Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Archive for Spin & Data

Trudo Lemmens of the University of Toronto critiques the recently distributed draft EMA Clinical Trials Data Release Policy.

[First published in the PLOS Blog.  Click here for the original post.]

Things were looking good recently in Europe for data transparency, a necessary, albeit not sufficient, tool to promote integrity of pharmaceutical data. The European Court’s Vice-President overturned in November 2013 two lower court interim suspensions of EMA’s data access decision in relation to Abbvie’s drug Humira and Intermune’s Esbriet, which had stalled EMA’s data release approach. Shortly after, Abbvie withdrew the Humira lawsuit. Then in April 2014, the European Parliament approved the new Clinical Trials Regulation that introduced a requirement to register all clinical trials and make all clinical study reports in relation to EMA approved drugs publicly available. These developments put EMA again in the driver’s seat for the further implementation of its promised prospective data release policy.

Yet, when EMA recently distributed the draft policy to participants of its Clinical Trials Data Policy advisory groups, scientists and patient advocacy groups were dismayed, and the European Ombudsman sent a letter to inquire about EMA’s apparent shift: the proposed “Terms of Use” (TOU) and “Redaction Principles” impose various technical restrictions on data access, which would make it practically impossible to conduct decent research. If it were only technicalities, further discussions with the scientific community could fix the problems. But in the fracas around the technicalities, the legal booby-traps hidden in the (admittedly still draft) TOU received little attention. I therefore sent a letter to EMA’s executive director Guido Rasi outlining several legal concerns. Combining these with the technical restrictions suggests a problematic legal hijacking by industry of the transparency agenda.

What are the legal traps? First, by signing the TOU, data users would “acknowledge […] that the Information is protected by copyright and proprietary rights … and can be considered commercially valuable”. Brand name pharmaceutical companies increasingly insist that clinical trials data are protected by copyright and proprietary rights, and considered commercial confidential information. In the European Court cases, companies even made the spurious claim that companies have a fundamental human right to privacy over the data. But the idea that data are protected by copyright is highly doubtful, and it is little wonder that companies like to use the vague notion of ‘proprietary rights’ and refrain from using more concrete terms. Simply put, whether they have any such rights in data remains hotly contested, and is not firmly established in law. Many have convincingly argued the opposite, that these data are public goods, and that case law supports access to data on the basis of health related human rights. Remarkably, EMA is now asking scientists to recognize these rights while it is still involved in one case before the European General Court―the Intermune case―where a company is invoking such rights to block EMA’s decision to grant access to data. In light of this case and possible future court challenges, EMA has an interest in arguing for the most narrow interpretation of companies’ rights over data.

Second, the documents also strengthen industry’s attempt to qualify some data as commercial confidential information, which would offer industry the most far-reaching data protection. The TOU only mentions that data ‘can be considered commercially valuable’, which is indeed different than ‘confidential’. But the draft Redaction Principles, which set out how information will be made public, state that “novel statistical or other analytical methods and exploratory endpoint results about potential new uses of a medicine that are not the subject of the marketing authorization application” can qualify as “commercial confidential information.”  Here again EMA embraces a questionable legal position that favours industry. Statistical methods are part of the scientific commons. It’s hard to see how they can be ‘unique’ enough to qualify as commercially confidential information while still providing reliable evidence according to widely accepted scientific methods. The ‘endpoint results of potential new uses’ appears to include clinical trials data related to off-label prescribed drugs. Some of the most troubling controversies that underlie the widely supported calls for data transparency involve pharmaceutical companies’ misrepresentation of data related to off-label prescribed drugs. These practices have impacted on the health, life and wellbeing of thousands of patients. Even if these ‘endpoint results of potential new uses’ are obtained at an exploratory stage with new statistical methods, accessing these data is of public health importance.

The “Redaction Principles” further grant industry much leeway in deciding what will be made public: companies would submit two different clinical study reports to EMA: a full report that EMA will keep hidden; and a redacted one that will be publicly available. What kind of information was hidden, and why, will likely be very difficult to know.

Third, EMA is also asking researchers to contractually agree that they can be sued under UK law “in accordance with the provisions of the Contracts (Rights of Third Parties) Act 1999.” As a result, pharmaceutical companies will be able to challenge researchers directly in court for violation of EMA’s TOU. This puts companies in a comfortable legal position, particularly when this is connected with the recognition of proprietary rights, copyrights, the commercial confidential nature of some information and the severe technical restrictions on data use, which make good faith violations of the TOU much more likely. This could have a significant chilling effect. The mere risk or threats of litigation could seriously hamper open scientific debate. Researchers may think twice about publicly challenging a company’s interpretation and representation of data or about correcting the published literature on the basis of EMA held data, as called for by the recent RIAT proposal.

