This post needs reading along with Silent Health and Silencing Safety. The Forgotten Woman in Silent Health is the Lonesome Heroine here.
Informed Consent
Someone, seriously injured by a medicine he had taken, got in touch this week asking if it was possible to take an action against his doctor or in some way get compensation for his drug inflicted damage. He was sure he had not been informed of the hazards when it was prescribed. He had a mild problem that didn’t ‘need’ treatment and if he’d known the risks he wouldn’t have taken them. Something was wrong with all this, he figured, and it should be possible to hold someone to account.
Another person has just posted a comment on Silencing Safety, part of which reads:
In complete contrast, BMJJ had a recent article on new Prescribing Safeguards about the risks linked to isotretinoin that dermatologists should convey when prescribing it. The full article is HERE. A month later Andrew Affleck responded – below and HERE complete with references.
I am extremely disappointed at the new MHRA legislation around the prescription of oral isotretinoin and I suspect all UK dermatologists feel the same way. Indeed, there are a list of words that I could use to try and express my feeling including angry, let down, incredulous, undermined and dejected. It is a sad day when evidence is not used to influence clinical practice and instead disproportionate weight is given to the overvalued views of a minority of individuals with significant personal agendas and emotional bias attending a stakeholder event. The silent vast majority of patients have not been heard. Hearsay has trumped science. The opinion of dermatologists working at the coal face, who have been the only prescribers of isotretinoin for 40 years has not been heard. We know that isotretinoin is a safe and highly effective medication. The only side effect tends to be dose-dependent mucocutaneous dryness. A so-called “expert group” with no experience with isotretinoin have bowed down to pressure from stakeholders’ views that isotretinoin causes depression and sexual dysfunction despite overwhelming evidence to the contrary accrued over many years and continuing to be produced. Certain individuals who have taken isotretinoin and at the same time or months or years later (which does not fit a scientific modal of causality) developed physical or psychological symptoms and had a vendetta against isotretinoin trying to get it banned completely. The persistent symptoms are often non-specific and could be consistent with somatic symptom disorder which is common in the population. It can be human nature to try and blame an external factor and in modern life, forums on social media develop which can perpetuate overvalued beliefs in keeping with an internet meme. The MHRA yellow card reporting system is inherently flawed as one apparent adverse event can be reported multiple times.
Many side effects even those listed as “common” on isotretinoin package inserts are spurious and merely found incidentally in the normal population with levels fluctuating up and down eg anaemia, neutropenia, thrombocytopenia and thrombocytosis. Despite these abnormalities of FBC being listed as occurring in up to 1 in 10 people FBC monitoring is not recommended which causes confusion and worry for patients This shows the lack of credibility in the MHRA. Surely clinical studies of hundreds of thousands of patients is superior.
To enforce asking about sexual health at baseline and at every consultation could cause significant harm via the nocebo effect in often young sexually immature individuals.
The vast majority of patients with acne do not have a mental illness before starting isotretinoin and their emotional health is not compromised when taking it. Most patients will be a bit demoralised, frustrated and have some minor affective symptoms which may reach the threshold of social anxiety disorder with reduced self-confidence and avoidance behaviour quite common. These patients will be helped by improving and likely clearing their acne but with the new legislation they may well be harmed by dermatologists being more reluctant to prescribe. Many studies have shown that isotretinoin can improve mental health and indeed may be protective against suicide with consistent finding of reduced rates of self-harm compared to the background population and in those taking antibiotics for acne.5 Also, to enforce regular use of 2 screening questionnaires (PHQ-9 and GAD) at baseline and for every consultation as part of the drug licence is unhelpful and a step too far. Of course, prescribers should be vigilant for signs of distress or a new or evolving mental illness in all dermatology patients but an impersonal tick box questionnaire is not a substitute for skilled talking and listening and asking the appropriate questions. The proforma can then be used if clinically indicated when it can indeed be a useful adjunct to check for any trend. There will always be a tiny minority of patients who have an undiagnosed mental illness when isotretinoin is initiated eg body dysmorphic disorder, emotionally labile personality disorder or an eating disorder or develop such a disorder incidentally during or after a course of isotretinoin. These illnesses are associated with an increased life time suicide risk.
