BACKGROUND Several clinical reports have documented a beneficial effect of the addition of a low dose of risperidone to the ongoing treatment with antidepressants, in particular selective serotonin reuptake inhibitors, in the treatment of drug resistant depression. The aim of our study was to understand the mechanism of the clinical efficacy of a combination of fluoxetine (FLU) and risperidone (RIS) in drug-resistant depression. We studied the effect of FLU and RIS, given separately or jointly on the extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex. METHODS Animals were given single intraperitoneal injections of RIS at a doses of 0.1 or 1 mg/kg and FLU at a dose of 10 mg/kg. The release of DA, 5-HT and NA in the rat frontal cortex was investigated using microdialysis in freely moving animals. The extracellular level of DA, 5-HT and NA was assayed by HPLC with coulochemical detection. RESULTS RIS (0.1 and 1 mg/kg) and FLU (10 mg/kg) increased the extracellular level of cortical DA, 5-HT and NA. Co-treatment of both drugs was more effective in increasing DA release than administration of each of the drugs alone at doses of RIS 1 mg/kg and FLU 10 mg/kg. Co-treatment of FLU and RIS 0.1 mg/kg was more potent than FLU alone, while the effect of joint injection of FLU and RIS 1 mg/kg was stronger than RIS 1 mg/kg alone on 5-HT release. The combination of FLU with both doses of RIS was not effective in increasing NA release as compared to drugs given alone. CONCLUSIONS Our data indicate that the effect of the combined administration of RIS and FLU on DA and 5-HT release in the rat frontal cortex may be of crucial importance to the pharmacotherapy of drug resistant depression.