Toward a better understanding of depression: New mechanistic considerations of antidepressant action provide a basis for development of delay-free drugs

Abstract

Presently accepted theories of the etiology of depression stem from the pharmacological evaluation of compounds serendipitously found to alleviate the disorder. It was assumed that their most potent pharmacological activities were responsible for their beneficial effects. This article questions these theories and argues that the prominent activities of the antidepressants may not in fact be beneficial. An alternative hypothesis is introduced, proposing that all these agents could alleviate depression by blocking neuronal potassium (K+) channels and by so doing interfere with the stress-induced activation of tryptophan hydroxylase responsible for excessive elevations of 5HT. In accordance with this hypothesis, a selective neuronal K+ channel blocker, capable of inhibiting tryptophan hydroxylase activation, has been reported to rapidly alleviate depression-like symptoms in an animal model of depression. Drug Dev. Res. 51:1–6, 2000. © 2000 Wiley-Liss, Inc.