Abstract
BackgroundUse of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction. It is presumed that there are interindividual differences in ANS dysfunction that correspond to pharmacogenetics. In this study, we investigated whether genetic polymorphisms in ABCB1, CYP1A2, and UGT1A4 are associated with this observed ANS dysfunction.MethodsA total of 91 schizophrenia patients treated with olanzapine monotherapy participated in this study. A power spectral analysis of heart rate variability was used to assess ANS activity. The TaqMan system was used to genotype seven single nucleotide polymorphisms (SNPs) in CYP1A2 (rs2069514 and rs762551), UGT1A4 (rs2011425), and ABCB1 (rs1045642, rs1128503, rs2032582, rs2235048).ResultsSympathetic nervous activity was significantly higher in individuals with the UGT1A4 rs2011425 G allele than in those with the UGT1A4 rs2011425 non-G allele (sympathetic activity, p = .001). Furthermore, sympathetic nervous activity was also significantly associated with UGT1A4 rs2011425 genotype as revealed by multiple regression analysis (sympathetic activity, p = .008).ConclusionsWe suggest that the UGT1A4 rs2011425 polymorphism affects olanzapine tolerability because it is associated with the observed side effects of olanzapine in schizophrenia patients, namely sympathetic dysfunction.
Highlights
Use of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction
In the present study involving patients with schizophrenia, we investigated whether seven single nucleotide polymorphisms (SNPs) in CYP1A2, UGT1A4, and ABCB1 are associated with side effects of olanzapine, including decreased ANS activity, to clarify the factors that affect interindividual differences in decreased ANS activity during olanzapine therapy and to provide safer medication that can be tailored to individual genotypes
The daily dosage of each antipsychotic drug was converted to an approximate chlorpromazine equivalent (CPZ), with a patient mean of 491.21 ± 247.05 mg/day
Summary
Use of the antipsychotic drug olanzapine by patients with schizophrenia is associated with autonomic nervous system (ANS) dysfunction. We investigated whether genetic polymorphisms in ABCB1, CYP1A2, and UGT1A4 are associated with this observed ANS dysfunction. Compared with the general population, patients with schizophrenia exhibit lower autonomic nervous system (ANS) activity [1]. ANS dysfunction in schizophrenia patients is exacerbated by antipsychotic medications [2,3,4], and diminished ANS activity is associated with sudden death resulting from cardiovascular disease and. We have reported that olanzapine appears to affect autonomic nervous activity strongly in comparison with other atypical antipsychotics such as risperidone or aripiprazole [6]. Many studies have reported that genetics influence therapeutic outcomes [7] and that the side effects of antipsychotics such as olanzapine are affected by pharmacogenetics [8]. A previous study has reported that the relevant polymorphisms in genes involved in olanzapine metabolism and bioavailability are related to patient responses to olanzapine [9]
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