The final unprecedented new legislation which will likely cause harm is the need to have 2 doctors approve the initiation of isotretinoin in under 18s. This goes against the autonomy of a doctor and shows a lack of respect and trust in dermatologists. If a dermatologist sees a patient under age 18 with acne then we should continue to let them do their job which they are trained to do and often have many years of experience prescribing isotretinoin. Why would a colleague ever wish to disagree? Thus will become a pointless tick-box exercise with no benefit to anyone and merely worry patients and their families unnecessarily as to why a second opinion is needed. They would be quite right in thinking, “gosh this must be a very dangerous drug if a second opinion is needed!”. To add to the nocebo effect we are creating for our vulnerable patients, a recent Patient Information Leaflet on mental health and isotretinoin has a link to a resource for children and young people , “When bad things happen”. You couldn’t make it up. If that wouldn’t put you off, what would.
Some of the parents lobbying for warnings on isotretinoin made mistakes – insisting isotretinoin should be removed from the market. The point with warnings is to alert a teenager in particular to the fact the drug might be triggering some of the weird thoughts or experiences they are now having.
Dermatologists have been among some of the most humane doctors and decent people I have known. Jonathan Rees’s The Last Three Patients – will leave most readers figuring he is the kind of doctor they would like to be treated by. I’m not sure Jonathan will have registered any of patients having sexual or suicidal problems on isotretinoin that have likely come his way.
But I do know in the case of other good dermatologists – something gets in the way of them seeing what’s in front of them. I get to see to person afterwards.
Has Andrew seen and not-seen them? Likely yes. The people who have lobbied for warnings have all themselves or their children taken Isotretinoin and were absolutely normal to begin with – they did not have borderline personality or depression. What teen is going to tell Andrew, or his or her parents, about weird new thoughts or numb genitals? Weird new thoughts that kill them before Andrew gets to follow them up.
Then there is the case of my second contact above, which should give Andrew food for thought. He is nervous about even mentioning the sex of the doctor in this case – its all they – for fear of reprisals. This is a common experience among patients. The Andrews of this world see themselves and are often seen by their friends as decent and approachable but its not how things work out. People with PSSD have been detained by shrinks for mentioning their crazy ideas about what the drugs have done to them.
In this case genital numbing happens almost universally on SSRIs and this is the main feature of PSSD. So it’s difficult to understand how most psychiatrists, including the current President of the Royal College of Psychiatrists, who has a background in drugs and sex and reproductive issues, can’t see what is happening. Something gets in the way.
Therapeutic Principles
There are two dynamics at play here. One stems from Paul Ehrlich’s concept of A Magic Bullet – a medicinal agent that targets a disease precisely, avoiding collateral damage. Magic Bullets are the Holy Grail for pharmaceutical companies – and their marketing departments. The Basic Rule of Combat advert above riffs on this theme. Another framing is in terms of Surgical Strikes – as with Cruise Missiles.
When drug receptors were discovered, in the 1980s companies turned to combinatorial chemistry, certain this would lead to hundreds of keys to receptor locks and cures for everything. This is not how things worked out. There have been fewer life-saving drugs since 1980 than before.
When the Human Genome Project was in full swing, companies expected it would lead to more rational drugs than before. This underpins the ideas of monoclonal antibodies and mRNA vaccines – but in terms of efficacy this is not how things have worked out, and in terms of safety the best way to put it is – Drugs Err but Monoclonal Antibodies can really foul things up.
Most recently Artificial Intelligence has led to claims we can now produce the drugs we really need. But this won’t happen. A.I. is binary – we and our responses to drugs are not binary. (I will pick this up in another post soon).
As the Has Healthcare Gone Mad post medicine makes clear A Magic Bullet narrative hands control to pharmaceutical companies. The only job remaining for a doctor is to prescribe the Magic. The only job for us is to give thanks for the Sacrament and not be tempted to blasphemy by claiming it has harmed us.
Isotretinoin and SSRIs whizz to the spot and fix the problem – if anything else goes wrong, as Andrew A mentions its down to some other fragility the person has like borderline personality or depression stemming from acne or whatever.
This line of thinking is bad for doctors and for us. Bad because most medicines are not Magic Bullets – they are Therapeutic Principles that compensate for some damage by acting on another system entirely – usually inhibiting it or even damaging it, as is most obviously the case in surgery.
