Clozapine-Induced Eosinophilia: a Case Report.

INTRODUCTION: Clozapine is an atypical antipsychotic drug eligible for treatment-resistant schizophrenia. It frequently represents the best and the only choice in resistant schizophrenia. However, its use is feared by many professionals due to its possible adverse effects, such as eosinophilia. CASE REPORT: We report a case of a young white male suffering from treatment-resistant schizophrenia who rapidly developed eosinophilia after starting clozapine. DISCUSSION: We present a case of a 26-year-old white man diagnosed with schizophrenia with poor clinical response to several antipsychotics owing to which clozapine was started. Psychotic symptoms improved dramatically but a progressively ascendant eosinophilia was reported during serial haematological analyses. The patient remained physically asymptomatic. An exhaustive assessment with ancillary diagnostic tests revealed no cause for eosinophilia. Thus, a diagnosis of clozapine-induced eosinophilia was made. The drug was discontinued and eosinophil count progressively returned to normal but psychotic symptoms worsened. CONCLUSIONS: Clozapine treatment is frequently feared due to its possible side effects and complications, delaying its use in refractory schizophrenia. Also, to our knowledge, there are no specific guidelines on how to manage haematological side effects such as eosinophilia. This is problematic as, in some cases, it may lead to an unnecessary withdrawal of clozapine with a worsening of psychotic symptoms. We present a brief discussion of the recent literature on the subject.

Schizophrenia and the COVID-19 pandemic: A narrative review from the biomedical perspective.

The outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic in 2020 caused a rapid worsening of global mental health. Patients with severe mental disorders, including schizophrenia, are at higher risk of being infected. The neuroinvasive potential of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has been confirmed. The aim of this article was to present a narrative and comprehensive review of multidimensional associations between schizophrenia and COVID-19 with special emphasis on common biological pathways. Online searches were performed in the PubMed database and covered the publication period until September 17, 2022. Search terms included "psychosis", "schizophrenia", "inflammation" and "COVID-19". Viewed as a neuroinflammatory state, schizophrenia shares several neurobiological mechanisms with the COVID-19. Environmental stress, common comorbidities of schizophrenia and adverse effects of antipsychotic treatment are associated with the higher severity and mortality of the COVID-19. Additionally, more frequent relapses of psychosis have been observed, and might be related to lower treatment adherence. In the context of clinical manifestation, higher level of negative symptoms has been identified among patients with schizophrenia during the pandemic. Improvements in mental health care policy and treatment adjustment are necessary to protect people with schizophrenia who are the population that is particularly vulnerable to the consequences of the COVID-19 pandemic. Future research will show if prenatal infection with the SARS-CoV-2 increases a risk of psychosis.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries.

INTRODUCTION: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. METHODS: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. RESULTS: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005-IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. CONCLUSIONS: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.

Valproate, obesity and other causes of clozapine poor metabolism in the context of rapid titration may explain clozapine-induced myocarditis: A re-analysis of a Turkish case series.

INTRODUCTION: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. METHODS: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. RESULTS: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. CONCLUSIONS: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.

Clozapine-Induced Eosinophilia: a Case Report.

INTRODUCTION: Clozapine is an atypical antipsychotic drug eligible for treatment-resistant schizophrenia. It frequently represents the best and the only choice in resistant schizophrenia. However, its use is feared by many professionals due to its possible adverse effects, such as eosinophilia. CASE REPORT: We report a case of a young white male suffering from treatment-resistant schizophrenia who rapidly developed eosinophilia after starting clozapine. DISCUSSION: We present a case of a 26-year-old white man diagnosed with schizophrenia with poor clinical response to several antipsychotics owing to which clozapine was started. Psychotic symptoms improved dramatically but a progressively ascendant eosinophilia was reported during serial haematological analyses. The patient remained physically asymptomatic. An exhaustive assessment with ancillary diagnostic tests revealed no cause for eosinophilia. Thus, a diagnosis of clozapine-induced eosinophilia was made. The drug was discontinued and eosinophil count progressively returned to normal but psychotic symptoms worsened. CONCLUSIONS: Clozapine treatment is frequently feared due to its possible side effects and complications, delaying its use in refractory schizophrenia. Also, to our knowledge, there are no specific guidelines on how to manage haematological side effects such as eosinophilia. This is problematic as, in some cases, it may lead to an unnecessary withdrawal of clozapine with a worsening of psychotic symptoms. We present a brief discussion of the recent literature on the subject.

