note that the guideline on clinical investigation of medicinal products in the treatment of depression

(https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigationmedicinal-products-treatment-depression en .pdf)

specifically states that investigators should pay “special attention to the effect on sexual function and libido”. PSSD has not been recognised before and the reasons are described in your letter but are also linked to their late onset making detection in an RCT setting difficult.

You challenge in your letter the way medicines are regulated. We would like to take this opportunity to clarify a few issues:

In line with current legislative requirements, EMA’s role is to establish full benefit-risk analyses for medicines. In order to do this EMA looks at all the evidence submitted to establish the benefits as well as the risk profile of a given medicine. Only if the benefits outweigh the risks for a given medicine can EMA recommend a medicine for marketing.

Like all medicines regulators worldwide, and in line with the principles of evidence-based medicine, EMA considers RCTs to be the gold standard for measuring medicine effects in most cases and provides guidance on their use to support licensing applications. For further information you may wish to consult the above-mentioned guideline which describes how this applies to antidepressants. It is not the case, as you claim, that a randomised controlled trial deliberately only looks at a particular benefit and ignores any side effects. RCTs are explicitly set up to investigate safety as well as efficacy and EMA assessment reports include extensive information on the safety profile of each medicine — indeed, it would scarcely be possible to provide a benefit-risk assessment if we did not require evidence on the risks to be collected. In this context the guidelines on clinical investigation also identify the specific side effects that should be monitored in clinical trials.

As for any clinical trial there is a legal obligation for companies to report all suspected side effects. For further information on the safety monitoring during clinical trials please refer to the following link:

https://ec.europa.eu/health/documents/eudralex/vol-10 en and in particular

htts://ec.europa.eu/health/sites/health/files/files/eudralex/vol10/2011 c172 01/2011 c172 01 en.pdf

Once authorised, the benefit risk balance of medicines is always monitored and confirmed through regular benefit risk analyses (so-called PSURs – https://www.ema.europa.eu/en/human—renulatory/nost-authorisation/pharmacovigilance/periodic-safety-undate-reports-psurs).

It is not only during clinical trials that side effects are closely monitored. Companies must always report any side effects that occur with a medicine worldwide, which are then analysed by regulators as part of their regular safety monitoring of medicines as mandated by legislation (Art 23 (2) of DIR200 1/83/EC).

We therefore strongly encourage you and affected patients to notify side effects to the relevant national competent authorities so that the reports can be taken into account for the safety monitoring of these medicines.

Please note that EMA, in collaboration with EU Member States, will continue to monitor sexual disorders as it does for all safety issues in general. EMA will take necessary action in case a new safety issue is identified. This may include a further update of the product information or other regulatory action. You can find more information about pharmacovigilance in the medicine lifecycle on EMA’s website:

https ://www.ema .europa.eu/en/human-regulatory/overview/pharmacovigilance

overview#pharmacovigilance-in-the-product-lifecycle-section

Finally, regarding your point on the redaction of personal data, please note that this is done to protect patients’ privacy, in line with current EU law which we are obliged to follow just like any private company or public institution. We would like to clarify that deleting personal patient data does by no means impact the causality assessment.

I assure you of EMA’s unwavering commitment to safeguard public health, and to do all it can to ensure that medicines are as safe as possible and that side effects are identified and assessed continuously, before and after marketing authonsation. In this context EMA acknowledges that despite many approved antidepressants (most of them approved many years before EMA came into being) and a reappraisal of the role of medicines vis-à-vis other treatments such as psychotherapy, there is still a need for new medicines with better efficacy and improved safety profile in patients with depression.

Yours sincerely,

Guido Rasi

February 29th

Dear Professor Rasi

Your February 26th letter elegantly slips by the points raised. Let me reframe them.

  1. Can EMA name a single medical or behavioural condition that leaves those affected able to rub chilli paste into their genitals or rub a hard-bristled brush up and down their genitals and not feel it? And for this condition to remain permanent?
  2. Your mention of the importance EMA attaches to sexual issues on antidepressants feels rather like closing the stable door after the horse has bolted. Genital numbness is still not mentioned the labels, even though SSSRIs can cause genital numbness within 30 minutes of a first tablet and EMA, when licensing dapoxetine, have had RCTs demonstrating essentially this.
    1. As described in the petition, two 1990s trials showed SSRIs reduce genital sensation.
    2. As described, all of the medical literature on PSSD identifies genital numbing as a side effect of these drugs, including a BMJ editorial this week.
    3. The named reports we provided from PSSD sufferers all identify genital numbing as a side effects of the drugs.

What else would it take to get genital numbing added to the label?

  1. As you can see from data sent to you over a year ago, full-blown PSSD can happen within days of a first dose so your point about it not happening in the timeframe of the usual RCT is irrelevant. Neither you nor I know if such cases have happened in RCTs without an RCT with this as a primary endpoint, especially when companies tell investigators not to ask any questions about sex. Are you waiting for one to be set up?
  2. I have indicated that there may be cases of PSSD in healthy volunteer studies of only 2 weeks duration carried out in the 1980s; has EMA reviewed any of these?
  3. You have not contested the point that between 50 and 100 million people across Europe are not able to make love the way they might wish. Given your reference to EMA concerns about public health, does EMA have any intentions of intervening in this public health matter of some political significance?
  4. Some people in contact with me have been affected for over a quarter of a century. Regulators in Britain seem to think British doctors can cure PSSD, but they have so far failed to name any doctors or treatments that might be used.  Does EMA know of any doctors or treatments able to cure or even significantly alleviate PSSD?
  5. Why do EMA and other regulators not take the same approach to establishing cause and effect in the case of adverse events as pharmaceutical companies?
  6. Given the necessity of interrogating patients in order to establish cause and effect in the case of adverse events, have EMA taken any steps to reconcile this need with issues of patient confidentiality?
  7. Would you accept that regulators and guideline makers essentially never discover treatment related adverse effects?

Risk-Benefit

Your letter doesn’t take up the risk-benefit challenge posed to you.  I’d appreciate any input on the origins and meaning of this term that EMA can offer.  As mentioned, Dr. Jordi Linares placed great, almost sole, weight on RCT data when making a risk benefit assessment, but the effects of SSRIs on sex and the ability of RCTs to make effects like these to disappear almost entirely seem to blow a hole in that strategy.

I was involved in several industry cost-benefit analyses in the early 1990s. It was wonderful to be able to “prove” drugs like the SSRIs that cost 50 times more than imipramine, or risperidone which was 100 times more expensive than chlorpromazine, were actually saving money. It all depends on the data and assumptions you feed into the system.  None of the SSRI modelling fed in figures of 5-10% of the population being hooked on them of the contribution this might make to declining birth rates in certain ethnic groups.

I’m sure that at some level you must see that it’s not realistic to view risk-benefit analyses as involving anything other than a baptizing of a new drug with a sprinkling of fairy dust.

On a wider front, it was clear in the RCTs used for licensing SSRIs there were more suicidal acts and both suicides and deaths on active treatment than on placebo in the subset of trials shown to regulators. I think it was right to license SSRIs, but I am flummoxed by your suggestion that the data allowed you to license them on the basis of a risk benefit analysis.  Perhaps you can explain?

