Serotonin releasing agents - Neurochemical therapeutic and adverse effects

This review summarizes the neurochemical, therapeutic and adverse effects of serotonin (5-HT) releasing agents. The 5-HT releaser (+/-)-fenfluramine is composed of two stereoisomers, (+)-fenfluramine and (-)-fenfluramine, which are N-de-ethylated to yield the metabolites, (+)-norfenfluramine and (-)-norfenfluramine. Fenfluramines and norfenfluramines are 5-HT transporter substrates and potent 5-HT releasers. Other 5-HT releasing agents include m-chlorophenylpiperazine (mCPP), a major metabolite of the antidepressant drug trazodone. Findings from in vitro and in vivo studies support the hypothesis that fenfluramines and mCPP release neuronal 5-HT via a nonexocytotic carrier-mediated exchange mechanism involving 5-HT transporters. (+)-Norfenfluramine is a potent 5-HT2B and 5-HT2C receptor agonist. The former activity may increase the risk of developing valvular heart disease (VHD), whereas the latter activity is implicated in the anorectic effect of systemic fenfluramine. Anorectic agents that increase the risk of developing primary pulmonary hypertension (PPH) share the common property of being 5-HT transporter substrates. However, these drugs vary considerably in their propensity to increase the risk of PPH. In this regard, neither trazodone nor mCPP is associated with PPH. Similarly, although some 5-HT substrates can deplete brain 5-HT (fenfluramine), others do not (mCPP). In addition to the established indication of obesity, 5-HT releasers may be helpful in treating psychiatric problems such as drug and alcohol dependence, depression and premenstrual syndrome. Viewed collectively, it seems possible to develop new medications that selectively release 5-HT without the adverse effects of PPH, VHD or neurotoxicity. Such agents may have utility in treating a variety of psychiatric disorders. (C) 2002 Elsevier Science Inc. All rights reserved.