- Not So Bad Pharma – March 28
- April Fool in Harlow: Anecdote Fishing in Harlow – April 1
- The Tragedy of Lou Lasagna – April 9
- The Empire of Humbug: Bad Pharma – April 15
The first RCT
In 1956, two of the creators of the modern RCT, Lou Lasagna and Michael Shepherd, met. The randomization in randomized placebo controlled trials came from Bradford Hill in Britain and placebo controls from Beecher, Gold and Lasagna in the US. In 1956, Michael Shepherd, Bradford-Hill’s representative in all things psychiatric, came on sabbatical to stay with Lasagna at Hopkins’.
In 1947 Bradford-Hill ran the first randomized trial. In 1955, Shepherd added in Lasagna and Beecher’s placebo to the original randomized design and published in the Lancet the first ever RCT of the type used today in drug trials submitted to FDA for regulatory approval. His trial compared reserpine to placebo in a group of outpatients with mixed anxiety and depression – similar patients to those later given Prozac and other SSRIs. Reserpine was better than Prozac and other SSRIs later were, and indeed did better than imipramine did a few years later in a trial run by Lasagna. There was no sign in Shepherd’s trial of the suicide hazard for which reserpine is now best remembered.
The two articles that immediately preceded Shepherd’s study in this issue of the Lancet described hypertensive patients being treated with reserpine who became suicidal. When later asked why his trial had almost no impact, Shepherd’s off-the-cuff response was that doctors were not used to seeing results being presented in this way. But there was in fact no commercial incentive for any company to use his results to relegate the accounts of suicide on reserpine to the status of anecdotes…The two articles that immediately preceded Shepherd’s study in this issue of the Lancet described hypertensive patients being treated with reserpine who became suicidal. When later asked why his trial had almost no impact, Shepherd’s off-the-cuff response was that doctors were not used to seeing results being presented in this way. But there was in fact no commercial incentive for any company to use his results to relegate the accounts of suicide on reserpine to the status of anecdotes…
Separate mention should be made of the side-effects among those patients who completed the six-week trial. These were all attributed by the patients to the substance which they were taking. Among the patients on reserpine, 3 complained of nasal stuffiness, 4 of what was described as " shivering," and 2 of giddiness and dizziness ; 1 commented on his large appetite, 1 on increased libido, and 1 of many somatic anxiety symptoms. Of the patients on placebo, 3 complained of fatigue, and 1 felt elated for the first day or two : the more dramatic side-effects displayed by 1 of the patients who did not continue with his tablets have already been mentioned.
Unfortunately about 10% of our patients who received reserpine, either alone or in combination with pentolinium, have experienced substantial degrees of mental depression and about 5% have required psychiatric treatment. Mild degrees of depression are even more frequent. Some patients on reserpine also complain of lassitude and sleepiness during the day and of disturbed sleep with nightmares at night.
The very encouraging reports of the effect on hyper-tension of the rauwolfia alkaloids, and of a combination of reserpine and pentolinium, encouraged me to use this form of treatment where possible. Until recently I thought that an almost ideal treatment had been achieved, but when the third case of melancholia in a severe hypertensive treated with this combination was observed, I became doubtful of the safety of the method.In 133 patients with hypertension, treated as private patients in a general practice over a period of thirty months, there was a group of severe hypertensives who benefited considerably from combined oral reserpine and pentolinium. No less than 4 patients out of 44 who received reserpine alone or in combination had severe mental depression amounting in 3 cases to melancholia with delusions.
Malignant hypertension is a killer. By the time the patient presents for treatment, there are usually signs of clouded consciousness and a intracerebral bleed [stroke] is just around the corner. It is common in the African American population that came to the large City Hospital in Memphis where I trained. If you needed to get the blood pressure down in a hurry, Resperpine was a first-line treatment. It had been introduced in 1952. After the crisis had passed, the next order of business was to change to another drug for maintenance, as the incidence of depressive illness on long term Reserpine was high [higher in my memory than reported here]. So here, even as it was being studied as an antidepressant/anxiolytic, we have two reports of its capacity to cause depression – one from a New Zealand research center trying an alternative drug and one from a practitioner in Australia who had noticed some hypertensive patients who became profoundly depressed on the drug and reviewed his practice. That’s how it used to work. A practitioner noticed something, looked into it, and let the rest of us in the world of medicine know with a report like this one in the Lancet. Both articles report that Resperpine is a good antihypertensive. Both give an approximate 10% incidence of depression.
And now for the problem that haunts us to the present. The six week clinical trial of Reserpine showed that it was useful in a number of psychiatric dimensions, proven by a statistically significant double-blind randomized placebo-controlled clinical trial – the first in history. And that’s correct. Reserpine has both antipsychotic and antidepressant properties. It was used as an early treatment for psychosis before the introduction of Thorazine a few years later. Unfortunately, in the long term, it can cause depressions indistinguishable from naturally occurring psychotic depressions – big ones. As we well know, generalizing from the brief clinical trials now used for approving drugs misses a lot of what can happen with prolonged use. It’s a lesson taught repeatedly with the antidepressants and antipsychotics well into the modern era.
An irony here is that Shepherd’s statistical calculations don’t hold up. Some years ago I checked them and found no significant advantage of reserpine over placebo for the data given in his Table 1. I have just now re-checked them and come to the same conclusion. Even if Shepherd’s claim were valid, it looks like a serious stretch for David Healy to say that reserpine was better than Prozac and other SSRIs later were, or even better than imipramine. The simplest explanation for reserpine being passed over in practice is just that it doesn’t work, pace Michael Shepherd. As always, the devil is in the details. Caveat lector!