Licensing, with an acknowledgment of hazards that ensured clinical discretion would be brought to bear on when to use these drugs and how to respond in the event of an apparent hazard, would have been appropriate.  But one of the first uses of risk-benefit terminology by regulators was in 1991 when FDA, faced with concerns about Prozac and suicide, opted not to warn stating this might put people off seeking a benefit.

This approach puts doctors in the firing line if they exercise clinical discretion or stick to their guns that SSRIs can and do make patients suicidal.  People with PSSD can also tell you what it’s like to be ridiculed and referred for counselling or treated as lepers by doctors who, understandably, in the absence of a warning figure regulators like EMA endorse their denying that PSSD can be triggered by treatment.

Whenever there is a dispute about issues, an operational approach – like your supposed risk-benefit analysis – can look appealing.  But, unless agreed to by all sides of a dispute, operational approaches are amoral. They do not take right and wrong or human suffering into account.  Were any PSSD sufferers contemplating suicide to take a comparable risk-benefit approach, they might well consider it would be of greater benefit to other PSSD sufferers to take a suicide bomb into the offices of a major regulator than to kill themselves in a manner that disturbed as few others as possible.  This would be immoral, however, and few people ever take an approach life this without the shield of a bureaucratic apparatus.

I hope you hear a call on your humanity here rather than a call to beef up the security of your building.  I am confident that those with PSSD will act with humanity but less confident that regulators will.

Nicola Blackwood

I attach a letter from Nicola Blackwood, then in Britain’s Dept of Health to Wera Hobhouse MP, in response to a letter occasioned by one Ms Hobhouse’s constituents who has PSSD.  This offers a galling example of politicians regurgitating stuff fed them by regulators that leads to patients and doctors being dismissed by people who know nothing.

Faced with an issue like PSSD, politicians say they are critically dependent on advice from regulators (MHRA now in Britain) and the framers of guidelines (like NICE).  NICE and MHRA have made it clear in correspondence with me that it’s not their job to sort out issues of access to clinical trial data or police the ghostwriting of the medical literature.  In a good example of the Deep State that fuels populist rage, both MHRA and NICE on one side and politicians on the other hide behind risk benefit mumbo-jumbo, which, deployed in sonorous tones like the Wizard of Oz once used, they hope will stop awkward questions.

It also leaves doctors, who in 1962 were thought to be a critical part of the regulatory apparatus, behind. Regulatory bureaucrats were supposed to listen to people like me but, when it comes to matters like this, doctors are like salt that has lost its saltiness – good for very little.  They act like politicians who wait on bureaucrats to tell them what’s what.

I hope you do not find the tone of this letter too hostile. I blame my profession more than I blame you.  I worry that our failure to recognize our role means that pretty soon we will survive in name only, effectively practicing as middle managers ensuring that nurses and others keep to guidelines and the labels of drugs regulators have approved – I initially said authorised.

I hope you appreciate the date of this proposal.

Yours sincerely

The Fault Lies in Our Stars

The Fault lies in our Stars not in Ourselves:
Randomized Controlled Trials & Clinical Knowledge

In the Beginning

In 1947, a trial of streptomycin introduced RCTs to medicine.  From then, through to their incorporation into the 1962 amendments to the Food, Drugs and Cosmetics Act, occasioned by the thalidomide tragedy, there were questions about the epistemological link between RCTs and clinical reality. Since 1962, there have been disputes about the best statistical approach to take to RCT data – whether confidence intervals are preferable to significance testing, for instance. There have also been efforts to account for a heterogeneity of treatment effects (HTE) within the wider Evidence Based Medicine (EBM) movement, which touch on the issues raised here, but this questioning assumes RCTs connect with clinical reality and the only task is one of smoothing some statistical edges.

Repeated characterizations of RCTs as offering gold-standard evidence likely leave many clinicians thinking these trials have a solid epistemological foundation, even as clinicians recognize difficulties in translating from population or average effects to individual patients. In legal settings, RCTs are pitched as generating evidence that is generalizable and knowledge that lies within confidence limits in contrast to the views of clinicians and case reports.

Pre 1962: Hill, Fisher and Randomization

A Medical Research Council trial of streptomycin in 1947 demonstrated the feasibility of randomization as a control of the subtle biases involved in evaluating a medicine. Tony Hill, the MRC trial lead, got the idea of randomization from a horticultural thought experiment about fertilizers outlined two decades previously in which Ronald Fisher proposed that randomization could control for unknown confounders. Hill thought that randomization might control for the difficult to detect ways in which clinicians steer patients likely to respond well into an active treatment arm.  Hill’s randomization was a method for fair allocation, not a means of controlling for the unknowns linked to doctors not knowing what they were doing (Healy 2020).

Hills’ trial missed the tolerance that develops to streptomycin and the deafness and other problems it causes – information evident in a prior trial of streptomycin that controlled for confounders in the then standard way and depended on clinical judgement (Healy 2020).

RCTs brought statistical significance in their wake because Fisher argued that the only things that can interfere with expert judgement not being correct every time are unknown confounders and chance. Significance testing could control for chance and randomization for unknown confounders. Fisher’s model had an anchor in the real world – an expert whose judgements were invariably correct – such as offering a view that wearing a parachute if you jump from a plane at 5,000 feet will save your life. For Fisher, experiments were a way of demonstrating that we knew what we were doing rather than a leap into the unknown. They should get the same result every time.

The more doctors know what they are doing, the more they approach Fisher’s expert, but no one runs RCTs in situations where we are likely to get the predicted result every time.

In the case of breast cancer, on the basis of advances in physiology, it was hoped that giving Herceptin to Her 2+ receptor breast cancers might produce better responses than cisplatin, a more indiscriminate toxin, which nevertheless extends longevity compared to placebo. Trials confirm this but also reveal that even using Herceptin in Her 2+ breast cancers, we do not get the same result every time – there is a lot we don’t know.

In contrast, in trials comparing stents to other cardiac procedures, doing what seems physiologically obvious does not produce the expected results.  The issue is not whether stents work but whether we know what we are doing, which we mostly don’t. While recent stent trials demonstrate the power of RCTs to stall a therapeutic bandwagon, the view that clearing blocked arteries might not produce a good outcome had been accepted clinical wisdom in vascular leg surgery and for stents in some quarters prior to any RCT.

Pre 1962: Neyman and Confidence Intervals

Jerzy Neyman and Egon Pearson took issue with Fisher’s real-world anchor – a semi-infallible expert. They borrowed from Carl Friedrich Gauss’ use of confidence intervals to manage the error in astronomical measurements of stars.  Gauss’ ideas were picked up by Pierre-Simon Laplace and their combined input (1809-1827) to the central limit theorem, least-squares optimization and efficient linear algebra provided celebrated benefits for the physical sciences, engineering, astronomy, and geodesy.

Applied to imprecise measuring instruments and invariant entities like stars, confidence intervals have an anchor in the real world, helping us to decide if our varying measures reflect the presence of one or two stars. Taking successive measurements of a pulse in an individual is similar to determining the precise location of a star – the tighter the confidence interval bounding our measurements the more apparent we can do things reliably.

Confidence intervals could be used in a manner consistent with their use in astronomy to distinguish between a repeated set of pulse measurements before and during (but not after) administration of a drug – to one individual. The current use of confidence intervals in RCTs seems predicated on the idea that a cohort of patients in standard parallel group trials can be regarded as a single object like a galaxy. But pulses can increase in response to a drug in one individual and decrease in a second in response to the same drug. This is not measurement error.

