Valproate Lowers Plasma Concentrations of Olanzapine

Olanzapine is an atyical antipsychotic from the thienobenzodiazapine group which is metabolized mainly in the liver and after N-glucuronidation it is catalyzed by oxidation reactions via the cytochrome P450 isoenzyme CYP1A2 and – to a lesser degree – via CYP2D6. Whereas data on the interaction of olanzapine with a number of psychotropic drugs are available, little is known about the effect of valproate on the plasma concentrations of olanzapine, although a combination of the two substances may be indicated and recommended in treating, for example, manic and mixed bipolar disorders. Therefore, we wanted to investigate whether valproate has a clinically relevant effect on the plasma concentration of olanzapine under naturalistic conditions.

In four patients between the ages of 32 and 42 years (mean [M]±standard deviation [SD]: 36.3±4.3; three women and one man; two smokers/two non-smokers) who had been receiving treatment with olanzapine, plasma concentrations of olanzapine were determined by high pressure liquid chromatography (HPLC) with electrochemical detection before and after receiving co-medication of valproate.

The patients received between 20 and 30mg olanzapine daily. In one patient the dose was reduced from 20 to 15mg per day. All patients demonstrated a significant decrease in plasma levels of olanzapine of between 32.3% and 78.8% after receiving valproate. The mean decrease in plasma olanzapine concentration was 53.6%. Before receiving valproate, the dose-corrected plasma concentrations of olanzapine were between 2.17 and 22.40 ng/ml mg (M±SD=9.36±8.81 ng/ml:mg) and after receiving valproate between 1.47 and 12.80 ng/ml:mg (M±SD=4.62±5.47 ng/ml:mg).

These data suggest an induction of olanzapine-metabolizing enzyme systems by valproate. In contrast to this mechanism a potential competitive inhibition of CYP1A2 by valproate does not seem to be clinically relevant.

The present results are clinically important, considering that it is not uncommon that treatment with both olanzapine and valproate is indicated.