In short, EMA’s approach is strengthening industry’s legal control over data, making it more difficult and legally risky for independent scientists to use them. These are in essence regulatory data, created for public interest use. For the EMA, a key public institution, to now support the privatizing of pharmaceutical knowledge through contractual affirmations of companies’ rights over these data is truly astounding. Dr. Rasi’s recent response to the Ombudsman, that EMA’s new policy is a ‘reasonable compromise’, and does not prevent researchers from asking for access to specific data sets on the basis of the existing access to information policy, does not reassure. His response does not recognize the legal concerns raised by the draft TOU and Redaction Principles, let alone justify the approach taken. And Abbvie’s withdrawal of the legal challenge of the Humira data release notwithstanding, EMA appears back in the business of imposing more extensive limits on what it gives access to in response to specific access requests.

This troubling development is not entirely surprising. Even if the transparency movement had some major victories, including the adoption of transparency requirements in the recent European Clinical Trials Regulation, opposition has been mounting. Industry may now employ other regulatory initiatives to fight transparency. The European commission recently released a draft directive aimed at streamlining and strengthening Trade Secret protection in Europe. The European Federation of Pharmaceutical Industries and Associations (EFPIA) jumped already enthusiastically on the occasion, emphasizing the need to protect the “proprietary know-how” of drug development, including in the “clinical trials phase”. In the context of ongoing and largely secret transatlantic trade negotiations between Europe and the United States and Canada, the pharmaceutical industry has also been lobbying hard to strengthen data and IP protection and to include better data protection in the package. EMA now appears to be lending a helping hand.

Trudo LemmensTrudo Lemmens is Associate Professor and Scholl Chair in Health Law and Policy at the Faculties of Law and Medicine of the University of Toronto. His research focuses on legal and ethical issues of biomedical research and pharmaceutical product development. Other than receiving royalties for books published with University of Toronto Press and Themis (University of Montreal) and having a University salary, he has no relevant financial interests. He has written about data access issues in the past and participated in the consultation process on EMA’s prospective data release policy.

Acknowledgments: thanks to Ariel Katz (University of Toronto) for useful comments on an earlier version and to Peter Maybarduk (Public Citizen) for sharing documents related to the international trade negotiations.

Odysseus come home

Odysseus was in his 70s. Coming up to the 50th anniversary of a very happy marriage. He had formerly been a respected professional, a longtime member of the bowling and social clubs – a pillar of the community.

He had had minor episodes of anxiety primarily since retirement but no diagnosis of nervous problems. He went to his primary care doctor and was given a sleeping pill for poor sleep but stopped it after the first pill knocked him out. A few weeks later he was brought back to the clinic by his wife and ended up on Cipramil (citalopram) for anxiety. In the following 9 days he had 3 nose-bleeds – an SSRI side effect not recognized by his doctor.

The medical records pointed to a deteriorating situation….but no risk was noted

He kept a diary while he was on Cipramil, which recorded that he was feeling worse and worse, and  becoming concerned that he might be going mad. He returned to the doctor and complained about his antidepressant but was persuaded to continue the pills – “these drugs take several weeks to work”. No risk of suicide was noted. The medical notes record his concerns about the stress he was causing his wife.

The medical records, the later testimony of acquaintances and family members all point to a deteriorating situation. His anxieties about trivial matters were escalating rapidly. He began voicing doubts about his wife’s commitment to him. This was exacerbated by a new anxiety about driving that led him to ask her to drive him everywhere which she would not do. He described himself as a fly in a jam jar and his diary records a fear that he might be committed to an asylum.

His son found him pacing restlessly and scratching himself furiously – the 10th day since starting citalopram

He mentioned suicide to neighbors but said he would never have the nerve. A daughter thought of flying home. A son came to visit, and found his father pacing restlessly, scratching himself furiously and unable to hold a coherent conversation. His son left the following morning for a work engagement – the 10th day since his father started Cipramil.

Shortly afterwards, Odysseus got a blunt instrument, went into the bedroom where his wife was sleeping and battered her to death. The transcript of his interview with the police later that day – after calling them to tell them what had happened – shows a man who was incoherent. Several weeks later, after Cipramil was stopped, when interviewed in hospital he was quite different.

 A clear cut case of SSRI induced violence

This was one of the most clear cut cases of SSRI induced violence that I’ve seen. His children were happy for him to come home to live with them if he were acquitted. I wrote a report supporting a not guilty by virtue of insanity case. In comparable cases elsewhere, such as David Hawkins in Sydney in 2001, people have walked out of Court effectively free (see Healy et al 2006).