In cases like this, claiming the true effect of the drug likely lies near some mean of the effects in a group of individuals, potentially giving us a best estimate of no effect, is wrong. A mechanism to decide whether there are one or two stars present should not turn up the answer there are none.  If the gap between Average Treatment Effects (ATE) and Heterogenous Treatment Effects (THE), despite trial designs to mitigate the problem, is too great, there is some recognition that the notion of ATE falls apart (Kravitz et al 2004).  In the case of stars, we knew enough about what we were doing to make reasonable inferences from varying measurements.  We need to know as much to make comparable inferences when giving medicines – and we rarely do.

1962: Lasagna, Hill & Primary Endpoints

The 1938 U.S. Food, Drugs and Cosmetics Act required pharmaceutical companies to establish the safety of their products. The birth defects thalidomide caused produced a political crisis in which something needed to be seen to be done.  Louis Lasagna, through Estes Kefauver, proposed that companies should also be required to demonstrate treatment effectiveness – an ineffective treatment cannot be safe. The 1962 Amendments to the 1938 Act paired the word Effectiveness with Safety throughout, with two placebo controlled RCTs later proposed by Lasagna as the means of demonstrating effectiveness.

These provisions were put in place before it was realized that demonstrating effectiveness rather than a treatment effect was not a realistic gateway to the market. In 1962, it was also assumed that RCTs offered generalizable knowledge and a positive result would invariably be replicated but this has not been borne out.

Before 1962, RCTs were not seen as offering gold standard knowledge about what drugs do. As Tony Hill put it in a 1965 lecture, RCTs have a place in the study of therapeutic efficacy, but they are only one way of doing so and any belief to the contrary is mad (Hill 1965). Hill’s lecture ties RCTs to the investigation of one effect and places the information they yield within the framework of clinical judgement.

Fisher’s significance testing, and Gauss’ confidence intervals, require a focus on one effect. In medical RCTs, a focus on a primary endpoint is key to ensuring that only chance or measurement error will get in way of the correct result.  Ipso facto, this means RCTs are not a good way to evaluate a medicine.

A horticultural expert focused on whether a fertilizer improved corn yield would likely have no more accurate a view of its effects on worms in the ground or insects in the air than a non-horticulturalist – in respect of whose views significance testing by Fisher’s definition would not be appropriate.  Similarly, Gauss’ confidence intervals applied to measurements of the location of a star are of little use when it comes to pinpointing the trajectories of satellites crossing the path of the observations.

It is often assumed that the primary endpoint in an RCT is the commonest effect of a drug. Treatment heterogeneity leading to wider confidence intervals than are ideal can be accommodated against this background as can missing other effects assumed to be rare or not appearing within the duration of the trial. But the RCT measuring process is often not trained on the commonest thing a drug does. The commonest effect of an SSRI is genital anesthesia, which appears almost universally and within 30 minutes of taking a first pill. It should not be possible to miss it, but this effect has been missed in all RCTs of these drugs for nervous conditions because of an RCT required focus on a primary endpoint.

The measuring attention given to a primary endpoint essentially creates an act of hypnosis in which common treatment effects can be missed entirely or given an incidental status. Casting RCTs as offering gold standard evidence about a drug, rather than one effect of the drug, creates an ignorance about the ignorance they generate.

RCT evidence should never trump an evident safety effect that appears after treatment.  If a person becomes suicidal after taking an antidepressant, the issue of what is happening in that case is a matter of assessing the effects of their condition, circumstances, prior exposure to similar drugs, dose changes on the medication and whether there are other evident effects of treatment consistent with a link between suicidality and treatment. Unless RCTs have been designed specifically to look at the effects of treatment on a possible emergence of an effect like suicidality (and there have been none), RCT evidence is irrelevant and it is pernicious to pitch irrelevant RCTs as science that should count for more than clinical “anecdotes” containing CDR, dose response, and other evidence.

The transformation of RCTs from a hurdle industry had to surmount to make gold into gold standard knowledge has made RCTs a gold standard way to hide a drug’s 99 other effects.

Post 1962: Confounding & Causality

Discussions of the results of epidemiological studies apparently linking drugs to treatment effects often caution that confounding by indication undercuts any easy assumption of a link.  RCTs, which are essentially epidemiological studies, rarely come with this rider.  Many clinicians likely think that randomization takes care of confounding by all unknown unknowns, including by indication, with many saying RCTs demonstrate cause and effect where other epidemiological studies produce correlations.

Consider scenarios involving the antidepressants imipramine and paroxetine.  Imipramine was discovered in 1957 and launched in 1958 without any RCT input. Among other actions, it is a serotonin reuptake inhibitor. In later RCTs, it (and other older antidepressants all discovered and marketed without RCTs) “beat” SSRI antidepressants in trials involving patients with melancholia (severe depression). Melancholic patients are 80 times more likely to commit suicide than mildly depressed patients.

By 1959, clinicians praising imipramine’s benefits also noted it could cause agitation and suicidality in some patients that cleared when the drug was stopped and reappeared when restarted. This Challenge-Dechallenge-Rechallenge (CDR) evidence, especially as it was replicated by several clinicians with different patients, offers close to Fisherian expert like certainty that imipramine causes suicide in certain individuals.

Despite being able to cause suicide, in an RCT of melancholic patients, imipramine seems likely to protect against suicide on average by reducing the risk from melancholia to a greater extent than placebo. In contrast, in the RCTs that brought SSRIs to the market, these drugs doubled the rate of suicidal acts. This was because, weaker than imipramine, SSRIs had to be tested in people with mild depression at little risk of suicide. The low placebo suicidal act rate revealed the risk from the SSRI – as it does for imipramine when put into trials of mild depression. RCTs can, in other words, mislead as regards cause and effect – potentially getting results all the way along a spectrum from “causes”, to possible risk, likely protective and “cannot cause”.

In any trial where both condition and treatment cause superficially similar problems, as when antidepressants and depression cause suicidality or bisphosphonates and osteoporosis both lead to fractures, a dependence on RCT data rather than clinical judgement risks misleading. This is likely the case for a majority of RCTs in clinical conditions, which are Treatment Trials rather than Drug Trials.

Drug Trials are done on healthy volunteers, and ordinarily do not have a primary endpoint.  In these, treatment effects stand out more clearly. SSRI Drug Trials in the 1980s demonstrated sexual effects were common, often debilitating, and might endure after treatment stopped, that agitation up to suicidality was common and that dependence commonly occurred after exposures of two weeks. The correct choice of primary endpoint in subsequent Treatment Trials could eliminate these effects. The non-confidential Drug Trial data remain unpublished.

Paroxetine was later put into Treatment Trials of patients with Major Depressive Disorder (MDD) and patients with Intermittent Brief Depressive Disorders (IBDD). IBDD patients (borderline personality disorder) are repeated self-harmers. The depressive features IBDD patients have mean that they can readily meet criteria for MDD.

In April 2006, GlaxoSmithKline (GSK) released RCT data showing a worrying increase in suicidal events in MDD patients on paroxetine (Table). The data from IBDD RCTs in the GSK release were better.  We can add 16 suicidal events to the paroxetine IBDD column and still get an apparently protective rather than problematic result for paroxetine when MDD and IBDD data are added together.

