Comparison of Effectiveness and Tolerability of Clonidine and Trihexyphenidyl in Clozapine-Induced Hypersalivation.

Purpose/background: Clozapine-induced hypersalivation is one of the most common bothersome adverse reactions of clozapine. The management strategies for this condition remain inadequately studied and understood. The objective of the study is to compare the effectiveness and tolerability of (1) trihexyphenidyl 5 mg/d, (2) clonidine 0.15 mg/d, or (3) a reduction of clozapine dosage by 25 to 50 mg/d for managing clozapine-induced hypersalivation.

Methods/procedures: A randomized, open-label, non-placebo-controlled clinical trial was conducted from December 2023 to May 2024. Eligible patients were randomly assigned to 1 of 3 groups. Primary outcomes were assessed using the Drooling Severity and Frequency Scale (DSFS) and the Nocturnal Hypersalivation Rating Scale (NHRS) at baseline, week 4, and week 8. Quality of life assessed using the pharmaceutical therapy for quality of life short version and adverse drug reactions were recorded as secondary outcomes.

Findings/results: A total of 67 patients were randomly assigned to 1 of 3 treatment groups. By week 8, significant reductions in DSFS and NHRS scores were observed in all groups, with clonidine showing the greatest improvement. Trihexyphenidyl was also effective, whereas reducing clozapine dose resulted in more modest improvements. Quality of life improved significantly across all groups, with the greatest improvement observed in the clonidine group. The most common adverse effects were dry mouth, constipation, drowsiness, and dizziness.

Implications/conclusions: Clonidine and trihexyphenidyl appear to be more effective options for managing clozapine-induced hypersalivation compared to clozapine dose reduction.