Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA ( n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39–6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00–3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65–3.77), propantheline (RR = 2.39, 95% C.I. = 1.97–2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88–2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59–3.38), doxepin (RR = 2.30, 95% C.I. = 1.85–2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30–3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67–2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34–3.26), atropine, (RR = 2.03, 95% C.I. = 1.22–3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28–2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91–2.68), benzamides (RR = 2.23, 95% C.I. = 1.75–3.10), TCAs (RR = 2.23, 95% C.I. = 1.83–2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83–2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes’ co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.