Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Data sources for drug utilization research in Latin American countries-A cross-national study: DASDUR-LATAM study.

PURPOSE: Drug utilization research (DUR) contributes to inform policymaking and to strengthen health systems. The availability of data sources is the first step for conducting DUR. However, documents that systematize these data sources in Latin American (LatAm) countries are not known. We compiled the potential data sources for DUR in the LatAm region. METHODS: A network of DUR experts from nine LatAm countries was assembled and experts conducted: (i) a website search of the government, academic, and private health institutions; (ii) screening of eligible data sources, and (iii) liaising with national experts in pharmacoepidemiology (via an online survey). The data sources were characterized by accessibility, geographic granularity, setting, sector of the data, sources and type of the data. Descriptive analyses were performed. RESULTS: We identified 125 data sources for DUR in nine LatAm countries. Thirty-eight (30%) of them were publicly and conveniently available; 89 (71%) were accessible with limitations, and 18 (14%) were not accessible or lacked clear rules for data access. From the 125 data sources, 76 (61%) were from the public sector only; 46 (37%) were from pharmacy records; 43 (34%) came from ambulatory settings and; 85 (68%) gave access to individual patient-level data. CONCLUSIONS: Although multiple sources for DUR are available in LatAm countries, the accessibility is a major challenge. The procedures for accessing DUR data should be transparent, feasible, affordable, and protocol-driven. This inventory could permit a comparison of drug utilization between countries identifying potential medication-related problems that need further exploration.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

European Whites May Need Lower Minimum Therapeutic Clozapine Doses Than Those Customarily Proposed.

PURPOSE/BACKGROUND: A nomogram from a British naturalistic study proposed that the clozapine dosing needed to reach a serum concentration of 350 ng/mL ranged from 265 mg/d (female nonsmokers) to 525 mg/d (male smokers). Some European reviews have used these dosing recommendations, which seem greater than what we found in an Italian White sample ranging from 245 mg/d (female nonsmokers) to 299 mg/d (male smokers). Five other published samples of European Whites were added to the Italian sample to estimate clozapine doses recommended for reaching 350 ng/mL. METHODS/PROCEDURES: Average clozapine metabolizers were obtained by eliminating outliers with confounding variables: (1) psychiatric inducers and inhibitors; (2) doses less than 100 mg/d; and (3) when possible, patients with inflammation, obesity, or using oral contraceptives. The study included 1363 average metabolizer European Whites: the Italian sample and 5 new samples. Mean averages that reached serum concentration levels of 350 ng/mL were calculated after stratification by sex and smoking status in each sample. Then, weighted mean averages were obtained by combining the 6 samples. FINDINGS/RESULTS: The estimated weighted mean clozapine dosages ranged from 236 to 368 mg/d (236 mg/d in 218 female nonsmokers, 256 mg/d in 340 male nonsmokers, 357 mg/d in 269 female smokers, and 368 mg/d in 546 male smokers). IMPLICATIONS/CONCLUSIONS: Our recommended dosages are less than those recommended in Europe. Future studies in European Whites need to replicate these recommended doses for average metabolizer patients after sex and smoking stratification and further explore clozapine dosing for those with relevant clinical confounders.

Clozapine safety monitoring and related research in psychiatry and neurology in South America: A scoping review.

The quality and quantity of clozapine safety monitoring considerably differs among South American countries and mainly focus on hematological surveillance. Few studies have been conducted on other clozapine-related adverse effects (ADRs) and mainly refer to case reports and literature reviews. We retrieved thirty-nine publications on clozapine related ADRs others than neutropenia. Studies in Brazil and Venezuela accounted for 67 % of all the publications, and 8 out of 12 countries published 2 or less manuscripts. Only Chile offers serum clozapine level measurement in public institutions. Given the recently recognized role of ethnicity, gender, smoking, obesity drug interactions in optimal clozapine administration, modernization of clozapine clinical use and research in psychiatry and neurology most be broadcasted and stimulated in South American countries.

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.

Clozapine ultrarapid metabolism during weak induction probably exists but requires careful diagnosis. A literature review, five new cases and a proposed definition.

