Buspirone

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Abstract
Synopsis: Buspirone hydrochloride (HCl)1 is a new anxiolytic with a unique chemical structure. Its mechanism of action remains to be elucidated. Unlike the benzodiazepines, buspirone lacks hypnotic, anticonvulsant and muscle relaxant properties, and hence has been termed ‘anxioselective’. As evidenced by a few double-blind clinical trials, buspirone 15 to 30 mg/day improves symptoms of anxiety assessed by standard rating scales similarly to diazepam, clorazepate, alprazolam and lorazepam. Like diazepam, buspirone is effective in patients with mixed anxiety/depression, although the number of patients studied to date is small. In several studies, a ‘lagtime’ of 1 to 2 weeks to the onset of anxiolytic effect has been noted; hence motivation of patient compliance may be necessary. Sedation occurs much less often after buspirone than after the benzodiazepines; other side effects are minor and infrequent. In healthy volunteers, buspirone does not impair psychomotor or cognitive function, and appears to have no additive effect with alcohol. Early evidence suggests that buspirone has limited potential for abuse and dependence. Thus, although only wider clinical use for longer periods of time will more clearly define some elements of its pharmacological profile, with its low incidence of sedation buspirone is a useful addition to the treatments available for generalised anxiety. It may well become the preferred therapy in patients in whom daytime alertness is particularly important. Pharmacodynamic Studies: Although the mechanism of the anxiolytic effect of buspirone is undetermined, complex interactions with several central nervous system neurotransmitters, especially serotonin, are thought to contribute. In animal studies, buspirone is inactive in tests of hypnotic, anticonvulsant and muscle relaxant properties, but shows an anxiolytic effect at doses equipotent to diazepam which has been demonstrated in therapeutic trials (see below). Available evidence has shown that neither cognitive nor psychomotor performance is impaired in healthy individuals following administration of buspirone. Moreover, the drug appears to lack any additive effect when combined with alcohol. While some investigators have concluded that buspirone has low potential for abuse and dependence, further evidence from wider clinical use is required to substantiate these findings. Pharmacokinetic Studies: Although absorption of buspirone from the gastrointestinal tract is virtually complete, ‘first-pass’ metabolism reduces the bioavailability of an oral dose of buspirone to about 4%. Peak plasma concentrations are attained less than 1 hour after a single 10mg dose and average 2 to 3 µg/L, but may vary 10-fold because of inter-individual variation. Administering the drug with food may reduce its rate of absorption, but may also decrease the extent of ‘first-pass’ effect. In healthy subjects, buspirone is more than 95% bound to plasma proteins, and has a volume of distribution of 5 L/kg. The extensive metabolism of buspirone results in less than 1% being excreted unchanged. It is unclear whether the active metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP), contributes significantly to the anxiolytic effects of buspirone. Urinary and faecal excretion account for 65% and 35%, respectively, of a dose. The elimination half-life of buspirone ranges from 2 to 8 hours in healthy subjects and is significantly lengthened in renal and hepatic disease. Therapeutic Trials: In parallel-group controlled trials usually of 4 weeks’ duration, buspirone 15 to 30 mg/day was superior to placebo and as effective as therapeutic doses of diazepam, clorazepate, alprazolam and lorazepam in treating patients with generalised anxiety, and relieved associated symptoms of depression as effectively as diazepam. In several studies, the onset of action of buspirone was slower than that of diazepam. Patients generally experienced much less sedation after buspirone than after a benzodiazepine. To date, there have been no reports of rebound anxiety occurring after abrupt discontinuation of buspirone. Side Effects: Interim data from an open study involving over 5000 patients confirm findings from controlled clinical trials which indicate a low overall incidence of side effects during treatment with buspirone. Headache, dizziness, nervousness, paraesthesia and gastrointestinal upset seen in less than 10% of patients were not severe. About 10% of patients receiving buspirone experienced sedation, which was similar to the incidence seen with placebo, compared with 30% to 40% of those treated with a benzodiazepine (diazepam or clorazepate). Side effects after diazepam, but not after clorazepate, tended to be of greater severity and required more frequent dosage adjustment than after buspirone. Dosage: The initial starting oral dosage of buspirone for the treatment of generalised anxiety in adults is 5mg given 3 times daily. If no response is seen after several weeks, upward adjustment of the dose may be required. Patients with impaired renal or hepatic function should be monitored for adverse effects and the dose decreased if necessary; no routine dose reduction is needed for the elderly.