Did Odysseus’s lawyers bottle it? Neither Odysseus nor his family saw my report. He was in prison, isolated from almost all contact and unable to test their view or intentions. He accepted their advice to plead guilty, which gave him 2 years in prison. No one it seemed had any incentive to help Odysseus get home. For the police, he kept their conviction rate up. For the lawyers, he was on legal aid and so they stood to make the same amount of money from a quiet day in the office. I wrote to the Judge but was blocked from sending the letter by advice that I would be in contempt of Court.

All of the biases outlined in these posts come into play when it comes to the issue of violence on prescription medication. We have no difficulty in believing that illegal drugs like cocaine or amphetamines, or over-the-counter drugs like alcohol can lead to violence, but extraordinary difficulties in believing that prescription drugs can do so.

The original insanity defense

Drugs formed the basis for the original insanity defense outlined by Chief Justice Matthew Hale in 1743 who stated that:

 “if a person by the unskillfulness of his physician or the contrivance of his enemies, eat or drinketh such a thing as causeth such a temporary or permanent frenzy, as aconitum or nux vomica, this puts him into the same condition, in reference to crimes as any other frenzy, and equally excuseth him”[1].

The frenzy Hale refers to here means delirious states, stemming from physical or other disorders, and only secondarily to what later came to be termed not guilty by virtue of insanity or psychiatric illness. Delirium refers to states induced by a fever, or toxic metabolism, or by a toxic agent such as a drug. Delirious states as instanced by the disordered mental states accompanying a high fever or delirium tremens offer an absolute defense against murder and provide a basis for a not guilty verdict because the capacity to form intent to kill could not have been present.

But 260 years later we have much greater difficulties with these issues than Hale had. In the Pittman case in South Carolina, a 12 year old boy who had murdered his grandparents several days after starting Zoloft, Judge Pieper was much less clear than Hale before him:

“There is no case in South Carolina that addresses involuntary intoxication by prescription drugs… It seems to turn the whole medical system on its side if you can’t rely on the medication your doctor prescribes… It potentially forces you into a situation of lifetime commitment if that drug induces an effect of which you are unaware. There’s something disconcerting about that, albeit probably of a legal nature that is troubling me”.

The idea that a doctor might have poisoned a person is close to unconscionable

Treatment induced violence may be the most neglected treatment related problem in all of medicine, despite an abundance of the most convincing data. How could something be so Evidence in the 18th century and cause such problems now?

This is one of the two places where the tensions in prescription only arrangements become most acute (the other is pregnancy). No doctors intend harm, and certainly not harm to an innocent third party. The idea that a doctor might have poisoned a person is close to unconscionable. The idea that the most poisonous aspect of what happened was the doctor’s advice to continue taking the pills or double the dose leads many doctors and lawyers to something close to a psychotic breakdown when it comes to violence on prescription drugs.

Easier boycott Odysseus than Lundbeck’s drugs

And so in the face of mass school shootings where the great majority of the perpetrators are on antidepressants, we stay silent. Odysseus only got two years – a small price to pay many will think for ensuring the guilty don’t walk free.

But Odysseus didn’t just get two years. Back in Ithaca, his friends who had once been willing to testify on his behalf in the belief he was not guilty now refuse to have anything to do with a guilty man. The social club and bowling club turned down his applications to rejoin. For medical care he has to go back to the same doctor. The people he now has most contact with are the checkout girls at a supermarket some miles away.

Dare he risk an appeal? The judicial system might opt to re-imprison him.

And of course Penelope is dead. Who was responsible for her death? Lundbeck? Easier boycott Odysseus than Lundbeck’s drug. The gods seem more likely to listen and bring Odysseus home than Lundbeck.

 


[1] Hale M (1736/2003) Historia Placitorum Coronae. Vol 1 Lawbook Exchange. Clark New Jersey, Chapter 4, Concerning the Defect of idiocy, madness and lunacy, in reference to criminal offences and punishments. page 30

The Dram of Eale

They told me the 80 year old man who’d had a stroke must be depressed – he wasn’t rehabilitating properly. Could I see him and look at whether the citalopram he’d been started on a week before needed tweaking?

Jeff was solidly middle class, professional. He had never been ill before his stroke and never ever been mentally ill. He had a large loving close-knit family who came to see him every day. He didn’t seem depressed to me. I stopped his SSRI and said I would come back in a week to see how things looked – perhaps his depression would be more obvious then.

A week later, Jeff seemed much better than he had been on citalopram. He clearly didn’t need an antidepressant – if he wasn’t rehabilitating it was because of where his stroke had struck.

‘While on those pills I had a terrible urge to get up and strangle him. I’ve never seen him before.’

I got up to leave just as his family came in. He grabbed my arm. ‘I’ve something to tell you before you go. You see the man across the room’. There was another older man confined to his bed.

‘Well while on those pills you know I had a terrible urge to get up from my bed in the night and go over and strangle him. I don’t know why. I’ve never seen him before. Those feelings have gone since you stopped my pills.’