Table: Suicidal Events in MDD & IBDD Trials

Paroxetine Placebo Relative Risk
MDD Trials Acts/Patients

IBDD Trials Acts/Patients

Combined Acts/Patients

11/2943

32/147

43/3090

0/1671

35/151

35/1822

Inf (1.3, inf)

0.9

0.7

This effect has been noted as a hazard of meta-analyses but it must apply to some extent in every trial that recruits patients who have a superficially similar but in fact heterogenous conditions such as depression, pain, breast cancer, Parkinson’s disease, diabetes or almost any medical disorder. Every time there is a mixture of more than one patient group in a trial, randomization will ensure some patients hide some treatment effects – good and bad. Trials of standard treatments for back pain, for instance, mask the beneficial treatment effects of an antibiotic on back pains linked to infections (up to 10% of back pains).

This is Heterogeneity of Treatment Conditions (HTC) rather than HTE. In epidemiological studies confounding by indication is commonly taken to mean that we should not for example interpret results apparently associating a treatment like an antidepressant with suicidality given the possibility that depression can cause suicidality, but in fact this effect likely more commonly hides the adverse effects of treatment. It is even possible to design Treatment Trials to hide adverse effects – as above.

The assumption is that in Treatment Trials placebos simply control for natural variation.  But placebos can have potent treatment effects, making them another treatment like an antibiotic in a backpain RCT. We do not know enough about placebo responses to know the extent to which, in the context of randomization, they might confound the data.

Every medicine that gets on the market, by definition, beats placebo (often inconsistently).  As a result, it has become unethical to use placebos in clinical practice, when for those for whom it works a placebo may be preferable to therapeutic poisoning.

A quantitative approach to data generated by algorithm rather than an approach based on judgement also increases the risk that minor events in a placebo arm will be offset against significant events in an “active” treatment arm creating an opportunity to claim that nothing specific has happened, when it has.

Finally, the suicidality, sexual dysfunction, agitation, and insomnia antidepressants cause in clinical trials are commonly folded into a primary endpoint, the Hamilton Depression Rating Scale (HDRS), which includes questions on suicidality, sexuality, sleep and agitation. These changes render confidence intervals around scores on these items meaningless, compromise the use of the scale more generally, and risk hiding a benefit.

Post 1980: From Therapeutic Poisoning to Sacraments

In 1947, treatment with medicines was viewed as therapeutic poisoning.  As of 1951, FDA made most new medicines prescription-only on the basis that they are unavoidably risky.  But from the mid-1990s, regulators have licensed drugs on the basis of a favorable risk-benefit profile. This implies a balance in which benefits and risks can be weighed, but there is no balance. One statistically significant effect is taken to count for more than all other effects, even serious effects that occur more frequently and can include death, but which by design are not significant, transforming poisons into sacraments (hyper-real agents from which only good can come).

In 1959, clinicians could readily distinguish between treatment emergent suicidality and suicidality caused by melancholia.  In 1961, Frank Ayd, the discoverer of amitriptyline a year before could distinguish the sexual dysfunction it causes from the sexual dysfunction melancholia causes. Through to 1991, clinical knowledge of the range of effects drugs can cause derived primarily from clinical experience, embodied in case reports and published in clinical journals. A steady rise of mechanical evaluations, however, allied to a sequestration of trial data, has relegated clinical evaluations that drug X causes effect Y, even when buttressed by evidence of CDR, to the status of anecdotes. From 1991, leading journals stopped taking anecdotes about “side” effects that almost by definition must be rare compared to the treatment effect.

As a result, where in the 1960s the harms of treatments took at most a few years to establish after a drug came on the market, by 1990 it could take decades for significant harms such as with impulse control disorders on dopamine agonists, persistent sexual dysfunction on isotretinoin, antibiotics, finasteride and other drugs, mental disorders on fluoroquinolones or leukotriene antagonists, or dependence on psychotropic drugs, to be accepted.

This growing delay underpins a perception that pharmacovigilance is in crisis. Proposed solutions mention the need for systems to detect rare treatment effects not found in RCTs. There is a turn to a mining of electronic medical records or other observational approaches. New signal detection methods and investigative approaches are always welcome, but these are not the answer to the problems we face, which lie not in a failure to detect rare effects but in a systematic failure to acknowledge common effects.

Through to 1991, clinical knowledge also derived from Drug Trials on healthy volunteers and this is almost self-evidently a better approach than relying on signal detection methods.

The ability of RCTs to focus on one effect suits Regulatory Trials but this focus does not suit an evaluation of treatments, the intention of which is to poison or mutilate in the hope of producing an overall benefit. Studies run on a primary endpoint chosen for commercial reasons cannot be expected to produce the kind of information that might inform therapeutic poisoning. Nor can we know a priori if data-handling methods developed for fertilizers and stars can encompass the complexity of therapeutic poisoning.

The question of whether the suicidality the patient in front of me is experiencing comes from their illness or their treatment is not a matter of deciding if there are 1 or 2 stars. In this case, we already know there are two stars and a lot about them, and one patient may have both kinds.  Instruments (checklists) specifically designed with the characteristics of each star in mind may facilitate the distinction between the two, but in practice it’s a case of pattern recognition and a judgement call as to whether increasing or reducing the dose of treatment is more appropriate. The high stakes may make the option of falling back on an operational approach appealing – but it is not good science or good medicine.

If registered on adverse event forms, treatment emergent suicidality or sexual dysfunction should almost de facto be causally linked to treatment. Without clinical context, and the opportunity to dechallenge and rechallenge, faced with a requirement to tick boxes as to the likelihood of a link, the ethos of RCTs, which replaces clinical judgement with decisions based on analytic processes rather than an interrogation of people, steers investigators toward designating the effect as possibly unrelated.

Facing claims in 1983 that spontaneous reporting of adverse events was unsophisticated and not scientifically rigorous, and the only proper method of establishing effects was through trials, Lasagna, once a leading advocate for RCTs, responded that “this was only the case in the dictionary sense of sophisticated meaning “adulterated” and spontaneous reporting was in fact more worldly-wise, knowing, subtle and intellectually appealing than [trials]” (Lasagna 1983).

Implications: Objectivity

A few years later, Lasagna offered the view that:

In contrast to my role in the 1950s which was trying to convince people to do controlled trials, now I find myself telling people that it’s not the only way to truth… Evidence Based Medicine has become synonymous with RCTs even though such trials invariably fail to tell the physician what he or she wants to know which is which drug is best for Mr Jones or Ms Smith – not what happens to a non-existent average person”.

Concerns about what is often termed the population effects of RCTs, or Average Treatment Effects (ATE) and the mismatch between these and the responses of individual patients has been framed in terms of HTE and recognized in EBM as needing an incorporation of RCT evidence into the judgement of clinicians and the values and preferences of patients.  Designating RCTs as offering gold standard evidence, however, effectively side-lines the judgements of clinicians and patients.

The view that RCTs give population or average treatment effects assumes a valid population with individual outliers. In the case of antidepressants, however, there is no knowing how any individual will respond. Fisher expected us to get the same result in every individual case, and within limits confidence intervals offer the same guarantee. Neither Fisher nor Gauss would recognize a problem in translating from a population to an individual level. Diagnostic imprecision, and individual heterogeneity, mean we do not have Gaussian populations. To adapt Shakespeare, the fault lies in our stars not in ourselves.

