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. FINDINGS/RESULTS: An incidence of 3.5% (4/76) was found in a US hospital, but US experts were the first to propose that clozapine-associated myocarditis may be a hypersensitivity reaction associated with rapid titration and possibly preventable. Koreans and Japanese are of Asian ancestry and need lower minimum therapeutic doses for clozapine than patients of European ancestry. A 0.1% (2/1408) incidence of myocarditis during clozapine titration was found in a Korean hospital, but pneumonia incidence was 3.7% (52/1408). In 7 Japanese hospitals, 34% (37/110) of cases of clozapine-associated inflammation were found during faster titrations (based on the official Japanese titration) versus 13% (17/131) during slower titrations (based on the international titration guideline for average Asian patients). Recent limited studies from Canada, New Zealand, and Turkey suggest that slower personalized titration considering ancestry may help prevent clozapine-associated myocarditis. IMPLICATIONS/CONCLUSIONS: Other countries have very limited published data on clozapine-associated myocarditis. Based on a recent Australian case series and these non-Australian studies, the author proposes that Australia (and other countries) should use slow personalized titration for clozapine based on ancestry and c-reactive protein monitoring.

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. The review was restricted to ASM with mood-stabilizing properties or with potential efficacy for resistant psychotic symptoms (valproate (VPA), lamotrigine, topiramate, carbamazepine, oxcarbazepine). EXPERT OPINION: VPA add-on to clozapine is associated with a high risk of serious ADR (myocarditis, neutropenia, pneumonia) mostly explained by complex time-dependent drug-drug interactions. The initial inhibitory effects on clozapine metabolism require slow titration to avoid immuno-allergic reactions. After the titration period, VPA has mainly inductive effects on clozapine metabolism that are more marked in smokers requiring therapeutic drug monitoring. Lamotrigine and topiramate add-on may be recommended as the first-line treatment for clozapine-related seizures, but there is limited evidence regarding the efficacy of this strategy for clozapine-resistant psychotic symptoms. Carbamazepine should not be co-prescribed with clozapine because of its potential for agranulocytosis and for inducing clozapine metabolism.

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.

Task Sharing and Remote Delivery of Brief Interpersonal Counseling for Venezuelan Migrants and Refugees Living in Peru during the COVID-19 Pandemic: A Mixed-Methods Pilot Study.

Refugees and migrants experience an elevated risk for mental health problems and face significant barriers to receiving services. Interpersonal counseling (IPC-3) is a three-session intervention that can be delivered by non-specialists to provide psychological support and facilitate referrals for individuals in need of specialized care. We piloted IPC-3 delivered remotely by eight Venezuelan refugee and migrant women living in Peru. These counselors provided IPC-3 to Venezuelan refugee and migrant clients in Peru (n = 32) who reported psychological distress. Clients completed assessments of mental health symptoms at baseline and one-month post-intervention. A subset of clients (n = 15) and providers (n = 8) completed post-implementation qualitative interviews. Results showed that IPC-3 filled a gap in the system of mental health care for refugees and migrants in Peru. Some adaptations were made to IPC-3 to promote its relevance to the population and context. Non-specialist providers developed the skills and confidence to provide IPC-3 competently. Clients displayed large reductions in symptoms of depression (d = 1.1), anxiety (d = 1.4), post-traumatic stress (d = 1.0), and functional impairment (d = 0.8). Remote delivery of IPC-3 by non-specialists appears to be a feasible, acceptable, and appropriate strategy to address gaps and improve efficiency within the mental health system and warrants testing in a fully powered effectiveness study.

