This series of blogs outlines a scandal that brings out the limitations of RCTs and evidence based medicine. Here are the first four installments, with two more to come shortly.
Post Number One: The Best Bias That Money Can Buy
Randomized controlled trials (RCTs) were adopted by FDA in 1962 following the thalidomide disaster. This was a way to manage the risks posed by potential poisons. If the toxicity from a drug could be shown to overcome to some extent the toxicity stemming from the illness, a risk-benefit ratio would be set up that would warrant taking the risk of giving the poison.
But what happens when both the poison and the disease produce superficially similar problems – when both an antidepressant and depression produce suicidality for instance? In this case there may be almost nothing that can be done to persuade people that it’s the poison and not the disease producing the effect. Even people of goodwill may look and look at the data and still not make the connection, as with the Shepard illusion (demonstrated in my previous post The Spin that no Data can overcome).
In the case of the antidepressants, given the controlled trial data they were faced with, the FDA had little option but to concede that the drugs caused suicide. Despite this and the Black Box warning put on the drugs, many (maybe most) doctors continue to believe that the FDA only did this because of political pressure from groups like the Church of Scientology.
Given a slightly different turn of events, it would have been possible to hide the problem forever – using controlled trials to do so. The only reason the problem ultimately showed up in SSRI RCTs was because the SSRIs were so weak they could only be given to people who were at almost no risk of committing suicide. In this group, the increased risk from the drugs became obvious.
Had the SSRIs been as effective as the older tricyclic antidepressants (TCAs), they could have been put into trials of more severely ill patients in which case the risk from the disease would have been greater and might have been greater than the risk from the drugs.
When in clinical trials the risk from the drugs is greater than the risk from the illness, the relative risk is greater than 1.0. For trials of the TCAs or effective antidepressants given to severely depressed patients, it would likely have been less than 1.0 – even for a medication that caused suicide. The fact that the risk from trials was less than 1.0 – that is, less people committed suicide or went on to a suicidal act on antidepressants than on placebo – would have been taken by the field as evidence the drugs didn’t and couldn’t cause suicide (seeHealy 2011: Science Rhetoric and Causality).
The field would have been wrong.
We know from meetings as early as the first scientific meetings held to discuss the effects of the first TCA (imipramine) in 1958 that clinicians using it had recognized it could cause suicide. These doctors could still believe the evidence of their own eyes; they were not inhibited by clinical trial data the way doctors are now.
The broader message though is this: RCTs in principle cannot solve the problem of whether a drug causes an injury or not. They may in fact contribute to answering the question, but if they do, it will be as much by accident as design. In the case of the antidepressants, it was by accident.
With the benefit of hindsight we can see what has happened in the case of antidepressants and suicide, and could design an RCT to confirm the risks from the treatment. But what happens in the case of other problems that might also stem from an illness, where we do not have the benefit of hindsight? How many of these problems have been hidden from view by RCTs?
There are two ways out of this bind. One is to get back to referring to drugs as poisons. We have no difficulties in recognizing the poisonous effects of illegal or over-the-counter drugs, and great difficulties in believing they could be beneficial. This is just the opposite bias. This is exactly the perspective we need to bring to today’s prescription drugs, about which we often know much less than we know about yesterday’s prescription drugs (now over-the-counter or illegal). Prescription drugs are prescription-only because they are riskier than other drugs, not because they are safer.
The other option is to run RCTs of the drugs. Isn’t this what we do at the moment?
At present our RCTs are of drugs used for an illness – or rather for a marketing indication. The illness backdrop hides all problems. Almost anything happening on the drug can be filed under the same codes as something happening in the illness. In depression, the drug may induce agitation; the illness does too. The drug-induced agitation may be much more severe than illness-related agitation, but companies will just present the frequencies of both, stripped of their severity codes, and the numbers will conceal the problem.
Worse again, the drug may prove marginally superior to placebo, perhaps only on a rating scale which shows a benefit because of a side effect – a sedative or anxiolytic effect – but this marginal benefit is taken as demonstrating the drug works and doctors are left with no evidence base for practicing the art of medicine – that is deciding when it would be best not to treat with an active agent.
If we want to design an RCT to reveal the effects of the drugs, the first step would be to run them in healthy volunteers. This would make it much easier to spot poisoning.
The immediate response of many to this will be that that would be unethical. Giving potential poisons to people who do not stand to benefit would not be right. Curiously, this mirrors the ethical dilemmas posed by the first RCT in tuberculosis patients where the concern was about whether it was ethical to give placebos to people who needed treatment.
