Sex, Race, and Smoking Impact Olanzapine Exposure

Bigos, Kristin L.; Pollock, Bruce G.; Coley, Kim C.; Miller, Del D.; Marder, Stephen R.; Aravagiri, Manickam; Kirshner, Margaret A.; Schneider, Lon S.; Bies, Robert R.

doi:10.1177/0091270007310385

Cited by 154 publications

(163 citation statements)

References 31 publications

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“…Although age-related changes in peripheral PK, which reduce drug clearance, contribute to adverse events by increasing blood concentration for a given dose of drug (Feng et al, 2008), this effect is not consistent across antipsychotics (Bigos et al, 2008). Occupancy studies in older patients with schizophrenia , Uchida et al, 2014, Graff-Guerrero et al, 2015 suggest that pharmacodynamic changes, which lower the threshold occupancy for response and EPS, may be important.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease

Reeves

McLachlan

Bertrand

et al. 2017

Brain

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Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side-effects (Simpson Angus Scale scores >3). Average steady state blood levels were low (71+-30 ng/ml), and associated with high D2/3 occupancies (65+-8%, caudate; 67+-11%, thalamus; 52+-11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20ng/ml and D2/3 occupancies of 43% (caudate), 25%(putamen), 43% (thalamus). Extrapyramidal side effects (n=7) emerged at a threshold 4 concentration of 60ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69%(thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer's disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer's disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer's disease and implicate the blood brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age-or disease-specific blood brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.5

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Section: Introductionmentioning

confidence: 99%

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease

Reeves

McLachlan

Bertrand

et al. 2017

Brain

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“…The higher bioavailability of aspirin in women than in men has been linked to decreased conjugation with glycine and glucuronic acid (Franconi et al, 2007). Men show a higher rate of clearance of the benzodiazepines diazepam, chlordiazepoxide, and olanzapine (MacLeod et al, 1979;Roberts et al, 1979;Bigos et al, 2008). Likewise, women display greater sensitivity to diazepam, which can lead to impairment of psychomotor skills (Palva, 1985).…”

Section: Sex Differences In Hepatic Drug Metabolismmentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

611

577

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Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

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“…Analysis was performed while controlling for age, years of treatment, and CPZEQ. Drug clearance was important in evaluating the antipsychotic drug response, and clearance data were obtained through an ancillary project to the CATIE study (Bigos et al, 2008(Bigos et al, , 2011. For clinical genetic association, main effect analyses of single SNPs were conducted using unconditional logistic regression models controlling for sex and age in the case-control sample and using the family-based association test (FBAT, www.biostat.harvard.edu/fbat/ fbat.htm) in families with permutation testing for significance assessment.…”

Section: Genotyping and Statistical Analysismentioning

confidence: 99%

Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia

Jenkins

Apud

Zhang

et al. 2014

Neuropsychopharmacol

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Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs.

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Sex, Race, and Smoking Impact Olanzapine Exposure

Cited by 154 publications

References 31 publications

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia

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