In the preset study, the authors investigated that effects of the antipsychotic drug risperidone on psychotic depression and examined the mechanism of risperidone to ameliorate psychotic depression. Fifteen patients met the DSM-IV criteria for major depressive disorder with psychotic features and the remaining five patients met those for bipolar I disorder (most recent episode depressed) with psychotic features (M/F: 8/12, age: 54+/-18). All patients were evaluated regarding their clinical improvement using the Hamilton Rating Scale for Depression (Ham-D), and Positive and Negative Syndrome Scale (PANSS). In addition, plasma concentrations of HVA and MHPG were analyzed by HPLC. Patients with a 50% or more improvement in Ham-D score were defined as responders. Three were prescribed risperidone alone, and the other 17 were administered risperidone as an addition to preexisting antidepressants or mood stabilizers. The preexisting antidepressants or mood stabilizers were as follows: paroxetine (6), lithium (3), valproic acid (3), clomipramine (2), fluvoxamine (1), amitriptyline (1), amoxapine (1). The average dose of risperidone was 1.8+/-0.5 mg/day. Eleven of twenty patients (55%) turned out to be responders 4 weeks after initiation of risperidone administration. No differences were observed between responders and nonresponders with respect to age, sex, Ham-D score before risperidone treatment, dose and plasma level of risperidone or its active metabolite, 9-hydroxyrisperidone. Plasma HVA levels before risperidone administration in responders were significantly higher than those in nonresponders. In addition, a significant correlation was observed between changes in plasma HVA level and the percentage improvement on Ham-D score. These results indicate that treatment with risperidone is effective to ameliorate psychotic depression, and the influence of risperidone on dopaminergic activity is associated with its efficacy.