Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by clozapine (GOTHIC1): study protocol for a randomised controlled feasibility study

Abstract

Background: Clozapine is the only medication licensed for the treatment of resistant schizophrenia in the UK. Although efficacious, a common and unpopular side effect of clozapine treatment is clozapine-induced hypersalivation (CIH), which can contribute to non-adherence. The standard treatment for CIH in the UK is hyoscine hydrobromide but this may aggravate cognitive deficits in patients with schizophrenia while glycopyrrolate may be an effective alternative with a more tolerable side effect profile. There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH. Methods/design: This is a multicentre randomised, double-blind, placebo-controlled feasibility study of glycopyrronium bromide (glycopyrrolate) and hyoscine hydrobromide (hyoscine) in patients with clozapine-induced hypersalivation. We aim to recruit 42 patients who have been prescribed clozapine and are experiencing hypersalivation, and randomise them to one of three study arms (either hyoscine, glycopyrrolate or placebo). The primary outcome measures will be the participant recruitment and attrition rates, and the secondary outcome will be the metrics of the daytime hypersalivation measure. After a 1-week washout period (discontinuing CIH medication, if any), there will be a 4-week treatment period where participants will be titrated up to the maximum tolerated dose of hyoscine, glycopyrrolate or placebo. Measurements of daytime salivation, nocturnal salivation, cognition and side effects will be taken during home visits in week 2 and week 5. Information on salivation and side effects will also be taken through telephone calls in week 3 and week 4. To gather information on the experience of study participants, exit interviews will also be requested with all participants who drop out of the study and a sample of participants who complete the study. Discussion: There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH. There is promising evidence that glycopyrrolate may be more successful in the treatment of CIH causing fewer cognitive side effects. We propose to conduct a randomised placebo-controlled feasibility study of glycopyrrolate and hyoscine in the treatment of clozapine-induced hypersalivation to inform the design of a future efficacy trial. Trial registration: Clinicaltrials.gov NCT02613494, 23 November 2015.

Perphenazine-induced sialorrhea successfully treated with sublingual atropine: A case report

“…In addition to atropine, glycopyrrolate is another antimuscarinic administered sublingually, with higher specificity for the M3-M5 muscarinic receptors. It has shown efficacy in multiple disorders of drooling, and researchers have proposed investigation into its efficacy in clozapine-induced sialorrhea [16]. Further approaches might include systemic antimuscarinics, other alphaadrenergic medications, and in serious cases, botulinum toxin injection into the salivary glands [7,8].…”

Therapie der Sialorrhoe mit Botulinumtoxin – ein Update

“…Die medikamentöse Therapie der Hypersalivation besteht in der Hemmung der Speichelsekretion durch antagonistische Anticholinergika. Im Wesentlichen sind dies Atropin [35][36][37], Scopolamin [38] und Glycopyrrolat (1-8 mg / d) [39][40][41][42][43][44][45][46][47][48], wobei letzteres den Vorteil von allenfalls gering ausgeprägten zentralnervösen Nebenwirkungen hat, eine intakte Blut-Hirn-Schranke vorausgesetzt. Für Kinder und Jugendliche ist seit dem Frühjahr 2018 das Präparat Sialanar ® (320 µg / ml Glycopyrronium) bei schwerer Sialorrhoe regulär rezeptierbar, da es in randomisierten, kontrollierten Studien einen positiven Nutzen bei akzeptablem Nebenwirkungsprofil bei kurzfristiger Anwendung zeigen konnte [49,50]…”

Therapy of Sialorrhea with Botulinum Neurotoxin

“…Medical treatment for hypersalivation aims at inhibiting salivary secretion through anticholinergic/antagonistic drugs. Essentially, these are atropine [36][37][38], scopolamine [39], and glycopyrrolate [40][41][42][43][44][45][46][47][48][49]; glycopyrrolate has the advantage of inducing weaker central nervous side effects. For children and adolescents in Germany a formula, Sialanar Ò (320 lg/ml glycopyrronium), became available for prescription since the spring 2018 because randomized controlled studies found a positive effect with a favorable side effect profile [50,51].…”