Nefazodone is a selective 5-HT2 receptor antagonist. Nefazodone has a pharmacologic profile similar to trazodone and other phenylpiperazine antidepressants, but distinct from nonselective first-generation agents and other selectively acting second-generation agents. Results of a multicenter, double-blind, fixed-dose trial indicate nefazodone is effective in improving depressive symptoms of outpatients with major depressive disorder treated with daily doses of 100 mg to 200 mg. A comparison of the fixed-dose trial design with an alternative design permitting dose titration within fixed ranges is presented. The relative merits of each design for establishing therapeutic dose ranges are discussed.