This is the first of 3 posts laying out the philosophical basis for RxISK.org which will be live in the next few weeks. The others are Once is Never & the Unbearable lightness of being.
“[I suggest] a meeting with yourself and your reviewers. I have spoken in public on these issues and offered to speak on any platform. I’ve visited the MHRA [British equivalent of FDA]. Part of my motivation has stemmed from a willingness, indeed almost a desire to be proven wrong, as the consequences of not being proven wrong are in many respects horrific. If you have a reviewer who can point out the error of my ways I will take any steps that might be called for in the light of any conversion”.
The consequences of not being proven wrong are horrific
This cri de coeur (cry from the heart) is from a letter I sent to Richard Horton, the editor of the Lancet, in 2000, when his journal was reviewing an article I had submitted (see Healyprozac.com). The Lancet didn’t hear my desperation or if they did didn’t take up my offer. I had been to and went again to the MHRA who listened to what I had to say, but never offered any evidence to make me change my view that SSRIs can cause suicide.
The point at the heart of the Lancet article that led to my offer to visit and be persuaded of the error of my ways remains unanswered to this day. It was not about whether antidepressants can cause suicide but about how we assess adverse events. Suicide on antidepressants provides the perfect natural experiment to bring out the problem.
Suicide on antidepressants the perfect natural experiment
In 1990 Martin Teicher, Carol Glod and Jonathan Cole triggered concerns about a suicide risk on Prozac. They outlined 6 cases in which patients became suicidal after treatment started, the problem cleared when treatment stopped and re-emerged when treatment was restarted. In a series of subsequent reports other groups found the emergence of suicidality could be blocked by an antidote.
These reports met all the standard judicial, clinical and scientific criteria for determining cause and effect (see Let Them Eat Prozac). Prozac caused suicide.
No-one was prepared to say RCTs were simply not the way to answer this problem
But Lilly’s response in 1990/1991 was that their clinical trial data showed no risk, and that reports of patients becoming suicidal were just anecdotes. Lilly took their trial data to FDA and published it in an article in the BMJ. In an Evidence Based Medicine era where randomized controlled trials (RCTs) are described as offering gold standard evidence and clinical experience is dismissed as anecdotal this argument worked extraordinarily well. No-one was prepared to say RCTs were simply not the way to answer this problem.
But RCTs are not the way to answer a problem like antidepressant induced suicidality. The repetition that RCTs are a gold standard for everything and good case reports are anecdotes is deliberate propaganda. It’s the effect of repetition that causes us to agree with something that in fact stands common sense on its head.
No-one stepped up to the plate
Evidence based medicine and RCTs are supposed to help us control the pharmaceutical industry. One might have expected some of the advocates of RCTs and EBM to step up to the plate and say that Lilly were misusing the clinical trial data – these trials were not designed to test whether SSRIs caused suicide.
No-one stepped up to the plate then. Will they flinch now?
We live in a world where EBM and RCTs have been effectively deployed as a means to silence people injured by treatment. Too many adherents of EBM acknowledge and bemoan this but say it is down to pharmaceutical company “fraud” – lack of publication, miscoding of data, lack of access to the data etc. If the fraud were eliminated RCTs would deliver the goods.
Trickery plays a part but… RCTs are not the answer
While such trickery undoubtedly plays a part, when it comes to adverse events, RCTs are simply not the answer to determining cause and effect.
In the case of SSRIs and suicide, we can now see that the anecdotes so called were from the start completely consistent with the trial data which in the case of Prozac showed a clear doubling (2.0) in the relative risk of suicidal acts on Prozac compared to placebo. The only company defence as of the 1990s was that the published data was not statistically significant (see Psychotic doubt).
Some 14 years later when a sufficiently large cohort of trials were assembled the relative risk of a suicidal act on SSRI antidepressants became statistically significant. At this point, FDA stated that this statistically significant doubling of the relative risk (2.0) of a suicidal act demonstrated a causal effect (where a close to statistically significant doubling of risk had not).
