Clinical studies in schizophrenia patients have shown that adding a selective serotonin reuptake inhibitor (SSRI) to antipsychotics can ameliorate negative symptoms that frequently resist standard treatments. It has been proposed that this combined treatment produces a 'net effect', different from that of the individual drugs and possibly common to that of the atypical antipsychotic, clozapine, which also ameliorates negative symptoms. The present study was initiated to determine the molecular events in the rat frontal cortex resulting from combined treatment of fluvoxamine and haloperidol compared to clozapine. Rats were allocated to five groups and received a daily intraperitoneal injection with one of the following: haloperidol (1 mg/kg), fluvoxamine (11 mg/kg), clozapine (11 mg/kg), haloperidol (1 mg/kg) plus fluvoxamine (11 mg/kg), or vehicle for 30 d. cDNA arrays were used to screen a broad range of genes in the frontal cortex. Several of the most prominent alterations were taken for analysis in real-time RT-PCR and their related proteins were examined by the Western-blotting technique. The gene expression profile of the combined fluvoxamine plus haloperidol treatment was different from that of the individual drugs. Moreover, clozapine showed some degree of homology with the dual treatment. The protein expression changes, specific to the combined treatment, included glutamic acid decarboxylase (GAD67) and protein kinase Cbeta (PKCbeta). The latter showed a similar trend following clozapine treatment. The present findings support the existence of a unique mechanism for SSRI-antipsychotic combination, different from that of the individual drugs and suggest that it may involve modification of the gamma aminobutyric acid (GABA) system.