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.

Stress

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OCD and Psychosis

From The Last Psychiatrist, April 4, 2006

Subtypes of OCD

CNS Spectr. 2006 Mar;11(3):179-86.

The authors examined the difference between two (theoretical) subtypes of OCD symptoms. Based on the earlier work of Lee and Kwon, obsessions can be divided into autogenous and reactive.

Autogenous: occur without identifiable or likely stimuli; repetitive; disturbing;
Examples: "sexual, aggressive, or immoral thoughts, images, or impulses." The sudden obsession to rape; or seeing a red shirt, which signifies raping.
Coping strategy: suppress these thoughts

Reactive: caused by identifiable external stimuli, including thoughts of contamination, asymmetry, loss; are realistic;
Coping strategy:reduce anxiety (e.g. wash hands.)

They found some interesting differences:

Autogenous obsessives were more likely to be male, and older (34) and have older ages of onset (27);

Reactive obsessives were more likely female (60/40), younger (27) and younger age of onset (19).

No difference in either group in education or marital status; nor were there any major psychiatric comorbidities.

But autogenous obsessives rarely (1%) dissociated; reactives did dissociate (10%).

A few points. That aggressive/sexual thoughts go with males is no surprise. But that they are found in the older people is interesting. If you can see how primitive thinking occurs in reactive OCD, it makes sense they would get their symptoms at a younger age. It is known that cleaning and checking obsessions are associated with an earlier age of onset.

The prevalence of dissociation in reactive patients- or the absence of it in autogenous patients-- had already been suspected. Checking and symmetry symptoms (associated here with reactive type) had already been found to be more commonly associated with dissociation. (Personal diversion: my own clinical experience with pedophiles supports this-- that those with sexual obsessions are fully conscious of them; obsess over them, are familiar with every nuance. They know to molecular detail what the child looks like, how it moves; and are totally aware of their own behavior at every step of the molestation, even when they pretend a quasi-dissociative experience as a defense. They wouldn't dissociate during the acts because, in effect, it defeats the purpose of committing the act.)

Additionally, in other studies, Lee and partners (Telch, Kwon, etc) found that autogenous obsessions were more associated with schizotypal personality than to other OCD symptoms themselves (while reactive obsessions had no association with schizotypal.) 1 The authors use this finding to support the idea that autogenous obsessions represent cognitive issues, while reactive represent behavioral ones; autogenous obsessives obsess; reactive obsessives are compulsives. This is further supported another study finding that on Rorshach, autogenous obsessives, like schizophrenics, have severe thought disorder, while reactive obsessives do not.2 The belief that merely thinking a thought could make it true (formally called the likelihood bias of though-action fusion) sounds like the magical thinking in schizotypal, and in fact TAF is seen in schizotypals 4 1. It would be interesting if it could be investigated in autogenous obsessives versus reactive obsessives separately, the hypothesis being that autogenous obsessives display likelihood TAF, while reactives do not.

Clinically, it may be fair to say that people with autogenous type obsessions share schizotypal features, and cognitive/perceptual distortions, while reactive obsessions go with OCPD features and compulsive behaviors. So, do antipsychotics help autogenous obsessives (and not (or better than) reactive obsessives?)

In line with this, there is some evidence that schizophrenics and OCDs share some neurodevelopmental pathology. For example, using fractal dimension and CSF volume, one could accurately categorize schizophrenics or OCD patients, vs controls, with 90% accuracy.3 It would be interesting to see if these obsessives, based on brain pathology alone, could be distinguished between autogenous and reactive types. I suspect the answer will be yes.

1. J Anxiety Disord. 2005;19(7):793-805. Epub 2005 Jan 5.
2. J Clin Psychol. 2005 Apr;61(4):401-13.

3. Neurosci Lett. 2005 Aug 12-19;384(1-2):172-6.

4. Behav Res Ther. 2005 Jan;43(1):29-41.