BRAIN-SEROTONIN NEUROTOXICITY AND PRIMARY PULMONARY-HYPERTENSION FROMFENFLURAMINE AND DEXFENFLURAMINE - A SYSTEMATIC REVIEW OF THE EVIDENCE

Objectives.-Obesity is an important clinical problem, and the use of d exfenfluramine hydrochloride for weight reduction has been widely publ icized since its approval by the Food and Drug Administration. However , animal and human studies have demonstrated toxic effects of fenflura mines that clinicians should be aware of when considering prescribing the drugs. Our purpose was to systematically review data on brain sero tonin neurotoxicity in animals treated with fenfluramines and the evid ence linking fenfluramines to primary pulmonary hypertension (PPH). Da ta Sources.-Archival articles and reviews identified through a compute rized search of MEDLINE from 1966 to April 1997 using ''fenfluramine(s ),'' ''serotonin,'' ''neurotoxicity,'' ''behavior,'' ''anorexigens,'' ''weight loss,'' and ''primary pulmonary hypertension'' as index terms . Study Selection.-Reports dealing with long-term effects of fenfluram ines on brain serotonin neurons, body weight, and pulmonary function i n animals and humans. Data Extraction.-Reports were reviewed by indivi duals with expertise in serotonin neurobiology, neurotoxicity, neurops ychiatry, and pulmonary medicine and evaluated for appropriateness for inclusion in this review, Data Synthesis.-Fenfluramines cause dose-re lated, long-lasting reductions in serotonin axonal markers in all the animal species tested and with all the routes of drug administration u sed. Doses of fenfluramines that produce signs of brain serotonin neur otoxicity in animals are on the same order as those used to treat huma ns for weight loss when one takes into account known relations between body mass and drug clearance. However, no human studies have been con ducted, and the pathological and clinical potential for neurotoxicity in humans is unknown. Appetite suppressants-most commonly fenfluramine s-increase the risk of developing PPH (odds ratio, 6.3), particularly when used for more than 3 months (odds ratio, >20). Conclusions.-Fenfl uramine and dexfenfluramine have been demonstrated to damage brain ser otonin neurons in animal studies. It is not known if such damage occur s in humans or if there are clinical consequences. Use of fenfluramine s is associated with an increased risk of PPH. Future studies should a ddress the long-term consequences of prolonged use of fenfluramines.