Nefazodone, a phenylpiperazine antidepressant, exhibits novel dual activity on serotonin (5-HT) neurons; it binds to 5-HT2 receptors and inhibits 5-HT reuptake. Flexible doses of nefazodone (100-400 mg/day) and amitriptyline (50-200 mg/day) were compared in 106 major depressive inpatients in a 6-week double-blind study. Results showed significant superiority of amitriptyline over nefazodone on all rating instruments: Montgomery and Asberg depression rating scale (P < 0.0001), Hamilton depression scale (P < 0.0006), Clinical Global Impressions (P < 0.0001) and Patient Global Assessment (P < 0.01). A total of 65% of patients under amitriptyline and 56% of patients under nefazodone reported adverse events during the study, with significantly more dry mouth in the amitriptyline group (39% versus 11%, P = 0.001). Modal daily doses within the last treatment week reached 242 mg with nefazodone and 124 mg with amitriptyline. The lower efficacy of nefazodone, which contradicts comparative trials with imipramine in US patients, is discussed with regard to the dose of nefazodone, probably below the optimal therapeutic range for melancholic patients, and to the clinical differences between the patient samples.