Safety, tolerance, and preliminary pharmacokinetics of nefazodone, a new antidepressant, were assessed in a randomized, double-blind, parallel group study carried out in two sequential segments: a single and a multiple daily dose segment. Nine subjects in the single daily dose segment were divided into three treatment groups and received nefazodone doses in a leapfrog fashion. Each day of treatment with nefazodone was followed by 2 days of placebo treatment and then administration of the next higher drug dose. Single doses ranged from 5-500 mg. 8 subjects enrolled in the multiple daily dose segment were divided into two treatment groups. In each group, 3 subjects received nefazodone and one received placebo 3 times a day. Each dosage level was administered for 2 days before proceeding to the next higher dose from 5 mg or 10 mg 3 times a day to a maximum of 500 mg 3 times a day. After the dose-escalation period, the subjects in the multiple daily dose segment underwent a 3-day washout, after which they received a single dose of nefazodone at the maximum tolerated level. Safety and tolerance assessment involved analyses of adverse events, laboratory tests, vital signs, ophthalmic examinations, and ECGs. Blood and urine samples were obtained only in the multiple daily dose segment and analyzed for nefazodone and its two pharmacologically active metabolites, hydroxynefazodone and mCPP. A single blood sample was collected on 8 different days for assessment of trough levels (Cmin) and serial samples were obtained on days 5, 9, and 22 of dosing for pharmacokinetic profiles. Additional serial samples were also obtained after the last single dose of 500 mg after a 3-day washout. Nefazodone was found to be safe and well-tolerated in total daily doses as high as 1350 mg (450 mg 3 times a day). Nefazodone was rapidly absorbed after oral administration and converted to hydroxynefazodone and mCPP. The pharmacokinetics of nefazodone, hydroxynefazodone, and mCPP were found to be dose-dependent, as evidenced by dose normalized values of Cmin, Cmax, and AUC0-8 that progressively increased with dose. Although exposure of normal subjects to nefazodone and its 2 pharmacologically active metabolites was disproportionately higher than the corresponding increase in dose, the safety and tolerance profiles did not show a parallel increase in adverse events. Nefazodone may be well-tolerated by patients receiving expected therapeutic doses from 200-600 mg per day when administered in divided doses every 8 to 12 hours.