I read the enfolding tale of how an “Empire of Humbug” colonized not only psychiatry, but corrupted much of academia and medical professionals as well, not to forget senators and politicians high and low, and organizations like NAMI, corrupted by Big Pharma money to the status of impotent lackeys.
Remedies for rebuilding necessary trust, i e the trust of us plebs, the commoners, the people, whose health and lives are at stake, can only be through the humble door of openness, transparency, honesty, through personal relationships that can bring healing, potentially teaching not-all-knowing doctors what you do not know/ can not know unless you listen intently to the main characters, the patients, the people and share with other honest researchers and colleagues, as demonstrated on this blog. Lessons of great value, thank you!.
Dr. Mickey, Dr. Mickey! Is there really research showing that reserpine can be antidepressant in the short run but cause worsening depression in the long run? Because that in my lil ol’ opinion is the biggest hidden skeleton in the closet of the SSRI’s and SNRI’s, and one that 99% of the medical establishment refuses to even consider. (Although I’ve been struck in recent years by how, each time a new “treatment” is rolled out, it comes with proclamations about the large number of people who “remain” seriously depressed “despite” multiple antidepressants.) This would be incredibly relevant stuff to go back and study it would seem.
FYI
Penis Size and the Primitive State of Sexual Consciousness
“There are two areas relevant to psychiatry that are the object of very little research and they are sex addiction and sexual consciousness. Consciousness in general has not been much of a focus by psychiatry since the advent of DSM atheoretical descriptors that in effect limited the focus of study to extremes of human behavior. The consciousness that I am referring to is the unique conscious state of individuals. The current diagnostic system does not presume to diagnose individuals ”
http://real-psychiatry.blogspot.com/2013/04/penis-size-and-primitive-state-of.html
check out the recent psychiatric times for the article “Psychiatric Liability: A french psychiatrist sentenced after a murder committed by her patient”. It seems our omnipotence is not good enough for society, eh?
You have to log in to access it, so be warned:
http://www.psychiatrictimes.com/home
Clinical trials do not even begin to demonstrate the long-term damage (or benefit) of psychiatric drugs. Since the purpose of the trials is to get FDA approval, that really should be the first step in drug testing, that, as you say, should be taken up and documented by clinicians who should (IMO) be required to note patient responses and opinions and report them, no matter what the clinician thinks of that input.
A trial– -especially a trial that has not been replicated and challenged repeatedly is not evidence of much of anything; much less “proof” of what a patient is suffering based on a reaction to a drug.
Being stressed is a chemical condition in the brain AND the body— long-term, insidious stress, even more so. Having been a caregiver for a patient waiting for a liver transplant (no he wasn’t an alcoholic or drug user, and he did not have hepatitis) the effects of stress can be seen in strong relief when a person’s body is unable to cope with it biologically. Stress and the moderation of the effects of stress are processes that are in no way limited to the brain or cognition, and is inevitably made worse by poor health, insufficient sleep, poor diet, and having no reasonable or safe way to foil or escape the stress that is reaping havoc on the person and the person’s life.
Being terrified of losing one’s job, for instant, when the consequences of that could be dire for oneself and those dear to the self is as much a physical blow as being punched in the face, except it’s harder to protect oneself from it and to recover from it. Fear is a physical state. How a drug effects that fear is not the same as dealing with the causes of that fear and its natural effects. To be stressed and afraid of the prospect of you by yourself, or you and your family being thrown onto the streets is not evidence of a “disorder” or a lack of “resilience.” A drug may help a person handle a situation well enough by taking the edge off so that they can deal more effectively with the problem in the short term, but the idea that the stressed person needs to take this drug for life because of having been overwhelmed is the product of a most malignant and privileged narcissism.
Either it’s malignant and privileged narcissism … or sheer, inhuman greed. Sometimes the chief medical officers signing off on such practices know damn well they are harming the patient, but the profits are too good to resist. Here in Chicago the FBI just raided the offices of a small, for-profit hospital called “Sacred Heart” (I kid you not) . The owners and several staff physicians were charged, among other things, with defrauding Medicare by “seeking payment for the sedation, intubation and subsequent performance of tracheotomy procedures on patients absent the medical necessity to perform these procedures.”
You read that right. You arrive, elderly and somewhat frail, for a “checkup” in the Sacred Heart ER. You are sedated and a vent tube is forced down your throat — a tube which you do not need. Your breathing is not compromised, but over the next week or so you are heavily sedated to the point where your breathing becomes compromised so that you can be trached and kept on a ventilator for the maximum 28 days your “healers” can extract from Medicare. Your chances of dying within 14 days of the trache are roughly one in six.
Now of course this is only happening to poor people, maybe 98% of them black, on the West Side of Chicago, so maybe the rest of us are expected to just shudder and turn the page. But to me it’s clear that these thugs in white coats are only taking their cue from their betters at the top of the health care food chain. Profit is what makes the system run. The sorry story of Sacred Heart is here:
http://chicagotonight.wttw.com/2013/04/17/sacred-heart-hospital-scandal
Why do I feel like hitting MY HEAD against the wall?! I almost want the F.B.I. to put their heads through a wall for me, but most especially for all the poor people they tortured with their Capitalist approach to Nazi medicine. The poor are the Jews of American fascism.
Rat bastards. A purge at the AMA, APA, and FDA is long overdue— something on the scale of the landing at Normandy and Allied bombing.
Before everyone goes off believing everything David Healy says, you might want to look into the life and contribution of Paul Meier to medical research. He was the force behind randomization in clinical trials and generally considered to have been the MOST significant improvement in clinical trial design. Oh and he also formulated the Kaplan-Meier survival function……