In fact companies do healthy volunteer trials. These are called phase 1 trials. Far from being well-designed or informative, as one might expect in such an ethically fraught situation, these studies are the most corrupt in medicine. An industry has been created that takes poor people or students in need of money and pays them to be guinea pigs in such trials.
The trials are designed solely to suit company purposes, such as looking at the half-life of the drug, rather than designed to shed light on the range of things a drug might actually be doing. The data from these studies is never released, and the non-publication rate in these trials is much greater than the non-publication rate in clinical trials – which approaches 50% in some cases. Finally, where clinical trials in patients are registered these days, healthy volunteer trials are not – so no one knows what’s going on. Without access to these studies it is close to impossible to practice medicine – doctors just become conduits for distribution of drugs.
Post Number Two: Mystery in Leeds
In post number one, The Best Bias that Money Can Buy, I outlined how doing trials of their drugs in conditions like depression is the ultimate way companies hide bodies. That what is needed instead are studies of drugs in healthy volunteers.
Here’s a good example of what a healthy volunteer (phase 1) study can show, and how the story of antidepressants and suicide might have unfolded in an entirely different manner had this study been in the public domain.
In early 1983, almost a decade before it launched in the US, a study of Zoloft (sertraline) was run by Dr. Ian Hindmarch in Leeds, UK. There were 12 female volunteers aged between 34 and 40, drawn from the control panel in the Department of Psychology in Leeds University. The study was supposed to randomize half its subjects to sertraline and half to placebo for a week followed by a cross-over between drugs. It was abandoned before the first week was out.
The medical report to Pfizer noted that the side effects reported in the study were all elicited independently, without communication between participants, that there was a clearcut difference in side effect reporting between placebo and sertraline, and that the volunteers on sertraline were experiencing marked discomfort. The study was accordingly terminated.
All of the sertraline subjects had problems, as had one of the placebo subjects. The placebo subject having problems, however, had sertraline levels in her blood, making the finding even more convincing. The side effects that seemed most clearly linked to sertraline were apprehension, insomnia, movement disorders, and tremors. There were wonderful descriptions of akathisia – the mechanism later linked to suicide induction on SSRIs.
The report to Pfizer noted that these side effects had been described previously by subjects on SSRIs (such as Zelmid, Luvox, and Celexa), that they were well known to be linked to SSRIs, and that as such these effects in this study were likely to be due to serotonin reuptake inhibition.
The volunteers kept diaries in which they reported clear behavioral effects consistent with the warnings that were put on sertraline and other SSRIs 21 years later (in 2004) for agitation and suicidality, as well as a range of other interesting effects.
The Hindmarch study was never published. I got to hear about it in 1998 from Ian Hindmarch himself when we were chatting about an article in the New Yorker by Andrew Solomon that compared the agitating effects of Zoloft to drinking 55 cups of black coffee. Hindmarch said he’d been involved in a study that mapped onto just what Solomon was describing.
Perhaps of considerable importance, despite the outcome of this study, Hindmarch later did another study of Zoloft in healthy volunteers in Leeds that was published in which the volunteers got a much lower single dose of Zoloft. If anyone tries to find a Hindmarch study of Zoloft in volunteers, they will find this one whose report seems completely innocuous.
Shortly after our conversation, I came upon Hindmarch’s first Leeds study when I was in Pfizer’s archives in New York acting as an expert witness in a case taken by the parents of Matt Miller.
Matt Miller was a 13-year-old boy who committed suicide a week after going on Zoloft. Quite extraordinarily, Pfizer argued that this was not suicide but auto-erotic asphyxiation gone wrong. Pfizer recruited Hindmarch as an expert witness in the case. In a pre-trial hearing, he said that nothing much had happened in his healthy volunteer study in Leeds – that the volunteers had been suggestible, as evidenced by the woman on placebo having side effects.
I tried to get the MHRA (the British regulator) to review the study, but am confident to this day they have not seen what I had seen. The correspondence was published on Charles Medawar’s Social Audit website at one point. Journalists applied under the Freedom of Information Act for the study and four years later got a version stripped of its most interesting details.
There are a few points worth noting. Blinding and randomization perhaps make this study more powerful, but the effects were Evident – see False friends. A controlled trial was not needed to show SSRIs can cause suicide, homicide, sexual dysfunction, and other effects. Pfizer monitors didn’t think they needed to test these findings for statistical significance before deciding what was happening.
Here, many years before these drugs triggered tens of thousands of suicides and acts of violence, was a great deal of evidence outlining the nature of the problem and their understanding of it.
