Ondansetron is a highly selective antagonist at the 5-HT 3 subtype of serotonin (5-HT) receptors . The 5-HT 3 receptors are the only receptors whose effects are mediated through the ion channels rather than the G-protein series . Ondansetron has no appreciable affinity for other 5-HT receptor subtypes, the 5-HT or other monoamine uptake sites, or the GABA/benzodiazepine receptor complex. Within the central nervous system, 5-HT 3 receptors are found in highest concentrations in cortical and limbic areas and may, thus, modulate higher cortical and emotional functions . In addition, ondansetron may have unique properties among 5-HT 3 antagonists. Toral et al. (1995) reported ondansetron's unique ability to block voltage gated potassium channels in human neuroblastoma cells compared to other 5-HT 3 antagonists, which may be independent of its 5-HT 3 properties.
Unlike benzodiazepines, ondansetron appears to be devoid of sedative effects . Furthermore, in animal models, ondansetron does not demonstrate potential for abuse, tolerance, or withdrawal symptoms following abrupt discontinuation ). Ondansetron has shown potential efficacy in the treatment of generalized anxiety disorder (GAD) in unpublished open-label and controlled clinical trials in the U.S. and Europe (Evoniuk, Glaxo personal communication). Studies in humans demonstrate no driving impairments and no acute reduction in cerebral blood flow or anxiety in GAD subjects when given intravenously (Matthew and Wilson, 1991), similar to other non benzodiazepine anti-anxiety agents.
An open-label pilot study and a multisite double blind clinical trial have suggested that ondansetron might have efficacy in the treatment of panic disorder. The objective of the present study was to assess the efficacy and safety of ondansetron in a double-blind, placebo-controlled pilot study in GAD.
This study was randomized, double-blinded, and placebocontrolled with a parallel multi-center group design, with eight participating groups. Fifty-four subjects diagnosed with GAD according to DSM-III-R criteria were randomized into this site's study. Subjects continuing in the active treatment phase were randomly allocated to four treatment groups using a balanced block design. Subjects entering the study met the following inclusion criteria: 18 years older, male or surgically sterilized or post-menopausal females; outpatients suffering