Schizophrenia is a highly heterogeneous psychiatric disorder, which is elicited by multiple genetic and non-genetic factors. It remains insufficiently treatable with the current pharmaceutical approaches. In this study, we describe a new pathological mechanism and identify a new pharmacological treatment target with the use of a recently introduced ligand for it. An initial analysis of human gene polymorphisms and brain gene expression in schizophrenia patients identified an association of Smpd1 and Smpd3 genes coding for acid- (ASM) and neutral sphingomyelinase (NSM). In a rat model of amphetamine-induced psychosis, we found a locally restricted increase of ASM activity in the prefrontal cortex (PFC) that responds to psychosis-induction and its treatment. Short-term chronic haloperidol (HAL) treatment reversed behavioural symptoms and the ASM activity increase. A sphingolipidomic analysis confirmed a disrupted ceramide metabolism in the PFC during psychosis. Targeting enhanced ASM activity in a psychotic-like state with a selective ASM inhibitor reversed psychotic-like behaviour. While effective HAL treatment led also to a locomotor decline and cognitive impairments, selective ASM inhibitor did not.