This makes it about as Evident as you can get that SSRIs cause violence. The only thing possibly more convincing would be data from healthy volunteer studies where aggressive episodes have been relatively common (see Mystery in Leeds).

Homeland security

In the latest hit series Homeland Claire Danes plays Carrie Mathison a CIA agent with bipolar disorder taking Clozapine. She takes the drug to prevent herself tipping over into frank paranoia in a world where being paranoid is necessary for survival.

Anyone who knows anything about Clozapine knows Claire Danes is definitely not on it – she would not be as slim and svelte as she is if she were taking it. Weight gain is something Evident about Clozapine that stands in contrast to the Evidence showing no weight gain that companies have gone out of their way to produce for Clozapine and related drugs like Zyprexa and Seroquel (see False Friends).

Should Claire Danes get paranoid?

The question is what does Claire Danes know about Clozapine and should she get paranoid rather than just play the paranoid? As an actress is she killing people playing the part she plays? Is there anything else Evident about Clozapine being hidden by the Evidence?

Clozapine began life in 1958. It was given to the world’s leading psychopharmacologist Pierre Deniker to assess. At the time the neuroleptic/antipsychotic group of drugs was regarded as very safe. Several of Deniker’s patients died on Clozapine and startled by the number and range of deaths he said it was Evident that it should not be developed.

Deniker said Clozapine was too dangerous to be developed.

The company who made Clozapine (Wander) paid no heed to him; business and clinical evidence are two different things. Clozapine’s development continued even after Wander was taken over by Sandoz. Then in 1975 a series of deaths on Clozapine following drops in white blood cell counts happened in Finland. Clozapine was removed from markets in Europe and never made it to the US – Homeland Security (aka the FDA) intervened.

But it re-emerged in 1988 in the United States, in part because of efforts within Homeland Security. The history of Clozapine’s return has been spun and respun – see The Creation of Psychopharmacology – in the course of which a myth has been created that Clozapine is more effective than other antipsychotics (very important for someone on whose wits the fate of America depends) even though head to head trials in first episode psychoses show Clozapine to be no better than older drugs like chlorpromazine.

Recently the Lancet published a large study by Jouko Tiihonen and colleagues, ironically from Finland, which has thrown the cat among the safety pigeons. In line with expectations, Tiihonen showed that patients treated with antipsychotics had higher mortality rates than patients not on antipsychotics. Except for Clozapine. Clozapine had a lower mortality rate than all other antipsychotics, lower even than non-treatment.

Did Deniker get it badly wrong?

So did Deniker get it badly wrong? Have the Lancet redressed an historical error and are they helping Homeland Security by getting Claire Danes on Clozapine – or has the Lancet been turned and is it also now a threat to the American people if not to US business?

Having spent several posts pointing up the limitations of randomized controlled trials (RCTs), and before going on to labor them further, this Finnish study offers a wonderful example of where RCTs really are needed. The need for an RCT in this case should have been very apparent to the Lancet and its reviewers, and probably should have led to the Tiihonen paper being turned down – other than as a marvelous illustration of how badly wrong cross-sectional outcome studies can get things.

Here’s the problem. Outcome studies like the Finnish one are not randomized. The investigators in a study like this just look at what happens in patients taking older antipsychotics like haloperidol, newer drugs like Zyprexa (olanzapine) or Clozapine. Given that thousands of patients may be on each drug and they were followed up over longer periods of time than the usual clinical trial would follow them up, is randomization we might ask a big deal? Does the accumulation of lots of patients not ultimately manage the bias that randomization helps us manage? If Clozapine is dangerous could it conceivably show up in a study like this as the safest drug in town?

Outcome studies can get things this badly wrong. Here’s how it can happen. Patients never get Clozapine first line. They have to have taken several other antipsychotics first. This means they will never get Clozapine in their first year of treatment and perhaps not in the first three to five years. The significance of this is that by far the greatest cause of mortality in patients on antipsychotics, over 50% of the mortality, comes from suicide, primarily in the first year of treatment.

The next biggest source of mortality comes from heart attacks and strokes. But these happen for the most part in older patients given antipsychotics for acute and transient psychoses or delusional disorders. These older patients are at some risk of heart attacks or strokes even before treatment. Again these are patients who rarely if ever get Clozapine. There were deaths in the group of patients who were not on any antipsychotic and these most likely came primarily from older patients with acute and transient psychoses.

This is how the most lethal drug in town can appear the safest

Add these two exclusions together and it becomes clear why there could be fewer deaths on Clozapine in Finland but how at the same time it can be the most lethal antipsychotic. Clozapine causes problems of unparalleled severity in every body system with deaths from myocarditis, interstitial nephritis, cardiomyopathy, diabetes, neuroleptic malignant syndrome and a range of other causes, including suicide, much more than other antipsychotics, but it is not ordinarily been given to the patients at greatest risk.

Clozapine is a wonderful drug – to have in reserve. It is not the drug that is going to help Danes keep the Homeland more secure than others.

But when even the most lethal of the antipsychotics, with a range of cautions like no other, can be billed as the safest, it’s clear we have a system that can induce paranoia. Here’s a question for Danes – is the Lancet one of our heroes or has it in some way been turned? A series of Lancet articles touting the benefits of Agomelatin, and the work of Robert Gibbons, and a more general track-record embracing the latest treatments would make anyone wonder.

The reality is more likely to be as Homeland Security might say that the price of security is eternal vigilance. The issues are tricky and expertise is needed. Beyond expertise we also need to shift orientation back to the future – away from the current adoption of the latest chemical as a wonder fertilizer to be spread as widely as possible, and back to a traditional medical view of chemicals as poisons to be used judiciously.

Clozapine really does deserve a poison sign

We used to have a poison sign on most medicines (see We need to talk about doctors). Among antipsychotics Clozapine is the most deserving of such a symbol still.

Medicines are chemicals that used to come with information about their use in people. The drugs are still poisonous and the art of medicine should still involve balancing the risks of the poison against the risks of the illness, but the information that comes with the drugs that portrays them as free of risks is increasingly poisonous in its own right. Is it time to introduce a poison symbol with articles touting the benefits of pharmaceuticals? Pharmaceutical companies campaign actively against any references to their chemicals as poisons. Medical journals would most likely be equally resistant to the use of such symbols on their articles.

For some of us having a poison symbol on articles might feel like the best way to avoid tipping over into paranoia. But this was tried with quality marking controlled trials and when this was done pharmaceutical company articles garnered all the best quality marks. It’s likely in just the same way that company articles touting the benefits of treatment would end up festooned with symbols of purity while other studies pointing to the risks of drugs would have a poison symbol. Time to reach for the Clozapine.

We need to talk about doctors

doctor with a stethoscope

Randomized controlled trials (RCTs) came into favor in the wake of thalidomide as a method to evaluate drugs and their risks.

They were supposed to keep ineffective drugs off the market, but companies have learned that you can do any number of trials and if even some show a marginal benefit they can get their drug on the market and the others can be suppressed so no one has a true picture of the effects of the drug. Once on the market, the favorable RCTs are turned into a turbo-charger to boost sales even for debatably effective drugs. The risks get written out of the script by ghostwriters and creative publication strategies.

Once on the market, the favorable RCTs are turned into a turbo-charger to boost sales even for debatably effective drugs.

RCTs in turn underpin the era of guidelines we are now in. As trials became more common, sooner or later, someone was bound to get the idea that all the “scientific evidence” accumulating could be assembled to show which treatments should be used first, which second, etc. This looked like another good way to control pharmaceutical companies and the risks of drugs but it soon became just the opposite. Neither managers nor pharmaceutical companies like the idea of doctors having clinical discretion, and guidelines based on the (published) evidence have become a way to standardize clinical practice and manage risks. What risks?

The formerly healthy tree of medicine is sapped by the ever more vigorous pharmaceutical  ivy growing on it

The irony is that a method introduced to manage the risks of drugs has become one that has been used to shift the blame for things going wrong over to doctors.  If the drugs work well and are safe, if anything then goes wrong, it must be the prescriber’s fault. The marketing of today’s drugs always spins them as safer and safer – if so, given that things still go wrong and in fact treatment induced injury is now a leading cause of death and disability, doctors must be becoming riskier and riskier. The effects of a prescription-only embrace has been to leave the formerly healthy tree of medicine sapped by the ever more vigorous pharmaceutical ivy growing on it — at risk of being brought down by the next storm.

If the drugs are becoming safer and safer, doctors must be becoming riskier and riskier.

Three symbols tell the story.

First there is the now ubiquitous seatbelt symbol. Over the last 30 years, safety features to help manage the risks of driving have become ever more common, from seatbelts to airbags, to cars engineered not to start if the driver is not belted up. In every area of life, except prescription-only medications,  there is an increasing emphasis on safety warnings; even in sports and war.

Seatbelt symbol

Second is the poison symbol that used to feature on many medicines, particularly those that were dangerous in overdose. It is now all but illegal to refer to a drug as a poison — see The spin that no data can overcome. These symbols have completely vanished. Ironically perhaps, one of the first drugs to advertise itself as not poisonous in this sense was thalidomide. Adverts for commonly showed it being taken accidentally by a child who, we were told, would not die as a result of taking it where they would likely have died if they had taken the alternate sleeping pill — a barbiturate.

Poison symbol

The third symbol comes from Gideon Koren, a researcher at Motherisk in Toronto, who has advocated putting a symbol featuring a pregnant woman on medications like the antidepressants in an attempt to overcome the reluctance of women to take these drugs in pregnancy.

Pregnancy symbol

This last symbol seems almost redundant, as despite increasing evidence that antidepressants double rates of birth defects and miscarriages and may cause mental handicap in the children born to mothers who have taken them through pregnancy, prescriptions for these drugs are escalating and they are now among the most common drugs taken in pregnancy.

Despite increasing evidence that antidepressants double rates of birth defects and miscarriages and may cause mental handicap, they are now among the most common drugs taken in pregnancy.

Medicine used to balance the risks of a poison against the risks from an illness, but now illnesses have become the unique source of risk. Drugs, which are prescription-only because their hazards are unknown and quite liable to exceed the risks of over-the-counter or illegal drugs, in contrast are portrayed as wonderfully safe, fertilizers rather than poisons.

We can hear the desperate plea from the doctor in the Woodley inquest (see Model doctors?), “If we left her untreated and things went wrong what would you say then?”

Doctors have regressed to childhood. They look to a father figure, in particular FDA, when things go wrong. But when they do they find they are not the pet child anymore. The pharmaceutical companies are. And companies are adept at smiling sweetly at Daddy and protesting their innocence.

Put another way, in controlled trials companies have found a Philosopher’s Stone to transform base metals into gold. These trials began as a means to manage clinical uncertainty, but now deliver commercial certainty instead. And under the spell of the Stone the magic that used to lie in Doctors like Dr Kildare and Marcus Welby has migrated into pills like Prozac, Lipitor and Fosamax, while the risks have moved in the opposite direction into doctors. We need to talk about doctors before Lionel Shriver writes a book about their involvement in a school shooting.

 

Notes on a scandal

In 1996 Zoe Heller, the author of Notes on a Scandal, took part in a widely reported debate with Roy Porter about Prozac. She defended the drug. It had restored her to life. He said today’s miracle invariably ended up in tomorrow’s tragedy and asked, Why is it that we never learn?

The story of a schoolteacher who seduced one of her male pupils.

In 2003, Notes on a Scandal came out. It was made into a stunning movie in 2006 starring Cate Blanchett. This was the story of a schoolteacher who had seduced and was having continuing sexual relations with one of her male pupils.

In 2006, Rosie Meysenburg started up SSRI Stories, a website for cases of violence triggered by SSRI drugs (see The story of SSRI Stories). To collect the material she posted, Rosie had to review reports of criminal and other legal cases in which media reports mentioned SSRIs. To her astonishment, she began to notice that she had a series of cases involving women teachers convicted for inappropriate sexual behavior toward male pupils — with the women typically taking an SSRI. For one woman, the Courts decided her drug had caused the problem. This was the plot of Notes on a Scandal.

The most obvious thing SSRIs do is change sexual functioning — almost all people on an SSRI will notice some change within hours of having had it. Ian Hindmarch’s women volunteers in Leeds in 1983 almost certainly all had changes in their sexuality or sexual behavior. Delayed orgasm is extraordinarily common to begin with; reduced libido comes later. In many cases, things return to normal when the drug is stopped. In a not inconsiderable number of cases the changes are permanent — we don’t know how often this happens.

Curing homosexuals?

At the start of the antidepressant story, Roland Kuhn celebrated the fact that imipramine, an SSRI, had cured some homosexuals he had seen (discussed in greater length in The Antidepressant Era). Thirty years later Peter Kramer celebrated in the same way for Prozac. No one argued this was impossible. There are good grounds to accept that SSRIs can shift some of us along the axis of our sexual orientation.

But it’s not reasonable to think the shifts are likely to be only one way — in the direction some would view as normalizing. For every one whose change in orientation the Catholic Church might celebrate, there is likely to be another whose change would pose problems for the bastions of morality. There won’t be one without the other.

In 1999, 13-year-old Matt Miller was taken by his parents to see a doctor, as he was unsettled in a new school. The doctor, who was on Pfizer’s speakers’ bureau, put him on Zoloft. Matt became restless on Zoloft. A week later he hung himself in the bathroom between his and his parents’ bedroom.

Auto-erotic asphyxiation gone wrong.

Pfizer argued Matt’s death wasn’t caused by Zoloft; it was a case of auto-erotic asphyxiation gone wrong. To argue their case, they wheeled in Parke Dietz, an expert who had offered the view that Anita Hill’s claims that she had been harassed by Supreme Court Judge Clarence Thomas were just fantasy. But Dietz didn’t come up with this idea of auto-erotic aphyxiation first — Pfizer did. Where did they get it from?

