TO THE EDITOR: Drooling, often manifested as pillow wetting during sleep, is a common adverse effect of the atypical antipsychotic clozapine (R1557291B). In light of clozapine's propensity to cause anticholinergic effects, it is surprising that patients complain of drooling rather than of dry mouth—the expected salivary anticholinergic response.

Olanzapine, a derivative of clozapine, is an atypical antipsychotic with a receptor-binding profile similar to that of clozapine (R1557292B). To our knowledge, there are no published descriptions besides the following one of drooling as a side effect of olanzapine treatment.

Among patients treated with antipsychotics, parkinsonism-related drooling is due to throat muscle rigidity and a resultant decrease in saliva swallowing. With clozapine, drooling and pillow wetting presumably result from increased saliva production (hence, the usual descriptors, "hypersalivation" and "sialorrhea"), although the mechanism has not been definitively demonstrated. It is unlikely that Ms. A's drooling was related to parkinsonism because she had no extrapyramidal symptoms.

Two proposed mechanisms for clozapine-induced hypersalivation may be relevant here (R1557293B–R1557295B). Increased saliva production results from salivary sympathetic α-adrenergic receptor antagonism or from parasympathetic cholinergic (muscarinic) receptor agonism. Ms. A's sialorrhea may have been a result of olanzapine's potent α-adrenergic antagonism. Alternatively, sialorrhea may stem from stimulation of salivary muscarinic receptors. Both clozapine and olanzapine have high affinity for the five muscarinic receptors (M1–M5), and both are antagonists at M1–M3 and M5, consistent with anticholinergic effects. Clozapine (R1557294B, R1557295B) and olanzapine (R1557295B) are reported to be agonists or partial agonists at M4 receptors. This explanation is speculative because the importance of M4 receptors in human saliva production is unknown.

While the cause of pillow wetting for Ms. A as well as clozapine-treated patients is not understood, anticholinergic and adrenergic agonist therapies are used for clozapine-induced pillow wetting (R1557291B, R1557293B). Although Ms. A declined pharmacological treatment, she welcomed discussion of nonpharmacological management (e.g., covering her pillow with a towel or sleeping on her side propped up with extra pillows). Physicians should monitor patients treated with olanzapine for this potentially troublesome adverse effect.