Will ChatGPT3 Substitute for us as Clozapine Experts?

CYP1A2 activity is an important determinant of clozapine dosage in schizophrenic patients.

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.

INTRODUCTION Cigarette smoking is prevalent among psychiatric patients, with rates several times higher than the general population. As an example, up to 80% of schizophrenic patients smoke cigarettes. Clozapine is extensively metabolized by cytochrome P450 isoenzyme 1A2 and polycyclic aromatic hydrocarbons (PAHs) present in cigarette smoke are thought to induce CYP 1A2. Therefore concurrent smoking with clozapine can potentially lead to decreased clozapine levels and decreased efficacy, while smoking cessation can potentially lead to increased levels and toxicity. Enzyme induction has been reported to result in a 20 to 40% lower mean clozapine concentration in smokers compared to nonsmokers. We present a case of altered serum drug concentrations in association with changes in smoking status in a patient upon admission to a nonsmoking inpatient psychiatric facility.

Background: Differences in tumor biology, genomics and health care delivery patterns contribute to breast cancer mortality gap between white women of European ancestry (EA) and black women of African ancestry (AA) in the US. Accumulating evidence suggest that the genetic architecture of breast cancer is different across race and ethnicity but individuals of African ancestry, with the oldest and most diverse genome, remain under represented in clinical trials. Beyond interventions to improve quality of guideline directed cancer care, there is an urgent need to implement and disseminate innovative interventions that promote health equity and inform evidence based interventions. Method: We established a breast cancer patient cohort by collecting clinical and epidemiological data via electronic medical records and interview as well as biospecimen banking at the University of Chicago Comprehensive Cancer Center. We compared overall survival and relapse-free survival between EA and AA patients using Cox models. We also examined racial difference in pathologic complete response (pCR) in patients receiving neoadjuvant therapy. Using the xT 595-gene panel (Tempus Labs, Inc.) with matched tumor-normal samples in a subset of the cohort (n=127), we evaluated genomic heterogeneity. Results: 2773 stage I-III breast cancer patients were enrolled in the cohort, including 54% white, 39% black and 7% Asian and Hispanic patients. Over a median follow-up of 5.8 years, 456 patients died and 301 patients had recurrent breast cancers. After adjusting for stage, age, and comorbidities, AA patients had higher mortality rate than EA patients, and the racial difference varied across molecular subtypes: the hazard ratios comparing AA vs. EA patients were 3.92 (95% CI 1.58-9.73) in the hormone receptor (HR)-/HER2+ group, 1.55 (1.20-2.01) in the HR+/HER2- group, 1.51 (0.81-2.80) in the HR+/HER2+ group, and 1.21 (0.82-1.80) in the triple negative group. Of the 560 patients undergoing neoadjuvant chemotherapy, 166 (30%) had pCR. AA patients had lower pCR rate than EA patients (26% vs. 34%, p=0.053). Of note, molecular subtype was a strong predictor for pCR (p&amp;lt;0.001), highest in HR-/HER2+ group (59%), followed by triple negative (32%), HR+/HER2- (26%), and HR+/HER2- (16%) groups. In patients with pCR, 4 died, compared to 78 deaths in patients with residual diseases after neoadjuvant therapy (hazard ratio 9.70, 95% CI 3.51-26.8; p&amp;lt;0.001). Genomic mutations for therapy resistance and relapse will be integrated before the meeting presentation. Conclusion: Racial differences in pCR in part explain the mortality disparity between AAs and EAs in the ChiMEC cohort. This underscores the need for broader access to adaptive biomarker based clinical trials in communities that serve predominantly AA breast cancer patients. Citation Format: Dezheng Huo, Nike Beaubier, Nora Jaskowiak, Rita Nanda, Gini Fleming, Masaya Hattori, Padma Sheila Rajagopal, Abiola Ibraheem, Brenda Copley, Qun Niu, Fang Liu, Elisabeth Sveen, Toshio Yoshimatsu, Galina Khramtsova, Yonglan Zheng, Taylor Abboushi, Kevin White, Olufunmilayo Olopade. Using eHealth and data science to dissect breast cancer heterogeneity in the Chicago Multi-Ethnic (ChiMEC) Breast Cancer Cohort [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B123.

