Teaching an Old Drug New Tricks

Chris Ballas, M.D.
Wednesday, April 02, 2008

There is some new data concerning an old drug. Mecamylamine is an old medication originally used to treat hypertension. It had numerous side effects, such as hypotension and sedation, and thus was not often used. It had a bit of a resurgence later on as an anti-smoking drug (it is a nicotine antagonist) but the overall efficacy was poor, and the side effects made it difficult to use. It was then suggested for use as an augmentation agent to traditional nicotine replacement drugs (gum, patch, etc.) It also has some off label and occasional use for autism, Tourette's, and OCD.

Recently, it has been tested for the treatment of depression. It was found to be better than placebo on the traditional rating scales for patients who had failed citalopram. While this is good, what made it particularly interesting is that the doses used were considerably less (by a factor of 10) than what had been used for hypertension—and at these low doses, mecamylamine only blocks central nervous system nicotinic receptors, not peripheral ones—resulting in much less sedation and hypotension.

It also had considerable efficacy in reducing irritability. Think what it may be like for a smoker to have a cigarette after a long plane ride.

All of this is well and good, but it brings up three questions:

First,why are we testing old medications? The answer probably has a lot to do with the current anti-Pharma climate. Antidepressants in general have already come under fire, both from researchers who have recently "discovered" they may not be very effective, as well as insurance companies, lawyers, and the media. Drug companies, even if they could, would be hard pressed to bring a novel compound for depression into an environment like this. It's easier to re-approve an existing drug. So you see repackaging of old drugs (consider Pristique), expanding the approval for medications already used in psychiatry (Abilify getting approval for adjunct use in MDD; Seroquel as monotherapy for bipolar depression), and looking through what already exists for new indications.

Second, if old drugs can be used for mood (in this case, specifically depression) then what does that say about depression itself? The norepinephrine hypothesis of depression was in vogue for some ten years, soon to be replaced by serotonin; but how do you explain how some people respond to Seroquel and others to Wellbutrin, when the two have nothing in common pharmacologically? More importantly, how do you explain it when the same person responds to both meds?

Third—and I've checked—there is no evidence so far that mecamylamine increases the suicide risk. (The same can be said of Seroquel and Abilify.) If mecamylamine does indeed get approval for depression, will it automatically inherit a black box warning for suicidality? The drug shares no chemical similarities to any existing antidepressant; but if we call it an antidepressant, does it inherit all the risks of one?

This isn't an idle question; warnings like this, attached to drugs which science has no reason to suspect—but which words indict—contribute to the environment I wrote about earlier, in which no one wants to try anything novel because it simply isn't worth it. And so we offer up the faint hope that old, barely tolerable blood pressure pills will save us.