Haloperidol Induces Early Neurotoxicity via Impaired Neurite Outgrowth in Human iPSC-Derived Neurons

Abstract

Haloperidol, a first-generation antipsychotic, remains effective for treating schizophrenia but has been associated with early neurotoxic effects. This study evaluated haloperidol-induced structural neurotoxicity using human induced pluripotent stem cell (hiPSC)-derived neurons. Cells were exposed to haloperidol for 24 or 48 hours, and neurite length and cell viability were quantitatively assessed. Haloperidol, when treated for 24 hours, significantly reduced neurite length at 30 µM without affecting cell viability, confirming that structural impairment precedes measurable cytotoxicity. Co-treatment with propionate, a short-chain fatty acid, restored neurite length and partially recovered cell number in a concentration-dependent manner, suggesting its protective role against haloperidol-induced stress. These findings demonstrate that haloperidol induces early neurotoxicity by impairing neurite outgrowth in human iPSC-derived neurons and support the use of this human-based platform to evaluate early neurotoxic responses and advance non-animal testing strategies.