When Arvid Carlsson created the first SSRI, Zelmid, he was making a therapeutic principle – a drug with an anxiolytic effect that might suit some people and not others. He did not think Zelmid was putting something right. Using it was necessarily harmful, and he accepted it might even cause suicide, if it was the wrong therapeutic principle for this patient.
The constipation and laxative image above doesn’t convey the harm element but does convey the idea that there are a lot of different ways to tackle constipation, some of which will be right for one person but not another. Similarly SSRIs, TCAs, noradrenaline reuptake inhibitors, and mirtazapine offer different antidepressant principles.
The idea we are using therapeutic principles hands the narrative back to doctors and to us. We need to talk to each other in order to work out, which of the different kinds of laxatives or antidepressants is likely to be the right one for us. Just giving a drug for constipation because a company is allowed to call it a laxative, or a drug for depression because a company can call it an antidepressant is not good practice. It also risks putting doctors out of business – nurses can do and increasingly are doing this.
In a great symbol of the way things were going 30 years ago, SmithKline’s marketing department transformed SSRI Therapeutic Principles into Magic Bullets, relieving doctors of any need to furrow their handsome brows when prescribing.
With Magic Bullets, there supposedly can be no collateral damage. With Therapeutic Principles there inevitably are harms. We harm in order to help. If this is what we are doing, there is an onus on us to let our patients know.
The message that the art of medicine lies in bringing good out of the use of poison seems to be too much for our current generation of doctors or liberal intelligentsia. Pharmaceutical company lawyers petition judges to have this hallowed phrase struck out of my testimony in legal cases. (See Silent Health to work out why the intelligentsia have snuck in here).
This brings us to the second dynamic. Doctors used to figure they had skills to read our personalities and our wish to be informed about risks. In 1950s court cases, women with breast cancer and people getting ECT changed this and created the idea of Informed Consent.
Since the SSRI and suicide controversies in 1990-1991, regulators and companies have taken on the role doctors once had – deciding what it is we should be let know. They have decided not to warn about suicide in order not to deter us from seeking treatment. They have decided not to mention the genital numbing caused by SSRIs even though it is by far the commonest effect of these drugs. Over thirty years after first knowing about PSSD, FDA in the US still does not warn about it.
In these cases its not just the person who takes the treatment who is affected, its their partner also and arguable the entire nation as fertility rates plummet roughly in line with rising SSRI consumption – Pharmageddon and Fertility.
In acting in this way, in going along with company non-science, rather than helping us to use company products wisely to live the lives we want to live, regulators are de facto getting us to live the lives Pfizer, GSK and Lilly want us to live and leaving a lot of lonesome heroines and forgotten women in their wake..
Lonesome Heroines
Dr Pedro says
Your faith was strong but you needed proof
Some interesting demographics of isotretinoin prescribing in different regions of NHS England
https://openprescribing.net/analyse/#org=regional_team&numIds=1306020J0&denom=total_list_size&selectedTab=chart
Hallelujah
Dr. David Healy says
There are interesting variations here. For those not used to this openprescribing system, let your cursor hover over any of the orange, green, blue dots and you will see the number of people given isotretinoin prescriptions as a proportion of the number of people in the area.
Would be good to see a breakout by age – an increasing number of women seem to get isotretinoin for rosacea, without trying anything else first. It almost seems like the rationale is that rosacea is sometimes called Acne Rosacea.
Some may see the ‘failings’ of MHRA on these issues as pretty egregious. Others may see MHRA filling their new role as the deciders of what we are allowed to know about the treatments we take. A good example of what they have done is to fob people who have been concerned off with data from Sweden showing that people with acne were committing suicide on doxycycline before they ever got isotretinoin and hence the argument was that it was acne causing the suicides. This ignores the hundreds of reports MHRA have of suicide on doxycycline given for malaria prophylaxis or just as a simple antibiotic. Doxycycline is a serotonin reuptake inhibitor and there are lots of RxISK posts some of which have led to published articles on doxycycline induced suicide
See Suicide is Painless. And RxISK says Doxycycline Causes Suicide. And Mentally Hijacked on Doxycycline. And Everything’s in Hand. Isotretinoin, MHRA and the Usual Guff.
My favorite story which has appeared in one post and almost on its own justifies the existence of RxISK involved a 14 year old boy who was put on doxycycline for acne and felt very strange. He googled doxycycline on is phone at school and found RxISK posts about it and put 2 and 2 together – and approached his teacher to call his mother telling both of them that he was feeling weird and thought this was what was wrong with him. His mother brought him to a doctor who agreed with him The pill was stopped.