In recent years, there has been sophisticated consideration of the statistical techniques employed in epidemiological studies, including RCTs (Greenland et al 2017), and of the merits of RCTs applied to complex situations in the social sciences (Deaton and Cartwright 2019).  Both considerations have stressed the role of judgement in deciding what populations and experimental design are appropriate, and how results should be interpreted. Both view RCTs, and related designs using statistics, as assay systems yielding results specific to the system, rather than experiments that generate the ‘knowledge from nowhere’ that means we don’t have to worry whether the laws of gravity will apply to the next patient.

These positions are compatible with the argument here, which is that rather than assay systems that might in the right circumstances offer applicable information, RCTs have become algorithmic or operational procedures.  DSM criteria in mental health, and the metrics for blood pressure, peak flow rates and bone densities are similarly operational. The creators of the DSM criteria claimed that of course just ostensibly meeting criteria for an illness doesn’t mean the person has the illness, clinical judgements are needed to establish what is really going on, just as they are in the case blood pressure, peak flow or bone density readings. In practice, however, operational exercises like RCTs, DSM criteria, and many medical metrics nudge us toward a suspension of judgement and put a third party, like the pharmaceutical industry, in a strong position to contest any introduction of judgement by a doctor or patient on the basis that the figures are supposedly more objective than any clinician or patient judgement can be.

Even facing strong epidemiological evidence that a drug causes birth defects or strokes, many clinicians will dismiss these as observational data and be unwilling to adjust practice until an RCT has demonstrated the effect.  Industry openly play on clinical difficulties in identifying RCTs as producing observational data.

Science traditionally generates data and challenges us to interpret them. New techniques (like a new drug) can throw up new observations (data) that challenge prior judgements. The application of statistical techniques to data yields outputs, not observations. While these techniques and their outputs can be useful, the mission of science has not been to replace judgement by technical outputs.

Individual judgement of course is suspect. This argument does not advocate replacing collective evaluation by a reliance on individuals or doctors; the argument is for collective evaluation rather than its replacement by algorithmic processes. Collective evaluation has a clear footing in the real world, as the Mayo Clinic streptomycin trial demonstrated.  The idea that clinical RCTs as happen now have as clear a footing is assumed not established.

Arguments favoring RCTs to point to a small series of treatments, such as internal mammary ligation, that RCTs demonstrated did not work, with the implication that clinical judgement can get things wrong. The internal mammary ligation trial only happened because the dominant clinical judgement was that this treatment didn’t work – an article in the Reader’s Digest notwithstanding. And randomization didn’t work in this 17-patient trial.

These arguments fail to note that most of the current treatment classes we have were introduced in the 1950s without RCTs. That the treatments introduced then from anti-hypertensives and hypoglycemics to psychotropic drugs are more effective than treatments introduced since.  That RCTs facilitate the introduction of treatments with lesser effects.

Our most important failure is our complicity in a sequestration of trial data, fooled perhaps in some instances into thinking that analytic outputs are data. Data means the people entering into a study, who lie behind any table of figures or the outputs of any analytic process applied to those figures. At present, with the exception of a very few RCTs, case reports with names attached are the only form of controlled clinical investigation that offer the possibility of interrogating the data and an opportunity to ground any conclusions in the real world.

Drug interventions (therapeutic poisoning) invariably harm; the hope is that some good can also be brought from their use.  Evaluations of a medicine by RCT harm (generate ignorance), but if used judiciously some good can be brought out of the ignorance they necessarily generate. It is less likely that good will be brought out of ignorance, if we rely solely on a data handling formula. Analytic methods can describe data but whether good comes from their use requires the kind of judgement calls that statistical approaches ordinarily make a virtue of side-lining. A recent study looking at 29 ways to analyze a dataset, generated from referees giving red cards to dark and light-skinned soccer players, demonstrated that different techniques can lead to a wide variation in results with none able to guarantee what is happening in the real world (Silberzahn et al. 2018).

Clinical practice is essentially a judicial rather than an algorithmic exercise.  The view offered here is that our best evidence as to what happens or is likely to happen on treatment lies in the ability to examine and cross-examine the persons (interrogate the data) given that treatment. What holds true at the individual level must be true at the population level also.  The evaluation of a treatment cannot be algorithmic.

An endorsement of clinical judgement does not suit health service managers or the pharmaceutical industry, for whom the supposed generalizability of RCT knowledge and confidence intervals that can be offered for such knowledge are legally appealing.

Implications: The Place for Randomized Controlled Trials

Randomization, placebo controls, confidence intervals and primary endpoints all have a place in the evaluation of treatments.  Confidence intervals are clearly appropriate in instances where measurement error is likely to play a part.  Randomization is an extra control on clinical bias. There is a place for it, unhooked from primary endpoints and statistical significance, as happens in large pragmatic trials – but here the word pragmatic concedes our limited understanding of what we are doing.

An increasing use of RCTs in social science, economic and political settings makes it clear that complexity is not a necessary bar to their use in trials with an appropriate focus on a primary endpoint. In medicine, the multidimensional nature of therapeutic poisoning adds an extra layer of complexity and makes a focus on a primary endpoint problematic, other than when a claimed benefit is contested.

RCTs may be better suited to evaluate time-limited surgical interventions as opposed to chronic therapeutic poisoning, as well as in studies to evaluate programs, and treatment studies that have an endpoint like all-cause mortality, but even here we risk being misled by findings of no change in mortality into missing a switch from cardiac events to cancers when many patients might prefer to die by heart attack (Mangin et al 2007).

RCTs also have a merit as a gateway to the market; randomization means that trials require less patients and can be run quickly. A positive result in commercial trials may indicate a compound has an “effect”. Trials aimed at establishing effectiveness, in contrast, require hard outcomes and time. This is not a realistic gateway to the market. Demonstration of an effect, as with SSRIs for depression, means it is not correct to say this drug does nothing and on this basis entry to the market could be permitted, although strictly speaking this is inconsistent with current statutes.

After 1962, RCTs became the standard through which industry would make gold, As they proliferated, the mantra that they provide gold standard medical evidence took hold. The ignorance of ignorance in claims that the only valid information on medicines comes from RCTs compounds a series of other factors that make RCTs a gold standard way to hide adverse events and encourage over-use of treatments.

The launch of a drug licensed on the basis of a treatment effect should be the point when more comprehensive clinical evaluations start, aimed at generating consensus as to the place of the drug in practice. As a general tool to evaluate the effects of a drug, Regulatory Trials should take second place to both the observations of a group of experienced clinicians, unconstrained by checklists and an investigation tailored to one effect, as well as to the values of patients who increasingly need to reduce their medication burden to achieve optimal benefits.

In addition, seasoned clinicians, allied to increasingly health-literate patients, are better placed than RCTs to determine cause in the case of the 99 other effects every drug has, especially effects such as sexual or suicidal effects of antidepressants, which need to be distinguished from superficially similar condition effects.

The fact that pharmaceutical companies run “RCTs” for regulatory and marketing purposes may have generated a belief that any problems with RCTs stem from a link to commerce.

The difficulty in recognizing adverse effects has for instance been compounded by company sequestration of trial data and ghostwriting of the clinical literature that hypes the benefits and hides the harms of treatments, compounded by a regulatory willingness to avoid deterring patients from treatment benefits by placing warnings on drugs.