FDA being plain bizarre
The idea that adding a few more patients to the mix should transform our views from this drug doesn’t cause suicidal acts to this drug causes suicidal acts should strike anyone who thinks about it as plain bizarre.
But here is Russell Katz, the Director of the Central Nervous System division of FDA saying essentially this when discussing the doubling of the relative risk of a suicidal act on anticonvulsants compared to placebo:
“We are unequivocally comfortable with using the word, the “c” word, with saying that this establishes causality. Again, we have talked about this a fair amount. This is how we determine causality, this is how we base our findings of effectiveness for drugs.
We do randomized trials, we analyze them prospectively, we have an outcome measure, and if it’s statistically significantly different from placebo, we say the drug caused it, you know, once you rule out chance and fraud and bias and that sort of thing, which we think we have done here”
There is a far deeper problem here than challenging FDA claims that they have ruled out chance, fraud and bias in these company trials in which it’s openly known some patients didn’t exist.
1958 – where the story really starts
To see the bigger problem we have to step back in time to a meeting in Cambridge, England in 1959. This was one of the earliest meetings at which psychiatrists had a chance to talk about their clinical experience with the first tricyclic antidepressant, imipramine. Imipramine had been introduced in 1958. Several of those there stated on the basis of their clinical observations that imipramine could cause suicide.
ECT had previously also been linked to suicide. ECT it was said and is still said could mobilize stuperose and suicidal patients so that they were able to carry out their plans before those plans began to fade. The doctors in Cambridge were aware of this “rollback” theory about ECT indirectly leading to suicides. But they said something else was happening on imipramine. It could directly cause suicide by increasing agitation. No one disagreed.
Unlike the later SSRIs, the tricyclic antidepressants could also bring about dramatic improvements in severe depression (melancholia). When the SSRIs were first produced in the 1970s, they very nearly didn’t become antidepressants because they were of no use in severe depression. Several companies almost binned their SSRIs after a series of studies showed them to be less effective than older non-selective serotonin reuptake inhibitors like imipramine, clomipramine and amitriptyline.
The tricyclic antidepressants are therefore effective in a patient group at a substantially higher risk of suicide than the patients entered into SSRI trials. Because SSRIs were ineffective in severe depression, the SSRI studies were conducted in mild to moderately depressed patients where there was so little risk of suicide from the illness that the risks from the drugs stood out.
How to hide a rabbit in a hat
So let’s mount a thought experiment. To pull a rabbit out of a hat, the first thing you have to do is put the rabbit in the hat. If we were to undertake a large placebo controlled trial of imipramine in severe depression we would expect the rate of suicidal acts on imipramine to be lower than the rate of suicidal acts on placebo because imipramine reduces the suicide risk from the illness more than any risk that stems from the drug. The relative risk of a suicidal act on imipramine in such trials would be less than 1.0, perhaps as low as 0.5.
Where would this leave FDA? Given the corner they have painted themselves into with the SSRIs, they could not agree imipramine causes suicide on the basis of trial data like this.
They cannot concede that imipramine causes suicide on the basis of the challenge-dechallenge–rechallenge reports from the 1950s or 1960s even though these criteria are still embodied in standard adverse event causality metrics – because they didn’t concede that SSRIs cause suicide on the basis of even better reports.
FDA and the politics of suicide
But FDA has in fact labelled imipramine and other tricyclic antidepressants as causing suicide. They did so for political reasons. In 2004, they put a class-wide labelling for suicide risk on all antidepressants so that the makers of the latest drugs would not be disadvantaged. They had in fact offered to put a class-wide warning on all antidepressants as early as 1990.
It must be clear from this that we are about to descend into a morass. This sequence of events poses far more problems than might be immediately apparent.
To be continued.
Yes, we are, indeed about to descend into a morass.
I have a letter dated 17th March, 1989 from the Nuffield Clinic which says “in reviewing her today, she was much more depressive despite an increase in Gaminil and she had rather vague suicidal thoughts. The patient is very complex and I am unsure as to the origins of her depression.”
Gaminil is a trycyclic with similar properties to imipramine.
I have another letter from Bon Secours Hospital, Glasgow, 13 June, 1988, “In the past week there had been a change in her level of anxiety such that during the past week she has felt “terrified all the time. That week coincided with her starting Lofepramine. The preceeding symptoms had consisted of feelings of depression with weepiness and emotional lability, impaired concentration and anexoria. Her sleep has been disturbed with intermittant wakening.
I think Miss Bevan has a depressive illness with a probable clear precipitating factor in her personal history. There is a genetic loading. I think it likely that the Lofepramine she received in the past week was over stimulant and did cause the worsening in her symptoms with the increased apprehension. This drug is rather notorious for doing that in anxious depressed patients. I thought the best bet would be to start her on Fluovoxamine up to 100mg noctre. If the Fluovoxamine does not work, then I think we should try an alternative class of antidepressant and use an MAOI.”
Two weeks later he said, “I have come to the conclusion that we should not pursue a pharmacological approach at the moment and I think the best option would be psychotherapy.”
Hallelujah, that was my brief foray into the world of pharmageddon.
He realises that these drugs are causing the problems BUT then fourteen years later I am taken off Seroxat almost cold turkey and, you know the rest………………………………………………………………………………………………………….
I appreciate your points about RCTs not being the most appropriate study design for adverse effects. But your implicit suggestion that EBM addicts only believe in RCTs as a source of good evidence (provided the trial has been performed in a right way) and your explicit idea that “EBM and RCTs have been effectively deployed as a means to silence people injured by treatment.” aren’t very helpful for the discussion.
Even David Sackett (often seen as the founding father of EBM) literally wrote that Evidence Based Medicine is not restricted to RCTs and meta-analyses.
David Sackett et al (1996). Evidence based medicine: what it is and what it isn’t BMJ, 312 (7023), 71-72 DOI: 10.1136/bmj.312.7023.71 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2349778/?tool=pubmed),
I also highly recommend vandenBroucke’s papers on observational studies and harm, like this one:
What is the best evidence for determining harms of medical treatment? CMAJ February 28, 2006 vol. 174 no. 5 doi: 10.1503/cmaj.051484 http://www.canadianmedicaljournal.ca/content/174/5/645.full
See also my posts addressing why EBM is not restricted to randomized trials and meta-analyses.
http://laikaspoetnik.wordpress.com/2010/02/01/notsofunny-ridiculing-rcts-and-ebm/
http://laikaspoetnik.wordpress.com/2012/05/02/can-guidelines-harm-patients/
Theoretically, that may be so. But psychiatry seems very, very resistant to surveying “anecdotal” reports of harm — unless they’re accompanied by a big lawsuit, a fuss in the press, or a ruling from a government body.
It’s true, RCTs with their small numbers even in the aggregate can never capture adverse effects that occur less than 1:10. Randomization may well exclude vulnerable individuals.
Then, there is also the problem of the adverse effects actually being recognized in the trials.
For example: Not a single case of antidepressant withdrawal syndrome has been found in any trial of antidepressant efficacy where discontinuation is included in the study design, even in STAR*D, which switched 4,000 people on and off antidepressants.
In this studies, symptoms after discontinuation are graded with a depression-oriented instrument, not an instrument to capture withdrawal symptoms. Any withdrawal symptoms show up as positives on depression, thereby demonstrating the efficacy of the absent antidepressant.
What should be recorded as drawbacks of the medication are recorded as positives.
And that is why there are hundreds of thousands of complaints about severe antidepressant withdrawal syndrome all over the Web that are completely ignored by medicine — the assumption is this adverse effect is extremely rare and cannot be anticipated.
Sackett et al:” Good doctors use both individual clinical expertise and the best available external evidence.”
Sackett and colleagues describe the time constraints on physicians trying to keep up with the literature. “The difficulties that clinicians face in keeping abreast of all the medical advances reported in primary journals are obvious from a comparison of the time required for reading (for general medicine, enough to examine 19 articles per 365 days per year9) with the time available (well under an hour a week by British medical consultants, even on self reports’).