Mal control y elevado riesgo cardiovascular en hipertensos de una universidad

Introducción: La hipertensión arterial es una enfermedad de alta prevalencia y complicaciones mortales. Debido a ello, se necesitan un adecuado manejo en la atención primaria y estrategias preventivas y de intervención, como la iniciativa HEARTS en las Américas. Se sabe también que entre los trabajadores de la Universidad de Ciencias Médicas de Matanzas existe una elevada prevalencia de hipertensos. Objetivo: Identificar el comportamiento del control de la enfermedad y la estratificación de riesgo cardiovascular global. Materiales y métodos: Estudio descriptivo transversal en el que se incluyeron los primeros 80 pacientes hipertensos valorados en la consulta de la mencionada institución. Los métodos empleados fueron el analítico-sintético, el inductivo-deductivo, el histórico-lógico y los estadísticos. Resultados: De 808 trabajadores, 276 eran hipertensos, para una prevalencia de 34,1 %. Dentro de los inadecuados estilos de vida, predominó el sedentarismo, con 59 pacientes (73,7 %); 40 de los 80 pacientes estudiados tenían un riesgo cardiovascular cuantitativo igual o mayor del 10 %, mientras que el riesgo cardiovascular cualitativo mostró que 68 (85 %) tenían un riesgo medio o alto. Dentro del daño en órganos diana predominaron las enfermedades cardiovasculares, con un 16,2 %. Conclusiones: La hipertensión arterial sigue siendo uno de los factores de riesgo más importantes de enfermedad cardiovascular y cerebrovascular. Su pesquisa, control y estimación del riesgo constituyen una prioridad de la atención médica a nivel primario.

Introduction: Arterial hypertension is a disease of high prevalence and fatal complications. Due to this, an adequate management is needed in the primary care, and also preventive and intervention strategies, as the HEARTS initiative in the Americas. It is also known that there is a high prevalence of hypertensive patients among the working staff of the Matanzas University of Medical Sciences. Objective: To identify the behavior of disease control and global cardiovascular risk stratification. Materials and methods: Cross-sectional descriptive study in which the first 80 hypertensive patients evaluated in the consultation of the aforementioned institution were included. The methods used were analytical-synthetic, inductive-deductive, historical-logical and statistical. Results: Of 808 workers, 276 were hypertensive, for a prevalence of 34.1%. Among the inadequate lifestyles, sedentary lifestyle predominated, with 59 patients (73.7%); 40 of the 80 patients studied had a quantitative cardiovascular risk equal to or greater than 10%, while qualitative cardiovascular risk showed that 68 (85%) had a medium or high risk. Cardiovascular diseases predominated within target organ damage, with 16.2%. Conclusions: Arterial hypertension continuous to be one of the most important risk factors for cardiovascular and cerebrovascular diseases. Its screening, control and risk assessment are a priority of the medical care at the primary level.

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. METHODS: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions. RESULTS: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number. CONCLUSIONS: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.

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). RESULTS: The PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC025 = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC025 = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases. CONCLUSIONS: Despite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration.

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. We compared quality aspects for papers published before and after 2000. RESULTS: A 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. CONCLUSIONS: Clozapine 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.

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. The pharmacokinetic quality of the studies was assessed, and clozapine C/D ratios were calculated using the sample mean clozapine dose and concentration. RESULTS: Of the 37 articles of potential interest, only 7 reported clozapine trough and steady-state concentrations. After excluding case reports and a study confounded by fluvoxamine, 4 studies on psychosis from Europe and the United States were included. The clozapine C/D ratios were similar to published adult values and ranged from 0.82 to 1.24 with a weighted mean of 1.08 ng/mL per mg/d. The weighted means were 334 mg/d for the dose and 380 ng/mL for the concentration. The stratified analysis of the weighted mean clozapine C/D ratios from 2 studies showed lower values in 52 male (1.05 ng/mL per mg/d) than in 46 female (1.46 ng/mL per mg/d) children and adolescents, with values similar to those reported for European adult nonsmokers. Two female adolescents had high clozapine C/D ratios (2.54 ng/mL per mg/d), an Asian American patient with borderline obesity and a patient with intellectual disability with low dosage (mean = 102 mg/d) and concentration (mean = 55 ng/mL). CONCLUSIONS: Reports on clozapine therapeutic drug monitoring in children and adolescents are limited in number and quality. Future studies should focus on basic pharmacokinetic issues, such as stratification by sex, smoking, and relevant comedications with inductive or inhibitory properties.