During weak induction (from smoking and/or valproate co-prescription), clozapine ultrarapid metabolizers (UMs) need very high daily doses to reach the minimum therapeutic concentration of 350 ng/ml in plasma; clozapine UMs need clozapine doses higher than: 1) 900 mg/day in patients of European/African ancestry, or 2) 600 mg/day in those of Asian ancestry. Published clozapine UMs include 10 males of European/African ancestry, mainly assessed with single concentrations. Five new clozapine UMs (two of European and three of Asian ancestry) with repeated assessments are described. A US double-blind randomized trial included a 32-year-old male smoking two packages/day with a minimum therapeutic dose of 1,591 mg/day from a single TDM during open treatment of 900 mg/day. In a Turkish inpatient study, a 30-year-old male smoker was a possible clozapine UM needing a minimum therapeutic dose of 1,029 mg/day estimated from two trough steady-state concentrations on 600 mg/day. In a Chinese study, three possible clozapine UMs (all male smokers) were identified. The clozapine minimum therapeutic dose estimated with trough steady-state concentrations >150 ng/ml was: 1) 625 mg/day, based on a mean of 20 concentrations in Case 3; 2) 673 mg/day, based on a mean of 4 concentrations in Case 4; and 3) 648 mg/day, based on a mean of 11 concentrations in Case 5. Based on these limited studies, clozapine UMs during weak induction may account for 1-2% of clozapine-treated patients of European ancestry and <1% of those of Asian ancestry. A clozapine-to-norclozapine ratio <0.5 should not be used to identify clozapine UMs.

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).

Tasas de suicidio y concentración de litio en agua corriente en Rocha y Montevideo: primer estudio en Uruguay, período 2019-2020 / Suicide rates and lithium concentration in tap water in Rocha and Montevideo: first study in Uruguay, period 2019-2020 / Taxas de suicídio e concentração de lítio na água encanada em Rocha e Montevidéu: primeiro estudo no Uruguai, período 2019-2020

El suicidio es un fenómeno que además de las pérdidas humanas que involucra, repercute negativamente en familiares y allegados, produciendo a su vez enormes gastos en el sistema sanitario. En Uruguay, la tasa de suicidio no solo ha experimentado un aumento sostenido, representando una preocupación constante para las autoridades, sino que suele ser una de la más altas de Latinoamérica, en 2022 fue de 23,08 cada 100.000 habitantes. Reconociendo que el suicidio es un fenómeno multifactorial grave, diversos estudios han indagado sobre la posible correlación entre la presencia de litio en agua corriente y tasas de suicidio, habiéndose observado una relación inversa, lo que permitiría considerar el litio como eventualmente protector de la conducta suicida. El presente estudio pretende abordar dicha correlación en los departamentos de Rocha y Montevideo, de Uruguay. Los resultados obtenidos no son concluyentes. En cuanto a las concentraciones de litio presentes en agua corriente, en general son menores a las señaladas en otros estudios como protectoras (30 µ/L). Es necesario profundizar en este eje de discusión, como en otros, para obtener un diagnóstico más detallado de este complejo y sentido fenómeno.

Suicide is a phenomenon that, in addition to the human losses it involves, has a negative impact on family members and acquaintances, leading to enormous costs in the healthcare system. In Uruguay, the suicide rate has not only experienced a sustained increase, representing a constant concern for authorities, but it also tends to be one of the highest in Latin America, reaching 23.08 per 100,000 inhabitants in 2022. Recognizing that suicide is a serious multifactorial phenomenon, several studies have investigated the possible correlation between the presence of lithium in tap water and suicide rates, noting an inverse relationship. This suggests that lithium could potentially be considered protective against suicidal behavior. This study aims to address this correlation in the departments of Rocha and Montevideo, Uruguay. The results obtained are inconclusive. Regarding the concentrations of lithium present in tap water, they are generally lower than those indicated in other studies as protective (30 µg/L). It is necessary to delve deeper into this axis of discussion, as in others, to obtain a more detailed diagnosis of this complex and profound phenomenon.

