The Relationship Between the Response of Clinical Symptoms and Plasma Olanzapine Concentration, Based on Pharmacogenetics

Abstract

The monitoring of plasma olanzapine concentrations has been found to be an important and useful tool for optimizing psychiatric treatment. The present study investigated the effect that clinical factors, such as smoking and age, and functional polymorphisms of UGT1A4, CYP1A2, and CYP2D6 genes have on plasma olanzapine concentration, as well as the effects of plasma olanzapine concentrations on Japanese schizophrenic patients' clinical symptoms. The subjects included 51 chronic schizophrenic patients whose symptoms were not controlled with chronic conventional antipsychotics and therefore were switched to olanzapine. Male smokers had a significantly lower olanzapine concentration-dose ratio and olanzapine/4'-N-desmethyl olanzapine ratio (which reflects CYP1A2 activity) than male nonsmokers and female nonsmokers. The results of a 2-way analysis of covariance showed that smoking had the main effect, rather than gender or age. The functional gene polymorphisms that were studied had no effect on the plasma olanzapine and metabolite concentrations. An improved total Brief Psychiatric Rating Scale (BPRS) score was not correlated with the plasma olanzapine concentration, but individual BPRS scores related to improvement of suspiciousness, hallucinations, and blunted affect were significantly correlated with plasma olanzapine concentration. Clinical factors, especially smoking, were more important modulators of olanzapine metabolism than the functional genotypes. Long-term olanzapine treatment with adequate plasma olanzapine concentrations could be more effective in improving some symptoms than treatment with conventional antipsychotics.

Use of very-high-dose olanzapine in treatment-resistant schizophrenia

“…This result is consistent with the literature (Callaghan et al, 1999;Mauri et al, 2007). Tobacco significantly decreased the olanzapine plasma concentration in our sample, in accordance with current knowledge (Callaghan et al, 1999;Carrillo et al, 2003;Mauri et al, 2007;Nozawa et al, 2008;Patel et al, 2011;Weiss et al, 2005): tobacco has been identified as an inducer of cytochrome P450 1A2, with a consequent multiplication of enzymatic activity by a factor of 2-6 (Carrillo et al, 2003). A negative effect of tea/coffee consumption was also found.…”

Pharmacogenetics and olanzapine treatment: CYP1A2*1F and serotonergic polymorphisms influence therapeutic outcome

“…33,34 In one study in Japanese patients, olanzapine concentrations were not affected by CYP1A2 polymorphisms but only by smoking. 35 This finding, however, may not be applicable for Caucasians due to further interethnic genetic differences as discussed previously. 19 The CYP1A2*1F (À163A) polymorphism was associated with higher clearance of the CYP1A2 substrate caffeine in Caucasian smokers 18,19 but not in nonsmokers or in Korean smokers.…”

Effects of 22 <b><i>CYP2D6</i></b> Genetic Variations Newly Identified in Chinese Population on Olanzapine Metabolism in vitro

“…[9,10] . In clinical practice, olanzapine showed obvious individual differences in plasma concentrations between patients given a normal dose, which necessitated the reasonable individual dosage, even therapeutic drug monitoring [11,12] . In vivo, olanzapine is metabolized to its 10-and 4'-N-glucuronides via UDP-glucuronosyltransferase (UGT1A4), to 4'-N-desmethyl-olanzapine via CYP1A2, to olanzapine N-oxide via flavin monooxygenase 3 and to 2-hydroxymethylolanzapine via CYP2D6 [2] .…”