Clozapine in patients with schizoaffective disorder: A systematic review.

Schizoaffective disorder is defined by the appearance of positive psychotic symptomatology as well as affective features, even when it is considered a controversial nosologic entity, proving difficult to accord on its definition or diagnostic criteria. Due to these conceptual differences, it has been a challenge to study effective therapeutic measures and, consequently, the availability of data in the current literature, resulting in the extrapolation of clinical guidelines and recommendations initially established for patients with schizophrenia or bipolar disorder. The current study aimed to systematically search and summarize the published evidence to date about the use of clozapine in patients with schizoaffective disorder. Seven studies were identified, that are heterogeneous on their designs and methodology, including samples of patients mixed with bipolar or schizophrenic disorders. The evidence was summarized both in a table and a narrative fashion, suggesting that clozapine may be an effective treatment for both psychotic and affective symptoms, indistinctively of an acute or maintenance phase.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries.

INTRODUCTION: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. METHODS: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. RESULTS: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005-IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. CONCLUSIONS: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.

Intra-individual variation of clozapine and norclozapine plasma levels in clinical practice. / Variación intraindividual en los niveles plasmáticos de clozapina y norclozapina en la práctica clínica.

INTRODUCTION: Clozapine plasma levels are useful to monitor drug compliance, and also to assess and to prevent some side effects. Recently, routine monitoring to all clozapine-treated patients has been proposed to prevent relapses. However, high intra-individual variability in plasma levels has been reported too, although these studies have some limitations. METHODS: We analysed differences between 2clozapine plasma levels separated by at least one year in a subgroup of 28 outpatients (82% male, mean age 47.9 years-old) with diagnosis of non-affective psychosis in clinical remission whose clozapine doses and smoking habits remained unchanged. RESULTS: We found a non-significant increase in clozapine plasma levels [.30mg/L (SD=.14) vs. .32 (SD=.17); t=-.858, p=.40] and a significant decrease in norclozapine plasma levels [.27 (SD=.11) vs. .22 (SD=.10); t=3.27; p=.003]. Absolute coefficient of variation (CV) between first and second assessment were calculated. Forty-six and fifty-seven percent of cases had CV 20% in clozapine and norclozapine, respectively. CV of 50% was seen in 20.7% and 13.8% of clozapine and norclozapine test respectively. We discussed potential causes of such high CV. CONCLUSIONS: Our study suggest high intra-individual variation even in a subgroup of very stable patients, which suggest that routine monitoring of these levels may be indicated in order to detect significant plasma variations. We think that clinicians should act with caution in case of a sudden decrease in plasma level. In the absence of obvious symptom severity variation, sources of intra-individual fluctuations might be considered first, before assuming poor compliance.

Pattern of use of clozapine in Spain. Variability and under-prescription. / Patrón de uso de clozapina en España. Variabilidad e infraprescripción.

INTRODUCTION: International studies on clozapine use usually show lower than expected prescription proportions, under-dosing and delayed initiation of treatment, which has led to a number of initiatives aimed at improving its use and reducing the striking variability observed among practitioners. There are no similar studies on the Spanish population. Therefore we planned initial data collection from 4 territorial samples. We hypothesized that clozapine prescription would also be low and variable in our country. If this hypothesis were confirmed, a reflection on possible strategies would be necessary. MATERIAL AND METHODS: We accessed data on clozapine prescription in Catalonia, Castile and Leon, the Basque Country and the Clinical Management Area of the Hospital 12 de Octubre (Madrid). RESULTS: Patients diagnosed with schizophrenia under treatment in these territories comprise around .3% of their total population; treatment with clozapine ranges between 33.0 and 57.0 per 10000 inhabitants; patients diagnosed with schizophrenia on current treatment with clozapine range between 13.7% and 18.6% of the total number of patients with this diagnosis. The coefficient of variation between centres and prescribers is often higher than 50%. CONCLUSIONS: Although below the figures suggested as desirable in the literature, global prescribing data for clozapine in the areas we studied are not as low as the data collected in other international studies, and are in the range of countries in our environment. However, the variability in prescription is large and apparently not justified; this heterogeneity increases as we focus on smaller areas, and there is great heterogeneity at the level of individual prescription.

