18 research outputs found
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Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A(TA)7TAA and UGT1A4 L48V polymorphisms
INTRODUCTIONClozapine (CLZ) is an FDA approved second-generation antipsychotic for refractory schizophrenia, and glucuronidation is an important pathway in its metabolism. The aim of this study was to fully characterize the CLZ glucuronidation pathway and examine whether polymorphisms in active glucuronidating enzymes could contribute to variability in CLZ metabolism.
METHODSCell lines overexpressing wild-type or variant uridine diphosphate-glucuronosyltransferase (UGT) enzymes were used to determine which UGTs show activity against CLZ and its major active metabolite N-desmethylclozapine (dmCLZ). Human liver microsomes (HLM) were used to compare hepatic glucuronidation activity against the UGT genotype.
RESULTSSeveral UGTs including 1A1 and 1A4 were active against CLZ; only UGT1A4 showed activity against dmCLZ. UGT1A1 showed a 2.1-fold (P<0.0001) higher Vmax/KM for formation of the CLZ-N-glucuronide than UGT1A4; UGT1A4 was the only UGT for which CLZ-5-N-glucuronide kinetics could be determined. The UGT1A4 variant showed a 5.2-, 2.0-, and 3.4-fold (P<0.0001 for all) higher Vmax/KM for the formation of CLZ-5-N-glucuronide, CLZ-N-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-type UGT1A4. There was a 37% (P<0.05) decrease in the rate of CLZ-N-glucuronide formation in HLM with the UGT1A1 (*28/*28)/UGT1A4 (*1/*1) genotype, and a 2.2- and 1.8-fold (P<0.05 for both) increase in the formation of CLZ-5-N-glucuronide and CLZ-N-glucuronide in UGT1A1 (*1/*1)/UGT1A4 (*3/*3) HLM compared with UGT1A1 (*1/*1)/UGT1A4 (*1/*1) HLM. The UGT1A1*28 allele was a significant (P=0.045) predictor of CLZ-N-glucuronide formation; the UGT1A4*3 allele was a significant (P<0.0001) predictor of CLZ-5-N-glucuronide and dmCLZ-glucuronide formation.
CONCLUSIONThese data suggest that the UGT1A1*28 and UGT1A4*3 alleles contribute significantly to the interindividual variability in CLZ and dmCLZ metabolism
Sudden-Onset Dystonia in a Patient Taking Asenapine: Interaction Between Ciprofloxacin and Asenapine Metabolism
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Olanzapine metabolism and the significance of UGT1A448V and UGT2B1067Y variants
Olanzapine is an antipsychotic used in the treatment of schizophrenia, bipolar disorder, and treatment-resistant depression. Glucuronidation by the UDP-glucuronosyltransferase (UGT) family of enzymes is the major mode of olanzapine metabolism, and polymorphisms in these enzymes could contribute to interindividual variability in olanzapine metabolism and therapeutic response.Cell lines overexpressing individual UGT enzymes were used to determine which UGTs have enzymatic activity against olanzapine, characterize the kinetics of this reaction, and examine the effects of UGT variants on olanzapine metabolism. A bank of 105 human liver microsomes (HLM) were used to perform a phenotype-genotype study comparing glucuronidation activity against UGT genotype.Cell lines overexpressing the individual UGTs 1A4 and 2B10 exhibited glucuronidation activity against olanzapine. The UGT1A4 variant exhibited a 3.7-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 1, and a 4.3-fold (P<0.0001) higher Vmax/KM for the formation of the olanzapine-10-N-glucuronide isomer 2 than wild-type UGT1A4. The UGT2B10 variant exhibited no glucuronidation activity against olanzapine. In a screening of 105 HLM specimens, there was a 2.1-fold (P=0.04) and 1.6-fold (P=0.0017) increase in the rate of olanzapine-10-N-glucuronide isomer 1 and olanzapine-4'-N-glucuronide formation, and a 2-fold (P=0.02) increase in the overall olanzapine glucuronidation formation, in HLM with the UGT1A4 (*3/*3)/UGT2B10 (*1/*1) genotype compared with HLM with the UGT1A4 (*1/*1)/UGT2B10 (*1/*1) genotype. There was a 1.9-fold (P<0.003) decrease in the formation of both isomers of the olanzapine-10-N-glucuronide, a 2.7-fold (P<0.0001) decrease in olanzapine-4'-N-glucuronide formation, and a 2.1-fold (P=0.0002) decrease in the overall olanzapine glucuronide formation in HLM with at least one UGT2B10*2 allele. In regression analysis, the UGT1A4*3 (P<0.02) and UGT2B10*2 (P<0.002) alleles were significant predictors of the formation of all olanzapine glucuronide isomers.The UGTs 1A4 and 2B10 glucuronidate olanzapine and functional variants of these UGTs significantly alter olanzapine glucuronidation in vitro. These data suggest that the UGT1A4*3 and UGT2B10*2 alleles contribute significantly to interindividual variability in olanzapine metabolism
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Adult Suicide-Related emergency department encounters during the COVID-19 Pandemic: a Cross-Sectional study
Background: The coronavirus disease 2019 (COVID-19) pandemic resulted in widespread psychosocial disruption, which may impact suicidal thoughts and behaviours. This study characterizes adult suicide-related emergency department (ED) encounters and patient characteristics during the COVID-19 pandemic in 2020 compared to the year prior. Methods: Retrospective cross-sectional study in a large, integrated, community-based health system of adults (≥18-years-old) with suicide-related ED encounters (defined by the Centres for Disease Control-recommended International Statistical Classification of Diseases [ICD-10-CM] codes) during the COVID-19 pandemic compared to the same period in 2019. Population-level incidence rate ratios (IRRs) compared suicide-related ED encounters in 2020 to 2019. Patient characteristics for the first suicide-related ED visit for each period were used to calculate percent relative change comparing 2020 to 2019. Findings: Of 10,651 suicide-related ED encounters in 2020 and 11,476 in 2019, 49.6% and 51.6% were for females and the mean age was 38±17 and 38±16 years-old, respectively. Suicide-related ED encounters significantly declined in each month of 2020 (IRR 0.71-0.91, p<.05), but were equivalent to 2019 levels June-August. Adults in 2020 were more likely to have co-occurring substance use disorders (+15•7%; 95% CI 7•0-24•4%) or have no mental health or suicide diagnosis associated with an outpatient visit in the last year (+21•1%, 95% CI: 12•5-29•6) compared to 2019. Interpretation: Adults with suicidal thoughts and behaviours during the COVID-19 pandemic in 2020 had distinct social and psychiatric characteristics compared to patients in the prior year. These findings can help inform health system responses to mental health needs
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Association Between Prenatal Cannabis Use and Psychotropic Medication Use in Pregnant Patients With Depression and Anxiety.
