Cano-Ramirez_2025_Expert.Opin.Drug.Discov__1

INTRODUCTION: Existing pharmacotherapies for schizophrenia have not progressed beyond targeting dopamine and serotonin neurotransmission. Rodent models of schizophrenia are a necessary tool for elucidating neuropathological processes and testing potential pharmacotherapies, but positive preclinical results in rodent models often do not translate to positive results in the clinic. AREAS COVERED: The authors reviewed PubMed for studies that applied rodent behavioral models of schizophrenia to assess the antipsychotic potential of several novel pharmacotherapies currently under investigation. These included acetylcholinesterase inhibitors, muscarinic and nicotinic acetylcholine (ACh) receptor agonists and positive allosteric modulators (PAMs), histamine H3 receptor antagonist/inverse, calcium channel modulators, trace amino acid receptor (TAAR) agonists, and phosphodiesterase 10A (PDE10A) inhibitors. The authors discuss the extent to which the results of preclinical studies of these drugs in rodent models have predicted clinical efficacy. EXPERT OPINION: Although published preclinical studies of these drugs were largely positive, clinical results were often modest or negative. This lack of correspondence is likely due to many factors, including differences in experimental design, poor translation of effective dosing from preclinical to clinical studies, and large inter-individual variation of the human population as compared to laboratory rodents. Closing the gap between preclinical and clinical studies will require strategies aimed at reducing the impact of these factors.