Serotonergic drugs and valvular heart disease.
BACKGROUND
The serotonin (5-HT) releasers (+/-)-fenfluramine and (+)-fenfluramine were withdrawn from clinical use owing to increased risk of valvular heart disease. One prevailing hypothesis (i.e., the '5-HT hypothesis') suggests that fenfluramine-induced increases in plasma 5-HT underlie the disease.


OBJECTIVE
Here, we critically evaluate the possible mechanisms responsible for fenfluramine-associated valve disease.


METHODS
Findings from in vitro and in vivo experiments performed in our laboratory are reviewed. The data are integrated with existing literature to address the validity of the 5-HT hypothesis and suggest alternative explanations.


CONCLUSIONS
The overwhelming majority of evidence refutes the 5-HT hypothesis. A more likely cause of fenfluramine-induced valvulopathy is activation of 5-HT(2B) receptors on heart valves by the metabolite norfenfluramine. Future serotonergic medications should be designed to lack 5-HT(2B) agonist activity.
Rothman
Richard B
RB
Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224, USA. rrothman@mail.nih.gov
Baumann
Michael H
MH
D000818:Animals; D005277:Fenfluramine / Q000009:adverse effects / Q000494:pharmacology; D006349:Heart Valve Diseases / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents / Q000009:adverse effects* / Q000494:pharmacology
D044403:Receptor, Serotonin, 5-HT2B; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin