Antipsychotics‐Induced Hyposalivation Mediated by Impaired Salivary Ca ²⁺ Signaling

ABSTRACT Objectives Antipsychotic‐induced salivary dysfunction such as hyposalivation is a prevalent clinical challenge that severely compromises oral health and quality of life. Although typical and atypical antipsychotics have their therapeutic target in the central nervous system, their direct molecular mechanisms within the salivary glands remain poorly understood. Here we investigated the molecular mechanism underlying hyposalivation induced by antipsychotics: olanzapine, haloperidol, and risperidone. Methods We reanalyzed scRNA‐seq data from salivary gland cells, measured the intracellular Ca 2+ ([Ca 2+ ] i ) in the human salivary gland NS‐SV‐AC cells, and salivary secretion in the mouse model. Results We found a complete absence of dopamine D2 and serotonin 5‐HT2A receptor expression in both human and mouse salivary gland cells. Functional assays demonstrated that olanzapine and haloperidol inhibited muscarinic receptor‐mediated [Ca 2+ ] i increases, whereas risperidone did not. Notably, these agents did not suppress store‐operated calcium entry (SOCE) or purinergic receptor‐mediated signaling. Olanzapine shows inhibition of the pilocarpine‐induced salivary secretion in a mouse model. Conclusions Our findings indicate that antipsychotic‐induced hyposalivation can be driven by the direct peripheral inhibition of muscarinic receptors within the salivary glands, rather than through dopaminergic or serotonergic antagonism, and support the mechanism‐based preventive protocols for patients on long‐term antipsychotic therapy.