Eastern State Hospital

ABSTRACT Background Clozapine is the best treatment for treatment-resistant schizophrenia (TRS) but is associated with metabolic adverse drug reactions (ADRs). Research Dosing/Methods The international pharmacovigilance database (VigiBase) uses the information component (IC) as a disproportionality analysis. On 1 July 2024, we studied in VigiBase: 1) the myocardial infarction (MI) ICs for antipsychotics and 2) clozapine reports for MI since clozapine’s introduction. After excluding 298 patients with incomplete data, 1490 adults were studied for fatal outcomes using logistic regression with adjusted odds ratios (aOR) and survival analysis. Results Clozapine was associated with the highest IC (IC = 0.903; IC025 = 0.835). Olanzapine (IC = 0.524; IC025 = 0.398) showed a lower but significant association. The ICs for quetiapine, risperidone and haloperidol were non-significant or negative. Mortality in 1490 adult clozapine-treated patients with MI was 68%. Using a baseline age 18–44 years, age 45–64 years had a significant (p < 0.001) aOR = 1.87 with CI 1.43–2.44, while age ≥65 years had a significant (p < 0.001) aOR = 4.07 with CI 2.77–5.97. High clozapine doses (>600 mg/day) displayed an aOR = 2.18 for fatal outcomes. Conclusion A MI IC around 0.9 is higher than that of other antipsychotics, but we cannot rule out that it is explained by TRS present in clozapine-treated patients.

ABSTRACT Objective To develop and validate a population pharmacokinetic (PPK) model of oral olanzapine in pediatric Chinese patients in order to individualize therapy in this population. Methods A total of 897 serum concentrations from 269 pediatric patients taking oral olanzapine (ages 8–17 years) were collected. Demographic parameters, biological characteristics and concomitant medications were investigated as covariates. The data were analyzed using a nonlinear mixed-effects modeling approach. Bootstrapping (1000 runs), normalized prediction distribution error (NPDE), and external validation of 62 patients were employed. Simulations were performed to explore the individualized dosing regimens in various situations. Results The one-compartment model with first-order absorption and elimination had an apparent clearance (CL/F) of 10.38 L/h, a distribution volume (V/F) of 9.41 L/kg and an absorption rate constant (Ka) fixed at 0.3 h−1. The equation was CL∕F (L∕h) = 10.38 × (body weight∕60)0.25 ×1.33 (if male) × 0.71 (if co-occurrence of infection) × 0.51 (if co-therapy with fluvoxamine) × 1.27 (if co-therapy with sertraline) × 1.43 (if co-therapy with valproate). The final model had satisfactory stability, robustness, and predictive ability. The results from a simulation suggested the oral olanzapine doses required for male and female pediatric patients weighing between 40 and 60 kg without co-medication were 10–15 mg/day and 7.5–10 mg/day, respectively, and dosage adjustments should be based on sex and body weight; and co-administrated with valproate, sertraline, or fluvoxamine. Conclusion This model may help individualize optimum dosing of oral olanzapine for pediatric patients.

Keywords: antipsychotic agentsbipolar disorderdrug monitoringpaliperidone palmitatepharmacokineticspsychopharmacologyschizophrenia

ABSTRACT Background The literature associates clozapine with pneumonia/aspiration pneumonia. Research design and methods The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023. Results There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9–38.0; risperidone OR = 18.6, CI, 11.4–30.4; valproic acid, OR = 5.5, CI, 4.5–6.6; and benzodiazepines OR = 5.5, CI, 4.5–6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with 1) very high titration doses, 2) very small doses in Parkinson’s disease, and 3) Japan vs other countries. Conclusions In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients with long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.

ObjectiveAs access to an essential part of clozapine research from the former Union of Soviet Socialist Republics (USSR) states is very limited, quality aspects have not gained attention so far, and harmonization with modern research standards remains unclear. MethodsWe performed a systematic search in PubMed, Embase and scientific indexes from former USSR states for articles published in Russian language till January 2023 (PROSPERO Reg. Number CRD42023386737) and assessed their quality using the modified Strengthening the reporting of observational studies in epidemiology (STROBE)-Checklist. We compared quality aspects for papers published before and after 2000. ResultsA total of 60 papers were considered. Conflicts of interests and funding sources were reported in 5 and 3 (8 % and 5 %) studies respectively; ethical approval was warranted in two studies (3 %). Statistical analysis was performed in 57 (95 %) studies, but statistical methods were described in 21 (35 %) studies. When comparing studies before and after 2000, there was a trend towards improvement for several aspects, with the only significant differences being the objectives' specification (43 vs 83 %, p < 0.003) and the reporting of statistical methodology (0.0 vs 46 %, p < 0.001), which were more frequently available in papers after 2000. ConclusionsClozapine papers in Russian language suffered from severe methodological drawbacks limiting generalizability. Changes regarding standardization, transparency, ethics, and good scientific practice are urgently required. Using reporting checklists and predefining protocols are the first steps towards quality upgrade and accelerate the integration of science from the former USSR states into the world scientific system.

ChatGPT3 is a new artificial intelligence program released on February 13, 2023. The authors tested ChatGPT3 on February 18, 2023, and repeated the test a week later. They used their expertise on the effects of ethnic ancestry in the stratification of clozapine dosing and the new idea that they published in March 2022 that African-Americans need higher clozapine doses because they have higher clozapine clearance. In the first interaction on February 18, ChatGPT3 provided reasonable and very up-to-date information, which included a comment that patients of African ancestry have higher clozapine metabolism. The other 4 interactions became progressively more concerning as we asked ChatGPT3 to provide references to justify the latter statement. ChatGPT3 provided non-existent "references" using articles from real journals, with real authors, false PubMed identifiers, and false titles. Moreover, ChatGPT3 said that the first author wrote in 2003 that African-Americans had higher CYP1A2 activity when that did not happen until 2022. One week later, the second author repeated the same set of questions. This time ChatGPT3 described the opposite, that African-Americans have "lower" CYP1A2 activity and "slower" metabolism. ChatGPT3 provided another set of articles to justify the information; some were real but did not comment on clozapine metabolism in African-Americans while others did not exist. ChatGPT3 provided a mixture of truth, twisted reality, and non-existent "facts." Within one week it defended opposite positions regarding a clinically relevant issue such as using higher or lower clozapine doses in African-Americans.