On behalf of FDA Commissioner Marty Makary, M.D., M.P.H., the FDA is holding a series of roundtable discussions with independent panels of scientific experts that will review the latest scientific evidence, evaluate potential health risks, explore safer alternatives, and may offer recommendations for regulatory action. This initiative is part of the FDA’s broader efforts to apply rigorous, evidence-based standards to ingredient safety and modernize regulatory oversight, thoroughly considering evolving science and consumer health.
Commissioner Makary would like to invite you to participate in person as an expert panelist for the FDA Expert Roundtable on Selective Serotonin Reuptake Inhibitors (SSRIs) and Pregnancy.
I was one of several who got this invite, 9 of whom volunteered to participate – list below. We were each given 5 minutes to speak to 1 slide with 5 points of our making. My pitch is or will be available on this link. The extended version with references is below.
Unsafe Safety
In 2009, the jury in the Kilker Paxil Birth Defects lawsuit returned a verdict against GSK that, as I understand it, ultimately cost GSK over $1 Billion.
Just before the trial began BMJ published an article saying – SSRIs safe in pregnancy. This was no accident. It was predictable and enabled GSK’s lawyers to wave a BMJ article in front of a jury.
I wrote a letter to BMJ about this predictability – who published it. See BMJ and Spam.
The Kilker Verdict vanished, as have others since. News about $3 Billion fines vanishes, replaced by pharma CEOs featuring on the front cover of BMJ as the saviors of healthcare.
Since Kilker, pharma’s skills at shaping what we understand is happening have grown greatly. They are better at this than at making new drugs. Why risk making new and needed drugs if you can persuade people they already have them? Why risk cracks through which the light might get in?
Autism Spectrum Disorder
After Kilker, Joanna Le Noury, Dee Mangin and I put together an article on SSRI links to Autism Spectrum Disorders (ASD), on which the epidemiological and epigenomic evidence was strong even a decade ago – see SSRIs and ASD. Any medicine that causes gross birth defects has to be assumed to cause behavioral problems also.
We referenced a Heidi Malm paper. Malm stumbled on a finding she couldn’t explain and didn’t incorporate in the text. But she couldn’t ignore this finding – so it was put in a footnote. Women taking SSRIs in pregnancy had a 10-fold higher rate of Fetal Alcohol Syndrome Disorder (FASD) than those not taking SSRIs.
We knew that SSRIs have a capacity to trigger compulsive alcohol drinking, which could explain Malm’s finding. This capacity is now embodied in Canadian Guidelines on SSRIs and Alcohol Use Disorder.
SSRIs have epigenomic effects that link them to neurodevelopmental delay (ASD) but their action to increase alcohol intake dramatically points to another way – FASD is ASD with an F.
Any pregnant women put on SSRIs who become agitated are 10 fold more likely to be put on an anticonvulsant. All anticonvulsants, not just valproate, can lead to FACS – ASD with a 2-letter change – Fetal AntiConvulsant Syndrome – See Patterns of Antidepressant Prescribing around Pregnancy.
Sensational SSRIs
Our SSRI and ASD article noted a growing literature showing the offspring of pregnant animals taking SSRIs were more likely to be asocial and asexual – more likely to have neurodevelopmental delay (ASD). BMJ Open, however, turned down a good paper saying the journal did not accept a paper that mentioned animal research.
You’ve all seen the girders, the skeletons of metal encased in concrete, driven into the ground in New York, Washington and anywhere skyscrapers are being built. The bricks and glass inserted in the interstices between these girders give the finished public face to a building.
It’s the same when building a person as the animal literature reveals – strikingly in this recent Nature article on Perinatal Serotonin Signaling. .
Sensory input, from very early on, provides the girders, the skeleton, for brain development. Weaken or distort these girders and brain development is in trouble. The central action of SSRIs is to mute sensory input. Whatever about the benefits of doing this later in life, it leads to a weakening of the girders when done in utero or early infant life.
Acetaminophen (Paracetamol) also impacts on our serotonin system and sensory input causing a sensory muting. It looks like this sensory muting helps underpin the analgesic effects SSRIs and Acetaminophen share. See Bauer Power, Pregnancy, Acetaminophen or Paracetamol, Epidemiology of Autism Spectrum Disorders.
Danish and Australian Women
A set of US-Danish studies have since supplemented the asocial and asexual data the animal studies reveal. These ABCD – Adolescent Brain Cognitive Development – studies mapped maternal depression effects on offspring. The research began with an expectation a mother’s depressive behavior would affect children. It found antidepressant use in pregnancy had a much bigger effect than expected. This became most obvious as girls approached puberty, when there were increased rates of anxiety, depression, ADHD, ASD and other diagnoses.
Like everywhere else, more women than men in Australia take antidepressants. Up to a decade ago it was women of middle years and older, who began taking them and then remained on them. A study by Julianna de Oliveira Costa, Sallie-Anne Pearson and colleagues from the University of New South Wales shows that In the last ten years, adolescent girls and women through to the age of 30 have become the group most likely to start on antidepressants, with growing numbers remaining on them.
Antidepressants have Black Box warnings for this age group. What on earth is happening?
FDA warnings have become May Contain Nuts labels. No one heeds them in the way they once heeded company Dear Doctor letters which stopped happening 20 years ago. Twenty years ago companies began portraying FDA as the agency that determines cause and effect links between drugs and adverse events and warns. These are not part of FDA’s role.