Clinical practice is also compromised by licensing indications and by guidelines.  There are no drugs licensed to treat adverse effects. When a person becomes suicidal on an SSRI, there is no treatment licensed to treat this toxicity. Clinicians wanting to help feel compelled to diagnose depression rather than toxicity but a depression diagnosis inevitably leads to a further treatment with an antidepressant rather than something more appropriate like a benzodiazepine, a beta-blocker, or red wine.

The incorporation of RCTs into the regulatory apparatus has introduced surrogate markers, which mean that in real life treatments may not show effectiveness consistent with RCT demonstrations of a treatment effect. Trials showing antidepressants work, for instance, have more deaths and both suicidal and homicidal events in their treatment arms compared to placebo.

Commercial trials have given rise to the idea of an abstract Risk-Benefit ratio which along with treatment effect sizes, the Number Needed to Treat (NNT) or to Harm (NNH) are based on the outputs from analytic processes rather than in clinical reality.

Possible answers to these problems lie with medical journals who should insist on the publication of data from Drug and Treatment Trials. Our hierarchies of evidence should come clean on whether they regard a ghostwritten article without access to trial data as better than or inferior to a Case Report that embodies dose responsiveness and CDR elements. And those deploying an analytic process should clarify how the resulting outputs might translate into the real world, rather than assuming they do.

It is not unreasonable to want to discard the industry bathwater but save the RCT baby. But doing so requires an explicit recognition that industry activities avail of an epistemological gap between the conduct of RCT assays and a consideration of the implication of their results rather than constitute the gap.

Coda

Evaluating treatment effects properly is hugely important. When drugs work, they can like parachutes save lives. Given the importance of the task, the notion of a hierarchy of evidence topped by mechanisms that do the deciding for us has a potent allure.

Relegating judgement to the bottom of the evidence hierarchy in medicine brings out our discomfort with judgement. Succumbing to an operational solution, however, is at least as dangerous as depending on judgement.

RCTs have led many to view drug treatments as comparable in effectiveness to parachutes.  As a result, by the age of 50, close to 50% of us are now on three or more drugs and by the age of 65 on 5 or more drugs. For the past five years, our life expectancies have been falling and admissions to hospital for treatment-induced morbidity rising, an outcome that contrasts with the added safety of having parachutes and other gadgets in planes (Healy 2020). Adding parachutes and gadgets that are effective (rather than just have an effect) enhances aviation safety, although recent Boeing crashes point to the perils of too great a reliance on automatic decision tools. Combining five pluripotent drug gadgets almost certainly brings risks of interactions that airplane gadgets don’t bring and current data indicates that reducing medication burden from 10 or more drugs to 5 or less reduces hospitalization, increases life expectancy and improves quality of life (Garfinkel and Mangin 2010). But if RCTs of medicines essentially produce evidence that it is not correct to say this drug has no possible benefit, rather than that they are effective, our methods of evaluation rather than just the chemicals we prescribe may be contributing to increasing levels of mortality and morbidity.

Recent data on life expectancies and treatment linked morbidities call for an evaluation of the role of RCTs in the evaluation of drug treatments (Healy 2020).  So does data indicating antidepressants are now the second most commonly used drugs by young women in the face of 30 out of 30 trials negative on the primary outcome, which advocates of RCTs, with no links to industry, claim to be able meta-analyze and extract positive effects from data taken from ghostwritten publications, without access to trial data.

References:

Deaton A, Cartwright N (2018).  Understanding and misunderstanding randomised controlled trials.  Social Science and Medicine 2018, 210, 2-21.

Garfinkel D, Mangin D.  Feasibility study of a systematic approach for discontinuation of multiple medications in older adults.  Arch Intern Med 2010, 170 1648-54.

Greenland S, Senn SJ, Rothman K, Carlin JB, Poole C, Goodman SN, Altman DG. Statistical tests, P values, confidence intervals, and power: a guide to misinterpretations.  Eur J Epidemiol, 2016, 31:337–350.

Healy D, The Shipwreck of the Singular; Healthcare’s Castaways. Samizdat Press, Toronto (Forthcoming 2020).

Hill A.B. Reflections on the Controlled Trial. Annals Rheum Disease 1966; 25, 107-113.

Kravitz RL, Duan N, Braslow J.  Evidence-based medicine, heterogeneity of treatment effects, and the trouble with averages.  Milbank Quarterly 2004; 82; 661-687.

Lasagna L. Discovering adverse drug reactions. JAMA 1983; 249: 2224-5

Mangin D, Sweeney K, Heath I.  Preventive health care in elderly people needs rethinking. BMJ 2007, 335 285-287.

Silberzahn S, Uhlmann EL, Martin DP, et al. Many Analysts, One Data Set: Making Transparent How Variations in Analytic Choices Affect Results. Advances in Methods and Practices in Psychological Science. 2018; 1:337-56.

Explanatory Note

An earlier version of this article was sent out to over 20 senior figures with expertise on areas to do with RCTs and Evidence, chosen mostly by Mark Wilson.  Their responses are reproduced in Fawlty Stars

Publication of the target piece and responses happens in some journals but throwing the argument open to anyone who wishes to contribute is a unique venture in peer review.

The argument lies at the heart of Chapter 6 of Shipwreck of the Singular which will be published in January 2021. The extra details in Shipwreck may help with getting to grips with what is going on.  

The Raine in June Falls Mainly in …

June Raine featured in the international media last week as the public face of Britain’s MHRA (drugs regulatory agency) when they became the first agency to license a Covid vaccine. A journalist, who had unearthed a letter of mine from 20 years ago, got in touch with me asking to talk by phone about whether I would be confident about JR’s claims that we all could have confidence in the vaccine.  We never got to talk. 

Dr June Raine, Director of
Post-Licensing Division, MCA
Market Towers, 1 Nine Elms Lane
LONDON SW8 5NQ

7 June 2000

Dear Dr Raine,

You may or may not have heard that yesterday in Cheyenne, Wyoming a Court found Glaxo SmithKline guilty on several accounts including the count that Paroxetine can cause suicidality, that it specifically did so and contributed to the wrongful death of Don and Rita Schell as well as Deborah and Alyssa Tobin and that the company had been responsible for a failure to test and a failure to warn. You may also be aware of a verdict in the Hawkins case in New South Wales some weeks ago where a Supreme Court Judge made it clear that in his opinion Mr David Hawkins would not have murdered his wife but for the influence of Sertraline.

In the course of my work as an expert witness in Tobin versus SmithKline I got the chance to look at SmithKline’s healthy volunteer database in Harlow. Their characterisation of this for you was that: “There were no reports of suicidal thoughts in any of the volunteer studies. There were few reports of ’emotional lability’, however these reactions were not found to be related to suicidal thoughts or behaviour. Some volunteers reported anxiety, nervousness and agitation while taking paroxetine, however the most commonly reported adverse events were nausea, diarrhoea, drowsiness and insomnia”.

What I found was that approximately 25% of the volunteers in the studies that I reviewed which were all of the healthy volunteer studies done prior to the filing of this drug for registration in the US and in the UK – 34 studies approximately in all. These yielded a 25% agitation, nervousness/akathisia rate. Some of the multiple dose studies in healthy volunteers lasting 2-3 weeks yielded an up to 85% withdrawal rate in the volunteers.

All of their healthy volunteer studies were supposed to have been made available to me but not all were. Of the ones that were missing there was trace correspondence left in once indicating that the investigator had never witnessed such a level of problems in a study with healthy volunteers. Another study was a single dose study which in a dose dependent fashion yielded a 75% rate of severe adverse events most of which involved the central nervous system. There were other disturbing indications from one of the other missing studies.