Everyone linked to RxISK figures its a good idea to have drugs like doxycycline but they don’t suit all people and in this young man’s case the benefit of some kind of warning becomes clear. People are pretty sensible – even 14 year old boys.
The question is would we all be better off if Doctors, Regulators and Drug Companies accepted this or is it better for us all to leave it to our Guardians to decide for us for what we should be let know?
David
On the points of warnings.
David
Anon says
Thank you Dr Healy for this post.
I am a bereaved parent who has ‘significant personal agendas and emotional bias’.
I sometimes wonder how things could be worse – but I have to check myself, I know they can get worse. These days, when I want to ‘speak’ to my son I go to the garden of remembrance. We paid a fair amount to put him in a peaceful spot, the last thing we could do for him; the money didn’t matter. Last time I went to his grave, ‘things got worse’, it was underwater, flooding and climate change, you see. The stones and memorabilia that were special to me/him had floated away. I couldn’t leave the flowers I had purchased, should I put them in a puddle? Last time we approached the garden of remembrance about this, they said, ‘sorry …nothing we can do…’ And this sentiment sums up my experience with everyone who “took care” of my son.
I do not write this post for sympathy…but, you see, to outline just, ‘how things are’. Your post signposts what happens to victims once they may have been injured by a drug. I am sure most dermatologists have never had to sit and talk to parent of a child who took his life suddenly and without warning while on Isotretinoin; the son who was a talented student, who was just about to succeed tremendously after working very hard for three years, who on the day he died, ‘booked himself’ into a job interview but did not live to the next day.
I will not go in to the details of why I find it so hard to meekly accept that my son spontaneously took his own life, that he was apparently suffering from mental illness that did not seem to intrude into his life in any way or department. It was decided that this is what he was suffering from, even though nobody, family, friends had noticed. Anyway, the dermatologist you highlight discusses the difficulties of filling in a screening questionnaire and the benefits of ‘talking to the patient’. But you see even this is an assumption! No one who ever prescribed Isotretinoin to my son ever saw his face in real time, he was only spoken to on the phone. No medical practitioner who participated in his treatment, from the start of his course of the tablets until the end of his inquest ever met him but were indeed prepared to comment on the state of his mental health after he died.
Dermatologists may be surprised to learn that I don’t feel overvalued. Some may feel a sense of personal and professional affront at having to work with a second prescriber when having to administer a powerful drug to minor. However, the MHRA report ultimately concluded in favour of dermatologist’s view that the benefits of the drug outweighed any risks. I am highly aware my story would be called ‘anecdotal’ and not based in evidence. But then you see, we can’t get my son back and ask him what happened, and this is the same for all those who have lost their children in similar circumstances. I do wish more could see the devastation that people in my position face and the absolute denial by the medical community that isotretinoin could have played a role in his death.
All we have ever asked is for someone in the medical community to take our concerns seriously and to engage with us. Our main question is why no one is the slightest bit curious about cases like ours, for we are not alone, where reasonable explanations are lacking. We remain open to the possibility that we are wrong. This dermatologist sets his professional experience against our knowledge of our children, in who we have invested – in our son’s case whole – a lifetime. He has all the power and in service of his certainty he labels us, who labour for just a little clarity, as bad actors.
Anyway…my lovely talented, funny boy…gone but not forgotten
Dr. David Healy says
I wrote a report for the inquest in this young man’s case. There was no other way to explain what happened other than the isotretinoin that he was on caused the problem. He was not depressed or borderline.
The inquest was brutal – as inquests commonly. Medical protection societies who insure doctors commonly advise the doctor never to admit the drug caused the problem and if the doctor has problems with this and thinks the drug did cause the problem they will often tell him or her that their lawyers will do the talking for him or her – and the lawyer will invent a non-existent other mental disturbance this young person clearly had.
How do I know this – well at inquests, insurers have told me this is what they want said. It is likely pretty easy to bamboozle a dermatologist on things like this – just as easy as it would be to bamboozle me about some skin issue.