Companies are responsible for warnings – the management of which increasingly involves contorting FDA into a pretzel shape. The SSRIs were a Trojan Horse for bamboozling FDA into accepting that ‘We’ (You FDA and us Company X) might have blood on our hands if we warn about things and deter people from getting the benefit of treatment.
This is similar to the conundrum that faced Popes contemplating AIDs and Condoms.
Averaging Machines
The 2004 Black Box Warnings were put there not because the suicide risk was greater in minors than adults – but because company licensing trials showed no apparent benefit in minors against which to offset risks. There was no escape.
With that in mind, let’s look at the data pointing to benefits from SSRIs and Acetaminophen in adults. The RCTs in both these cases is pretty marginal. Many people view it as suggesting SSRIs only have placebo effects and Cochrane says it is not clear Acetaminophen works at all.
This is bananas. Speak to someone on an SSRI having good effects or bad effects they will tell you these effects are not placebo effects. Ditto for someone for whom Acetaminophen works.
The RCT data is better explained as showing that marginally over 50% of us show a benefit on either of these treatments and the rest of us aren’t helped. You’d get the same results for another drug acting on the serotonin system – LSD. Average the data and you get apparently weak effects. RCTs are Averaging Machines.
What about warnings for the close to 50% of us who get no benefit from SSRIs or Acetaminophen?
Would I give an SSRI to a minor – Yes. Just because s/he is one of the less than 50% does not mean she should be compulsorily deprived of a possible benefit. But I’d make sure s/he was benefitting.
How do we establish if these drugs suit you? Patients in a mental health unit can spot if a doctor is taking an SSRI within 48 hours and if its helping him or not. Prisoners in prison can do the same with inmates. The only people who can’t do this are healthcare professionals. This is strange because we only have SSRIs now as once upon a time these effects were very obvious to healthcare professionals – See Restoring the Magic to Healthcare.
Something now blocks people working in healthcare from spotting what is obvious to everyone else.
In lawsuits like the Kilker case, Juries try facts. Faced with a lawyer telling them you can’t convict this husband of murdering his wife because our Science shows even husbands with criminal records, legal and financial problems and wives no-one likes, on average don’t murder wives, a Jury would say this lawyer is mad. We want to see the specific details of this case based on which we will decide.
The job of anyone working in healthcare is to try facts. But we can’t now do this. We can’t deliver good healthcare or give the people who bring problems to us a fair hearing. Why because lawyers tell us that an Averaging Machine (they dont call it this) tells us that what the patient is telling us is Anecdotal – misinformation.
A medicine is a hazardous chemical combined with information originally aimed at making the use of this chemical safer than the use of hazardous street chemicals. But the information now gets processed through the Averaging Machine which transforms our medicines into Probity blockers. See Probity Blockers and Trans Medicine. We are not being let grow up.
Role of FDA
The gross birth defects thalidomide caused put our current Averaging Machinery (Auto-pilot) in place.
It also led to regulations – requirements for paperwork – on the effects of drugs taken in the first but not the second half of pregnancy. Trials of maternal RSV vaccines in pregnancy, beginning over a decade ago, have been run Wild West like with no regulations in place for monitoring this period of pregnancy – which is key to ASD development.
Regulators began meeting in Harmonization Committees 3 years ago to formulate guidelines – see Selley and Healy – for the monitoring of safety in the second half of pregnancy. A Draft Guidance – at present full of industry current buzz-words like Weight of Evidence analyses – has just been issued for consultation. There is a Slide Version also. The new Guidelines are scheduled for adoption in 2028.
Everything about this is bound to lead to criticism of FDA. Have critics misunderstood the role of FDA? FDA’s role is not to dictate practice. No-one in FDA tries facts. Doctors are supposed to do this when we bring a problem to them. Companies are notionally obliged to do it.
FDA like FAA license paperwork. When a plane takes off pilots not FAA keep us safe by keeping an eye on the facts. In medicine a patient who tries to draw a medical-pilot’s attention to a door blowing off the plane is liable to be thrown out through the open door for spreading Misinformation.
Who in their right mind would fly an airline with a track record like this?
We need more input from Marty Makary as in his recent Face the Nation interview with Margaret Brennan (Marty and Margaret) when he told Margaret we have to Let doctors be doctors. I would say we have to Get doctors to be doctors. Maybe even Let’s Make Doctors Great Again.
Or we could Let them be Dispensers of Medicines rather than Triers of Fact – but pay them much less, perhaps call them nurses or pharmacists as is increasingly happening.
Footnotes
May Contain Nuts and Probity Blockers and Unsafe Safety are Dee Mangin Creations.
The roundtable participants included:
- Anick Berard
- Jay Gingrich
- Jeffrey Lacasse
- Michael Levin
- Roger McFillin
- Joanna Moncrieff
- Adam Urato
- Josef Witt-Doerring
Mission Impossible?
The US DHHS is on a mission to nail down the causes of rising cases of ASD and turn the tide around. This is quite a mission – unlikely to be completed in one political term.
But if they want some low hanging fruit that being plucked might make a difference, there few better options than putting warnings to the effect that SSRIs and Acetaminophen do not suit all of us and might lead to ASD when used in pregnancy.
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