Influence of fluoxetine on olanzapine pharmacokinetics.
Conventional antidepressant treatment fails for up to 30% of patients with major depression. When there are concomitant psychotic symptoms, response rates are even worse. Thus, subsequent treatment often includes combinations of antidepressants or augmentation with antipsychotic agents. Atypical antipsychotic agents such as olanzapine cause fewer extrapyramidal adverse effects than conventional antipsychotics; for that reason, they are an advantageous augmentation strategy for treatment-resistant and psychotic depression. The purpose of this study was to assess the potential for pharmacokinetic interaction between olanzapine and fluoxetine, a popular antidepressant that is a selective serotonin reuptake inhibitor. The pharmacokinetics of 3 identical single therapeutic doses of olanzapine (5 mg) were determined in 15 healthy nonsmoking volunteers. The first dose of olanzapine was taken alone, the second given after a single oral dose of fluoxetine (60 mg), and the third given after 8 days of treatment with fluoxetine 60 mg, qd. Olanzapine mean Cmax was slightly higher (by about 18%) and mean CL/F was slightly lower (by about 15%) when olanzapine was coadministered with fluoxetine in single or multiple doses. Olanzapine mean t((1/2)) and median t(max) did not change. Although the pharmacokinetic effects of fluoxetine on olanzapine were statistically significant, the effects were small and are unlikely to modify olanzapine's safety profile. The mechanism of influence is consistent with an inhibition of CYP2D6, which is known to control a minor pathway of olanzapine metabolism.
Gossen
Denis
D
Lilly Research Laboratories, Lilly Development Centre, rue Granbonpre 11, B-1348 Mont-Saint-Guibert, Belgium.
de Suray
Jean-Marie
JM
Vandenhende
Francois
F
Onkelinx
Claude
C
Gangji
Diamon
D
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001247:Asthenia / Q000139:chemically induced; D001569:Benzodiazepines; D018592:Cross-Over Studies; D003866:Depressive Disorder / Q000150:complications / Q000188:drug therapy; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D000077152:Olanzapine; D010890:Pirenzepine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D014987:Xerostomia / Q000139:chemically induced
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D005473:Fluoxetine; D000077152:Olanzapine; D010890:Pirenzepine; D017367:Selective Serotonin Reuptake Inhibitors