Unexpected salivary secretory effects of some atypical antipsychotics - preclinical studies on clozapine, N-desmethylclozapine, amisulpride and olanzapine

Abstract

Antipsychotics are generally associated with dry mouth and deterioration of the oral health. However, clozapine, the archetype of the atypical antipsychotics, is reported to induce not only mouth dryness but also, in about one-third of the patients, hypersalivation, the latter resulting in disturbed sleep, coughing and choking sensations during the night and drooling during the day. Nevertheless, the hypersalivation is questioned and, in some studies, related to a weakened swallowing reflex. Clinical studies are inconclusive and based on subjective drooling scores and indirect measurements of the saliva secreted. Preclinical studies on the effect of clozapine on the salivary flow are lacking. The aim of this Thesis was to explore the salivary secretory role of some atypical antipsychotics in an animal model, with clozapine-induced sialorrhea in focus. A secretory role for clozapine and its metabolite N-desmethylclozapine was established: saliva was secreted from duct-cannulated submandibular and parotid glands in the rat. The action was direct, independent on circulatory catecholamines and nerves, and mediated via muscarinic M1 receptors. Together, the weaker agonist clozapine prevented its metabolite from exerting full agonistic effect. Thus, the sialorrhea in the clinic may be explained by a continuous bombardment of muscarinic M1 receptors. At higher demands on the flow-rate, such as during a meal, the patient is, however, likely to experience insufficient salivation due to the clozapine/N-desmethylclozapine blockade of muscarinic M3 and α1 adrenergic receptors. Since clozapine/N-desmethylclozapine did not antagonize the β1 adrenergic receptor, a sympathetic β1-mediated salivary response can be expected to add to the muscarinic M1 -mediated response during daytime; moreover stimulation of the two receptor types interacted positively. The antipsychotic drug amisulpride, reported to abolish the clozapine-induced sialorrhea, failed in the preclinical model. In contrast, it potentiated the secretory response to nervous activity as well as to autonomimetics, without causing secretion per se. Amisulpride exerted its effect at gland level but the mechanism is currently unknown. Amisulpride may be a potential drug for dry mouth treatment. Olanzapine, with a reported receptor profile similar to that of clozapine, evoked secretion, like clozapine but by other receptors, involving the substance P-type. In human salivary glands, acini but not vessels, lack substance P innervation. Therefore, olanzapine, in the clinic, is not a secretagogue via this receptor but may cause vasodilation and edema formation as a part of an inflammatory response.