O suicídio é um fenómeno que, além das perdas humanas que envolve, tem um impacto negativo nos familiares e amigos, produzindo enormes gastos no sistema de saúde. No Uruguai, a taxa de suicídio não só tem registado um aumento sustentado, representando uma preocupação constante para as autoridades, mas geralmente é uma das mais altas da América Latina, sendo de 23,08 por 100.000 habitantes em 2022. Reconhecendo que o suicídio é um fenómeno multifatorial grave, vários estudos têm investigado a possível correlação entre a presença de lítio na água encanada e as taxas de suicídio; observa-se uma relação inversa, o que permitiria considerá-lo como um possível protetor do comportamento suicida. O presente estudo visa abordar esta correlação nos departamentos de Rocha e Montevidéu no Uruguai. Os resultados obtidos não são conclusivos. Quanto às concentrações de litio presentes na água corrente, são geralmente inferiores às indicadas em outros estudos como protetoras (30 µ/L). É necessário aprofundar esta área de discussão como em outras linhas de pesquisa, e obter um diagnóstico mais detalhado deste fenômeno complexo e significativo.

Population Pharmacokinetics of Clozapine and Norclozapine and Switchability Assessment between Brands in Uruguayan Patients with Schizophrenia.

Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.

Seguridad del paciente: análisis de la prescripción en adultos mayores de una policlínica de salud mental del Hospital Vilardebó, Uruguay / Patient safety: analysis of prescriptions in older adults in a Mental Health Outpatient Clinic at Vilardebó Hospital, Uruguay / Segurança do paciente: análise da prescrição em idosos de uma Policlínica de Saúde Mental do Hospital Vilardebó, Uruguai

Introducción: los pacientes con 65 años o más, por su condición fisiológica, tienen mayor probabilidad de estar expuestos a reacciones adversas a medicamentos. Algunos riesgos están asociados a la carga anticolinérgica de la medicación, y otros al perfil de seguridad de cada uno de los fármacos. Objetivo: realizar un análisis de los tratamientos farmacológicos para los pacientes ≥65 años y su posible implicancia en la clínica, por los riesgos potenciales debido a reacciones adversas. Método: se realizó un estudio descriptivo, transversal, observacional, naturalístico, del tratamiento farmacológico de los pacientes ≥65 años de la policlínica del Hospital Vilardebó, entre mayo y agosto de 2021. Se calculó la carga anticolinérgica de los tratamientos y se efectuó una comparación de dicha carga con la de una muestra de pacientes menores de 65 años. Resultados: 356 pacientes (83,0%) ≥65 años tenían un riesgo alto de tener algún efecto por su carga anticolinérgica y este riesgo fue similar a los pacientes menores de 65 años. Un total de 344 pacientes estaban en tratamiento con alguna benzodiazepina, destacándose el uso de flunitrazepam (47,6%) y clonazepam (32,6%). A 289 pacientes (67,4%) se le prescribió algún antipsicótico y nueve pacientes estaban con más de dos antipsicóticos. Dos pacientes estaban en tratamiento con imipramina y 49 pacientes recibían algún antiparkisoniano. Conclusiones: los pacientes mayores de 65 años están expuestos a riesgos altos de padecer reacciones adversas a medicamentos como consecuencia de una alta carga anticolinérgica (similar a la de la población más joven estudiada) y de una acentuada polifarmacia. Además, se deberían evitar algunas prácticas, como la prescripción de ciertos tipos de benzodiacepinas, así como minimizar el uso de imipramina y antiparkisonianos. Es necesario buscar estrategias de formación que disminuyan o minimicen este potencial riesgo que repercute adversamente en la salud de los pacientes.

Summary: Introduction: patients aged 65 years or older are at increased risk for exposure to adverse drug reactions because of their physiological status. Some risks are associated with the anticholinergic burden of medication, and others with the safety profile of each drug. Objective: to perform an analysis of pharmacological treatments for patients aged 65 years old or older and their possible clinical implications, given the potential risks of adverse drug reactions. Method: a descriptive, cross-sectional, observational, naturalistic, observational study of the pharmacological treatment of users aged 65 years old or older of the outpatient service at Vilardebó Hospital, between May and August 2021, was performed. A calculation was made of the anticholinergic burden of treatments and a comparison of this burden was made with a sample of patients under 65 years of age. Results: 356 patients (83.0%) ≥ 65 years old were at high risk of having some kind of effect from their anticholinergic burden and this risk was similar to patients younger than 65 years. A total of 344 patients were in treatment with a benzodiazepine. The prescription of flunitrazepam (47.6%) and clonazepam (32.6%) stood out. While 289 patients (67.4%) were in treatment with an antipsychotic, 9 patients were on more than 2 antipsychotics. Two patients were on imipramine and 49 patients were in treatment with some antiparkinsonian drugs. Conclusions: patients older than 65 years old are exposed to a high risk of suffering adverse drug reactions as a consequence of a high anticholinergic load (similar to that of the younger population studied) and a marked polypharmacy. In addition, some practices should be avoided, such as the prescription of certain types of benzodiazepines used in this population, as well as minimizing the use of imipramine and antiparkinsonian drugs. It is necessary to look for training strategies to minimize this potential risk that adversely affects the health of patients.

