Aunts, Ants and Regulators

Thanks for this post goes to Annie Bevan who for over a decade has made some amazing contributions to DH and RxISK. None more so than finding a document sitting in front of all of us for two decades that should make regulators blush, squirm and wish the ground would open and swallow them.

Thomas Kingston

Tom Kingston’s unfortunate death earlier this year led to an inquest a week ago, which heard that in response to work stress, possibly aggravated by a sleeping pill his doctor gave him, a good doctor, who then slipped into giving him Sertraline to which he reacted badly.

Katinka Newman’s recent article on SSRIs and Suicide brings out the key point – no one is supposed to feel worse on an antidepressant than they felt before starting it.  If they do feel worse, they are at serious risk.

Tom had the good sense to take himself off sertraline. His doctor, following the advice of MHRA and NICE Guidelines started him on another SSRI, which he would likely have had the sense to refuse if he had known what was happening. He did stop it as well pretty quickly after starting. but by then the damage had been done.

An Unnecessary Death

SSRIs and lots of other drugs can cause suicide. MHRA, FDA and other regulators were forced into issuing warnings about this in 2004.  These warnings however were couched in language about the treatment of depression being tricky – your patient’s condition can get worse.  The wording left it open to doctors to decide if it was the illness causing problems in which case double the dose. If the view was that the drug was causing the problem, which you or I on the experiencing end of things might be sure was the case but which doctors who wanted to help us find it difficult to recognize, then the answer was to stop the treatment and ideally switch to something completely different.

The issue here is risk communication which is where MHRA and other regulators come in. Their failures in this area killed Thomas Kingston, have killed tens of thousands and, unless there is a drastic change, will kill many others.

At the heart of regulatory failure is matter of common sense. Someone who responds poorly to an antidepressant should neither be continued on that antidepressant nor switched to one with a similar mode of action.  We have many different types of antidepressants and have recognized for over 60 years that people who respond poorly to an antidepressant from one group, a tricyclic for instance, commonly respond much better to an antidepressant from another group such as an MAOI.

Part of the case that SSRIs can cause suicide, in the earliest reports (from 35 years ago), mentioned that people who became suicidal on an SSRI did much better when switched to an MAOI.

This might seem like common sense and until 30 years ago when companies began defending their products and the doctors who consume these products by putting them in our mouths, it made perfect sense to most doctors and to me.

From 2002 to 2004, in Britain, GSK and MHRA were being hauled over the coals by Panorama who made a series of programs on them and Paxil and suicide. European Regulators asked Britain and GSK to address the issues. In tackling this very point, GSK cited a 1994 article by me – see below – about the need to switch when faced with a poor response.

But as you will see below in 2004 GSK (in line with other companies) dismissed this common sense approach.  This is where the Ants start to emerge but you will have to read to the end of the post to get the full horror of what happened and is still happening.

The GSK document linked here is dated January 2004.  The key section is 8.1.2 Akathisia.  For people new to this problem, the Greek word Akathisia translates as Feeling Worse:

8.1.2. Akathisia

It has been proposed that SSRIs, such as paroxetine, may induce agitation or akathisia like events soon after therapy is started and that the distress this causes in an already vulnerable group leads to suicidal behaviour [Healy, 1994]. However this suggestion is not supported by the findings from the adult clinical studies with paroxetine or the postmarketing adverse event data.

Hence, establishing whether paroxetine (or a concurrent medication or underlying psychiatric disorder) is the most likely cause of the onset of akathisia-like symptoms in any individual patient may not be straightforward. However, given that an association between the onset of akathisia or agitation and the development of suicidal behaviour is not supported by the data on paroxetine, there is not an absolute need for therapy to be immediately withdrawn. Rather, the physician will need to consider the range of management options available in the context of the severity of the akathisia symptoms and the potential benefit the patient may derive from continued therapy.

No additional guidance regarding the management of patients presenting with akathisia-like symptoms is considered appropriate, as the prescribing physician should consider each individual patient on a case-by-case basis.

GSK Spring a Surprise

The date of the document points to something astonishing that few people know about.

FDA had scheduled a hearing, a month later, in February 2004, on the question of whether antidepressants can cause suicide. GSK look like they knew that FDA would say Nothing to See here – Move Along.  And they had good grounds to think this.

Tom Laughren of FDA had briefed the media 3 months beforehand saying that, while there had been a scare earlier in 2003 about all this suicide stuff, FDA no longer believed there was a problem

I am pretty certain that during the morning of February 2nd, the day of the meeting, FDA were confident they could brush the problem under the carpet. But they reckoned without Panorama’s Andy Bell who put a document in my hands to release to the media just before midday. The document clearly stated GSK knew that in their Study 329 trial of Paxil in depressed adolescents, Paxil had not worked and not just that but it was also hazardous.

By that afternoon the vibe from FDA had changed. They were stymied. The ball was kicked into the long grass – FDA ended up saying they were going to look at the data more closely and would reconvene in September.

In the meantime, based on the Panorama document, New York’s Attorney General filed a fraud action against GSK.  Congress scheduled hearings on why one of FDA’s staff, Andy Mosholder, had been muzzled and not let present data on the suicide risk in company trials.  And FDA’s Bob Temple had a phone call after which FDA raised a white flag.  See Children of the Cure.

FDA were still fighting a rearguard action in September, even though it was clear there would be warnings. Senior FDA honchoes accepted that antidepressants can cause suicide. But while conceding on the record that the correct word was ’caused’ suicide, they left it uncertain as to whether or how this happens.

It just happens – how do we know what goes wrong?

Neither FDA nor MHRA nor EMA have been willing to put clearly in print that even healthy volunteers put on these drugs can end up committing suicide. That 100% of the volunteers put on sertraline in one Pfizer trial became badly agitated and all stopped the drug on their 4th day on it – the same day Tom Kingston stopped it.

Neither FDA nor MHRA ever mention a Pfizer document from over 40 years ago, saying sertraline caused these volunteers to react in this way.

No regulator has been prepared to endorse an obvious step and agree that all things being equal suicides are more likely to come from the group of patients who early on in treatment say they are agitated and suicidal rather than from the group whom the drugs suit – who say almost from day 1 that they feel more relaxed and this effect suits them.

Instead we hear that these drugs can take 6 weeks to work. This is baloney. If they are suiting you you can tell in a day or two and for the most part it’s the same if they are not suiting you and if they are not suiting you are not going to be helped.  The condition may clear weeks later but it will do so despite the drug not because of it.

The 6 weeks to work idea came from older wisdom about patients who were melancholic – very severely depressed – taking 2 weeks to respond to much more potent antidepressants than SSRIs.  But even then Arvid Carlsson was able to spot that some people on a serotonin reuptake inhibiting older tricyclic could spot when it was helping them and when not. This is where he got the idea for an SSRI.

The SSRIs are much weaker antidepressants than the tricyclics. They don’t help melancholia. They are given to people who have mild problems likely to clear up spontaneously if left without treatment. But in line with the weak evidence from clinical trials that SSRIs worked at all, the idea that the drugs take time to work stretched from 2 weeks out to 6 weeks and more – by which time spontaneous recoveries were likely.

Or by which time people taking things into their own hands, like Tom Kingston, stopped them and ,when asked by their doctors how they were, reported feeling much better – without mentioning they had stopped the treatment, even to the point of continuing to collect the scripts.  Most of us don’t feel comfortable telling doctors they got things wrong.

In practice, someone like Tom Kingston may have been feeling very very bad and might have been almost certain that if he told his doctor what he was thinking and feeling she would have felt forced to compulsorily detain him in hospital.

Ten years ago, I interviewed James Holmes – the Batman Killer – who in Aurora Colarado killed 12 and injured 72 others.  Prior to being on an antidepressant he was shy and inhibited and not likely to hurt a fly. His doctor put him on Sertraline – the same drug Tom was given.  Holmes told his doctor ‘If you knew what I was thinking you would lock me up’.  She responded that he was responsible for his actions and did not change his treatment.

The Wrong Calculus

The advice that killed Tom Kingston was put in place by companies 20 years ago and has not been corrected by MHRA since.

No-one in MHRA, FDA or EMA practices medicine. They aren’t faced with real people. They deal with non-existent averages who don’t commit suicide.

Whatever about an unlikely benefit after a bad start. if even 50.1% of those who feel worse early on don’t kill themselves, perhaps because put on benzodiazepines – as companies did in their trials and advised doctors to give patients who became agitated on an SSRI rather than stop the drug – regulators can persuade themselves not warning comes with a positive Benefit-Risk ratio.

Regulators and doctors are told they will have blood on their hands if they warn clearly.

This is like a problem in calculus, where if an ant has a head-start on a hare and every second or so the hare makes up 9/10s of the distance between them, can it ever catch up with the ant?  This is the nit-picking world regulators operate in.

The Dutch for nit-picking is mierenneuker, a word which literally translates as ant-fucker.  The Dutch, interestingly, do not regard this word as offensive.  Some of us who have not lost anyone to these drugs on meeting regulators might figure they are decent enough people and their nit-picking dilemmas are amusing.

Zombie Ants

The ant kingdom has real live, but shortly going to die, Zombie Ants. The ant below is one. When these poor guys accidentally eat certain fungi – the fun guys take them over, control their actions and grow inside them until they explode.