Volunteers who had participated in the programme went on to suicidal acts. The relationship between their intake of paroxetine and later suicidal acts is a matter about which neither you nor SmithKline Beecham should be sanguine.

These studies were for the most part done on company employees. None of the studies bar the missing ones were done by investigators with a background in psychiatry. The investigators were general physicians with a primary interest in gastrointestinal problems who could not have been expected to detect mental problems of this sort that have concerned me and I would have thought should concern you.

My testimony in this case also bore witness to sealed studies and other unreported data. It commented on the Montgomery Baldwin Study which yielded a projected rate of 45 suicide attempts in a group of recurrent brief depressive disordered patients on paroxetine per annum versus 12 on placebo. The figures were not statistically significant in great part one has to suggest because the company had terminated the study early. This termination and subsequent non-publication I would imagine the jury will have found and others will find significant.

[Addition Dec 2020:  Montgomery was a member of the CSM-MHRA apparatus at the time licensing these drugs – see attached Montgomery Notes].

Dr Hudson, currently of the MCA, was a witness for SmithKline in this case. He may well be able to give you further details on some of the issues involved. His testimony involved repeated reference to the fact that SmithKline Beecham cannot decide whether their drug had caused problems such as the wrongful death of Don and Rita Schell or Deborah and Alyssa Tobin or the wrongful deaths of many other people whose deaths have been reported to SmithKline even when these reports have been accompanied by the opinions of their treating physicians that the drug had indeed contributed to the problem. Dr Hudson’s testimony was that until controlled trials or other similar studies had proven in general that paroxetine could cause such problems that the company could not make decisions on any specific case.

[Addition Dec 2020:  Hudson left GSK in the midst of this trial and joined MHRA later becoming its CEO – succeeded now by June Raine].

This appears to me a Black Hole defence. It is entirely conceivable that tens of thousands of suicides could disappear into this Black Hole without either SmithKline Beecham, Pfizer or Eli Lilly being called upon to make any judgements as to whether their drug was contributing to the problem. The lack of evidence from randomised controlled trials or epidemiological studies in this context is not evidence of a lack of a problem. It stems explicitly from failures of SmithKline Beecham, Pfizer or Lilly to do the requisite studies. Both David Wheadon and Christine Blumhardt from SmithKline as well as Roger Lane from Pfizer and Charles Beasley from Eli Lilly along with outside experts such as Daniel Casey and John Mann have testified under oath in the course of the last year that there have been no studies undertaken by any of these companies or others that have been designed to test whether the SSRIs could cause a problem. I believe that this will in due course be seen for the extraordinary state of affairs that it is.

I think what will also be clear is that SmithKline Beecham recognised the presence of withdrawal syndromes in their volunteers from the early to mid 1980s. That withdrawal syndromes occurred at a much higher rate than occur on benzodiazepines. Nevertheless they applied for and have received from you and other regulators a licence to claim that their drug is effective in the prophylaxis of depression and these claims have been based on designs which almost certainly are designs better suited to show the presence of a withdrawal syndrome than designs suited to demonstrate prophylaxis in depressive disorders. A great number of people have in recent years been told that when they begin to feel ill on discontinuing treatment that this is the recrudescence of their mood disorder rather than a discontinuation syndrome from their drug. I would imagine that a great many such people and others on their behalf will feel extraordinarily let down and angry when faced with the evidence that I’ve been faced with.

Yours sincerely

David Healy MD FRCPsych
Director, North Wales Department of Psychological Medicine

A copy of the Original Letter is Here.

 

Frontiers in Psychiatry: Elena Vicario

Some weeks ago, following the publication of an article by Andrea Cipriani in their journal, Jim Gottstein and I wrote to the Frontiers in Psychiatry Bigwigs asking for the Cipriani article to be removed – Meta-Analytic SuperSpreader.

They have since replied Vicariously through Elena Vicario.

From: Editorial Office <editorial.office@frontiersin.org>
Date: Tue, 3 Nov 2020 at 04:34
Subject: Re: Letter re Retraction
To: David Healy <david.healy54@googlemail.com>

Dear Dr. Healy,

I am writing with an update on our investigation into the concerns raised about article “Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment”.

Following the assessment of the journal Chief Editor, the methodology and systematic protocol used in the article is in line with PRISMA guidelines and the articles included in the systematic review are clearly outlined and available for consultation by the readers. In addition, we note that the conclusions drawn by the authors from the meta-analysis are cautious and broad.

We recognize the importance of the subject matter and thank you again for bringing this to our attention.

Best regards,

Elena Vicario, PhD

Senior Manager, Research Integrity: Elena Vicario, PhD
Frontiers | London Office
12 Moorgate
EC2R 6DA
London

Most people reviewing the issue of the journal, likely Elena too, figure matters are pretty balanced overall with all other articles skeptical about the use of antidepressants for children and teenagers and a hard hitting editorial from Michael Hengartner to make matters absolutely clear.

This not however how the system works.  Decades back, at academic meetings, in what seem like more innocent times, pharmaceutical companies were good at having someone talk about CBT, or another therapy, for depression on a program mostly dedicated to selling some antidepressant.

It looked like there was a degree of balance you might expect from a scientific meeting but the idea of having a therapist in practice came closer to the vaudeville model of having a comedian come on stage in between striptease acts.  The customers needed a chance to draw breath and relax and perhaps an excuse to tell people where they had been – they weren’t there for the comedian.

Its the same in this case, even though there are eight or nine comedians and only one stripper. The internet and open access makes it possible for industry to distribute the Cipriani article far and wide and for free and even to be able to point to its publication in a virtuous setting – almost nothing but comedians – while doing so.  The eight or nine other pieces will go nowhere fast.

There is probably an appropriate riff on the old line about lies getting half way around the world before the truth gets its boots on.

There is another unsettling angle.  The editors are essentially blaming Michael H.  They’ve deferred to his judgment call as to whether there is an issue here.

It’s what Jose-Mario Bergoglio, Donald Trump, Joe Biden, Emanuel Macron and any other ‘leader’ you care to mention would do.  When asked about ghost-writing combined with a lack of access to trial data, something that is not acceptable in any conceivable scientific universe,  the fall-back line is ‘we’re not scientists, we will check with EMA or FDA or MHRA or whoever’ and ‘we’re sure you will understand we have no option but to do as they advise us’.  See The Perfect Killing Machine.

To be absolutely clear, my problem if I were one of the comedians in this show is not that there is a paper offering another point of view, its that there is a paper masquerading as science, which is just not science.  A cuckoo in the scientific nest.

Its a bit like if in the old Vaudevillian days a Drag Queen had done a striptease.  The audience would likely have seen this as a comic act.  These days apparently Drag Queens do striptease’s in front of children – for equality’s sake.  And, besides what their advisers say, for equality’s sake Jose and Joe and Emanuel likely feel they cannot prevent a Cipriani article (of this type) being passed off as science.

In this case Michael Hengartner has no option but to take the blame. Once the requirements of the algorithm are satisfied, two positive reviews, there is no option but to publish.

There was a notable fuss last week about a Danish Mask Trial, which failed to show a convincing benefit for Masks in the current pandemic – perhaps because it didn’t ask the right questions.  It was nevertheless a trial – the only trial of Masks in a time of Covid.  When several doctors linked to it on Facebook pages, they found their link was blocked on the basis that they were posting misinformation.