Introdução: pacientes com 65 anos ou mais, devido à sua condição fisiológica, estão mais propensos a serem expostos a reações adversas a medicamentos. Alguns riscos estão associados à carga anticolinérgica do fármaco e outros ao perfil de segurança de cada um dos medicamentos. Objetivo: realizar uma análise dos tratamentos farmacológicos para pacientes ≥ 65 anos de idade e sua possível implicação clínica, devido aos riscos potenciais decorrentes de reações adversas. Método: foi realizado um estudo descritivo, transversal, observacional, naturalístico do tratamento farmacológico de pacientes ≥ 65 anos da Policlínica Hospitalar de Vilardebó, entre maio e agosto de 2021. A carga anticolinérgica dos tratamentos foi calculada e foi feita uma comparação com a de uma amostra de pacientes com menos de 65 anos. Resultados: 356 pacientes (83,0%) ≥ 65 anos apresentaram alto risco de ter algum efeito devido à sua carga anticolinérgica e esse risco foi semelhante aos pacientes com menos de 65 anos. Um total de 344 pacientes estava em tratamento com algum benzodiazepínico, com destaque para o uso de flunitrazepam (47,6%) e clonazepam (32,6%). 289 pacientes (67,4%) receberam algum antipsicótico e 9 pacientes estavam tomando mais de 2 antipsicóticos. Dois pacientes estavam sendo tratados com imipramina e 49 estavam recebendo um antiparkisoniano. Conclusões: pacientes com mais de 65 anos estão expostos a um alto risco de sofrer reações adversas a medicamentos em decorrência de uma carga anticolinérgica elevada (semelhante à da população mais jovem estudada) e de uma polifarmácia acentuada. Além disso, algumas práticas devem ser evitadas, como a prescrição de determinados tipos de benzodiazepínicos que são utilizados nessa população, além de minimizar o uso de imipramina e antiparkinsonianos. É necessário buscar estratégias de formação que reduzam ou minimizem esse risco potencial que afeta negativamente a saúde dos pacientes.

Hyperammonemia associated with valproic acid concentrations.

Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing ß -oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.

Evolución del consumo de antipsicóticos en la Policlínica Psiquiátrica del Hospital Vilardebó / Evolution of antipsychotic consumption in the Psychiatric Polyclinic of Vilardebó Hospital

Los antipsicóticos han demostrado eficaciaen el tratamiento de los trastornos severos y persistentes. La utilización de antipsicóticos se ha incrementado en los últimos años a expensas de los antipsicóticos atípicos. Se realizó un estudio descriptivo, observacional y retrospectivo del consumo de antipsicóticos en la Policlínica Psiquiátrica del Hospital Vilardebó en el período 2009-2015. El consumo de antipsicóticos en el período representa un aumento del 7.7 %. Durante el período en estudio ha ocurrido un leve aumento de pacientes en monoterapia (61,2 %a 65.4 %); la polifarmacia de 2 antipsicóticos se mantiene relativamente estable (27.5 % a 28.3 %); la polifarmacia de más de 2 antipsicóticos ha disminuido (11.3 % a 7.2 %). La polifarmaciatiene casi el mismo impacto en el gasto que la monoterapia.

Antipsychotics have shown efficacy in the treatment of severe and persistent disorders. The use of antipsychotics has increased in recent years at the expense of atypical antipsychotics. A descriptive, observational and retrospective study of the antipsychotic consumption in the Psychiatric Polyclinic of the Hospital Vilardebó in the 2009-2015 period was carried out. The consumption of antipsychotics in the period represents an increase of 7.7%. During the study period there has been a slight increase in patients on monotherapy (61.2% to 65.4%); the polypharmacy of 2 antipsychotics remains relatively stable (27.5% to 28.3%); the polypharmacy of more than 2 antipsychotics has decreased (11.3% to 7.2%). Polypharmacy has almost the same impact on spending as monotherapy.