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. Only two countries have the minimum recommended number of psychiatric beds (15 per 100,000 residents): Uruguay (N = 34.9) and Argentina (N = 17). Bolivia is the only country where clozapine is unavailable. Nine out of twenty countries (45 %) reported ADRs to VigiBase. Argentina, Brazil, Chile, Colombia, and Mexico published national guidelines for schizophrenia treatment. Chile is the sole country with clozapine clinics with drug serum monitoring. Ethnicity-related drug titration in not described in package inserts in any country. We examined in detail the 9 most frequent and important clozapine ADRs in the worldwide database (pneumonia, sudden death, cardiac arrest, agranulocytosis, myocarditis, constipation, arrhythmia, seizure, and syncope). These 9 ADRs led to 294 reports with fatal outcomes in Argentina (N = 3), Brazil (N = 3), Chile (N = 2), and Peru (N = 1). Agranulocytosis was reported from 7 countries: constipation or seizures from 8 countries. Only two countries reported pneumonia and one country reported myocarditis. The number of clozapine reports in VigiBase has no relationship to the country's population. All Latin American countries underreport clozapine associated ADRs. Latin American governments, along with clinicians, researchers, and educators, should optimize clozapine use and monitoring for the benefit of people with severe mental and some neurological disorders.

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. RESULTS: ADRs are most often induced by the co-prescription of antidepressants that inhibit CYP enzymes (fluvoxamine, fluoxetine, paroxetine). Fluvoxamine add-on is hazardous because of its potent inhibition of clozapine metabolism and has few indications (lowering daily number of clozapine tablets, reducing norclozapine-induced metabolic disturbances and other dose-dependent clozapine-induced ADRs). ADR frequency may be reduced by therapeutic drug monitoring and knowledge of other factors impacting clozapine metabolism (pneumonia, inflammation, smoking, etc.). Improvement of negative symptoms is the most documented beneficial effect of antidepressant add-on for clozapine-resistant psychotic symptoms. The add-on antidepressant should be chosen according to its safety profile regarding DDI with clozapine: antidepressants inhibiting clozapine metabolism or increasing the anticholinergic load should be avoided. Other indications of antidepressant add-on (affective or obsessive compulsive symptoms, sialorrhea, and enuresis) are poorly documented. CONCLUSION: Antidepressant add-on to clozapine is associated with potential benefits in clozapine users as this strategy may contribute to reduce the burden of clozapine-resistant symptoms or of clozapine-induced ADRs. Further studies are needed to determine whether antidepressant add-on can reduce the risk of clozapine discontinuation.

An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance.

OBJECTIVES: To compare the prevalence, regulations, and pharmacovigilance practices of clozapine use in Eastern European countries (except Russia). METHODS: Questionnaires and data from administrative databases (2016 and 2021), package inserts and national guidelines were collected from 21 co-authors from 21 countries. Reports of clozapine adverse drug reactions (ADRs) sent to the global pharmacovigilance database (VigiBase™) were analyzed from introduction to December 31, 2022. RESULTS: Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold. CONCLUSION: Clozapine is under-utilized in Eastern European countries. Introducing individualized clozapine treatment schedules may help to maximize clozapine benefits and safety. Major improvement is needed in reporting clozapine ADRs and fatal outcomes in Eastern European countries.

Estrategia metodológica para la prevención de los problemas de salud bucal en la educación primaria

Introducción: Las transformaciones que se evidencian en la sociedad, hace que surjan, en las instituciones educativas, exigencias referidas a la preparación de los profesionales para enfrentar los nuevos desafíos y lograr ciudadanos con una formación integral y responsables con el cuidado de su salud. Ahí es donde ocupan un lugar privilegiado los aspectos relacionados con la prevención de los problemas de salud bucal en la educación primaria. Objetivo: Diseñar una estrategia metodológica para la prevención de los problemas de salud bucal en la educación primaria. Materiales y métodos: La estrategia fue diseñada en cuatro etapas: diagnóstico, planeación, instrumentación, y control y evaluación. Para su elaboración se consideró el diagnóstico realizado en el curso escolar 2021-2022 a tres escuelas primarias pertenecientes al municipio Matanzas. Se definió la variable fundamental de la investigación y, a partir de su operacionalización, se establecieron las dimensiones e indicadores. Se aplicaron métodos del nivel teórico y empírico del conocimiento, así como métodos estadísticos. Resultados: Se evidencian limitadas acciones de preparación metodológica que inciden en el tratamiento a la prevención de los problemas de salud bucal desde el contexto escolar. Para transformar los resultados obtenidos se diseñó la estrategia metodológica. Conclusiones: El diseño de la estrategia metodológica revela una manera novedosa de organizar y realizar actividades en el sistema de trabajo metodológico de la escuela primaria, para contribuir a la preparación metodológica del maestro primario en la temática.