Miocarditis inducida por Clozapina: Revisión y protocolo de Screening

Clozapina, el gold standard en esquizofrenia refractaria, presenta algunos efectos adversos que ocasionalmente pueden ser graves. Entre ellos, la miocarditis precoz es un efecto cardiovascular severo poco frecuente que puede aparecer en las primeras 4-6 semanas. Las cifras de incidencia oscilan entre el 0,015-0.188% en el mundo, siendo más altas en Australia. La etiología es desconocida, postulándose hipersensibilidad mediada por Ig E; hipereosinofilia y hiperadrenergia. Múltiples investigaciones avalan a la ecocardiografía como una de las técnicas más útiles para el diagnóstico. La biopsia endomiocárdica es definitoria pero no viable. Existen, asimismo, criterios de RNM indicativos de inflamación miocárdica. Para facilitar el diagnóstico, se han propuesto criterios clínicos y analíticos de screening (hemograma, ECG, CK, PCR, troponinas). En caso de sospecha de miocarditis, el cese de clozapina y el tratamiento de soporte es la actitud a seguir, habitualmente con buenos resultados.

Although Clozapine is the gold standard treatment in resistant-schizophrenia, severe or even life-threatening adverse effects must be taked into account. Early myocarditis, a severe but unusual cardiovascular effect, can appear in the first 4-6 weeks of initiation. Incidence rates of myocarditis are about 0,015-0,188% around the world, being more elevated in Australia. Aethiology is unknown, suggesting Ig E mediated hipersensibility, hiperaeosinophilia and hiperadrenergy. Echocardiography seems to be one of the most helpful tools for diagnosing myocarditis. Endomyocardial biopsy is definitive, but not usually available. A role for cardiac magnetic resonance imaging (MRI) also has been proposed (findings of inflammation). In order to make an early diagnosis, several screening-criteria, considering clinical and laboratory ones, have been proposed: aeosinophylia, creatininkinase, C Reactive Proteine, troponin, and EKG. If we suspected clozapine-induced myocarditis, the drug must be removed and support medical treatment must be indicated.

Clozapine-Induced Eosinophilia: a Case Report

Introduction: Clozapine is an atypical antipsychotic drug eligible for treatment-resistant schizophrenia. It frequently represents the best and the only choice in resistant schizophrenia. However, its use is feared by many professionals due to its possible adverse effects, such as eosinophilia. Case report: We report a case of a young white male suffering from treatment-resistant schizophrenia who rapidly developed eosinophilia after starting clozapine. Discussion: We present a case of a 26-year-old white man diagnosed with schizophrenia with poor clinical response to several antipsychotics owing to which clozapine was started. Psychotic symptoms improved dramatically but a progressively ascendant eosinophilia was reported during serial haematological analyses. The patient remained physically asymptomatic. An exhaustive assessment with ancillary diagnostic tests revealed no cause for eosinophilia. Thus, a diagnosis of clozapine-induced eosinophilia was made. The drug was discontinued and eosinophil count progressively returned to normal but psychotic symptoms worsened. Conclusions: Clozapine treatment is frequently feared due to its possible side effects and complications, delaying its use in refractory schizophrenia. Also, to our knowledge, there are no specific guidelines on how to manage haematological side effects such as eosinophilia. This is problematic as, in some cases, it may lead to an unnecessary withdrawal of clozapine with a worsening of psychotic symptoms. We present a brief discussion of the recent literature on the subject.

