Sublingual Atropine for the Treatment of Clozapine-Induced Hypersalivation and Drooling

Abstract

Hypersalivation and drooling are common adverse effects reported in patients treated with clozapine. The aim of the research in this thesis is to explore the management of Clozapine-Induced Hypersalivation (CIH) and Clozapine-Induced Drooling (CID) among psychiatrists in Australia, measure the effect of the most prescribed medication (sublingual atropine) on saliva secretion, measure the atropine plasma concentration after sublingual administration, and investigate the safety profile of sublingual atropine. Atropine sulfate 1% solution was prescribed in 9 of the 11 patients prescribed a medication to treat the condition as reported by a surveyed sample of psychiatry registrars. Two drops of the 1% eye drops solution (delivering approximately 600 µg of atropine sulfate) administered sublingually were recorded to decrease unstimulated nocturnal saliva secretion rate (mean difference from the placebo=-57.2%, 95% CI: -104.3, -10.1, P=0.02, n=21). An LC-MS/MS assay was developed and validated in this thesis to measure the atropine plasma concentrations over 9 hours after dosing. The dose adjusted relative bioavailability (mean ± SD) of the 1.2 mg SL atropine solution and 0.6 mg tablet relative to the 0.6 mg SL solution was 0.98 ± 0.01 and 1.54 ± 0.30, respectively. Most participants (6 out of 7) had a significant decrease (mean percentage change -40.5%, CI: -59.3, -21.7%) in saliva secretion after the 0.6 mg sublingual atropine solution administration. A reduction in sitting and standing systolic and diastolic BP as well as pulse rate was recorded. A crimped metered dose sublingual spray is recommended for the administration of sublingual atropine. In conclusion, small atropine doses (0.6 or 1.2 mg) were found to significantly reduce daytime and nighttime saliva secretion. The use of the small doses tested of sublingual or oral atropine are found to be well tolerated.