It still sits in Pfizer’s archives.
There were other healthy volunteer trials of Zoloft and other SSRIs in which every single volunteer dropped out – with FDA reviewers aware of this but explaining it away. In a study of another SSRI one of the most distinguished psychopharmacologists in the world at the time stated he had never seen effects like this after a psychotropic drug was given to volunteers and strongly recommended against the drug being developed further. Many of these studies have correspondence that should see the light of day. In a Cymbalta healthy volunteer study, Traci Johnson committed suicide. At least one other volunteer has committed suicide. Other volunteers have become aggressive. None of this has happened on placebo.
The seven women in Leeds who got Zoloft may not know to this day what they had or that they are at greater risk of comparable reactions from an SSRI than others. These women are likely to have many more experiences than they committed to their diaries. What did they notice when they got into bed at night? Have any gone on to commit suicide? It is quite possible that becoming agitated in this way has put each of these volunteers at greater risk of suicide.
Social media are reputed to all but bring people back from the dead. If alive, the women would be between 61 and 69. They may be living near Leeds still.
There are almost certainly others from other studies with stories worth hearing. But there is a bias that even social media cannot overcome – those who were most badly affected if exposed to a further SSRI are more likely to be dead now from suicide or another serious problem.
Maybe this story will resonate with children or partners or friends.
Post Number Three: Professional Suicide
On October 15, 2004, after FDA had put a Black Box Warning on antidepressants to draw attention to the risk that they can cause suicide, the American Psychiatric Association (APA) came out with a news release whose key statement was:
“The American Psychiatric Association believes that Antidepressants save lives.”
This was perhaps the first professional suicide note in history, but there have been several since.
On January 31, 2005, US News and World Report ran a front cover featuring an attractive nurse in a white coat with a stethoscope around her neck with a strapline “Who Needs Doctors? Your future physician might not be an MD and you might be better off.”
If modern medicines like the antidepressants are pretty effective and relatively free of hazards, then who does need doctors — doctors who fail to keep to guidelines and treatment algorithms and who cost far more as prescribers than nurses or clinical psychologists or pharmacists would?
The American Psychiatric Association statement should have read:
“The American Psychiatric Association believes that Psychiatrists save lives.”
If medicine is to survive we need to restore the professionalism it takes to manage risky drugs appropriately. If the drugs aren’t risky and things go wrong, it must be the prescribers who are risky. And if the prescribers are risky, they need to be constrained within guidelines and protocols; and if they don ‘t keep to them…well, it ‘s safer for the organization to sack them.
Locked into the distribution channel for prescription-only drugs, hemmed in by the science, doctors increasingly resemble the employees of the occupational health department of a factory that in the course of business exposes its workers to disability-inducing chemicals.
These doctors are all too aware that their ongoing employment depends on keeping quiet about any problems the workers may be having and learning to recommend laying off workers at the first signs of any ill-health — having persuaded them that they aren’t fit for the job rather than conceding that job conditions might be the problem.
Factory doctors like this were traditionally portrayed as uncaring, as opposed to the best of family doctors, who care and speak out. But we are all rapidly becoming factory doctors now.
On February 19, 2012, 60 Minutes ran a program about antidepressants, featuring the work of Irving Kirsch whose central claim was that controlled trials showed minimal benefits for these drugs.
True to form, the APA reacted a few days later, on February 22, 2012, with this response:
“Claiming there is no effective difference between antidepressants and placebos is…not just wrong, but irresponsible and dangerous reporting.”
APA went on to say that FDA do not endorse the findings of the 60 Minutes program.
In fact, FDA’s assessment of the data from all placebo-controlled trials of antidepressants, as of 2006, is that these trials combined show an odds ratio for a benefit of antidepressant over placebo as follows:
- In 18–25 year olds: 1.54 (95% C.I., 1.34, 1.76)
- In 25–64 year olds: 1.84 (95% C.I., 1.77, 1.93)
- In 65 years and over: 1.39 (95% C.I., 1.24, 1.57)
These are figures that fit very well with Irving Kirsch’s position.
There is a raft of public domain documents in which FDA officials express doubts that drugs like Zoloft work at all. There are even documents from Pfizer expressing surprise that the regulator has not pushed them harder on the question of efficacy:
On the contrary, one of the things that seems wrong with Kirsch ‘s argument is the idea that antidepressants work for severe depression. It is widely known that companies did not study their drugs in hospital settings because they knew the drugs did not work in more severe cases.
What are APA doing hiding behind a group of bureaucrats (FDA)? This is a further abnegation of professionalism.
