One hundred two healthy men were evaluated in one of three studies conducted to evaluate the coadministration of
nefazodone, 200 mg twice daily, and three
benzodiazepines:
triazolam, 0.25 mg;
alprazolam, 1 mg twice daily; or
lorazepam, 2 mg twice daily. In the first study, psychomotor performance, memory, and sedation were assessed at 0, 0.5, 1.5, 2.5, and 9 hours after single doses of
triazolam alone and again after 7 days of
nefazodone. Data from 6 of 12 subjects in this study were evaluable because of a dosing error in the other 6 subjects. In the subsequent two parallel design studies, groups of 12 volunteers received 7 days of either placebo;
nefazodone, 200 mg;
alprazolam, 1 mg twice daily; or
alprazolam plus
nefazodone or, in the second study, either placebo;
nefazodone;
lorazepam, 2 mg twice daily; or
lorazepam plus
nefazodone; the studies were identical, double-dummy, double-blind designs. Psychomotor performance, memory, and sedation were assessed at 0, 1, 3, and 8 hours after the 8 a.m. dose on days 1, 3, 5, and 7 of the studies. In all studies, blood samples were also obtained at testing times so that effect/concentration comparisons could be made and so full pharmacokinetic analyses could be done for separate studies.
Nefazodone had no effect on psychomotor performance, memory, or sedation relative to placebo in any study. The mean maximum observed effect (MaxOE) on psychomotor performance and sedation were increased when
triazolam was given after 7 days of
nefazodone (p < 0.05); also,
triazolam concentration was 60% higher at this time.
Alprazolam and
lorazepam impaired performance on day 1 (mean MaxOE, 34 and 30%, respectively) relative to placebo and
nefazodone. By day 7 of
alprazolam or
lorazepam,
psychomotor impairment decreased, indicating the development of tolerance.
Alprazolam plus
nefazodone increased
psychomotor impairment (MaxOE, approximately 50%) and sedation relative to
alprazolam alone on days 3, 5, and 7 (p < 0.05). Higher
alprazolam concentrations explained the increased impairment in the
alprazolam plus
nefazodone treatment group; however, it is also possible that there was a delay in the development of tolerance. There were no differences in
psychomotor impairment, memory, sedation, or
lorazepam concentration detected between the
lorazepam alone and
lorazepam plus
nefazodone treatments. This is consistent with the absence of a pharmacokinetic interaction between
nefazodone and
lorazepam. These results indicate that if the coadministration of a
benzodiazepine is required in patients receiving
nefazodone therapy, clinically significant interactions would be less likely with those eliminated by conjugative metabolism such as
lorazepam. In cases where a
benzodiazepine eliminated by oxidative metabolism is required, a reduction in initial dosage and careful clinical evaluation for signs of
psychomotor impairment may be appropriate.