In my blog post 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.
How might the story of antidepressants and suicide unfolded had this Zoloft study by Dr. Hindmarch 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 side effects that seemed most clearly linked to sertraline were apprehension, insomnia, movement disorders, and tremors.
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.
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.
Hindmarch 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. It still sits in Pfizer’s archives.
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.
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