A lot of mostly male docs were offended – how dare Facebook do this.  But there is no-one doing this to anyone.  The algorithm is doing it.

It hasn’t fully drawn all power to itself – there is still a missing ring, a precious, that needs retrieving.  Soon now…

 

 

Michael Hengartner, Andrea Cipriani and Frontiers in Psychiatry

Meta-Analytic SuperSpreader outlined a disturbing sequence of events leading up to the publication of an article by Andrea Cipriani and colleagues effectively promoting the benefits of antidepressants.  Andrea and colleagues are part of an Oxford University Precision Psychiatry ‘lab’.  The idea that this article in some way helps move us toward a precision psychiatry is mind-boggling.

Michael Hengartner ended up as the only editor standing for the issue of Frontiers Psychiatry in which the Cipriani article appeared.  He wrote a covering editorial for the collection of articles that mentions the Cipriani article and that most readers will think tries hard to get over a ‘decent’ message – there will be more on being decent in a follow-up post.

Antidepressant Prescriptions in Children and Adolescents

The use of antidepressants in children and adolescents has a troubled history, for almost all principles of good evidence-based medicine were violated or compromised. It is a history characterized by systematically biased research, financial conflicts of interest, and professional recklessness (13). In 2004, the Lancet Editors (4), in an article titled “Depressing research” bluntly stated that “The story of research into selective serotonin reuptake inhibitor (SSRI) use in childhood depression is one of confusion, manipulation, and institutional failure” (p. 1335). It is now well-established that most pediatric antidepressant trials were industry-sponsored and had serious methodological limitations; many trials remained unpublished due to unfavorable results, and those published were mostly ghost-written, selectively reported efficacy outcomes and misrepresented the true rate of treatment-emergent suicidal events (59). Drug regulators issued a suicidality warning for pediatric antidepressant use in 2003 (MHRA) and 2004 (FDA) and advised to use fluoxetine only. By consequence, some authors argued that SSRI should be reserved as a second-line option for youth with severe and resistant forms of depression (10).

However, in most countries antidepressant use has considerably increased in children and adolescent over the last 10–15 years (1113), despite suicidality warnings, the serious limitations of the evidence-base (14), and ongoing controversies surrounding risks and benefits (15) as well as the placebo response (16). The aim of this special topic was thus to provide a collection of articles broadly focused on two main issues; first, on the current scientific evidence for the efficacy and safety of antidepressants, with a special emphasis on suicidality and related regulatory warnings, and, second, on recent trends in prescription rates and patterns of utilization, including antidepressant overuse, and the increasingly medicalized approach to mental health.

Safer and Zito reviewed the efficacy of new-generation antidepressants for pediatric depression. They found no meaningful benefits in children and only marginal benefits in adolescents based on placebo-controlled short-term trials. Moreover, they considered the evidence for maintenance treatment based on discontinuation (placebo-substitution) trials problematic and inconclusive due to high dropout rates, potential withdrawal syndromes that mimic relapse, and relapse rates not dissimilar from the natural course of the disorder.

Boaden et al. conducted a meta-review on the efficacy, tolerability, and suicidality-risk of antidepressants for the treatment of various pediatric disorders. The meta-review found that just a few antidepressants were effective and well-tolerated. For instance, only fluoxetine was more effective than placebo in major depression, and only fluvoxamine and paroxetine were effective in anxiety disorders. Venlafaxine (in major depression) and paroxetine (in anxiety disorders) were associated with significantly increased risk of suicidality. However, of the nine meta-analyses included, only one met criteria of high quality; five were rated moderate quality, one was of low quality and two of critically low quality. The authors further state that the quality of the available evidence is inadequate due to short trial duration, selective reporting and publication bias, and they emphasize the paucity of data on suicidal ideation and behavior in antidepressant trials.

The issue of increased risk of suicidality with antidepressants was specifically addressed in two articles. In the first, Spielmans et al. review the scientific evidence and conclude that the FDA black-box suicidality warning was justified and firmly rooted in solid data from placebo-controlled antidepressant trials. They further detail that prominent claims suggesting that the FDA warning has led to decreasing prescription rates and thus increasing suicide rates were based on methodologically weak and potentially misleading ecological studies.

In the second, Whitely et al. describe how prominent psychiatrists and influential mental health organizations challenged the black-box suicidality warning for adolescents and young adults. The authors argue that various ecological studies were cited misleadingly as evidence that increased antidepressant use reduces youth suicide risk. Contrary to these claims, they further show that, in Australia, both antidepressant use and suicide rates increased substantially from 2008 to 2018.

Another serious safety issue was addressed by Kapra et al.. In their mini review they discuss the evidence for and against a potential effect of antidepressant use during pregnancy on autism spectrum disorders in the offspring. The authors found evidence for an association between prenatal SSRI exposure and an increased risk of autism spectrum disorders based on several observational studies, but caution that causality has not been demonstrated yet due to confounding by indication. The authors conclude that there is a need for more research on this serious safety issue, as accumulating data from animal studies suggest that SSRI exposure may alter normal brain development.

Trends of increasing antidepressant use in young people were addressed in two articles. In the first, Zito et al. analyzed administrative claims of Medicaid-insured youth aged <20 years from 1987 to 2014. During this 28-year period, antidepressant use grew 14-fold. They further show that in 2014, antidepressants were prescribed six times more often for youth in foster care than for their income-eligible Medicaid-counterparts. Off-label prescribing was also very common: a quarter of antidepressant-medicated youth were diagnosed with a behavioral disorder.

In the second, Cosgrove et al. state that antidepressant use in children and adolescents rose substantially over the last 15 years in part due to commercially driven off-label prescriptions, despite ongoing controversy over their effectiveness and safety. From the perspective of institutional corruption, they discuss two drivers of overuse resulting from an increasingly medicalised approach to mental health. The first is the empirically unsupported demand for depression screenings in youth and the second the emphasis on scaling up diagnosis and treatment of mental disorders as part of a renewed Global Mental Health Movement.

Last but not least, Locher et al. make an interesting case for open-label placebos in the treatment of chronic pain conditions in children and adolescents as an alternative to long-term antidepressant use. The authors acknowledge that this approach still lacks empirical evidence, but also stress that open-label placebos constitute a promising avenue for future research as they may help to mitigate the serious adverse effects of antidepressants.

In conclusion, the articles in this special topic demonstrate that pediatric antidepressant use is still controversial. Although antidepressant use in children and adolescents has increased substantially over the last 10–15 years, convincing evidence that the benefits outweigh the risks is lacking and treatment-emergent suicidality remains a major concern. Overuse and off-label prescribing are pressing issues, and there certainly is a need for safer and more effective treatments, both pharmacological and psychological (17). It is hoped that this article collection will spur innovative research and critical discussion.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

I thank David Healy and Irving Kirsch for their help in recruiting authors for this special topic.

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Keywords: antidepressant, pediatric, prescribing, children, adolescents, efficacy, safety, suicidality

Citation: Hengartner MP (2020) Editorial: Antidepressant Prescriptions in Children and Adolescents. Front. Psychiatry 11:600283. doi: 10.3389/fpsyt.2020.600283

Received: 29 August 2020; Accepted: 30 September 2020;
Published: 30 October 2020.