About 30% of patients with schizophrenia do not respond to antipsychotic drugs. The authors showed that chronic administration of atypical antipsychotics downregulates metabotropic glutamate 2 receptor (mGlu2) expression in the frontal cortex in mice and in patients with schizophrenia, and this was due to a serotonin receptor 2A-dependent increase in histone deacetylase 2 (Hdac2) expression and HDAC2 binding to the mGlu2 promoter. Chronic administration of HDAC inhibitors improved the effects of antipsychotic drugs in a mouse model of schizophrenia, pointing to their potential clinical use in treatment-resistant schizophrenia.