Introducción: La clozapina es un fármaco antipsicótico atípico eligible para la esquizofrenia resistente al tratamiento. Con frecuencia representa la mejor y la única opción para la esquizofrenia resistente. Sin embargo, muchos profesionales temen utilizarla por sus posibles efectos adversos, como la eosinofilia. Reporte de caso: Se expone el caso de un joven blanco que sufre esquizofrenia resistente al tratamiento y desarrolló eosinofilia rápidamente tras comenzar el tratamiento con clozapina. Discusión: Varón de 26 años con diagnóstico de esquizofrenia y mala respuesta clínica a varios antipsicóticos, por lo que se inició clozapina. Los síntomas psicóticos mejoraron drásticamente, pero los análisis hematológicos seriados informaron una eosinofilia en ascenso progresivo. El paciente permaneció físicamente asintomático. Una evaluación exhaustiva con pruebas de diagnóstico complementarias no reveló ninguna causa de eosinofilia. Por lo tanto, se diagnosticó eosinofilia inducida por clozapina. Se suspendió el fármaco, el recuento de eosinófilos volvió progresivamente a la normalidad, pero los síntomas psicóticos empeoraron. Conclusiones: A menudo se teme tratar con clozapina por sus posibles efectos secundarios y sus complicaciones, lo cual retrasa su uso en la esquizofrenia refractaria. Además, hasta donde sabemos, no existen pautas específicas sobre cómo tratar los efectos secundarios hematológicos como la eosinofilia. Esto es problemático porque, en algunos casos, puede conducir a suspender innecesariamente la clozapina y que empeoren los síntomas psicóticos. Se presenta una breve discusión de la literatura reciente sobre el tema.

Increase in white cell and neutrophil counts during the first eighteen weeks of treatment with clozapine in patients admitted to a long-term psychiatric care inpatient unit. / Aumento en los recuentos de leucocitos y neutrófilos durante las primeras 18semanas de tratamiento con clozapina en pacientes ingresadas en una unidad de cuidados psiquiátricos prolongados.

INTRODUCTION: Clozapine is an antipsychotic drug that has shown to be more effective than other antipsychotics in the treatment of schizophrenia, but its use is limited due to its side effects, particularly by the risk of causing agranulocytosis. A study was made on the variations in white cell and neutrophil counts in patients treated with clozapine in a Long-term Psychiatric Unit. METHODS: A retrospective observational study was conducted with a sample of women of our long-term psychiatric care unit who had been treated with clozapine. A study was made on the variations in white cell and neutrophil counts during the first 18 weeks of treatment, as well as the onset of leukopenia, neutropenia, agranulocytosis, and the influence of concomitant drugs. RESULTS AND CONCLUSIONS: The study included 55 patients on treatment with clozapine. The incidence rate of neutropenia was 1.82% (95% CI; 0.05-10.13). The incidence rate of leukopenia and agranulocytosis was 0%. An increase in white cell and neutrophil counts from baseline to week 3-4 was observed. Only small variations were observed after this time, but the counts remained higher than the initial values. These changes were statistically significant in the white cell count: One-way repeated ANOVA with Greenhouse-Geisser correction F (11.47, 37) = 2.114 (P= .011); and in neutrophils: One-way repeated ANOVA with Greenhouse-Geisser correction F (10.3, 37)=3.312 (P=.0002), and MANOVA F (18, 37)=2.693 (P=.005), ŋ2P=0.567. The influence of concomitant drugs (lithium, valproic and biperiden) was not significant on the overall increase found in white cells or neutrophils (MANOVA).

Guía práctica para el uso de clozapina en niños/as y adolescentes / Practical guidelines for the use of clozapine in children and adolescents

El uso de clozapina (CZP) en niños/as y adolescentes ha estado históricamente limitado, debido a los efectos adversos y riesgos médicos asociados al fármaco, a pesar de ser una herramienta farmacológica de gran efectividad en la psiquiatría general. A continuación, se presenta una guía clínica con los siguientes objetivos: 1) identificar los criterios de indicación de CZP en niños, niñas y adolescentes (NNA) según la evidencia disponible; 2) entregar algunas directrices a los clínicos y profesionales de salud respecto a la prescripción de CZP y precauciones a tener en consideración en esta población y; 3) entregar algunos datos comparativos del uso de CZP entre población infantojuvenil y población adulta. Todo lo anterior tiene como finalidad poder entregar la información necesaria para que los clínicos no limiten el uso de este fármaco y puedan prescribirlo de acuerdo con la evidencia científica disponible.