Correlación de las concentraciones plasmáticas de clozapina con el síndrome metabólico / Correlation of plasma concentrations of clozapine with the metabolic syndrome

La clozapina ha demostrado ser el antipsicóticomás efectivo para la esquizofrenia resistente, perotambién está vinculada con un mayor riesgo de producir alteraciones metabólicas en los pacientes. Se realizó un estudio prospectivo de pacientes de la Policlínica del Hospital Vilardebó donde se correlacionaron las siguientes variables: dosis diaria de clozapina, concentración plasmática de clozapina y su principal metabolito norclozapinaa predosis, cociente metabólico clozapina/norclozapina, sexo, edad, estatus fumador, duración del tratamiento con clozapina, marca comercialde clozapina utilizada, comedicación con ácido valproico, comedicación con antipsicóticos, comedicación con litio y consumo de café enrelación con el síndrome metabólico (definido porla Asociación Latinoamericana de Diabetes). Laúnica covariable significativa como dependiente del síndrome metabólico fue la concentración plasmática en valle de clozapina. El modelo que se encontró para dicha explicación es el siguiente: P(SM)=Exp(-1.69+0.00358*CZP)/((1+Exp(-1.69+0.00358*CZP)). A mayores concentraciones de clozapina el riesgo de síndrome metabólico aumenta. Esto puede tener implicancias en la clínica, ya que a pacientes con altas concentraciones de clozapina se deberían buscar estrategias para disminuir el impacto metabólico que pueda existir.

Clozapine has proven to be the most effective antipsychotic for resistant schizophrenia, but it is also linked to an increased risk of producing metabolic alterations in patients. A prospective study of patients from the Vilardebó Hospital Polyclinic where the following variables were correlated: daily dose of clozapine, plasma concentration of clozapine and its main metabolite norclozapinaa predose, metabolic ratio clozapine / norclozapine, sex, age, smoking status, duration of the treatment with clozapine, trademark of clozapine used, comedication with valproic acid, comedication with antipsychotics, comedication with lithium and consumption of coffee related to the metabolic syndrome (defined by the Latin American Diabetes Association). The only significant covariate as dependent on the metabolic syndrome was the plasma concentration in clozapine. The model found for this explanation is as follows: P (SM) = Exp (-1.69 + 0.00358 * CZP) / ((1 + Exp (-1.69 + 0.00358 * CZP)) At higher concentrations of clozapine the risk of Metabolic syndrome increases This may have clinical implications, since patients with high concentrations of clozapine should seek strategies to reduce the metabolic impact that may exist.

Experiencia de cambio de marcas comerciales de lamotrigina en una paciente ambulatoria del Hospital Vilardebó / Experience of changing commercial brands of lamotrigine in an outpatient of the Vilardebó Hospital

Se desarrolló una experiencia en una pacientede cambio entre dos marcas comerciales de lamotrigina: Lamictal (referencia) y Epilepax (test). Esto fue motivado por notificaciones sobre sospecha de falta de eficacia de una de las citadas presentaciones farmacéuticas utilizada en el Hospital Vilardebó. Se realizó la comparación de las curvas salivales de lamotrigina versus tiempo para las dos marcas, determinándose parámetros clínicos, farmacocinéticos y de seguridad. La experiencia de cambio entre las dos marcas en la paciente no evidenció diferencias en ninguno de los parámetros mencionados.

An experience was developed in a patient of change between two commercial brands of lamotrigine: Lamictal (reference) and Epilepax (test). This was motivated by notifications on suspicion of lack of efficacy of one of the aforementioned pharmaceutical presentations used in the Vilardebó Hospital. The comparison of salivary curves of lamotrigine versus time for the two brands was made, determining clinical, pharmacokinetic and safety parameters. The experience of change between the two brands in the patient did not show any differences in any of the mentioned parameters.