Genome-Wide Association Study Identifies PNPLA3 I148M Variant Associated with Elevated Transaminase Levels after Induction Therapy in Pediatric ALL Patients

Here, we characterize differences in the genetic and microbial profiles of GC in patients of African (AFR), European, and Asian ancestry. Gastric cancer (GC) is a heterogeneous disease with clinicopathologic variations due to a complex interplay of environmental and biological factors, which may affect disparities in oncologic outcomes.. We identified 1042 patients with GC with next-generation sequencing data from an institutional Integrated Mutation Profiling of Actionable Cancer Targets assay and the Cancer Genomic Atlas group. Genetic ancestry was inferred from markers captured by the Integrated Mutation Profiling of Actionable Cancer Targets and the Cancer Genomic Atlas whole exome sequencing panels. Tumor microbial profiles were inferred from sequencing data using a validated microbiome bioinformatics pipeline. Genomic alterations and microbial profiles were compared among patients with GC of different ancestries. We assessed 8023 genomic alterations. The most frequently altered genes were TP53 , ARID1A , KRAS , ERBB2 , and CDH1 . Patients of AFR ancestry had a significantly higher rate of CCNE1 alterations and a lower rate of KRAS alterations ( P < 0.05), and patients of East Asian ancestry had a significantly lower rate of PI3K pathway alterations ( P < 0.05) compared with other ancestries. Microbial diversity and enrichment did not differ significantly across ancestry groups ( P > 0.05). Distinct patterns of genomic alterations and variations in microbial profiles were identified in patients with GC of AFR, European, and Asian ancestry. Our findings of variation in the prevalence of clinically actionable tumor alterations among ancestry groups suggest that precision medicine can mitigate oncologic disparities.

AimsClinical research shows that compared to Caucasian patients, Asian patients appear to have a lower clozapine dose requirement for clinical efficacy. Hence, appropriate dose adjustment should be considered in Asian patients receiving maintenance clozapine therapy. Secondly, studies in the UK report that Asian patients with treatment-resistant schizophrenia were less likely to receive clozapine than Caucasian patients. The objectives of this study were to find out the ethnic difference in dose and levels of clozapine in ethnic minority patient (BME (Black and minority ethnic) populations and to explore if there is a need for any specific monitoring.MethodsDemographic (age, gender, and ethnicity) and clinical variables (diagnosis, clozapine dose, plasma level of clozapine and nor-clozapine, smoking status, side effect profile, and physical comorbidities) were collected from the electronic patient records and analysed.ResultsThe sample consisted of 66 (56.4%) Caucasians, 22 (18.8%) Asians, 21 (17.9%) African-Caribbean, and 8 (6.8%) mixed ethnicity patients. Their age range was 19-80, with an average of 46.9 ±11.9 years.Among the ethnic groups, age, clozapine, nor-clozapine level and QTc were comparable, except for the dose of clozapine; Caucasian had the highest dose (414.8±140.0 mg), followed by African-Caribbean (373.8±163.7 mg), Asian (333.8±121.2 mg) and mixed (260.7±110.7 mg) (F3.68, p<0.05). The difference remained significant when all the BME groups were combined as well.Side effects such as hypersalivation, drowsiness, blurred vision, polyuria, sore throat, headache, vomiting (none), dizziness, difficulty passing urine, urine incontinence, flu-like symptoms, nausea, were comparable among ethnic groups.There was no difference in smoking among the groups. Considering comorbidities compared to BME, Caucasians had significantly lower rate of hypertension (27.1% vs 9.1%, p<0.01); diabetes (18.6% vs 4.5%, p<0.05), however dyslipidemia (5.1% vs 3.0%) was comparable.In addition to the above, the dose of clozapine was positively correlated with clozapine and norclozapine levels (p<0.05). Clozapine and norclozapine levels correlated significantly (p<0.001). Age was negatively correlated with norclozapine assay (p<0.05) and positively with the number of cigarettes. It appears as the age increases, the number of cigarettes goes up, and norclozapine levels come down.ConclusionThere are a few variations of clozapine prescribing in different ethnic groups. Although the Caucasians had higher doses, they had comparable blood levels. A higher proportion of BME patients on clozapine had hypertension and diabetes, emphasizing metabolic risk. Our study findings suggest clozapine monitoring should look into ethnicity related risk factors.