The use of clozapine (CZP) in children and adolescents has historically been limited due to the adverse effects and medical risks commonly associated with the drug, despite being a highly effective pharmacological tool in general psychiatry. Below we developed a clinical guideline with the following objectives: 1) identify the indication criteria for CZP in children and adolescents (NNA) according to the available evidence; 2) provide some guidelines to clinicians and health professionals regarding the prescription of CZP and precautions to be taken into account in this population and; 3) provide some comparative data on the use of CZP between the pediatric and adult population. The purpose of the guideline is to provide the necessary information so that clinicians do not limit the use of CLZ when needed and can prescribe it safely and according to the available scientific evidence.

Concentrations in plasma clozapine levels in schizophrenic and schizoaffective patients. / Variaciones en las concentraciones plasmáticas de clozapina en pacientes con esquizofrenia y trastorno esquizoafectivo.

INTRODUCTION: There is great variability in plasma levels of clozapine. The objective of this study is to know the characteristics of patients treated with clozapine and the relationship between them and the variability of plasma levels. MATERIAL AND METHODS: Descriptive, cross-sectional study of all patients currently treated with clozapine in a Psychiatric Service with a diagnosis of schizophrenic psychosis or schizoaffective disorder. The present study assessed physical situation, psychopathology and functionality of the patients and explored the associations and correlations between clinical variables and plasma levels. RESULTS: We studied 39 patients, predominantly men, with negative and depressive symptoms and cardiovascular risk factors (metabolic syndrome and smoking). Significant variability in dose and even greater in clozapine levels were observed. The levels of clozapine at equal doses/kg of body weight were higher in non-smokers, they had positive correlation with BMI and negative correlation with systolic BP, disruptive behaviors and number of cigarettes consumed. CONCLUSION: Plasma level monitoring clozapine is an important tool to avoid clozapine plasma levels monitoring and minimize undesirable clinical situations (metabolic syndrome, sedation, negative symptoms and functional impairment). It is also important to control the effects of a smoking habit for optimum drug bioavailability.

Agranulocitosis inducida por clozapina / Clozapine-induced agranulocytosis

RESUMEN Clozapina, actualmente, sigue siendo el gold standard para la esquizofrenia resistente al tratamiento, pero solo bajo un adecuado monitoreo hematológico, porque está asociada a agranulocitosis. Clozapina se metaboliza produciendo N-desmetilclozapina (farmacológicamente activa), el N-óxido de clozapina (inactivo) y especies reactivas de oxígeno (ion nitrenio). El recuento de neutrófilos <1000 células/mm3 corresponde a un estado de neutropenia. La agranulocitosis es un estado grave de neutropenia con un recuento absoluto de neutrófilos <500 células/mm3. Clozapina se asocia con la agranulocitosis en aproximadamente el 0,8 % de los pacientes, y el riesgo aumenta con la edad y en mujeres. Existen dos mecanismos que explican la agranulocitosis inducida por clozapina: inmunológico (respuesta mediada por el sistema inmunitario contra neutrófilos haptenizados) y tóxico (por acción de los metabolitos N-desmetilclozapina y ion nitrenio). La farmacogenética es una herramienta valiosa para conseguir la referida medicina personalizada, al adaptar e individualizar el tratamiento basado en los marcadores genéticos de cada paciente. Numerosos estudios han demostrado una asociación potencial de la agranulocitosis inducida por clozapina con ciertos haplotipos HLA (HLA-B38, DR4, DQw3, DQB1). Luego que un paciente ha presentado agranulocitosis, se conocen tres mecanismos de reexposición a clozapina: simple, con litio y con factores estimuladores de colonias de granulocitos. Debido al riesgo de agranulocitosis, las formulaciones de clozapina están disponibles solo a través de una distribución controlada, con un registro detallado de los pacientes y con una farmacovigilancia sistematizada y obligatoria.

