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AUDIENCE COMMENTS
After I wrote my summary and comments on this article, I had an interesting e-mail exchange with the reader whose note first decided me to present this article.
I had pointed out to her that the equation of trazodoneDesyrel (or nefazodone/Serzone) with increased serotonin activity was oversimplified, because of the facts that (a) any single change made in neuronal activity in the brain tends to lead to a cascade of other changes, quite likely involving other neurotransmitters and even opposite effects, like reduced sensitivity of the receptors for the transmitter which is supposedly being "enhanced" by a given drug; and (b) the brain, like the rest of the body, has a strong tendency to respond to induced changes with changes to counteract them, which is often referred to as "maintaining heomeostasis."
Our reader responded with an interpretation of my point that actually was a lot more basic: a drug's first effects on an initial "acute" dose may change, even to the reverse effects, on prolonged administration. For example, in the use of antidepressants (such as trazodone or nefazodone), it is common observation that the "real" (i.e., lasting) antidepressant effects take a few weeks to materialize; the first few doses may induce only side-effects, or a "placebo" (temporary and presumably more psychological than pharmacological) benefit. Psychiatrists have learned to extend the duration of their clinical trials accordingly, and to attach little significance to the effects of an "acute" (that is to say, one-time or short-term) administration of an antidepressant in judging what it will ultimately do. The same should apply to any chronic disorder, like sleep apnea, and to animal as well as human subjects. In the case of this specific study, the drugs used were not intended as even potentially therapeutic; yet the same principles should apply. Even more than one should be cautious in extending animal research to humans, one should take care in extending the results of "acute" studies to the outcome of "chronic" treatment which is almost always the subject of interest in the area of chronic diseases.
However, the same reader went on to note that she had heard from several people on the "phenfen listerv" that their snoring had stopped while on this combination regimen, and that at least one person's sleep apnea symptoms exacerbated after being withdrawn from fenfluramine, although her own didn't, presumably because of the therapeutic effects of major weight loss. This kind of casual clinical observation actually impresses me more than tightly controlled but often clinically irrelevant laboratory research. However, once again we shouldn't simply equate fenfluramine with increased serotonin activity, for the reasons I gave in the first paragraph.
The reader did provide me with two abstracts of animal studies which also suggested an effect of serotonin in increasing the activity of the hypoglossal nerve, controlling muscular activity of the upper airway. I won't review them individually because they are fairly remote from clinical sleep apnea. She provided another abstract, from an article published in 1995, of a study suggesting that brain serotonergic activity may be decreased in sleep apnea, on the basis of an increased secretory response of cortisol to adrenocorticotropic hormone (ACTH) in sleep apneics pretreated with a serotonin precursor, L-5-hydroxytryptophan, which theyt interpreted as suggesting increased sensitivity to serotonin in brain serotonin receptors in sleep apneics because of a deficiency of serotonin during sleep in OSA. Again, the steps necessary to proceed from the experimental observation to the clinically meaningful conclusion are a bit much for me, though many biologically oriented psychiatrists might find them quite relevant.
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