Metoclopramide as Treatment of Clozapine-induced Hypersalivation

Hypersalivation (sialorrhea or ptyalism) is known as a frequent, disturbing, uncomfortable adverse effect of clozapine therapy that may persist for several years. This side effect is usually dose-related. It may occur all over the day, but it is most pronounced during night sleep, since swallowing reflex is diminished, and patients usually complain of wakening with a wet pillow (sometimes called as "wet pillow" sign).

Salivation is regulated by sympathetic (adrenergic) and parasympathetic (cholinergic) tones. The phenomenon of clozapine-induced hypersalivation (CIH) remains mysterious since the drug has potent α2 antagonistic, M4 - muscarinic agonistic, and anticholinergic (M1, M2, M3, and M5) activities and each of these has a different effect on the control of salivation. While α2 antagonistic and M4 - muscarinic agonistic effects increase salivation, the anticholinergic effect leads to diminished saliva secretion. It has been reported that CIH is observed from 10 to 80% of patients according to various sources, an average rate is 30% of clozapine-treated patients. Further to the social embarrassment related to hypersalivation, additional consequences of CIH include painful parotid gland swelling and parotid duct obstruction due to the formation of calculi.

Clozapine is a second generation neuroleptic agent whose structure consists of a dibenzodiazepine derivative with a piperazinyl side chain. It has a unique neuropharmacologic profile, which is attributed to atypical antipsychotic agents with proven efficacy in refractory schizophrenia, but its widespread use is limited by adverse effects such as agranulocytosis, seizures, sedation, weight gain, and sialorrhea. Clozapine has a weak binding affinity for dopamine D1 and D2 receptors by its slightly greater preference for D1 receptors, as noted with a D1:D2 receptor binding ratio of 1:3. Furthermore the drug has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2, and also antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties.

Sialorrhea is troublesome its stigmatizing nature results for a schizophrenia patient led to massive compliance problems. For management of this distressing side effect have been recommended different pharmacological agents such as α2 - adrenoreceptor agonists, including clonidine, and lofexidine, but these treatments have unwanted side effects, no proved effectiveness. They are not been routinely used. These publications show that CIH probably might have a different neurobiological basis rather than the proposed mediation by the M4 - muscarinic receptor.

Previous studies found that substitute benzamide derivatives with higher selective binding to the D2/D3 dopamine receptors - amisulpride, sulpiride as well moclobemide (reversible inhibitor of monoamine oxidase A, which inhibits the deamination of serotonin, norepinephrine and dopamine) may be effective in treatment of CIH without additional adverse effects. Unfortunately, these medications are not effective in all patients who suffered from CIH.