In terms of professional survival, APA might have usefully said that, “Claiming there is no effective difference between antidepressants and placebo is not just wrong, but irresponsible and dangerous reporting — placebos do not come with a risk of suicide, homicide, birth defects, physical dependence, or sexual dysfunction. It takes an expert to know when to take these risks, and FDA badly mislead people by failing to warn of these hazards in the first place.”
Meanwhile 60 Minutes had had their chance to save lives (and save psychiatry) 11 years earlier. Against the backdrop of the Miller case (see Mystery in Leeds), they approached the Millers and their lawyer, Andy Vickery. Vickery asked first if they would back down under pressure — as they had infamously done with Jeffery Wigand (“The Insider”). They said, No, it would be the death of 60 Minutes to ever do that again (See Vickery email).
The program had Pfizer documents in which the attempted suicide of an 8-year-old boy had been put down by Pfizer monitors to Zoloft-induced activation. It had entirely independent academics with nothing to do with the case reporting that Zoloft could definitely trigger suicide.
Ed Bradley interviewed me, the Millers, Andy Vickery, and others. More than $50,000 had been put into the making of this show, and, at that kind of money, few 60 Minutes segments are ever canned (which is why The Insider was so famous).
But the producers came under pressure not to air. The show had been waiting to air for more than eight months when 9/11 happened, and the producer contacted the Millers to say that this was the reason why it wouldn’t air.
The tapes probably still exist in some CBS storage room.
The difference in 2012 is that the antidepressants are off-patent, and as long as 60 Minutes doesn’t cast doubt on the safety of psychotropic drugs in general, it suits the pharmaceutical industry to have the antidepressants pushed aside in favor of mood-stabilizers.
So the antidepressants weren’t quite as effective as we thought, and maybe insurance companies or the government paid over the odds for them. Where’s the big deal in that?
The next series of posts will undertake an autopsy on the body of professional medicine in an attempt to pinpoint the cause of its death.
Marks on the body suggest the cause of death may be more shocking than readers expect.
Post Number Four: Professional Suicide — The Clancy Case
Shane Clancy, a 22-year-old going to University in Dublin, broke up with his girlfriend, Jennifer Hannigan, in April 2009. Despite his having broken the relationship off, he found it difficult without her. She, meanwhile, had found someone new: Sebastian Creane.
Shane took a trip to Thailand and Australia, but aborted his travel and came home unhappy. His mother took him to his doctor on July 18. The doctor told him to go away and exercise and eat properly for a week to see if that would make him feel any better. A week later, his mother took him back to the clinic, and on July 27, he was prescribed a month’s supply of citalopram 20mg. He took them as prescribed but after the first few days began to get agitated. He rang the doctor on July 31 to say his tongue felt very swollen (a recognized side effect of citalopram). He left a message but got no response.
On August 3 he wrote on Facebook that he felt unwell and thought he had the flu (this is consistent with the effects of the drug). On August 5, feeling increasingly unwell, Shane took the remainder of his month’s supply of tablets in an attempted suicide. He slept for 24 hours and only then told a friend what he had done. His mother brought him back to the clinic where he saw a different doctor who continued the prescription for citalopram.
On August 15, Shane was with friends at The Eagle House. Sebastian Creane was also there with friends. Shane gave them a lift home, leaving Sebastian to his house last. He came in and spent time chatting before leaving. Jennifer Hannigan came round to Sebastian’s house later, where she had a phone call from Shane who was outside. He asked her to send Sebastian out saying he was hurt and needed help. Sebastian went out and was attacked and stabbed fatally. Jennifer was also stabbed, as was Sebastian’s brother who emerged from bed to find out what was going on. Shane was later found dead in the garden having stabbed himself 19 times.
Ireland was shocked. The case was all over the media for several days. Everyone’s sympathies were and continue to be with the families of Sebastian Creane and Jennifer Hannigan, who bore themselves with remarkable dignity throughout.
Based on media reporting, that at times approached the horrors of Heinrich Boll’s masterpiece The Lost Honor of Katherina Blum, pretty well everyone thought Shane Clancy guilty. Every scrap of evidence that pointed to pre-meditation was a nail in his coffin. It almost has to be this way, given how many Irish youngsters are on SSRIs.
But, as Rosie Meysenburg brings out (see The story of SSRI Stories), once you are exposed to more and more of these cases, those put on antidepressants appear as much the victims as anyone else. At first there was no mention of antidepressants, but Leonie Fennell, Shane’s mother, feeling guilty for having engineered her son onto citalopram, raised the issue. The Irish College of Psychiatrists responded that there was no absolutely no evidence that antidepressants could cause problems and to say so was dangerous and irresponsible.