THU0255 AUTOANTIBODY PROFILE AND ETHNICITY: RISK FACTORS FOR ACCELERATED DEVELOPMENT OF LUPUS NEPHRITIS

Smoking enhances plasma clozapine clearance, but the magnitude of the effect across the dose and age ranges is unclear. We audited clozapine dose and predose plasma clozapine and N -desmethylclozapine (norclozapine) concentrations by sex and smoking habit in samples submitted for clozapine TDM, 1996-2017. There were 105,316/60,792 and 34,288/31,309 samples from male/female smokers/nonsmokers, respectively. There were distinct dose-median plasma concentration trajectories for male/female smokers/nonsmokers across the range <50 to >850 mg d -1 . For both sexes, the percentage difference in median plasma clozapine in nonsmokers versus smokers averaged 50% but was greatest for men (76%) and women (59%) in the 151 to 250 mg d -1 dose band. In men, the percentage difference declined steadily to 34% at doses of ≥850 mg d -1 . In women, the difference after falling initially remained relatively constant at 40% to 54%. The pattern in median plasma clozapine/norclozapine ratio by plasma clozapine concentration and dose groups was independent of sex and smoking habit, but increased with plasma clozapine concentration (higher ratio at higher concentrations) and also changed with dose. Median plasma clozapine concentration and median clozapine dose by sex and smoking habit were similar up to age 60 years. Proportional weight gain was similar over time in smokers and nonsmokers of either sex. These data explain the variations in the effect size of starting or stopping smoking on plasma clozapine concentration at constant dose reported in different studies. Changes in smoking habit in patients prescribed clozapine require prompt dose adjustment.

In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries

Multiple myeloma genetic alterations have distinct repertoires and prognostic implications in African and european ancestries

Aim/background: The use of clozapine is restricted due to its serious side effects, particularly bone marrow suppression, which occurs at an average rate of 1%. These side effects are markedly related to blood concentrations of clozapine and its metabolite nor-clozapine. Therefore, therapeutic drug monitoring is recommended for clozapine. Currently, laboratory monitoring of bone marrow suppression includes neutrophil count follow-up. However, using early-changing biomarkers may be more effective in detecting and preventing this side effect before neutropenia develops. Therefore, we aimed to evaluate serum clozapine and nor-clozapine levels and their relationship with early parameters reflecting bone marrow activity in complete blood count (CBC), immature granulocyte (IG) for neutrophils, mean platelet volume (MPV) and platelet-to-large cell ratio (P-LCR) for platelets in patients with schizophrenia receiving clozapine. Methods: Fifty-one patients with schizophrenia receiving clozapine were included in the study. Of these, 49% (n=25) were on a low dose (&lt;300 mg/day), 49% (n=25) on a middle dose (300-600 mg/day), and one patient was on a high dose (&gt;600 mg/day) clozapine. CBC parameters—especially IG, MPV and P-LCR—and serum clozapine/nor-clozapine levels along with clozapine doses were recorded on the same day. The relationship between serum drug concentrations and CBC parameters was evaluated separately for the total patients and dose groups. Results: There was no correlation between clozapine dose and serum clozapine or nor-clozapine concentrations. None of the patients had neutropenia or agranulocytosis. Serum clozapine and nor-clozapine levels negatively correlated with P-LCR (r=-0.402, p=0.006 and r=-0.465, p=0.001, respectively) and MPV (r=-0.294, p=0.036 and r=-0.397, p=0.004, respectively); positively correlated with neutrophil (r=0.381, p=0.011 and r=0.387, p=0.009, respectively) and IG counts (r=0.346, p=0.018 and r=0.335, p=0.023, respectively); but not with other CBC sub-parameters. Although the clozapine dosing differed between the two groups, the serum levels of clozapine and nor-clozapine were not significantly different (p=0.078 and p=0.058, respectively). Furthermore, in the middle dose group, serum clozapine and nor-clozapine levels were negatively correlated with P-LCR (rho=-0.547, p=0.007 and rho=-0.636, p=0.001, respectively), consistent with the total group. Conclusion: Monitoring early biomarkers reflecting bone marrow activity, such as P-LCR for platelets and IG for neutrophils, alongside serum clozapine and nor-clozapine levels, is promising for predicting and preventing bone marrow suppression in patients receiving clozapine, thereby protecting against this serious side effect. However, our findings need to be supported by further research.

Trabeculectomy in African ancestry individuals with primary open angle glaucoma (POAG) shows a 46% success rate and frequent complications, indicating that younger age and family history are significant predictors of surgical failure in this high-risk population. To investigate outcomes of trabeculectomy ab externo in African ancestry POAG patients and to analyze the impact of demographic and phenotypic factors on surgical success and complication rates. A retrospective case-control study enrolled 63 eyes of 55 POAG cases who underwent trabeculectomy ab externo. Data on demographics, family glaucoma history, surgical specifics, and pre/postoperative measures (intraocular pressure, visual acuity, visual field, medication usage, complications within 1 year) were collected. The analysis included linear/logistic regression models adjusting for inter-eye correlation. Trabeculectomy yielded success without additional medication in 46%, qualified success with medication in 22%, and surgical failure necessitating further intervention in 32% within 1 year. Subjects experienced a reduction in intraocular pressure (IOP) (46%), daily glaucoma medication (73%), and eye drop usage (67%) 1-year post-trabeculectomy (all P <0.001). However, there was a postoperative decline of 56% in visual acuity (VA) ( P <0.001) and a significant worsening of visual field parameters, including a 14% decrease in mean deviation ( P =0.02) and a 19% decrease in visual field index ( P =0.004). Fifty-nine percent of patient eyes experienced complications within 1 year of surgery. Univariate analysis of predictive factors for surgical outcomes revealed that younger age at surgery ( P =0.01) and family history of glaucoma ( P =0.046) were predictive of lower rates of surgical success. Multivariable analysis revealed worse preoperative VA (OR: 0.79 per 0.1 LogMAR increases, P =0.02) was associated with a lower likelihood of surgical success. This study underscores the low rates of trabeculectomy success and high rates of complications in an African ancestry population with POAG. While the procedure exhibited positive effects on IOP control and medication reduction, our analysis found that multiple factors, particularly age, family history, and worse preoperative VA play crucial roles in influencing surgical success.

