Flash: see the press release from the Nordic Cochrane center et al: Backpedalling on EMA’s “proactive publication of clinical-data” draft policy…
Well, today is International Clinical Trials Day once again – celebrated from all sides of the controversies.The AllTrials campaign has a new video about Data Transparency:
… while Clinical Research Organizations have many things planned around the world. I’m spending the afternoon celebrating by going over Clinical Report Forms from an old trial that was misreported. My favorite part of the festivities is a simulated ClinicalTrials.gov write up for James Lind‘s first ever clinical trial on Scurvy in 1747 – Study of the Effects of Multiple Medicines on Scorbutic Sailors Upon The High Seas.
When I think back to 1963 when I started medical school, I never thought about clinical trials. To be honest, I didn’t really know what they were. I learned pharmacology as a discipline much like chemistry where the mechanism of drug action was front and center. In an Internal Medicine Residency, that continued and the use of drugs was based on more apprentice learning and practical experience. Drugs that had a small or variable effects were not prominent on my [or anyone else’s] radar. The focus was on treating the [very] sick, learning how to use toxic chemicals safely. Like saving the life of a patient with septic shock with Kanomycin without ending up with a live, but totally deaf patient. In those days, the class of a drug mattered more that the particular member of the class. I always used Digoxin in heart failure because I knew how to dose it in the various situations where it was called for. A good friend always used Digitoxin because that’s what he learned with. The old doc in the clinic used Digitalis leaf, one step removed from the aboriginal who discovered that chewing certain leaves treated his dropsy. We all did fine and never argued about the choice.
A Psychiatry residency was my first encounter with the endless discussion of small differences among members of a class of drugs. On the in-patient unit, there were a lot of discussions about the differences among the [first generation] neuroleptic drugs and the [tricyclic] antidepressants. I’m a good boy so I learned what I was taught and used the drugs accordingly. But I’ll admit that privately, early on, I didn’t see that much difference. At first, I think I thought that since there were so few drugs available, Psychiatrists needed something to talk about. Later, I came around to seeing that there were side effect differences that were important – though I continued to think that there was a lot more talk than was warranted.
I met Clinical Trials late in my career, actually when I began to wake up to their corruption – after I retired. I’m afraid my old Internist Chauvinism reared its ugly head when I realized that these differences among drugs was being measured with statistics, because the actual differences were so slight. Antipsychotics were like the drugs of my youth. They worked, but they could be plenty toxic and needed to be treated with much respect. Antidepressants were "light and variable" [and toxic], so I mostly stayed away from them when I practiced. When I started looking at the RCTs [Randomized Clinical Trials], I saw what small differences there really were, and how vulnerable these trials were to the analysts who converted the results into papers in a journal. But that’s old news.
I grew up with these psychiatric medicines in the same era, Dr. Mickey. In 1961 I was in a Pharmacology lab where the hot new drug was imipramine (Tofranil) – an early antidepressant drug. Across town, John Cade treated manic patients with lithium, which he discovered in 1948. A landmark trial of imipramine appeared in 1959 from Richard Ball and Leslie Kiloh in Newcastle, UK. One of the memorable observations in that report was “It has certainly been obvious in this department that since the introduction of iproniazid and imipramine the amount of in-patient and out-patient E.C.T. given has fallen sharply.” That’s what I call ecological validity. There was no argument in those early days that the new drugs worked. By 1965, the monoamine theory of depression had gone mainstream, though it was foreshadowed as early as 1959. By 1967 I was a psychiatry resident, and I saw the efficacy of Tofranil and lithium first hand.
In agreement with your post, over the past 50 years emphases on increasing sales, on gaming the clinical trials system, on dumbing down the index disorder so as to expand the market, and on voodoo neurochemical explanations of depression supplanted the critical scientific stance in psychopharmacology. That is how we got the plague of KOLs, infomercials, experimercials, CME hijacking, and regulatory capture by PhRMA. A foundational principle in this slide was the US Congress-dispensed concession that clinical trials data are proprietary secrets. That has hamstrung the FDA for over 50 years. Our legacy, then, is serious doubt about whether the current antidepressant drugs even work at all.
