Pharmacovigilance in Action: Utilizing VigiBase Data to Improve Clozapine Safety.

Purpose: Clozapine is an antipsychotic which was approved in 1989 for treatment-resistant schizophrenia in the United States (US). There were few randomized trials before its approval and potentially lethal clozapine adverse drug reactions (ADRs), such as agranulocytosis and myocarditis were identified by pharmacovigilance. VigiBase, the WHO global database, is a cornerstone of international pharmacovigilance efforts for ADR identification during post-marketing surveillance.

Clozapine for persons with neurodevelopmental disorders: a systematic review and expert recommendations for clinical practice.

Introduction: We aimed to synthesize the information on the risks and benefits of clozapine prescription for resistant challenging behavior in persons with neurodevelopmental disorders.

Methods: Articles were identified with MEDLINE, Web of Sciences, and PsycINFO search from inception through January 2024. The review was restricted to persons with intellectual disability (ID) and/or autism spectrum disorder (ASD) without comorbid psychotic or affective disorder.

How can we better address the pharmacokinetics of antipsychotics in children and adolescents?

Introduction: Despite a steady increase of antipsychotic prescriptions in children and adolescents, knowledge about pharmacokinetics and dosing of antipsychotics in children and adolescents remains limited.

Areas Covered: We discuss seven issues with major impact on the pharmacokinetics of antipsychotics in youth: estrogens, ii) obesity, iii) ethnicity, iv) smoking, v) inflammation, vi) drug-drug interactions (DDIs), and vii) pharmacogenetics. Despite their major impact, these issues have not been adequately considered in the context of dosing algorithms for antipsychotics in youth.

Optimizing co-prescription of clozapine and antiseizure medications: a systematic review and expert recommendations for clinical practice.

Introduction: Antiseizure medication (ASM) add-on to clozapine may be efficient to target clozapine-resistant mood or psychotic symptoms or clozapine-related adverse drug reactions (ADR) such as seizures. We aimed to synthesize the information relevant for clinical practice on the risks and benefits of clozapine-ASM co-prescription.

Areas Covered: Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through October 2023.

Can Slow Personalized Titration Using C-Reactive Protein Monitoring Decrease the High Rates and Mortality of Clozapine-Associated Myocarditis Seen in Some Countries? A Call for Research.

Purpose/background: The hypothesis that slower personalized titration may prevent clozapine-associated myocarditis and decrease the disproportion incidence of 3% found in Australia was not described in a recent Australian article in this journal.

Methods: Six countries in addition to Australia have published information suggesting a similar incidence of clozapine-associated myocarditis. On September 19, 2023, PubMed searches were updated for articles from the United States, Korea, Japan, Canada, New Zealand, and Turkey.

Promoting safer and wider worldwide use of clozapine.

This issue focuses on the past, the present and the future of clozapine. Of the 43 clozapine articles, nine are historical articles dealing with the past, 29 deal with the present and five with laboratory assays which may influence its future use. These 43 articles include 219 different authors from 56 countries/regions and five continents.

Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK.

Background: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs).

Objective: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality.

A Systematic Review of Clozapine Concentration-Dose Ratio from Therapeutic Drug Monitoring Studies in Children and Adolescents Treated with Clozapine for Mental Disorders.

Background: Therapeutic drug monitoring of clozapine in children and adolescents has received insufficient attention. Calculation of concentration-to-dose (C/D) ratios from trough steady-state concentrations estimate drug clearance.

Methods: A systematic electronic literature search was conducted in 3 article databases from inception until January 10, 2023, and articles reporting clozapine concentrations in children and adolescents were retrieved.

An expert review of clozapine in Latin American countries: Use, monitoring, and pharmacovigilance.

There is growing interest in clozapine clinical use, monitoring, and research, particularly adverse drug reactions (ADRs) other than agranulocytosis. In this study we focused on clozapine pharmacovigilance. Hence, we contacted clinicians and researchers in Latin America and requested information about local psychiatric services, clozapine availability, clinical use, and ADR monitoring with the VigiBase system.

Clozapine-associated pericarditis and pancreatitis in children and adolescents: A systematic literature review and pharmacovigilance study using the VigiBase database.

Background: The literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents.

Methods: Cases of clozapine-associated pericarditis and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC).

Clozapine research standards in former USSR states: A systematic review of quality issues with recommendations for future harmonization with modern research standards.

Objective: As 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.

Methods: We 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.

Optimizing antidepressant and clozapine co-prescription in clinical practice: A systematic review and expert recommendations.

Objectives: To synthesize the information relevant for clinical practice on clozapine-antidepressant co-prescription concerning pharmacokinetic drug-drug interactions (DDI), adverse drug reactions (ADRs) associated with the co-prescription, antidepressant add-on for clozapine-resistant symptoms and antidepressant add-on for clozapine-induced ADRs.

Methods: Articles were identified with MEDLINE, Web of Sciences and PsycINFO search from inception through April 2023. Data were synthesized narratively.

A Chinese medicine called Danggui Longhui may be a new clinically relevant clozapine inducer: Two case reports identified by therapeutic drug monitoring.

Background: Danggui Longhui is a traditional Chinese medicine made from the dried root of Angelica sinensis. It is used in psychiatric patients in China to reduce associated constipation. In a population pharmacokinetic model in olanzapine patients from Beijing Anding Hospital, we demonstrate that dangguilonghui tablets doubled olanzapine clearance, indicating the induction of olanzapine metabolism.

The introduction of clozapine at the Nathan Kline Institute in New York and its long-term consequences.

Nathan S. Kline was a pioneer in psychopharmacology in the United States (US). In 1952, Kline started a research unit at Rockland State Hospital, New York.

Will ChatGPT3 Substitute for us as Clozapine Experts?

Background: ChatGPT3 is a new artificial intelligence program released on February 13, 2023.

Method: 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.

Brief report: Revealing the nuance: Examining approaches for research with adolescents who identify with multiple racial/ethnic groups.

Introduction: Increasing racial/ethnic diversity in the United States calls for methodological approaches that capture participants who identify with multiple racial/ethnic groups. Existing approaches are oriented toward large samples (N > 500); yet, we do not know how effective these approaches are with more common smaller convenience samples. We explored how several approaches were associated with the sample distribution of racial/ethnic groups and ethnic identity using a small convenience sample.