Antidepresivos: controversia sobre su eficaciaen el trastorno depresivo mayor / Antidepressants: controversy over its efficacy in major depressive disorder

En los últimos años se ha observado un aumento sistemático del consumo de antidepresivos. Sin embargo, la eficacia en el tratamiento del trastorno depresivo mayor es objeto de debate. El objetivo del presente trabajo es analizar algunos factores que hacen a la construcción de la evidencia. Se presentan algunos estudios que han tenido impacto y controversia en este tema.

In recent years there has been a systematic increase in the use of antidepressants. However, efficacy in the treatment of major depressive disorder is the subject of debate. The objective of this paper is to analyze some factors that make the construction of evidence. Some studies that have had impact and controversy on this topic are presented.

Consumo de benzodiazepinas en la población uruguaya: un posible problema de salud pública / Consumption of benzodiazepines in the Uruguayan population: a possible public health problem

Resumen Objetivo: conocer el consumo de benzodiazepinas en Uruguay entre 2010 y 2012. Material y método: se realizó un estudio de utilización de medicamentos para evaluar el consumo de benzodiazepinas usando la dispensación de las farmacias de las instituciones participantes. Se utilizó la variable dosis diaria definida (DDD) por 1.000 habitantes/día (DHD). Se compararon las DHD anuales según el perfil hipnótico o ansiolítico y el subsector de asistencia, público o privado. Resultados: se incluyó el 62% de la población uruguaya. Las DHD globales de benzodiazepinas para los años 2010, 2011 y 2012 fueron 74,97, 75,17 y 71,14 DDD/1.000 personas/día, respectivamente (promedio 73,76). La benzodiazepina ansiolítica más consumida en el período analizado fue alprazolam (promedio 25,09). La benzodiazepina hipnótica más consumida fue flunitrazepam (promedio 18,69). Incluyendo clonazepam, esta fue la benzodiazepina más consumida (promedio 36,51) y los valores de consumo global aumentan a 106,36, 110,86 y 113,61 DDD/1.000 personas/día, respectivamente (promedio 110,28). Clonazepam fue la que presentó mayor incremento (35,29%), mientras que midazolam (-46,15%) y diazepam (-18,83%) fueron las que descendieron en mayor medida. El subsector público contribuyó principalmente al consumo global y el privado fue el que mayor aumento porcentual tuvo. Conclusión: Uruguay presenta un elevado consumo de benzodiazepinas, similar al hallado en otros países, pudiendo constituir un problema de salud pública. Este dato constituye el primero disponible en nuestro país y será útil para realizar futuras comparaciones. Es necesario implementar estrategias a nivel nacional que favorezcan un uso racional de benzodiazepinas.

Abstract Objective: To quantify and evaluate benzodiazepines consumption in Uruguay between 2010 and 2012. Method: A study of utilization of drugs was conducted to assess benzodiazepines consumption in our population. Drug utilization data refers to oral benzodiazepines dispensed by the pharmacy departments from the participating health institutions. The unit of measurement was the defined daily doses (DDD) per 1000 inhabitants per day (DHD). DHD of hypnotic and anxiolytic benzodiazepines and DHD from public and private health care institutions were compared. Results were described as absolute values and percentage of changes. Results: Sixty two percent of the Uruguayan population was included in the study. Global DHD for 2010, 2011 and 2012 were 74.97, 75.17 and 71.14 (mean 73.76) DDD/1000 inhabitants/day respectively. Alprazolam was the most widely consumed anxiolytic benzodiazepine (mean 25.09) and flunitrazepam was the most commonly consumed hypnotic benzodiazepine (mean 18.69). If clonazepam is included, it becomes the most commonly consumed benzodiazepine (mean 36.51) and global DHD increases up to 106.36, 110.86 and 113.61 (mean 110.28) DDD/1000 inhabitants/day respectively. Clonazepam showed the higher consumption increase from 2010 to 2012 (35.29%), while the use of midazolam (-46.15%) and diazepam (-18.83%) gradually decreased. Public health institutions were responsible for most of the general consumption, whereas private institutions showed the higher increase in benzodiazepines consumption during the evaluated period. Conclusions: Uruguay showed high benzodiazepines consumption, similar to that reported by other countries and it seems to be an issue of public health concern. These are the first available benzodiazepines consumption data in our country and will be useful to perform future comparisons.

