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.

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  1. Neil Gorman says:

    I watch homeland and noticed the same things. Its actually a bit of a problem in American TV shows. I have seen and episode of House, where they pushed the whole ‘Chemical Imbalance’ theory of depression, and a episode of Glee that was more like a advertisement for SSRI pills.

    I wonder sometimes if this is just due to poor research on the part of the writers, or if its a little more sinister than that. Sometimes, like in Glee, the story came out of the blue and seemed almost forced into the show.

  2. http://www.independent.ie/health/health-news/split-personality-disorder-youve-got-it-all-wrong-3046623.html

    Last week this Article was in the Irish Independent. It’s about Schizophrenia and quotes Professor Patricia Casey, a member of the Irish College of Psychiatry, who gives her opinion on Clozapine. No mention of any side effects though…

    “Schizophrenia is treated with anti-psychotic medication and most people do well, but a small proportion go on to develop negative symptoms which consist of social withdrawal, apathy, poor self-care, lack of motivation.

    “Clozapine is used to treat this stage of the illness, but it is first important to identify the acute illness as early as possible in order to prevent the transition to negative symptoms.”

    Generally, she says, about one-third of patients do well and experience a complete recovery. About one-third do moderately well and can function but, she says, perhaps not to the level they previously did.

    “A further third do badly, although that figure has probably improved in recent years with the availability of Clozapine and the realisation that early detection of the illness itself and aggressive treatment is crucial.”

  3. Thank you for pointing out the misconceptions about psych meds fed to the public in various forms, including popular television shows.

    In a real life case, Deidra Sanbourne, named as the plaintiff in Florida’s landmark civil rights case, Sanbourne v. Chiles, spent nearly twenty years being treated unsuccessfully in Florida’s state mental hospitals.

    A Google search on Deidra’s name will result in dozens of sites listing her death was a result of neglect while living in a boarding house.

    The source of this information is cited as being from Pete Earley’s book Crazy: A Father’s Search through America’s Mental Health Madness:

    Diedra Sanbourne’s death, as reported in the book Crazy, occurred from a bowel obstruction while being treated in a psychiatric unit at Westchester General Hospital and not from neglect in a boarding home.

    Deidra’s symptoms were diagnosed as schizoaffective disorder and she spent over 20 years being treated unsuccessfully in psychiatric wards. When I read the fact the cause of her death was from a bowel obstruction I immediately considered the possibility that a psychiatric medication prescribed to Deidra could have caused the bowel obstruction that led to her death.

    A quick search on Medline revealed the medication Clozapine is used to treat severe cases of schizophrenia. Clinical research suggests Clozapine has caused bowel obstructions leading to death in individuals being treated for symptoms described as schizophrenia.

    It is unfortuante that Deidra has been made into a “poster child” for advocates of forced treatment with psych meds when there is a likely chance the medications and treatment in a psych ward could have been the cause of her death.


  4. In Tonights Waterloo Road On BBC 1. A teenage boy has been prescrbed clozapine after having a psychotic episode after smoking cannabis.

  5. Johanna Ryan says:

    There’s no way on earth that clozapine is showing up in these TV shows accidentally or through sloppy research. A few celebrity cuss-words may slip through … but this is Product Placement, which is taken VERY seriously (and usually paid top dollar for!) Just as no TV character “just happens” to sip Diet Coke or drive a Jeep, none will “just happen” to take a certain drug.

    Here in the U.S., NAMI has apparently endorsed “Homeland Security” as a great antidote to stigma against the mentally ill:


    I guess the show has already incorporated the key NAMI subplot: at one point the character STOPS TAKING HER MEDICATION, leading first to her own collapse and then bringing us all to the brink of “international devastation.” Given NAMI’s tight relationship with pharma companies, this blog post may itself be a piece of Product Placement.

    A scandal broke in Chicago a few years ago about a psychiatrist named Reinstein with 1,200 patients on clozapine and three wrongful-death lawsuits … so far. He’s now promoting the one form of the drug that’s on-patent: FazaClo, a dissolvable formulation with a pleasant minty taste. Currently marketed by Jazz Pharmaceuticals of Ireland. I have to wonder if this has provoked Dr. Casey’s enthusiasm. It is startling to read a popular press article in which this very risky drug is the ONLY one mentioned for the treatment of schizophrenia.

  6. There is a major area of psychotropic risk that is mentioned in the medical literature from time to time but has not been adequately exposed, probably because it affects mainly the elderly and psychiatric inpatients. The incidence of asphyxia due to psychotropic drugs, mainly antipsychotics, has been noted since the 1950s as being common in psychiatric patients but only relatively recently in the elderly in nursing homes. While choking deaths are not only tragic, they are dramatic and notable, but there is a far more pernicious adverse effect in the institutionalized elderly viz. malnutrition and dehydration. The parkinsonian adverse effects of many psychotropic drugs affect the ability to chew and swallow. It takes much longer to feed a dependent older person who has swallowing impairment so that many fail to receive the full, prescribed diet. Contrary to popular belief, the most difficult substance to swallow without misdirection, is water and, because of a completely misguided concern about the aspiration of water, a majority of these patients are either directly deprived of adequate liquids or supplied with unpalatable “thickened” liquids that have been proven to contribute to dehydration. In spite of the availability of simple ways of compensating for the impairment, the cascade of disaster proceeds thus: psychotropic medications, impaired swallowing, reduced food and water intake, increased weakness, blood pressure fluctuations due to dehydration, falls, broken bones – usually hips or skulls- acute hospital admission, pneumonia and death.
    Yet we continue to allow, even recommend in some cases, the use of antipsychotics in the elderly.

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