Clozapine is recommended for patients with schizophrenia and tardive dystonia (TD); however, the appropriate dose remains unclear. In this case, a low dose (150 mg/day) of clozapine improved refractory TD and further ameliorated psychiatric symptoms. Herein, we report on a 41-year-old female with schizophrenia and TD who was treated with a low clozapine dose. After eight weeks of continuous clozapine at 150 mg/day (16 weeks after clozapine initiation), her TD dramatically improved, and her psychiatric symptoms were relieved. Low clozapine doses could ameliorate refractory TD. However, this effect might require up to several weeks. Clinicians should be patient unless they consider it better to increase the clozapine dose.

Introduction: Multiple Myeloma (MM) is a complex malignancy of plasma cells triggered by immunoglobulin gene rearrangements and well-described hyperdyploidy, accounting for slightly more than 10% of all hematologic cancers. MM is the most common hematologic malignancy in African American population with conspicuous racial disparities in both, mortality rates and incidence in cancer compared to European American. This observation evolved into a central hypothesis that MM has distinct biological differences across different ethnicities with yet unidentified race specific markers of tumor heterogeneity. Clear understanding of these molecular differences among ethnic minorities with MM will fulfill a major unmet medical need and eliminate racial disparity. Methods: We acquired data from the Multiple Myeloma Research Foundation (MMRF) initiated comprehensive longitudinal study (CoMMpass) with an overall goal to profile 1,000 multiple myeloma patients at diagnosis, with multiple follow-up points throughout the course of the disease. To generate population subgroups based on genetic ancestry, we used a population stratification principle component analysis (PCA) and STRUCTURE to stratify myeloma patients by Ancestry Informative Markers. These well-established methods have allowed us to avoid confounders associated with self-reporting, and thus stratify the myeloma samples by genetic ancestry mapped along with anchor populations developed by 1000 genome project. We then assessed mutational frequencies as a function of PCA for each ancestry group using complex bioinformatics algorithms. Results: We confirmed known commonly mutated genes in MM including KRAS, NRAS, FAM46C, and DIS3. Among the most striking and novel observations in our preliminary analysis of CoMMpass data using genetic ancestry and PCA was a significant difference in the frequency of nonsilent mutations in TP53, with a frequency of 7.1% (33/464) in patients clustering within the European ancestry compared to none (0/142) in African ancestry populations. Further analysis of enrichment of differentially mutated key factors within the TP53 pathway showed ATM as another gene with a significantly (p= 0.019) higher mutation frequency in EA PCA 4.7% (22/464) compared to AA PCA 0.7% (1/142). Analysis of clinical outcomes data showed poorer overall survival in patients harboring TP53 alterations. Furthermore, a comprehensive mutation analysis across samples identified a novel candidate PTCHD3 (p = 7.07E-06) with a significantly higher mutation occurrence in patients of African ancestry. Moreover, the frequency of copy number alterations known to be associated with poor prognosis revealed notable, but not significant (p=0.259) lower frequency of 1q gain in tumors from African compared to European descent. Lastly, we also observed a significant (p=0.0157) two-fold increase in early age of onset of MM in patients of African descent compared to those of European descent. Conclusion: CoMMpass has constructed a fruitful discovery environment at nexus of high-resolution next generation deep sequencing with detailed clinical data allowing to elucidate potential ancestral drivers of MM paving the way to personalized treatments. Ultimately, these data may help us further delineate the influence of percent admixture on biological factors that drive differences in incidence and outcomes among multi-ethnic MM patients. Citation Format: Zarko Manojlovic, Austin Christofferson, Gil Speyer, Seungchan Kim, Winnie Liang, Mary Derome, Daniel Auclair, David Craig, Jonathan Keats, John Carpten. Comprehensive analysis of molecular pathogenesis of multiple myeloma by genetic ancestry [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A32.