He goes on to say: “Evidence based medicine is not restricted to randomised
trials and meta-analyses. It involves tracking down the best external evidence with which to answer our clinical questions.” How is the average physician going to find the time needed for this “tracking”? Will he/she recognize the “best external evidence” when found? Or rely on someone else’s decision about its validity?
He seems to support not only the randomized trial but the comparison of several:
“Because the randomised trial, and especially the systematic review of several randomised trials, is so much more likely to inform us and so much less likely to
mislead us, it has become the “gold standard” for judging whether a treatment does more good than harm.”
How refreshingly naive.
Dear David. You know all about what I’m going to say. Just a reminder and a thank you, this post is.
When my 19 year old daughter Caitlin hanged herself at home after 63 days on fluoxetine [Prozac], I knew nothing about serotonin re-uptake inhibitors. It was 1998. Everything they say about the grief after losing a child thundered into my life. I regret to say that such tragedies change everything.
Caitlin had never had psychiatric treatment and was not a depressed girl; she just saw an ad on tv on holiday in the USA and asked friends what Prozac was like. They told her you lose weight and feel great. She was worried about exams and boyfriends etc. so thought a pill would be just the ticket. [If you know a teenager who doesn’t share similar worries let me know].
David you found out about Caitlin I guess through an article I wrote in the Guardian or some programme on the BBC. To hear your support and to realize that my growing concerns over the connection between Caitlin’s suicide and the prescription drug she was taking didn’t make your eyes glaze over with an expression of –‘oh no not another grief-crazed parent trying to blame medicine’– was little short of miraculous.
Thank you.
The comment above, that I have read before with both sorrow and anger made me think of what I believe to be the particular danger that women of all ages experience in health care generally. The tens of thousands of unnecessary gynecological surgeries every year is testimony to that. In psychiatry, I believe it is well established that, for various reasons, women have always been more liable to receive medication as a solution to what are often life stage issues that eventually take care of themselves.
I decided to do some simple number crunching and check the census figures for conditions that are commonly reported. I don’t believe that Statistics Canada has any particular axe to grind with respect to health care and causes of death – but then, these days, who knows?
The population of Canada is about 33 million. The most recent figures available are for 2008.
Consider suicide rates by age.
For women, from 2004-2008 the all ages rate is steady at about 5.0 / 100,000 but rises between the ages of 50 to 64 with an average of 9.1 / 100,000. It then drops rapidly to age 90 with a rate of 2.8 /100,000.
The highest number reporting contact with a medical doctor in the preceding 12 months is found in females aged 45 to 64 years.
The Centers for Disease Control in the US report that most antidepressants are prescribed for persons between ages 40 and 59 (both genders).
A comparison between Nova Scotia and Australia where each has a program of subsidy for prescriptions for seniors and families with low income, and has access to information on actual drugs prescribed, found that the most commonly prescribed antidepressants were the SSRIs. It seems likely that similar comparisons would be found throughout the world.
Keeping in mind that correlation does not mean causation, the numbers are intriguing. Correlation is, we must remember, acknowledged as providing a strong statistical hint.
It is probably no coincidence that the highest rate of suicide for women falls in the perimenopausal years when “depression” is most likely to be diagnosed based on the normal events of hormonal and societal changes that take place during a physiological life stage. Women need to be made more aware of the real dangers that exist in buying into the medicalization of a condition that, while often excruciatingly miserable for many, can be handled by a variety of non-medical means, just as their mothers and grandmothers did, if they lived that long.
Having said all that, the suicide rates in men are:
All ages: Relatively steady at about 17 per 100,000
Start to rise at age 30 (18.2/ 100,000) and peak at ages 40 to 44 (27.4) then decline to ages 50 to 54 (24.7) and go down to 18.1 at ages 70 to 74 with a rise to 22.0 at ages 75 to 79. The reasons for the significantly higher rates in the early forties remain speculative. There are various theories such as greater alcohol abuse, PTSD in military/firefighters/police etc. but who knows? The CDC figures cited above show that most antidepressants (and, of course, the most common are the SSRIs) are prescribed for both genders starting at age 40 so that it remains an open question. Do men seek treatment for depression at the perceived beginning of middle age and therefore, experience its adverse effects at younger ages?