OBJECTIVES: This cross-sectional study examined associations between prenatal cannabis use and prescribed psychotropic medication use among pregnant patients with depression or anxiety in a large, integrated healthcare system. METHODS: Study patients had a confirmed pregnancy and a depressive or anxiety disorder defined by International Classification of Diseases codes between 2012 and 2018 at Kaiser Permanente Northern California. Patients were screened for prenatal substance use via a self-reported questionnaire and urine toxicology test as part of standard prenatal care. Generalized estimating equation models tested for associations between prenatal cannabis use and any dispensation of antidepressants, benzodiazepines, and hypnotics during gestation. Models were stratified by diagnosis (depression or anxiety) and depression symptom severity. RESULTS: This study included 35,047 pregnancies (32,278 patients; 17.6% aged <25 years, 48.1% non-Hispanic White). Adjusting for patient age, income, race/ethnicity, and depression symptom severity, the 12.6% of patients who screened positive for prenatal cannabis use demonstrated higher odds of prenatal benzodiazepine (adjusted odds ratios [aOR] = 1.40; 95% confidence interval [CI] = 1.20-1.62) and hypnotic (aOR = 1.28; 95% CI = 1.11-1.48), but not antidepressants (aOR = 1.05, 95% CI = 0.96-1.14) use. This pattern persisted when diagnostic groups were examined separately. The odds of prenatal benzodiazepine and hypnotic use associated with prenatal cannabis use were higher among pregnancies with severe depression symptom severity (31.8% of the sample). CONCLUSIONS: Among pregnant patients with depression or anxiety, prenatal cannabis use was associated with higher odds of prenatal benzodiazepine and hypnotic use. As patients may be using cannabis to address depression and anxiety, prescribers should remain vigilant for under- or untreated psychiatric symptoms among pregnant patients and provide evidence-based treatments
Childhood adversity and epigenetic regulation of glucocorticoid signaling genes: Associations in children and adults
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Associations between Adverse Childhood Experiences (ACEs) and Prenatal Mental Health and Substance Use.
Adverse childhood experiences (ACEs) are common and increase the risk of poor health outcomes. Resilience may offer protection against the impacts of ACEs. This study examined the association between maternal ACEs and mental/behavioral health outcomes during pregnancy overall and by resilience. The sample comprised pregnant patients in two pilot studies screened for eight ACEs and resilience during standard prenatal care in Kaiser Permanente Northern California from 1 March 2016 to 30 July 2016 (Study 1, medical centers A, B) and from 1 April 2018 to 31 March 2019 (Study 2, medical centers A, C). Early pregnancy outcomes included anxiety and depressive disorders, depression symptoms, intimate partner violence (IPV), and substance use. Multivariable logistic regression was used in this cross-sectional study to examine associations between maternal ACEs (0, 1-2, ≥3) and mental/behavioral health outcomes overall and among those with low and high resilience. Patients (n = 1084) averaged 30.8 years (SD 5.1); 41.7% were non-Hispanic White; 41.7% experienced ≥1 ACE, and 40.3% had low resilience. Patients with 1-2 ACEs or ≥3 ACEs (versus 0 ACEs) had higher odds of anxiety and depressive disorders, depressive symptoms, IPV, and any prenatal substance use (OR 1.44-4.40, p < 0.05). Each individual ACE was associated with ≥2 mental/behavioral health outcomes. In stratified analyses, having ≥1 ACE (vs. 0) was associated with a greater number of mental/behavioral health outcomes among patients with low versus high resilience. ACEs were associated with prenatal mental/behavioral health conditions, particularly in the context of low resilience, highlighting the importance of trauma-informed prenatal care and the need to study resilience-building interventions during pregnancy