The selective serotonin reuptake inhibitor antidepressant fluoxetine inhibits alprazolam metabolism in vivo by inhibition of the cytochrome P450 3A4 enzyme. Citalopram is a selective serotonin reuptake inhibitor antidepressant that has not yet been fully evaluated with respect to its potential for cytochrome P450 3A4-mediated drug interactions in vivo. Building on the existing in vitro and in vivo evidence that suggest a minimal effect of citalopram on cytochrome P450 3A4, we hypothesized that therapeutic doses of citalopram (20 mg/d), as compared with fluoxetine (20 mg/d), would cause less impairment in the metabolism of the probe drug alprazolam (1 mg) through inhibition of the cytochrome P450 3A4 isozyme as measured by pharmacokinetic and pharmacodynamic parameters in vivo. We found that fluoxetine prolonged the half-life of alprazolam by 16% and increased the area under the curve 0-infinity of alprazolam by 32%, while citalopram did not affect these parameters, although the time of maximum concentration of alprazolam was prolonged by 30 minutes after citalopram administration. Neither selective serotonin reuptake inhibitor significantly affected the pharmacodynamic profile of alprazolam. This experiment suggests differential effects by citalopram and fluoxetine on alprazolam kinetics.