The very elderly face mortality induced by SSRIs for reasons apart from although including suicide, such as dehydration, falls, GI bleeds, stroke and heart attacks all of which are deemed to be “expected” in the very old. That may very well be, but they certainly don’t need an extra push off this mortal coil.
Rxisk is coming together.
Just a few thoughts.
Should not a Rxisk leaflet with feedback form be available in every surgery in the UK.
Should not Rxisk be at the end of every article produced by journalists who muster articles on the efficacy of anti-ds primarily because, every article is a perception by a journalist who usually doesn’t have a clue as to what they are talking about.
Should not Rxisk introduce itself in every newspaper in the country as a precursor to the dangers of anti-d medication and the drugging of children and the elderly.
Should not Rxisk introduce articles in the press on a daily basis with facts, case histories, results of clinical trials, the constant battle with the MHRA, MHC, etc.
Should not Rxisk write articles for the Lancet, for Medicine Today, for all the mags that purport to engage gps, psychiatrists.
Should not Rxisk, perhaps, open some clinics which assist people who have gone through serious adverse discontinuation symptoms and have nowhere to go.
Should not Rxisk start talking to Health Ministers, Prime Ministers, and circumvent the ridiculous MHRA and MHC.
Should not Rxisk become the norm and reduce pharma to it’s knees.
People have to start thinking about the medication they are handed out and unless they start thinking for themselves and, perhaps, start questionning the logic in it then it will all be a morass and there are so many people who have been let down so badly, to the point of death, that unless this Rxisk is pushed to it’s limits then I dread to think about the way all this is going.
It is non-evidence based medicine and David, cannot do all this by himself. So, are we all in this together and are we all going to start kicking up a bit of a fuss?
The only route is media and it is powerful and persuasive and it is the only way to knock this medical inertia on it’s head.
These drugs kill people and unnacceptable as it may be to query it, it is a fact.
We need some action, pontificating it all will get us nowhere.
Thanks, David, for kicking it all off and also, for providing a platform for muses such as I have outlined above.
You are the most significant and genuine person we all have and we all appreciate you greatly.
Dr. Healy, to be fair it looks like Rxisk.org should include non-drug treatments such as ECT and transcranial magnetic stimulation (TMS).
It will start with all drugs but will hopefully include all devices in due course
One of the major difficulties in establishing the rate of suicide due to psychotropic medications lies in the inaccuracies of certificates of death. Over several years, I have had more to do with certification of death than I would wish but the experience has made several things clear. Certificates of death are notorious for mistakes made by completing physicians who, given this task, seem to be suddenly stricken by an inability to think logically – assuming they ever had the ability in the first place. Certification of suicide is even more subject to both error and deliberate falsification. Several factors, e.g., uncertainty about what evidence is necessary and pressures from families or communities, may influence a physician, coroner or medical examiner not to certify a specific death as a suicide. The extent to which suicides are underreported or misclassified is unknown. Because suicide is particularly subject to inaccurate determination, the incidence of suicide may be underestimated by as much as 50%. Some medical examiners require a suicide note to certify a death as suicide although only about one third leave notes. Forensic science experts also differ on the proper certification of deaths for psychotic, very young, or intoxicated persons. The determination of suicide requires that the death be established as both self-inflicted and intentional. For most physicians, medical examiners in particular, establishing intentionality is the most difficult issue. A coroner or medical examiner who suspects suicide may be reluctant to impose social stigma, guilt, and loss of insurance benefits on the victim’s family. A certifier might conclude that a death was not a suicide because information proving intent was not collected. However, absence of evidence is not evidence of absence.
