title: The Effect of Glycopyrrolate on Nocturnal Sialorrhea in Patients Using Clozapine: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial.
abstract: BACKGROUND
  Nocturnal sialorrhea is one of the most frequent adverse events in clozapine treatment. Symptomatic management of sialorrhea usually consists of off-label treatment with anticholinergic agents. The aim of the current study is to evaluate the efficacy and safety of glycopyrrolate in patients using clozapine that experience sialorrhea.
  
  
  METHODS
  In a double-blind randomized crossover trial, patients with nocturnal sialorrhea (n = 32) were randomized to treatment with glycopyrrolate 1 mg or placebo. This double-blinded phase was followed by an optional open label extension phase with glycopyrrolate 2 mg. Exposure periods consisted of 6 consecutive days and were separated with 1 washout week. The primary outcome was clinical improvement of nocturnal sialorrhea assessed by the Patient Global Impression of Improvement (PGI-I).
  
  
  RESULTS
  The proportion of patients with a clinical improvement according to PGI-I did not significantly differ between 1 mg and placebo (18.8% vs 6.3%, P = 0.289); however, in patients using glycopyrrolate 2 mg once daily versus placebo, it did (43.5% vs 6.3%, P = 0.039). Glycopyrrolate was not associated with severe adverse events or worsening of cognitive adverse events.
  
  
  CONCLUSIONS
  Glycopyrrolate 1 mg was not superior to placebo, whereas 2 mg showed a significant clinical improvement of nocturnal sialorrhea compared with placebo. Glycopyrrolate seemed to be a tolerable anticholinergic agent in the treatment of clozapine-associated sialorrhea.
authors.affiliation: From the *Department of Clinical Pharmacy, University Medical Center Utrecht; †Department of Clinical Pharmacy, Medical Centrum Alkmaar; ‡Mental Health Services North-Holland North, Heerhugowaard; §Department of Psychiatry, University Medical Center Utrecht; and ∥Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands.
authors.forename: Wai Hong
authors.initials: WH
authors.lastname: Man
authors.forename: Jantine C A
authors.initials: JC
authors.lastname: Colen-de Koning
authors.forename: Peter F J
authors.initials: PF
authors.lastname: Schulte
authors.forename: Wiepke
authors.initials: W
authors.lastname: Cahn
authors.forename: Ingrid M M
authors.initials: IM
authors.lastname: van Haelst
authors.forename: Hieronymus J
authors.initials: HJ
authors.lastname: Doodeman
authors.forename: Toine C G
authors.initials: TC
authors.lastname: Egberts
authors.forename: Eibert R
authors.initials: ER
authors.lastname: Heerdink
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Wilting
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects*; D003024:Clozapine / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017063:Outcome Assessment, Health Care; D012798:Sialorrhea / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D014150:Antipsychotic Agents; D018727:Muscarinic Antagonists; D003024:Clozapine; D006024:Glycopyrrolate