Therapeutic Options in the Treatment of Clozapine-Induced Sialorrhea

Donald P. Rogers, Pharm.D., and Jennifer K. Shramko, Pharm.D.

Pharmacotherapy. 2000;20(9) 

In This Article

Reported Treatment Options

Case reports indicate the effectiveness of clonidine, a centrally acting a2 agonist, in the treatment of clozapine-induced hypersalivation. This is reasonable based on the agent's mechanism of action.[5] Although the dosage is unclear, it appears that two of four patients achieved a substantial response, most likely with 0.1 mg/day from a transdermal patch. A third patient developed tolerance to the drug after 2 weeks; the dosage was increased to 0.2 mg/day, but after another 2 weeks, the patient again developed tolerance. The fourth patient did not receive any benefit.

Amitriptyline 75-100 mg/day was given to four treatment-resistant schizophrenic patients who developed persistent drooling and reported choking on saliva after taking clozapine.[11] These patients also were taking anticholinergic antiparkinson agents. The drooling in all four patients was greatly reduced or subsided altogether. No adverse effects were reported.

A retrospective study compared benztropine, a centrally acting muscarinic antagonist, and terazosin, an a1-antagonist, in the treatment of clozapine-induced hypersalivation.[12] The study consisted of four treatment groups of 15 patients each, all of whom developed sialorrhea within the first month of treatment. The groups received no treatment, benztropine alone 1 mg twice/day, terazosin alone 2 mg once/day, or both agents. After 4 weeks, 60% of patients receiving benztropine alone no longer experienced the unwanted effect, compared with 86.7% and 93.3% in the terazosin and combination groups, respectively. In addition, 100% of patients receiving combination therapy had complete resolution of hypersalivation within 12 weeks, compared with 66.7% given benztropine alone and 93.3% given terazosin alone. In the control group, 33.33% of patients discontinued clozapine therapy, 33.33% continued therapy despite the side effect, and 33.33% developed tolerance to the side effect after 12 weeks at the same dosage or through dosage reduction.

The investigational drug pirenzepine is a selective antagonist at M1 and M4 muscarinic receptor subtypes. Approved for treating ulcers in some European countries, it inhibits gastric acid secretion. Salivary secretions are also especially sensitive to inhibition by selective muscarinic receptor antagonists.[13] Although no placebo-controlled trials have been conducted, dosages of 25-100 mg/day have successfully treated clozapine-induced hypersalivation in 120 patients since 1987.[14] The only adverse effect reported was mild diarrhea.

Other authors reported isolated treatment options including all the drugs discussed as well as trihexyphenidyl,[15] another centrally acting M1 antagonist, the antimuscarinic atropine 1% solution given sublingually,[16] and chewing gum.[17]These are only case reports, and larger studies must be done to evaluate these options in the treatment of sialorrhea.


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