A Chief Medical Examiner of my acquaintance, spends much of his time lecturing to physicians about the completion of death certificates and confirms that a majority of those he teaches claim that suicide, unless very obvious, is the most difficult determination to make – and to report. He describes a method many employ to cover the inaccuracy of the certificate. In Canada and the US, Part 1 of the certificate gives the actual, anatomical cause of death-always on the bottom, not the top line which is reserved for the immediate cause of death e.g. pneumonia then “due to” on the next line and so on until the underlying (actual) cause is noted at the bottom. Instructions are that one must never put “cardio-pulmonary arrest” in Part 1 since everyone dies of cardiopulmonary arrest yet this is what will often be noted. Part II gives significant contributing factors to death and here, many will identify some kind of psychiatric condition in the expectation that someone will accept that there was actually a suicide although it may be further identified as “accidental” or “not known”. In England and Wales it is even easier to avoid the identification of suicide as (if I remember correctly) only cause of death is required, not manner.
It may be a vain hope, but if MEs were more able and willing to identify suicide as the manner of death, and those left behind were encouraged to act by reporting the circumstances and aggravating the politicians, the numbers affected by inappropriate medication might be easier to ascertain and prevent.
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In order to determine the best means by which a drug may be either withdrawn or significantly controlled, it may be useful to examine the means by which some have already been identified as dangerous and removed from the market. Let’s consider cisapride, a motility modifier i.e a drug that speeded up stomach emptying and was used mainly in persons with gastroesophageal reflux disease or hiatal hernia. It was a very effective drug for both children and adults with, it appeared, few adverse effects and those that did occur were considered to be manageable. In 1997, according to Prescription Event Monitoring, it was concluded “that cisapride is a safe and effective prokinetic agent causing few serious side-effects when prescribed in general practice.”
In 2000 it was withdrawn from the market because of an adverse reaction that hadn’t been considered – death. When taken together with certain other drugs, including cardiac drugs and a particular type of antibiotic, it caused serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation all of which can cause sudden death. The actual number of deaths was relatively small; for example it was linked to 80 deaths in Canada and the US. Of course, even one death is one too many but in this case it would seem that a drug was identified as being too dangerous for general use based on a very small percentage of deaths among the millions using the drug while SSRIs that may very well be responsible for a far greater number of deaths, not only by suicide, but by several other means, are handed out like candy at Halloween.
Deaths from SSRIs are not limited to suicide. The most common adverse reactions that are admitted and described in the literature are hyponatremia (low sodium), parkinsonian effects and low thyroid function (hypothyroidism.)
The frequency of hyponatremia in elderly female patients receiving fluoxetine has been estimated to be as high as 8/1000. The risk seems to be highest during the first few weeks of treatment during which, the side effects may be mistaken for a new disorder. Imbalances of sodium/potassium commonly cause cardiac problems.
SSRIs have a negative effect on dopamine causing elements of parkinsonism. These effects include akathesia (the inability to remain still), tardive dyskinesia (constant abnormal mouth and tongue movements known to cause asphyxia by choking). Akathesia is considered by some to be an indicator of possible suicidal ideation.
Elevated thyrotropin is admitted. Thyrotropin is the substance that essentially makes the thyroid work properly. The influence of the thyroid on many bodily functions as well as mood is grossly underestimated even by physicians. These effects have been admitted and described many times. For example, with respect to elevated thyrotropin Pfizer’s response was that “Hypothyroidism is listed in the new product labeling for sertraline as an adverse event observed during post-marketing evaluation.” In my experience, this is almost unknown by many physicians who regularly prescribe these drugs.
So the question remains. What did it take for a drug like cisapride to be removed from the market pretty quickly after introduction and for the manufacturer to admit to certain lethal effects? Could it have been because of unarguable physiological evidence i.e. abnormal hormone levels and cardiac arrhythmias, that are easier to identify than worsening depression and/or suicide? My comment elsewhere about autopsy findings apply here. ME’s have little difficulty in reporting heart problems or related issues as cause of death and manner as either “natural” or “accidental”, usually the former.
What would be the equivalent, unarguable factor for removal because of elevated risk of suicide?