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).

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.

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.

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.

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.