The idea almost certainly came from their studies, whether healthy volunteer trials like the Leeds study (see Mystery in Leeds), or in one of their trials for other purposes or in convincing reports to the company. This idea didn’t come from anyone’s understanding of what 13-year-old boys normally do.

Would Zoloft-induced impulses to auto-erotic asphyxiation be more or less plausible than a 13 year old spontaneously turning to this sexual expression? If it seems more plausible that Zoloft had induced auto-erotic asphyxiation, then whose fault would this death have been given the volume of data on Zoloft and sex that Pfizer had?

If Matt had practiced auto-erotic asphyxiation regularly (before starting Zoloft), another set of complications opens up. Zoloft inhibits orgasm. Could Zoloft have changed things, leading him to go too far? If so, whose fault would his death have been then, given that Pfizer had not warned about this? Knowing what they knew, Pfizer should have been honor-bound to warn anyone else who engages in auto-erotic sexual play or any form of sexual play, about this possibility.

Pfizer really should have told us what they knew about sex.

It was one thing for Pfizer to argue for auto-erotic asphyxiation gone wrong, but they really should have told the court of the range of sexual changes they knew about.

In the Miller case, Pfizer flew Ian Hindmarch over to a pre-trial hearing. At this he claimed that the volunteers in his Zoloft study in Leeds (see Mystery in Leeds) were just suggestible. Nothing much had happened to any of these women. But the study remained unpublished, and its full details have probably never been seen by any regulator.

Four years later, the FDA put a Black Box warning of the risk of suicide in children taking Zoloft and other SSRIs. It’s difficult to believe that many people will have ever thought that Matt Miller died because of auto-erotic asphyxiation rather than a straightforward Zoloft-induced suicide. This warning should drive a stake through the heart of Pfizer’s argument.

Professional auto-erotic asphyxiation?

For most people, the only remaining unanswered question of interest is likely to be where Pfizer got the auto-erotic asphyxiation idea from in the first place. The only remaining question for most people, that is, except the American Psychiatric Association, who after the Black Box warning rushed out a statement that the APA believes Antidepressants save lives. As outlined in Professional Suicide, this is an extraordinary example of a professional suicide note.

But perhaps what the APA, and more recently the Irish College of Psychiatrists, has been doing is not suicide after all — perhaps it is auto-erotic asphyxiation?  Let’s hope it doesn’t go wrong.

Model doctors?

Another inquest may bring out the risks to doctors from their professional associations behaving as the American Psychiatric Association (APA) or the Irish College of Psychiatry has done (see Professional suicide – the Clancy case).

She posed no suicide risk. She was put on citalopram.

Yvonne Woodley, a 42-year-old woman with two young daughters, ran into difficulties with her husband. They began talking of separation. Under stress, she visited her primary care doctor who noted that she was not depressed, and that she posed no suicide risk. She was put on 10mg of citalopram.

A week later she was noted by the doctor who saw her to be more anxious and for the first time as having voiced thoughts of harming herself, but she was still viewed as being at no risk of suicide. The dose of citalopram was increased after which she talked about suicidal impulses to her mother and made a suicide gesture — taking 100 analgesics to a remote place from which she phoned her husband and told him she was thinking about overdosing. He came to get her, brought her to the doctors, and from there she was referred to a mental health team.

Yvonne hung herself with her daughters downstairs watching television.

A further assessment concluded that she was at minimal or no risk of suicide. She dropped her contact with the mental health team and went back to her primary care doctor who doubled the dose of citalopram yet again. A few days later, Yvonne hung herself in the attic of her house with her daughters downstairs watching television.

Lundbeck, the makers of citalopram in Europe, sent a former medical director from their UK division to the inquest, Dr Chris Muldoon. The coroner, Aiden Cotter (AC), heard testimony from the family, from me, from Chris Muldoon, from one of the primary care doctors, and from the consultant psychiatrist linked to the mental health team.

Each of the doctors was asked two questions in common: “Can citalopram cause someone to commit suicide?” and “Did it cause Yvonne Woodley to commit suicide?” I answered that it can cause suicide and that Yvonne Woodley’s case bore the classic fingerprint of a treatment-induced death.

It was then Chris Muldoon’s turn:

AC: I would like you to answer the next two questions either yes, no or I don’t know. Then you can talk for as long as you wish as to why you’ve reached those decisions. But let’s just try to have yes, no, or don’t know.

CM: Ok.

AC: Do you believe that citalopram can cause somebody who would not otherwise take their own life to do so?

CM: Yes.

AC: And is that what you think happened to Yvonne Woodley?

CM: No.