ABSTRACT Clozapine currently remains the gold standard for treatment-resistant schizophrenia, but only under an adequate hematological monitoring, because it is associated with agranulocytosis. Clozapine is metabolized to produce pharmacologically active N-desmethylclozapine, inactive clozapine N-oxide and reactive oxygen species (nitrenium ion). A neutrophil count < 1000 cells/mm3 corresponds to a state of neutropenia. Agranulocytosis is a severe state of neutropenia with an absolute neutrophil count < 500 cells/mm3. Clozapine is associated with agranulocytosis in approximately 0.8 % of the patients, with an increased risk in older people and women. There are two mechanisms that explain the clozapine- induced agranulocytosis: immunological (response mediated by the immune system against haptenized neutrophils) and toxic (by the action of the metabolites N-desmethylclozapine and nitrenium ion). Pharmacogenetics represents a valuable tool to achieve the so-called personalized medicine by adapting and individualizing the treatment based on the genetic markers of each patient. Several studies have shown a potential association of clozapine-induced agranulocytosis with certain HLA haplotypes (HLA-B38, DR4, DQw3 and DQB1). After a patient has presented agranulocytosis, three mechanisms of clozapine rechallenge are known: simple, with lithium and with factors that stimulate granulocyte colonies. Due to the risk of agranulocytosis, clozapine formulations are available only through a controlled distribution, with a detailed record of the patients, and with a mandatory and systematized pharmacovigilance.

Esquizofrenia resistente: Definiciones e Implicancias del concepto de Esquizofrenia Resistente a tratamiento / Treatment resistant schizophrenia: definitions and implications of the Treatment Resistant Schizophrenia concept

Resumen La esquizofrenia (EQZ) es una entidad clínica altamente heterogénea. Determina un severo impacto en la calidad de vida de los pacientes y un alto costo para la sociedad. Los antipsicóticos son la primera línea de tratamiento, sin embargo, hasta un tercio de los pacientes presentaran una esquizofrenia resistente a tratamiento (ERT). Se ha propuesto que la ERT podría corresponder a un grupo neurobiológicamente distinto de la enfermedad con una arquitectura genética particular y no solo al extremo del espectro de severidad de la misma. A pesar de ello, actualmente no existe consenso en la literatura en torno a la definición de ERT. En este trabajo presentamos una revisión de diferentes definiciones de ERT centrándonos principalmente en las guías clínicas publicadas. Además se discuten las alternativas terapéuticas en ERT y, finalmente, se proponen perspectivas futuras en torno a la necesidad de desarrollar predictores de respuesta a antipsicóticos de primera y segunda línea, así como también la posibilidad de comprender la neurobiología de la ERT.

Schizophrenia (SZ) is a highly heterogeneous clinical entity. It causes a severe disruption in quality of life, and it imposes a significant burden to society. Antipsychotics are the first line treatment, however up to a 30% of the patients will present resistance to treatment. Treatment resistant schizophrenia (TRS) could be a neurobiologically distinct disorder and not merely an extremely severe form of SZ. However, there is no consensus in the literature as to the definition of TRS. In the present work we review different definitions of TRS, mainly from clinical guidelines. Furthermore, we discuss therapeutic alternatives for TRS and suggest future perspectives regarding the identification of response predictors and understanding the neurobiology of TRS.

¿La exposición a clozapina en el adulto mayor está asociada a riesgo de leucopenia? / Is exposure to clozapine in the elderly adult associated with risk of leukopenia?

Resumen Introducción: La clozapina es un antipsicótico atípico usado en esquizofrenia refractaria. Es el único antipsicótico que requiere control hematológico debido a que el riesgo de agranulocitosis potencialmente mortal, limita su uso. No está claro si este riesgo aumenta en los adultos mayores; algunos estudios han demostrado que la neutropenia inducida por clozapina es más prevalente en la vejez, mientras que otros no han demostrado tal aumento. Objetivo: Cuantificar el riesgo de leucopenia en pacientes adultos mayores usuarios de clozapina. Material y Método: Se realizó un estudio de casos y controles en adultos mayores usuarios de clozapina del HHHA durante los años 2001-2016. Se revisó los tarjetones del programa de clozapina, las bases digitales de estadística del HHHA y del Programa Nacional de Clozapina. Se cuantificó el número de usuarios con eventos adversos hematológicos y la edad de los pacientes para diferenciarlos en mayores (expuestos) o menores de 60 años (no expuestos) y si estos tuvieron (casos) o no (controles), eventos de alarma. Se realizó un análisis estratificado. Resultados: El uso de clozapina en adultos mayores, resultó protector para el desarrollo de leucopenia.

Introduction: Clozapine is an atypical antipsychotic used in refractory schizophrenia. It is the only antipsychotic that requires hematological control because the risk of agranulocytosis is potentially fatal, limiting its use. It is not clear if this risk increases in older adults: some studies have shown that clozapine-induced neutropenia is moreprevalent in old age, while others have not shown such an increase. Objetive: Quantify the risk of leukopenia in elderly patients who are clozapine users. Material and Method: A case-control study was conducted in elderly users of clozapine from HHHA during theyears 2001-2016. The clozapineprogram cards, the HHHA digital statistical databases and the National Clozapine Program were reviewed. The number of users with adverse hematological events and the age of the patients were quantified to differentiate them in patients older patients (exposed) or under 60 years old (not exposed), and if these had (cases) or not, alarm events (controls). A stratified analysis was performed. Results: The use of clozapine in older adults was protective for the development of leukopenia.

Prevalence of polymorphisms in the ANKK1, DRD2, DRD3 genes and metabolic syndrome in refractory schizophrenia / Prevalência de polimorfismos nos genes ANKK1, DRD2, DRD3 e síndrome metabólica na esquizofrenia refratária / Prevalencia de polimorfismos en los genes ANKK1, DRD2, DRD3 y síndrome metabólico en la esquizofrenia refractária

ABSTRACT Objective: to estimate the prevalence of TaqIA, -141C and rs6280 polymorphisms of the ANKK1, DRD2 and DRD3 genes and evaluate their association with the occurrence of metabolic syndrome in patients with refractory schizophrenia. Method: cross-sectional study conducted in the Extended Western Region of Minas Gerais, with refractory schizophrenic patients using the antipsychotic clozapine. Sociodemographic, clinical, anthropometric, biochemical and genetic data were collected. Univariate analysis of the data was performed. Results: seventy-two patients participated in the study and the occurrence of Metabolic Syndrome was observed in 47.2% of them. There was no association between Metabolic Syndrome and the studied polymorphisms. There was a statistically significant difference in the low HDL parameter with homozygous genotype for the C allele of the -141C polymorphism of the DRD2 gene. Conclusion: a high prevalence of MS was evidenced. The -141C polymorphism was associated with low HDL. Genetic analysis and identification of metabolic alterations in this group of patients can guide drug treatment and provide a better quality of life.

RESUMO Objetivo: estimar a prevalência dos polimorfismos TaqIA, -141C e rs6280 dos genes ANKK1, DRD2 e DRD3 e avaliar sua associação com a ocorrência de síndrome metabólica em pacientes com esquizofrenia refratária. Método: estudo de delineamento transversal, realizado na Região Ampliada Oeste de Minas Gerais, que incluiu pacientes com esquizofrenia refratária em uso do antipsicótico clozapina. Foram coletados dados sociodemográficos, clínicos, antropométricos, bioquímicos e genéticos. Realizou-se análise univariada dos dados. Resultados: participaram 72 pacientes e observou-se a ocorrência de Síndrome Metabólica em 47,2%, não sendo encontrada associação da Síndrome Metabólica com os polimorfismos estudados. Houve diferença estatisticamente significante com o parâmetro do baixo HDL com genótipo homozigoto para alelo C do polimorfismo -141C do gene DRD2. Conclusão: evidenciou-se prevalência de SM elevada. O polimorfismo -141C associou-se ao baixo HDL. A análise genética e a identificação de alterações metabólicas, neste grupo de pacientes, podem nortear o tratamento medicamentoso e propiciar melhor qualidade de vida.