Resumo Objetivo: conhecer o consumo de benzodiazepinas no Uruguai no período 2010-2012. Material e método: foi realizado um estudo sobre a utilização de medicamentos para avaliar o consumo de benzodiazepinas usando a dispensação nas farmácias das instituições participantes. A variável dose diária definida (DDD) por 1.000 habitantes/dia (DHD) foi utilizada. As DHD anuais foram comparadas segundo o perfil, hipnótico ou ansiolítico, e subsector de assistência, público ou privado. Resultados: 62% da população uruguaia foi incluída. As DHD globais de benzodiazepinas para os anos 2010, 2011 e 2012 foram 74,97, 75,17 e 71,14 DDD/1.000 pessoas/dia, respectivamente (média 73,76). A benzodiazepina ansiolítica mais consumida no período analisado foi alprazolam (média 25,09) e a hipnótica com maior consumo foi flunitrazepam (média 18,69). Incluindo clonazepam, esta foi a benzodiazepina mais consumida (média 36,51) e os valores de consumo global aumentam a 106,36, 110,86 e 113,61 DDD/1.000 pessoas/dia, respectivamente (média 110,28). O clonazepam foi a que apresentou o maior incremento (35,29%), sendo que o midazolam (-46,15%) e o diazepam (-18,83%) as que apresentaram uma maior redução de consumo. O subsector público contribuiu principalmente ao consumo global e o privado o que apresentou o maior aumento porcentual. Conclusão: o Uruguai apresenta um consumo elevado de benzodiazepinas, similar ao descrito em outros países, podendo ser um problema de saúde pública. Estes dados são os primeiros disponíveis no nosso país e serão úteis para futuras comparações. É necessário implementar estratégias a nível nacional que favoreçam um uso racional de benzodiazepinas.

Prescripción de antipsicóticos al egreso hospitalario durante el período abril-setiembre de 2012 en el Hospital Vilardebó de Montevideo, Uruguay / Prescribing antipsychotics to hospital discharge during the period April-September 2012 Vilardebó Hospital in Montevideo, Uruguay

Las guías clínicas recomiendan la monoterapia antipsicótica (mta). La polifarmacia antipsicótica (pfa, uso concomitante de dos o más antipsicóticos) es una práctica clínica frecuente. El objetivo del trabajo fue determinar el perfil de prescripción antipsicótica y su uso en mta o pfa, al egreso hospitalario durante el período abril setiembre de 2012 en el Hospital Vilardebó. Se realizó un estudio descriptivo, observacional y retrospectivo. Las variables estudiadas fueron sexo, edad, medicación y diagnóstico. Se definió mta para los que egresaron con un antipsicótico y pfa para aquellos que egresaron con dos o más antipsicóticos. El 52 % egresó con mta, de los cuales el 42% recibió un antipsicótico atípico y el 10%, uno típico. El 48 % restante egresó con dos o más antipsicóticos (pfa). El 19 % de los pacientes con pfa egresó con tres o más antipsicóticos. Es elevado el uso de pfa al egreso hospitalario.

Notas de farmacología: estudios de disolución de medicamentos del sistema nervioso central / Pharmacology notes: drug dissolution studies of the central nervous system

El propósito de los estudios in vitro es comparar las características de liberación del principio activo contenido en una forma farmacéutica sólida oral mediante la cantidad, o porcentaje de la dosis, disuelta en función del tiempo en condiciones controladas y validadas. Se realizó una comparación de disolución in vitro de flunitrazepam (Rohypnol®, Somnidual® e Inervon®) y de lamotrigina (Lamictal® y Epilepax®). Para los perfiles de disolución de flunitrazepam, una de las marcas comerciales tuvo un perfil de disolución muy diferente a las otras dos marcas. Para el caso de lamotriginano existió diferencia para aquellos pH que se consideran fundamentales para la disolución del comprimido en el tracto gastrointestinal. Los resultados obtenidos de los estudios in vitro son simplemente orientadores, permiten tan solo guiar la puesta en marcha del ensayo de bioequivalencia entre el test evaluado in vitro y la referencia utilizada en el mismo ensayo. No obstante, estos resultados pueden constituirse en un elemento de apoyo a la presunción de bioinequivalencia como causa de un evento adverso (ineficacia o toxicidad) detectado en los programas de farmacovigilancia actualmente en marcha.