So How Long Is Too Long?
Dr. Ghaemi: Dr. Culpepper and I agree in general, but in the interests of advancing a discussion, I will just focus on our partial disagreement on the issue of whether one should use a drug for 2 months and 1 day, when it is only proven effective for 2 months.
Obviously, stated thus, the claim is silly, but it makes a point. If 2 months and 1 day is okay, how is 2 months and 2 days? Three months? Six months? One year? Two years? Twenty years?
Where do you draw the line? And when? And why?
I believe the scientific evidence suggests that atypical neuroleptics do not have the long-term efficacy often claimed for them.[5,10] These studies demonstrate that neuroleptics do not prevent depressive episodes, by themselves, in the long-term in bipolar disorder; and since the next episode in those studies, which began with acute mania, is typically depressive, the lack of benefit for depression benefit throws into doubt whether there is any monotherapy preventive benefit at all for these agents in bipolar disorder in general. I base these statements on my own analysis of those randomized studies, some of which I have previously published,[4,5,11] and some of which is in press in a more detailed analysis along with my colleague Frederick Goodwin, of the maintenance studies of these drugs in bipolar disorder.
But for the purposes of the present discussion, let's just presume that there is not sufficient scientific evidence to make reasonable judgments about long-term efficacy with atypical neuroleptics in mood conditions. In that case, what should the average clinician do?
There are many scenarios in medicine like this one; one cannot expect the taxpayers to fund an RCT for every medical question. Thus, it will always be the case that it will be false to claim that "evidence" or "evidence-based medicine" (EBM) is the answer. Of course we don't have enough "evidence" to answer, in the case of neuroleptics for acute depression, 2 months and a day, or 2 days, or 3 days, or 4 days -- but that is a straw man argument. It is not really informative to make an extreme claim, and then "refute" it.
So, though I fully agree with Dr. Culpepper's explanation about how, in primary care, one has to individualize treatment and pay attention to social context (believe me, psychiatry has prayed this mantra for decades), I worry that "science" is underappreciated in this context.
"Evidence" and EBM are just synonyms for science. So, if I may translate and simplify, I believe medicine is not just a science, pure and simple. Again, this is a straw man: of course, this is the case. Humans are not rats; doctors are not laboratory scientists; we can't create genomes, and control environments like we do in laboratory rat experiments.
This, too, goes back to the Hippocratics, who said that medicine involves 3 factors: the doctor, the patient, and the disease. Osler always emphasized that medicine is, first and foremost, an art, but it is an art based on science. Osler defined the "art" of medicine as the art of balancing probabilities. That art is most effective when we don't have to guess on the probabilities; the role of science is to provide us as much real knowledge as possible about the probabilities.
Now in the case of 2 months of treatment vs 2 months and 1 day, I fully agree that we need to make decisions that go beyond the knowledge provided by our science. My only claim is this: we should not sanguine about it. Let's be honest, in these cases, we are guessing.
The wisdom of the Hippocratic tradition is just in guiding us about what to do when we do not know, when the evidence is not there. Most of the time in medicine, what we should do is nothing. Nothing is a very hard thing to do, and nothing is not nothing. Nothing is a very powerful intervention, because we let nature heal, we get out of the way, instead of adding to the harm by guessing at treatments when we really don't know if they work.
Dr. Culpepper makes a rational case for long-term treatment with neuroleptics when they seem helpful. But, the same case was made for 40 years for hormone replacement therapy (HRT), and after a decade-long randomized trial of over 16,000 women, it turned out that HRT increased breast cancer rates by 26% (which is not much, and was not detectable in daily clinical practice based on the observations of clinicians). This translates, in my calculations, to about 5000 excess deaths per year for women in the United States. (I know this example generates many passions among PCPs; I know that HRT is effective for some things, such as fracture prevention and menopausal psychological symptoms, but this does not refute the proven increase in breast and uterine cancer mortality, not to mention the randomized trial result of increased cardiovascular mortality).
It turns out that atypical neuroleptics are carcinogenic in animal studies, so are many of our other drugs.[11,12] I am not claiming that these agents are carcinogenic in humans also; I am stating that, like HRT, there's a chance that they could be. This is exactly the reason why the Hippocratic tradition urges us to err on the side of not treating, rather than treating, when our scientific knowledge does not prove that the benefits outweigh any harms.
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