RESUMEN Objetivo: estimar la prevalencia de los polimorfismos TaqIA, -141C y rs6280 de los genes ANKK1, DRD2 y DRD3 y evaluar su asociación con el síndrome metabólico en pacientes con esquizofrenia refractária. Método: estudio de delineamiento transversal, realizado en la Región Ampliada Oeste de Minas Gerais, que incluye pacientes con esquizofrenia refractária usando el antipsicótico clozapina. Fueron recogidos datos sociodemográficos, clínicos, antropométricos, bioquímicos y genéticos. Se realizó um análisis univariada de los datos. Resultados: participaron 72 pacientes y se observó el Síndrome Metabólico en 47,2%, no siendo encontrada una asociación del Síndrome Metabólico con los polimorfismos estudiados. Hubo diferencia estadísticamente significante con el parámetro del bajo HDL con genotipo homozigoto para alelo C del polimorfismo -141C del gen DRD2. Conclusión: se vio una prevalencia de SM elevada. El polimorfismo -141C se asoció al bajo HDL. El análisis genético y la identificación de alteraciones metabólicas, en este grupo de pacientes, pueden guiar al tratamiento medicamentoso y propiciar mejor calidad de vida.

Psicosis, Discapacidad intelectual y trastornos conductuales: enfoque biopsicosocial / Psychosis, intellectual disability and behavioral disorders: biopsychosocial approach

Caso Clínico: Mujer, 23 años. Discapacidad intelectual. Asiste a colegio especial (no lee ni escribe). Institucionalizada. Motivo de ingreso: Paciente ingresa en octubre del 2017 traída por carabineros por ser encontrada en la calle bajo el efecto de múltiples sustancias, con ideación suicida. Días antes fue expulsada del hogar por agresión a cuidadoras. Diagnósticos de ingreso: Discapacidad intelectual moderado. Síndrome suicidal, Trastorno por dependencia a drogas. ¿Esquizofrenia hebefrénica? Evolución: Mantiene desajustes conductuales severos fluctuantes, con serias dificultades para manejar la rabia, lo que la lleva a tener conductas hetero y autoagresivas. Plan de tratamiento: Farmacológico (clozapina), Psicológico (TCC), Social (dispositivo adecuado post-alta). Clozapina para trastornos psicóticos en adultos con discapacidad intelectual. El principal riesgo de atribuir alguno de estos comportamientos a una supuesta "psicosis", es el de "medicalizar" y tratar de forma poco acertada. Es importante descartar factores ambientales y del aprendizaje (hábitos y conductas aprendidas, institucionalización, reacciones ante el estrés agudo.) La prevalencia de abuso y dependencia de sustancias en población con DI va desde el 0,5% al 2,6%. Lo cual es menor que la población general. Pacientes con DI y dependencia a drogas se asocia a otras enfermedades psiquiátricas (42-54%). Se ha informado que las personas con discapacidad intelectual en América Latina a menudo están institucionalizadas y escondidas de la sociedad en instalaciones deficientes y superpobladas.

Clinical Case: Female, 23 years old. Intellectual disability. He attends a special school (she does not read or write). Institutionalized. Reason for admission: Patient enters in October 2017 brought by police officers to be found in the street under the effect of multiple substances, with suicidal ideation. Days before she was expelled from the home because of assaulting caregivers. Admission diagnoses: Moderate intellectual disability. Suicidal syndrome, Disorder due to drug dependence. Hebephrenic schizophrenia? Evolution: Maintains fluctuating severe behavioral imbalances, with serious difficulties in managing rage, which leads to hetero and self-aggressive behaviors. Treatment plan: pharmacological (clozapine), Psychological (CBT), Social (adequate post-hospitalization discharge device). Clozapine for psychotic disorders in adults with intellectual disabilities. The main risk of attributing some of these behaviors to a supposed "psychosis" is that of "medicalizing" and dealing inappropriately. It is important to rule out environmental and learning factors (habits and behaviors learned, institutionalization, reactions to acute stress. The prevalence of substance abuse and dependence in the population with ID ranges from 0.5% to 2.6%. Which is less than the general population. Patients with ID and drug dependence are associated with other psychiatric illnesses (42-54%). It is reported that people with intellectual disabilty in Latin America are often institutionalized and hidden from society in poor and overcrowded facilities.

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.