Olanzapine is an ''atypical'' antipsychotic agent with a high affinity
for serotonin 5HT(2A/C), 5HT(3), 5HT(6), and dopamine D-1, D-2, D-3,
D-4 receptors. Depressed patients with psychotic disorders frequently
require treatment with concomitant antipsychotic and antidepressant me
dications. Imipramine pharmacokinetics serve as a marker for hepatic C
YP2D6, CYP1A2, CYP3A activity. An open-label, three-way randomized cro
ssover study was done to determine the safety, pharmacokinetics, and p
otential for a drug interaction between olanzapine (5 mg) and imiprami
ne (75 mg). Each drug was administered alone and in combination. Nine
healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor p
erformance capacities, plasma olanzapine, imipramine, desipramine conc
entrations, and clinical laboratory tests were measured. Pharmacokinet
ic variables, vital signs, subjective tests for liveliness, and psycho
motor outcomes were analyzed using a two-way ANOVA. Olanzapine was saf
e. Sedation, postural hypotension, and minor vital sign alterations oc
curred during all treatments. On the liveliness questionnaire, patient
s generally reported poorer (less lively) scores with olanzapine alone
or coadministered with imipramine versus baseline scores. These effec
ts disappeared within 24 hours after administration. Olanzapine alone
and in combination decreased motor-speed tasks (finger tapping and vis
ual-arm random reach) compared with baseline or imipramine treatment.
Peak 6-hour changes were statistically significant but clinical import
ance was only marginal. Olanzapine concentrations were <19% greater th
an with imipramine. But olanzapine did not affect the kinetics of imip
ramine or desipramine and, therefore, did not show a metabolic drug in
teraction involving CYP2D6.