He then went on to outline that there had been debate about the issue that had led to a range of warnings and he cited the National Institute for Healthcare and Clinical Excellence (NICE) guidance, which said:

NICE Guideline
Monitoring risk (page 8):
Monitor for signs of akathisia, suicidal ideas, and increased anxiety and agitation, particularly in the early stages of treatment with an SSRI.
Advise patients of the risk of these symptoms, and that they should seek help promptly if these are at all distressing.
If a patient develops marked and/or prolonged akathisia or agitation while taking an antidepressant, review the use of the drug.
Choice of antidepressant (page 9):
If increased agitation develops early in treatment with an SSRI, provide appropriate information and, if the patient prefers, either change to a different antidepressant or consider a brief period of concomitant treatment with a benzodiazepine followed by a clinical review within 2 weeks.

 

The doctors to blame?

The effect of this being read out in court was of a company saying we’ve done all we can in terms of warnings. If something went wrong therefore it must have been the doctor’s fault.

Having listened to themselves being put in the frame for blame and in particular having heard the company say their drug can cause suicide, what was the response from the doctors?

Here is the primary care doctor:

AC: And do you believe Citalopram does make people take their own life?

Doc 1: No actually. I think I’m going to say that, because we prescribed her Citalopram in the hope to make her feel better. That was the whole point of her taking it as an antidepressant, to help her to feel better. This is the risk that is reported by BNF and NICE. That is not to say that we’re actually prescribing somebody something that is going to make them kill themselves. I think if we had not prescribed her anything what would be the conclusion then if she’d hung herself? That she hadn’t been treated?

And here the psychiatrist:

AC: Let me ask the same questions I have previously asked the doctors. First do you believe that citalopram can make somebody who would not otherwise take their own life, do so?

Doc 2: I don’t.

AC: You don’t believe it?

Doc 2: No.

AC: So it follows from that that you don’t think that’s what happened to Yvonne?

Doc 2: No.

This exchange makes a number of things clear.

In the Clancy and Woodley cases and in other cases, if asked if their drug has caused this person to commit suicide or homicide, Lundbeck and other companies will always answer No. If asked can your drug cause suicide, they will always contrive to answer the question as though it refers to a particular person and give the impression that there have been no cases where their drug has caused a problem. In a previous post (Psychotic doubt) we have seen Ian Hudson do this.

Companies are legally obliged to say that their drug “can” cause suicide. But doctors are under no such obligation — even under oath.

But if asked up front under oath, they are legally obliged to say that their drug can cause suicide. This is like Philip Morris agreeing smoking can cause lung cancer but denying that it has caused this death or that death from lung cancer.

But an academic, such as an Irish Professor of Psychiatry, or a professional body, like the Irish College of Psychiatrists, are under no such obligation, and they can state even under oath that these drugs do not and cannot cause someone to take their own or another’s life.

The dictionary definition of a model is “a shrunken replica of the real thing.”

So if stuck with a tricky question, other than in court, Lundbeck and other companies can and do defer the questioner to an academic — or to the APA or the Irish College of Psychiatry. They don’t even have to lift the phone. It’s all part of a complete doctoring service.

As the response from Tom Fahy in Professional suicide – the Clancy case shows, this is a new service. One question for those of us who have not retired is whether we want to be represented in this way.

Why call these new doctors “model doctors”? Well, the dictionary definition of a model is “a shrunken replica of the real thing.”

For doctors this is a matter of professional politics. 

There are some doctors for whom academics defending drugs like the APA or Irish College have done might be  morally distasteful, but for all doctors it is a matter of professional politics. If medications are perfectly safe and very effective, there are much cheaper prescribers, who are much more likely to stick to guidelines than doctors.

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 5, feeling increasingly unwell, Shane took the remainder of his month’s supply of tablets in an attempted suicide. 

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.

 Shane stabbed Sebastian (fatally), Jennifer, and Sebastian’s brother. He was later found dead having stabbed himself 23 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.

Before the 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.

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.

In this case, an open verdict would be more appropriate than a suicide verdict.

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.

Pharmaceutical companies will send academics and high-powered lawyers to a humble inquest in a small town to ensure the coroner or the jury returns a suicide verdict.

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.

The Irish College of Psychiatrists went into overdrive issuing statements left, right, and center that there was no evidence that citalopram could cause suicide or violence. 

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.

Drinking the Kool-Aid?

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.

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.

We are all rapidly becoming factory doctors now.

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 are even documents from Pfizer expressing surprise that the regulator has not pushed them harder on the question of efficacy.

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.

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.”

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.”

In 2001, 60 Minutes backed down under pressure – The Insider II.

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 it suits the pharmaceutical industry to have the antidepressants pushed aside in favor of mood-stabilizers.

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?

An autopsy on the body of professional medicine coming soon…

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.

 

Mystery in Leeds

Sherlock-Holmes

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.

Maybe this story will resonate with children or partners or friends.