An inquest was scheduled for April 2010 in Wicklow, a town south of Dublin. Before this hearing there was an extraordinary letter to the national newspapers from all professors of psychiatry in Ireland, stating that there was no evidence that antidepressants could cause harm. One of these professors, Patricia Casey, sought leave to testify at the inquest but was denied by the coroner.
The seven jurors, men and women, who appeared to be shop owners or farmers, with an average age close to 60, heard witness statements from Sebastian’s friends at the public house on the night of August 15, 2009, from Jennifer Hannigan and Sebastian’s brother, as well as from the Clancy family, in addition to hearing from the pathologist and from me.
The facts were not in question – no one disputed that Shane Clancy’s actions had led to Sebastian Creane’s death and that he took his own life. The jurors, however, were asked to recommend whether the verdict should be suicide or an open verdict.
With a verdict of murder, a jury has to agree that the person intended to kill their victim. So also to return a verdict of suicide, the jury has to be satisfied that the subject intended to take his own life.
When someone else is killed, if there is no clear intention to kill them, the appropriate verdict is homicide. If someone jumps to their death from a 10th floor balcony under the influence of LSD, unless there is clear evidence beforehand that this was what was planned, an open verdict would be more appropriate than a suicide verdict.
In cases like the SSRI suicides and homicides, families who are convinced that their husband, wife, parent, or child did not intend to kill themselves (or others) but was acting under the influence of a drug-induced state are keen to get an open verdict. In European countries this is not an initial step to suing a pharmaceutical company, as it is almost impossible to sue a pharmaceutical company in Europe.
When it comes to cocaine, crystal meth, or LSD, we have no difficulty thinking a drug might contribute – the drug is guilty and the person innocent. But in the case of prescription drugs, the drug is always innocent and the person guilty.
In fact, citalopram and other SSRIs can cause a delirium and lead to homicide this way, but this is not ordinarily what happens. They can also cause entirely normal volunteers to start thinking aggressive and violent thoughts they had never had before, as they did to some volunteers in Leeds (see Mystery in Leeds). And they can switch off anxiety so that someone coldly starts to plan something they would be too scared to do ordinarily – so there can be pre-meditation (see article on Antidepressants & Violence). The problems can happen within 48 hours, as in the Tobin case (discussed at greater length in Let Them Eat Prozac), or build up over 2-3 weeks, as in Shane Clancy’s case.
Returning an open verdict in England or Ireland does not blame the drug. It simply means in this case that the jurors have decided that the killings and the events did not permit a straightforward answer. But even so, pharmaceutical companies will send academics such as Professor Guy Goodwin from Oxford, along with several high-powered lawyers to a humble inquest in a small town to ensure the coroner or the jury returns a suicide verdict.
In the Clancy case, the jury returned an open verdict. Just like the American Psychiatric Association (APA) before and since, The Irish College of Psychiatrists went into overdrive issuing statements left, right, and center to anyone who would listen that there was no evidence that citalopram could cause suicide or violence. Here is one example: Experts clash over anti-depressant link to homicides.
This led to a letter to the Irish College by a retired professor of psychiatry, Tom Fahy:“I am afraid the College is plain wrong. There is no such thing as a college statement which is circulated to the membership simultaneous with its publication, without opportunity for comment or vote and “in unison” with a body 100% financed by drug companies, and with personal hostile references to expert testimony at an inquest with families still in grief. And this on the heels of a dreadful multiprofessorial letter even before the inquest began. Extraordinary and outside my experience. If I were not retired I’d dissociate and publicly resign.”
Both the Irish College and Lundbeck, the makers of citalopram, issued statements about the matter. Reminiscent of debates in Ireland on matters of Catholic ethics, where the College of Obstetricians could always be depended on to be somewhere to the right of the Catholic Church, the Irish College of Psychiatry’s position was far more extreme than Lundbeck’s, as we shall see in the next blog post, Model doctors.
Is this professional suicide on the part of the Irish College, like that of the APA in Professional suicide, or should we return an open verdict?
Unfortunately when it comes to murder or suicide, the fact that the College is laboring under a delusion is not grounds for returning a not guilty verdict. It is only if they are laboring under the influence of a biological disorder, drug-induced or not, that they have a chance of being declared not guilty by virtue of insanity.
Drinking the Kool-Aid is no defense.
Suicide, or open verdict? There is another intriguing option that will be outlined in an upcoming post: Notes on a Scandal.