COADMINISTRATION OF NEFAZODONE AND BENZODIAZEPINES .1. PHARMACODYNAMIC ASSESSMENT

One hundred two healthy men were evaluated in one of three studies con ducted to evaluate the coadministration of nefazodone, 200 mg twice da ily, and three benzodiazepines: triazolam, 0.25 mg; alprazolam, 1 mg t wice daily; or lorazepam, 2 mg twice daily. In the first study, psycho motor 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 e valuable because of a dosing error in the other 6 subjects. In the sub sequent two parallel design studies, groups of 12 volunteers received 7 days of either placebo; nefazodone, 200 mg; alprazolam, 1 mg twice d aily; or alprazolam plus nefazodone or, in the second study, either pl acebo; nefazodone; lorazepam, 2 mg twice daily; or lorazepam plus nefa zodone; 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 st udies. In all studies, blood samples were also obtained at testing tim es so that effect/concentration comparisons could be made and so full pharmacokinetic analyses could be done for separate studies. Nefazodon e had no effect on psychomotor performance, memory, or sedation relati ve to placebo in any study. The mean maximum observed effect (MaxOE) o n psychomotor performance and sedation were increased when triazolam w as given after 7 days of nefazodone (p < 0.05); also, triazolam concen tration 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, psycho motor impairment decreased, indicating the development of tolerance. A lprazolam plus nefazodone increased psychomotor impairment (MaxOE, app roximately 50%) and sedation relative to alprazolam alone on days 3, 5 , and 7 (p < 0.05). Higher alprazolam concentrations explained the inc reased impairment in the alprazolam plus nefazodone treatment group; h owever, it is also possible that there was a delay in the development of tolerance. There were no differences in psychomotor impairment, mem ory, sedation, or lorazepam concentration detected between the lorazep am alone and lorazepam plus nefazodone treatments. This is consistent with the absence of a pharmacokinetic interaction between nefazodone a nd 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 el iminated by conjugative metabolism such as lorazepam. In cases where a benzodiazepine eliminated by oxidative metabolism is required, a redu ction in initial dosage and careful clinical evaluation for signs of p sychomotor impairment may be appropriate.