Introduction: The transformations that are evident in society cause to arise, in educational institutions, demands regarding to the training of professionals to face the new challenges and achieve citizens with comprehensive training and responsible with the care of their health. That is where aspects related to the prevention of oral health problems in primary education occupy a privileged place. Objective: To design a methodological strategy for the prevention of oral health problems in primary education. Materials and methods: The strategy was designed in four stages: diagnosis, planning, implementation; and evaluation and control. For its elaboration, the diagnosis carried out during the 2021-2022 school year in three primary schools belonging to the municipality of Matanzas was considered. The fundamental variable of the research was defined and the dimensions and indicators were established, on the basis of its operationalization. Methods of the theoretical and empirical level of knowledge were applied, as well as statistical methods. Results: It is evidenced that methodological preparation actions that have repercussion on the prevention of oral health problems from the school context are not enough. To transform the results obtained, the methodological strategy was designed. Conclusions: The design of the methodological strategy reveals a new way of organizing and carrying out activities in the methodological work system of the primary school, to contribute to the methodological preparation of primary teacher on the topic.

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. RESULTS: 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. CONCLUSIONS: 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.

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. METHODS: In 2017, 320 U.S. adolescents (Mage = 16.04 years, SDage = 1.33; 59% female) responded to an open-ended question regarding their racial/ethnic group(s) in a cross-sectional survey. Seventy-five (23%) adolescents identified with multiple racial/ethnic groups. Remaining adolescents identified solely with the Asian/Hawaiian Native/Pacific Islander (19%), Black/African American (3%), European American (21%), Latinx (34%), or Native American/Alaska Native (<1%) group. RESULTS: Three approaches for adolescents with multiple racial/ethnic groups were employed. Findings indicated that the sample distributions differed across the approaches. The greatest differences were shown for Black/African American, Native American/Alaska Native, and Other Race/Ethnicity groups. Descriptively, ethnic identity also differed across the approaches. For example, multiracial/ethnic adolescents reported greater ethnic identity-exploration than their European American counterparts in one approach than in others. CONCLUSIONS: Researchers should carefully consider approaches to research with adolescents who identify with multiple racial/ethnic groups given implications for the literature. This study demonstrates the critical need to further develop approaches for capturing the complexity of race/ethnicity.

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. Kline brought clozapine from Switzerland since it was not yet available in the US. At Rockland State Hospital, George Simpson had conducted antipsychotic trials and had developed scales to assess movement disorders. In 1974, Simpson published the first US clozapine trial. In 1978, he published on 1) the effect of clozapine on tardive dyskinesia and 2) high plasma clozapine concentrations in two patients with seizures. His experience of clozapine withdrawal symptoms in his first 2 trials led in the future to more articles in this area. In Philadelphia, Simpson designed a double-blind randomized clinical trial (RCT) with 3 doses (100, 300 and 600 mg/day) which was published in 1999. From the 50 patients started on the RCT, 47 provided repeated plasma clozapine concentrations every other week of the RCT. This rich database of plasma clozapine concentrations under controlled conditions has contributed to many of the advances in clozapine pharmacokinetics in the last 5 years including: 1) obesity can be associated with clozapine poor metabolism (PM) status, 2) a clozapine ultrarapid metabolizer (UM) with a minimum therapeutic dose of 1591 mg/day, 3) a case of clozapine intoxication dropped from the RCT due to pneumonia, 4) cases of increased plasma concentrations during clozapine-induced fever, 5) the possibility that African-Americans may need higher clozapine doses than those of European ancestry, and 6) three indices of non-adherence.