Time and again it is clear from the record that a person who has never googled schizophrenia or depression in their life does in the week or two after they’ve been put on drugs like this – seeking to understand what is going on and thinking they have depression or schizophrenia or a permanent sexual problem when a warning before that would have oriented them to the role the drug is likely playing and the need to stop it. And definitely not to start or increase an antidepressant – this is not the answer to drug induced toxicity.
There is one other notable problem to what MHRA has done – in suggesting screening or prior mental health problems they imply it is these that cause the bad reaction. It isn’t. Totally healthy volunteers in company trials have become suicidal and committed suicide There needs to be a clear statement to the effect that the drug will not suit all people and it alone can cause suicide and should be stopped if there is any hint it is not suiting.
David
UK Guy says
Disappointing set of statements from Mr Affleck.
The working day of a dermatologist tends not to expose them to patients with the nasty side-effects. If the Accutane solves the acne problem, the patient is discharged. If the patient ends up with unwanted effects – sexual dysfunction, mood disturbances – these are dealt with by others. I doubt notification ever gets back to the dermatologist, from whoever has to pick up the pieces. Could be wrong – correct me if so – but I doubt it. The dermatologist wants to solve the acne problem and go onto the next patient. This is why Mr Affleck isn’t seeing the issues himself. The patient is no longer in the room.
Mr Affleck talks about patients having an emotional bias. How about the bias of the prescribing doctor? The entire identity of the doctor is based around improving a patient’s condition. If they start to find out that a drug they’ve prescribed for decades is dangerous or doing harm they didn’t know about .. this is going to be exceptionally difficult to stomach. So, you get consistency bias. The dermatology community has a plain motivation to resist any bad news on Accutane.
In the end, the regulator is there to pick up the signal in the noise. They have correctly identified that some patients have been harmed in unforeseen ways. The story is the same with finasteride and the SSRIs, and so the situation will likely snowball. In effect, we are seeing a slow-moving public health crisis.
As a patient harmed by Accutane, I welcome the changes in the prescribing rules. If I knew 20 years ago that it could cause sexual dysfunction, I wouldn’t have taken it.
Dr. David Healy says
The only comment I would add is its not the regulators job to pick up signals – its the doctors job and companies also. For whatever reason I think in this case I think we can forget companies from Roche who launched first to all the generic companies who’ve made it since.
So it comes down to doctors to recognize the harms and insist regulators require companies to include a mention of these in the label – for the sake of everyone having some degree of confidence that the people taking the risks with a relatively toxic drugs that can do good are being kept as safe as possible
David
Dr. David Healy says
A colleague got in touch with the following comment:
I haven’t prescribed systemic isotretinoin for over twenty years, nor have I followed the issue raised closely. I did work on the ‘molecular biology’ of retinoid receptors for a couple of years in England and in the lab of Pierre Chambon in Strasbourg who cloned most of them (steroid/ retinoid/ vita D superfamily. This was well after the chance observation that systemic isotretinoin was therapeutically effective — the logic of its efficacy came after the trials demonstrating its efficacy. These drugs revolutionized acne management; I can remember males who, prior to isotretinoin, would rather be made impotent by anti-androgens than leave their acne untreated.
Very little surprises me about systemic retinoids, and I have often joked that if you can find a model system that is unaffected by retinoids you should publish. They are widely distributed, complicated at the molecular level and tightly regulated in the embryo and postnatal life. The ‘dream’ of the earlier work was to identify ‘specific’ receptors subtypes and dissociate toxicity from efficacy. It didn’t work out well. Note: all of the members of this group of hormone receptors have multisystem effects, and many may be subtle but real.
Acne care from what I see is worse now that it was thirty years ago. Patients are not followed up, care is fragmented, and treatment not titrated. Clinical skills atrophy, and blind faith in protocols spreads. Poor people are managed by nurses or pharmacists; richer patients go private and see doctors. The NHS cannot tell the difference between painting-by-numbers and art.
I do not think anybody but doctors should prescribe isotretinoin. I would use Seamus O’Mahony’s wonderful phrase: if your name is on the sticker you should control and own all aspects of care. I don’t buy the need for two consultants to see the patient — this is a cop out. If you don’t trust a single doctor (in this particular context), then remove them from clinical practice.
The issue of side effects of isotretinoin and the mind is hard to study, because of the potential for confounding between disease->low mood, and therapy-> low mood (or any other reported side effect that may be linked to other mental states). Any epidemiology has to admit of more than one pathway, with each pathway working to produce opposite effects in different patients.
But I have always viewed seeing a patient once, then pushing them through care that is based on how MacDonalds staff their shops, as clinically negligent. We used to follow these patients up for years after treatment. If you don’t look, you never find anything out. We know that RCTs are poor guides to wider clinical practice.
Some of the villains in this story are UK dermatologists who accept patronage from the NHS and bend to people who know nothing of clinical medicine. My mother would have said there is a special place in hell reserved for them.
UK Guy says
Interesting note: “I can remember males who, prior to isotretinoin, would rather be made impotent by anti-androgens than leave their acne untreated.”
Well, under the new regime – patients will at least know they are taking this choice.
Dr. David Healy says
And another colleague, someone who would completely endorse Jonathan Rees’ comments in the The Three Last Patients – which is well worth a read – commented:
The Medicine I knew is becoming unrecognisable.
Dr. David Healy says
These two comments from doctors might sound old-school but they are very much what RxISK is all about. This is what is needed. And its not a case of going back to the past. Medicine is changing for the worse – it is leaving a middle ground and becoming an anonymous sausage mill. Its not a case of we need to get back to what we had – its more we need to move forward to the once and future medicine – if we don’t move forward to it medicine will no longer exist. It will have been replaced by a sausage factory.
RCTs are among the factors in the way – as the first colleague semi-comments. These obliterate informed consent. They seem to offer the only rational way forward.
As another wonderful colleague, Agnes Higgins – a Professor of Mental Health Nursing in Trinity College Dublin put it – Sure we professionals are happy to sit around the table with patients – and hear their voice. Pause – sit around the table we have constructed – (RCTS providing the 4 legs to this table). The Patient Voice immediately becomes Anecdotal.
Another factor is the extent to which regulators and companies now take it upon themselves to decide what we get to know about what they know
D
annie says
Agnes, Dublin – Olly Roberts
Stunned.
Hearsay has trumped science.
the demonising of isotretinoin.
We know that isotretinoin is a safe and highly effective medication.
Most of those harmed would like some sort of recourse and admonition that a particular drug caused unbelievable harm or even death.
Maybe we should think on that if Dexter had two doctors overseeing the under-age use and warnings about Fluoxetine, he might still be alive. Or Romain with Paroxetine.
Two very recent, very young deaths which burn the cockles of your heart.
OR, as is more preferable, the prescribing clinician should have Leonard Cohen sitting on their shoulder
“There is a crack in everything, that’s how the light gets in”
The ‘hearsay’ of Olly Roberts, not quite so ‘safe and effective’ when from isotretinoin, Olly was given Seroxat. Someone has to pick up the pieces from that particular ‘hearsay’ and it all but destroyed his mother Heather, whose bravery and acumen bounced off the pages of Rxisk for many years.
“What they know” –
Some young people are DYING FOR CLEAR SKIN
http://www.ollysfriendshipfoundation.org.uk/about-roaccutane
‘The Olly Story’ by his mum and dad
http://www.ollysfriendshipfoundation.org.uk/
We feel that neither Olly nor we were listened to by clinicians when we tried to explain about the RoAccutane, and because he voiced worries about his suicidal thoughts, he was branded as attention-seeking. This was one thing he never ever was. He gave up hope we believe, because he was totally misunderstood.
Magic bullets
https://davidhealy.org/club-329-part-3/
Some people ‘dream on’ …
Sarah Browne says
So Affleck says:
“The vast majority of patients with acne do not have a mental illness before starting isotretinoin…”
But conversely:
“Most patients will be a bit demoralised, frustrated and have some minor affective symptoms which may reach the threshold of social anxiety disorder…”
And:
“Many studies have shown that isotretinoin can improve mental health and indeed may be protective against suicide…”
Does anyone see the inconsistencies in his argument?
If people with acne aren’t mentally ill, surely the suicides and permanent sexual dysfunction of people on isotretinoin should stick out like a sore thumb as they can’t be attributed to underlyling mental illness!
It’s interesting that he is cross that people with no experience of isotretinoin have joined the ‘expert group’ yet he is quite happy to pontificate on possible psychiatric causes of the side effects of isotretinoin. Like Drs who are PSSD skeptics, he has not mentioned which mental illnesses he believes cause genital numbness…
Richard says
So what is the conclusion? Can we take action against doctors for not informing of life changing side effects when prescribing. Can we take action against pharmaceutical companies for producing these dangerous drugs in the first place?
Dr. David Healy says
You can definitely take action and need to take action. But if you mean a legal action – then at the moment no you can’t – the system is heavily loaded against you. You are going to have to get creative about something to do that will at least puzzle the system.
D
David T Healy says
BMJ Rapid Response:
Re: Isotretinoin: Regulator adds prescribing safeguards after review of side effects
Dear Editor
I prescribed isotretinoin for acne patients for 35 years as senior dermatologist at the Hammersmith Hospital. I have not encountered any severe side effects in my patients but I strictly followed the guidelines of the British Association of Dermatologists (BAD) and NICE and discussed all potential side effects. I am aware that many consultants use this drug off licence in mild to moderate acne and it is thus grossly over prescribed.
I ran a tertiary referral clinic for acne with UK wide referrals. I saw cases of isotretinoin-induced acne fulminans [1] where relatively mild acne developed into catastrophic nodulo-cyctic acne, resulting in severe keloid scarring. A common problem was persistent xerosis. First described by Goulden et al in 1994. 7.2% of 720 patients had persistent cutaneous, mucocutaneous or musculoskeletal side effects after follow up for up to 4.9 years, which could be distressing [2].
The issue of isotretinoin and severe depression, suicide and sexual dysfunction is contentious. However, there is good scientific and clinical evidence that isotretinoin in susceptible patients can be responsible. This is certainly not hearsay as suggested by Dr Affleck.
Vitamin A is essential for normal development of the brain and in adults there is extensive retinoic acid signalling [3]. Hypervitaminosis A leads to lethargy, depression, irritability, and psychosis which resolve on withdrawal [4]. Published reports describing patients who developed depression on isotretinoin that resolved after discontinuation and recurred on reintroduction [5] provide compelling evidence that the depression is linked to the drug.
A study analysing data from Roche (manufacturers of isotretinoin), WHO and United Kingdom Medicines Control Agency from 1982-1998 found the association between isotretinoin and suicides or psychiatric adverse events was greater than that of antibiotics when used in acne [3].
Preclinical animal studies have demonstrated that intraperitoneal isotretinoin at therapeutic doses induced depression-related behaviour in mice [7] and in Wistar rats [8]. Studies in patients treated with isotretinoin using positron emission tomography scans showed that after 4 months, there was decreased metabolism in the orbitofrontal cortex [9]. This area of the brain is one of few in the adult brain where retinoic acid is synthesized and damage to this area results in impairment in emotional regulation [10].
The issue of sexual dysfunction is one that has been raised more recently although first reported to Roche in 1983. Enduring sexual dysfunction has been reported in anti-depressants, 5-reductase inhibitors and oral isotretinoin [11].
The psychological and sexual side effects of oral isotretinoin are rare and there are no tests that can predict who will develop these side effects. Patients offered this drug must be allowed to make an informed decision.
The MHRA review was well publicized and open to all. Families of patients who had suffered from severe side effects as well as patients who had been successfully treated with no side effects contributed. The BAD representative also contributed. Overall, I felt this was a good balance and the expert group listened to all arguments. Their findings and the additional safeguards they introduced are there to ensure patients are given full information and is certainly in line with the ethos of “Cause No Harm”.
The final point made by Dr Affleck concerned the need for 2 consultant signatures when prescribing for children under 18 years. No mention has been made of possible suppression of growth in these children. Vitamin A can induce premature epiphyseal closure and a review identified cases of premature epiphyseal closure in patients treated with therapeutic doses of isotretinoin for acne [12]. The two signatures now demanded by the MHRA will hopefully prevent over prescribing in this age group.
1. Li AW, Antaya RJ. Isotretinoin induced acne fulminans without systemic symptoms with concurrent exuberant granulation tissue. J Pediatr Dermatol. 2018;35:257-258
2. Goulden V et al. Long-term safety of isotretinoin as a treatment for acne vulgaris. Br J Dermatol.1994;131:360-363
3. Fragoso YD et al. High expression of retinoic acid receptors and synthetic enzymes in the human hippocanthus, Brain Struct Funct. 2012:217:473-483
4. Muenster MD et al. Chronic vitamin A intoxication in adults. Hepatic, neurologic and dermatologic complications Am J Med. 1971;50:129-136
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