We come back to Jane Jacobs: the guardian ethic (professionalism) is incompatible with the commercial ethic (PhRMA). No man can serve two masters. When you sup with the devil use a long spoon. Amen to ALLTRIALS!
From experience as a patient, I find significant differences. Desipramine, for instance is the only drug that makes me hypomanic. It seems that the side effects and how the drugs combine can also be very different. I just so happened to be taking Buproprion when I was first prescribed Ritalin. When I stopped taking Buproprion, the effects of the Ritalin became unbearable.
Remeron made me ravenously hungry all the time. For the last twenty-five years, I’ve been having my meals on a salad plate. I never liked feeling full, but on Remeron I could eat three to infinite times more than what I normally eat while feeling ravenously hungry. I had to stop it because I found this effect unbearably perverse. Whether an antidepressant is activating or makes me sleepy varies from one to the next, and I figure such things are true for just about everyone.
I’m convinced now that I’ve never suffered an endogenous depression; but am taking Trazodone as a sleep aid, and Amitriptyline for sleep and nerve pain. Now that hormone replacements have radically reduced my MS pain, I want to start reducing the Amitriptyline because I just found out that it increases the risk of heart attack by 35% and because polypharmacy itself is taxing and risky. Amitriptyline is one of the most difficult antidepressants to discontinue so I suspect it will take me a year or more just to safely get down to 25 milligrams a day without having horrific symptoms.
My prescribing nurse at the V.A. is very serious about side effects and risks, so I’m going to seek her counsel for a plan to discontinue the Amitriptyline. She’s very diligent about side-effects and risks. Whatever clinical differences psyche drugs may have on depression or “depression”, the other effects can be more serious than feeling blue, or tired, or exhausted, or fatigued, or mired in grief.
What percentage of people taking psyche drugs aren’t really depressed? What percentage are taking drugs to treat a depression they don’t have while taking on serious health risks from the drugs they don’t need? How many people are taking so many drugs that pass the blood/brain barrier while they and their prescribing physicians or nurses have no idea what drugs are having what effects on them? What percentage of people are taking psyche drugs for what is a medical illness that is being dangerously unidentified and neglected?
Does the medical/psychiatry field need to start over? Most industry funded “research” is bunk, so how does our increasingly psyche-drugged species get off the crazy train?
Back in the day, when a difficult patient for whom medications had failed was admitted to a psychiatry inpatient unit, the first step was to taper the current drugs for the excellent reason that they clearly weren’t helping. This phase of management might take 10 days and it was conducted with the patient under close observation in a safe environment. Then, we were able to make a diagnostic reassessment without the contamination of drug effects. This time spent on the front end paid off in terms of future rational management.
But that was in the days when the average length of stay was 6 weeks, when inpatient units were genuinely therapeutic environments, when multi-modal interventions were brought to bear on a patient’s problems and needs. None of that happens nowadays. Only brief crisis inpatient care is allowed, even though the hospital milieu can be a powerful therapeutic agent.
There were abuses, of course. In my first job after fellowship I took over a 30-bed self-styled psychoanalytic inpatient unit where the average length of stay was 18 months and the outcomes were terrible – a lot like the Osheroff case that Dr. Mickey has written about. We got it down to 6 weeks, and the staff agreed that patients were having better outcomes. But now with managed care we are down to just a few days.
The current commercialization of medicine has pushed the pendulum too far in the direction of ultra-short stays, not because that is best for the patients but because it is best for the insurance companies. The APA was useless in arguing for a system that served patients better. I think a key mistake was to go along with billing the hospital-wide daily bed rate for psychiatric beds. As a clinical administrator, I never thought that was justified, and that is one point of possible leverage for future efforts to change the system.