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. Olanzapine metabolism is similar to clozapine metabolism. METHODS: Two cases of possible clozapine induction using dangguilonghui tablets 4 g/day were identified in Beijing Anding Hospital. Dividing the minimum therapeutic concentration of 350 ng/mL by the concentration-to-dose (C/D) ratio provides the minimum therapeutic dose. RESULTS: Case 1 was a female smoker on clozapine for 415 days. The mean of 6 clozapine C/D ratios associated with smoking provided a minimum therapeutic dose of 267 mg/day. There were 6 steady-state concentrations on the combination of valproic acid and dangguilonghui tablets, which provided a much higher minimum therapeutic dose of 833 mg/day. Four steady-state clozapine C/D ratios based on smoking and valproate after 4 months of carbamazepine 200 mg/day provided a minimum therapeutic dose of 603 mg/day. Case 2 was a female non-smoker on clozapine for 58 days. She had 3 clozapine C/D ratios on dangguilonghui tablets with a mean of 0.30 ng/mL providing a minimum therapeutic dose of 1167 mg/day. CONCLUSION: Future clinical studies with repeated measures need to replicate the possibility that dangguilonghui tablets are a moderate-to-strong inducer of clozapine metabolism as suggested by these two limited cases.

Etiquetado frontal de advertencia nutricional de alimentos y bebidas pre-envasados. Postura intersectorial de expertos en Centro América y República Dominicana / Front-of-package warning labelling system for pre-packaged foods and beverages: an intersectoral position of expertsin Central American and Dominican Republic

La región latinoamericana ha sido pionera en la implementación del etiquetado frontal de advertencia nutricional (EFAN), mismo que ha demostrado su eficacia y efectividad para identificar correctamente cuando un producto contiene cantidades excesivas de nutrientes asociados a Enfermedades no transmisibles (ENT). Sin embargo, ningún país del Sistema de la Integración Centroamericana (SICA); que incluye a Belice, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panamá y República Dominicana, lo ha adoptado. Por esta razón, el Instituto de Nutrición de Centro América y Panamá, convocó a un grupo de expertos de la academia y la sociedad civil con el objetivo de establecer una postura técnica, basada en la mejor evidencia científica, en relación al etiquetado frontal para los nutrientes críticos de alimentos y bebidas pre- envasados en la región centroamericana. Se presenta evidencia específica de la región del SICA que demuestran la superioridad del EFAN frente a otros etiquetados como las Guías Diarias de Alimentación (GDA), el semáforo y el Nutriscore para seleccionar opciones más saludables. Dentro del marco de los derechos de la niñez y de los consumidores, se brindan argumentos y se hace un llamado a los gobiernos para la pronta adopción del EFAN como una política costo-efectiva para la prevención de ENT. Además, se proveen recomendaciones para su monitoreo y evaluación, así como recomendaciones de otras políticas costo-efectivas como la regulación de la publicidad de alimentos no saludables dirigido a la niñez y adolescencia, entre otros, para la prevención de las ENT y la creación de ambientes y sistemas alimentarios más saludables y sostenibles(AU)

The Latin American region has been a pioneer in the implementation of a front- of-pack warning labeling system (FOPWL), which has demonstrated its efficacy and effectiveness in correctly identifying when a product contains excessive amounts of nutrients associated with Non-Communicable Diseases (NCDs). However, countries of the Central American Integration System (SICA); which includes Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama and the Dominican Republic, have no adopted it. For this reason, the Institute of Nutrition of Central America and Panama convened a group of experts from academia and civil society with the aim of establishing an evidence-based technical position, in relation to front-of-pack labelling for critical nutrients of pre-packaged foods and beverages in the Central American region. Specific evidence from the SICA region demonstrating the superiority of FOPWL over other labels such as the Guideline Daily Amount (GDA), the traffic light and Nutriscore to select healthier choices is presented. Within the framework of children's and consumer rights, arguments are provided, and a call is made to governments for the prompt adoption of FOPWL as a cost-effective policy for the prevention of NCDs. In addition, recommendations for its monitoring and evaluation are provided, as well as recommendations for other cost-effective policies such as the regulation of unhealthy food advertising aimed at children and adolescents, among others, for the prevention of NCDs and the creation ofhealthier and more sustainable environments and food systems(AU)

Exploring low clozapine C/D ratios, inverted clozapine-norclozapine ratios and undetectable concentrations as measures of non-adherence in clozapine patients: A literature review and a case series of 17 patients from 3 studies.

BACKGROUND: Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. METHODS: These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. RESULTS: The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9-11). CONCLUSION: Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented).