Following the death of their 16-year-old son Romain, who had been put on paroxetine with Tercian later added, Yoko Motohama and Vincent Schmitt began asking questions of GSK, Sanofi, the French ANSM (Agence nationale de sécurité du medicament), and others.
Romain’s case features on Qu’ils mangent des médicaments – Let Them Eat Meds – a talk recently given in Paris, Voiron and Aix-en-Provence. A related talk was given earlier this year on Dexter Johnson’s similar prescripticide – Beware Doctors Bearing Gifts. Samuel Morgan’s case, another very similar one, features on Morgan v Morgan and earlier posts.
The pattern is key to Romain’s and these other cases. He had a minor problem, which might have been a slight obsessiveness or a Tic. He was put on 10 mg of paroxetine and the minor problem got worse. The dose of paroxetine was raised, his problems got clearly worse. The dose of paroxetine was raised further, and his condition deteriorated. The dose of paroxetine was further raised, with Romain getting worse again.
FDA or EMA can license a drug on the basis of an increasing benefit as a drug dose rises. A clear dose response is strong evidence of cause and effect – for events good or bad. If my hair turns pale blue on a drug dose, a deeper shade of blue on a higher dose, and navy blue on a higher dose again, you don’t need expertise in drug levels, or genetics, to know the drug is doing it – a 4-year-old child could likely make a link to a drug effect whatever the how might be.
Hair turning blue is not irrelevant. A lot of our drugs began as dyes. The first antipsychotic was methylene blue. The first antidepressant was summer blue. Knowing this historical detail is interesting but 4-year-olds wouldn’t need it to comment Daddy your hair has gone blue.
After he reached 40mg of paroxetine, Tercian was added to the mix Romain was on. Tercian, cyamemazine, is one of the most widely used antipsychotics in France. It is an old drug, first licensed in 1972. It is sedative, like Mellaril, Seroquel or Clozaril, and like them is often used as a sleeping pill. Haloperidol in contrast is not sedative. All antipsychotics can aggravate the agitation, akathisia and disinhibition SSRIs can cause. Haloperidol, however, is useful for Tics, Tourette Syndrome, where sedative antipsychotics often make Tics worse.
Despite being widely used, there are almost no articles on Tercian. Yoko found one with Sylvain Couderc, a hospital pharmacist in Limoges, as an author. She wrote to him asking about its effects. He took time to answer and then responded asking why she was asking and could she give more precise questions. Yoko emailed some precise questions.
De : Yoko M Envoyé : mercredi 24 mai 2023 08:36
À : COUDERC Sylvain Objet : Re: cyamémazine
Dear Dr Couderc,
Thank you very much for your answer. I read the notice and the labels of paroxetine and Tercian (Cyamemazine) but there are many things that remain unclear to me.
Is Tercian authorised or recommended for prescription to a 16-year old patient with obsessive compulsive disorder or Tourette’s syndrome and who is also taking an SSRI (paroxetine)?
Is Tercian authorised or recommended as a prescription to a patient on an SSRI, who has developed a sleeping problem, as a sedative?
Are you aware of any studies or evidence, especially randomized controlled trials, which led to the ANSM approval for Tercian in France? If yes, could you let me know which studies?
Is the concomitant use of Tercian with paroxetine clinically safe? Is there any guideline for health professionals recommending Tercian to patients on SSRI? Are there any safety studies regarding the concomitant use of Tercian and SSRI?
(In the FDA label, one finds a warning regarding the concomitant use of Paxil with other drugs metabolized by CYP2D6. One is warned to be cautious since no formal studies regarding that topic has yet been done. But I have a lack of basic knowledge of pharmacokinetics, so I have no idea about the danger or possible outcomes.)
Are there any warnings to health professionals regarding interactions of antipsychotics in general and SSRI, apart from the rcp notices of these drugs?
Can the following symptoms happen to patients with OCD, Tourette’s syndrome or any other indications, or even to healthy volunteers, due to treatment with Tercian, an SSRI or association of both Tercian and an SSRI:
- suicidality (suicide attempt, overdose, self harm, …)
- violent behaviour (homicide, physical assault, physical abuse, homicidal ideation, violence-related symptoms (e.g., criminal behaviour, antisocial behaviour))
- emotional disturbance (anhedonia, apathy, depersonalization, derealization, disinhibition, emotional detachment, emotional lability, flat affect, impulsivity, lack of empathy)
- psychotic behaviour (abnormal thinking, confusion, delirium, delusion, hallucination, hysteria, manic reaction, paranoia, psychosis)
- activation (agitation (aggression, hostility), akathisia, anxiety, increased energy (euphoria, irritability, jittering, mania), restlessness (hyperactivity), shakiness)
- activation symptoms defined by FDA (Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania)
- abolition of discernment
Regarding my motivation. My 16-year old son sought help for his eating habit. We guessed OCD and visited a psychiatrist. The doctor prescribed him paroxetine, gradually increased the dose up to 40 mg, and Tercian (liquid) was then added for one month. After 6 months of paroxetine treatment, my son committed the suicide. I am suspicious that his suicide is a consequence of iatrogenic symptoms of the drugs: akathisia and disinhibition.
As you know, cyamemazine is authorised only in a limited number of countries. I cannot find many scientific research papers about Tercian. Moreover, controlled studies on antipsychotics, especially for paediatric use seem very limited in number. So, I would like to learn from you about scientific evidence in pharmacology. I would also be pleased to hear your opinion regarding my son’s medication, if possible. Thank you very much in advance. I look forward to hearing from you.
Sincerely Yours, Yoko Motohama
Ask an Expert
After another delay, Yoko had an email from Marie-Laure Laroche, the director of a regional pharmaco-vigilance centre in Limoges, where Dr Couderc works. She is listed as having expertise in polypharmacy.
From: LAROCHE Marie-Laure Date: Tue, Jul 25, 2023
Subject: TR: cyamémazine DR23-268
To: email@example.com Cc: COUDERC Sylvain
Dr Couderc sent me your questions. As the Director of the Regional Center for Pharmacovigilance (CRPV) in Limoges, Dr. Couderc contacted me because you mentioned an iatrogenic cause in the sad event that occurred in your family.
First of all, I apologize for the delay in my response. Reviewing the national pharmacovigilance database, I was able to confirm that you had declared this event in pharmacovigilance and that the CRPV on which you depend had been provided with the first elements of answers.
You have asked a series of precise questions, but with clinical elements that are confusing for an expert.
All the questions you ask require a specialist in psychopharmacology, which I am not. I have notions but not precise enough to answer your questions.
I suggest contacting a specialist from this domain to get a fair opinion supported by expertise.
Clinical Details Confuse Experts
We have reached an extraordinary position when the director of a pharmacovigilance centre says that clinical details are confusing for an expert.
Experts have got too used to the idea that Science involves generating figures such as the levels of drug in a blood several hours after taking it. But these figures rarely have much to do with cause and effect. Like the history of psychotropic drugs, figures might hint at how a drug is causing something, but they are almost irrelevant to the question of whether it has caused an event.
If like The Muppets’ Sam Eagle, I turn Blue and Grow Feathers on a drug, my 4-year-old and I do not need to know anything about how the drug works to make a link?
The problem is doctors who should be at least as capable of making cause and effect connections as a 4-year-old, particularly if they saw the patient before and then on the drug, don’t seem to be able to do it anymore.
If things aren’t working out on a drug, doctors are now likely to increase the dose or think our drugs just aren’t strong enough. They miss, as Romain’s doctor did, and it seems Drs Couderc and Laroche have done, the fact that clinical science, as all science, involves coming to a consensus view as to how best to explain what is happening right in front of the doctor and the patient’s family. To get this right all observers need to pay special heed to what the person on the drug thinks – they are a privileged observer and the apparatus in which the experiment is taking place.
Clinical science depends on clinical details – not on figures. Judges and juries are often better placed than experts who deal only in figures to say ‘hey, its interesting to hear these drugs all come from blue dyes but the obvious explanation is that the drug has agitated these young men to the point they killed themselves – must have been a nightmare for them’.
What Drs Laroche and Couderc should have done was to pick up a phone or send a Zoom link to Yoko and Vincent and asked them questions rather than ask Yoko to ask the experts questions. It doesn’t take a psychopharmacologist to ask the right questions.
Yoko and Vincent’s mission has revealed that few French doctors seem able or willing to offer a view on a case like Romain’s – which is tantamount to saying they are not fit to practice medicine. How can you practice medicine, if you cannot spot a drug is causing a problem and act accordingly?
For doctors who are able to spot a problem, the problem seems to be they are able to spot a problem. What does this mean? It means they are practising good clinical science, in a tricky situation, where increasing or reducing the dose of a drug might kill their patient. They have great expertise but in a 21st century version of Molière’s Bourgeois Gentilhomme, who was surprised to find he could now speak prose, they don’t realise they have, the whole time, been exercising the expertise they don’t seem to realise they have.
Yoko and Vincent’s mission has generated some extraordinary correspondence with the European Medicines’ Agency and other experts and agencies that will feature in posts to come.
Meanwhile, Ariane Denoyel’s article tells you more about Romain’s case – see Un antidépresseur a-t-il tué Romain?
What would Molière, who loved to laugh at doctors, have made of an expert doctor who is Confused by Clinical Details? Whose medical knowledge seems inversely proportional to their knowledge of medicines?