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

BACKGROUND: Pharmacovigilance studies indicate clozapine history is marked by adverse drug reactions (ADRs). OBJECTIVE: In a 2021 article, the United Kingdom (UK) had >90 % of European clozapine-related fatal outcomes in VigiBase, the World Health Organization's pharmacovigilance database. Two possibly opposing hypotheses could explain this disparity: 1) fewer reported fatal outcomes in other Western European countries mainly reflect underreporting to VigiBase, and 2) the higher number of UK reports reflects higher real relative mortality. METHODS: VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions. RESULTS: The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label "death" was the top cause in the world (46 %) and in the UK (33 %). "Pneumonia" was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1-10 % of the UK clozapine fatal outcome number. CONCLUSIONS: Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases.

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.

Clozapine-induced myocarditis in children and adolescents: a pharmacovigilance study using VigiBase and a systematic literature review.

INTRODUCTION: Clozapine-induced myocarditis in children (age ≤18 yo) was studied from a PubMed search (18 July 2022) (9 cases) and from the World Health Organization's pharmacovigilance database, called Vigibase, of adverse drug reaction (ADR) reports (72 non-duplicated cases). VigiBase uses a logarithmic measure of disproportionality called the information component (IC). A logistic regression model of presence/absence (40/32) of seriousness in VigiBase was developed. AREAS COVERED: VigiBase provided a significant myocarditis IC = 4.2 with an IC025 = 3.8; only 4 clozapine-induced myocarditis cases were expected, while 72 were observed. The PubMed search identified 9 cases, while VigiBase identified 72 cases (of which 67 did not overlap with published cases). These 76 combined cases included 35 doubtful (most with missing information on the day of diagnosis), 19 possible and 22 probable, according to the ADR scale. After adjusting for confounders, quetiapine increased the risk of seriousness with an odds ratio (OR) of 17.6 (95% confidence interval CI, 1.56 to 198.6), while Australian origin decreased it with an OR = 0.13 (CI, 0.04 to 0.47). EXPERT OPINION: These 41 cases of at least possible clozapine-induced myocarditis indicated that this ADR can definitively occur in children, particularly in the first 30 days of up-titration. Children's and adult cases appeared similar.

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.

Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics.

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit-risk balance and, consequently, patients' quality of life.

Duration of Untreated Psychosis in First-Episode Psychosis is not Associated With Common Genetic Variants for Major Psychiatric Conditions: Results From the Multi-Center EU-GEI Study.

Duration of untreated psychosis (DUP) is associated with clinical outcomes in people with a diagnosis of first-episode psychosis (FEP), but factors associated with length of DUP are still poorly understood. Aiming to obtain insights into the possible biological impact on DUP, we report genetic analyses of a large multi-center phenotypically well-defined sample encompassing individuals with a diagnosis of FEP recruited from 6 countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Genetic propensity was measured using polygenic scores for schizophrenia (SZ-PGS), bipolar disorder (BD-PGS), major depressive disorder (MDD-PGS), and intelligence (IQ-PGS), which were calculated based on the results from the most recent genome-wide association meta-analyses. Following imputation for missing data and log transformation of DUP to handle skewedness, the association between DUP and polygenic scores (PGS), adjusting for important confounders, was investigated with multivariable linear regression models. The sample comprised 619 individuals with a diagnosis of FEP disorders with a median age at first contact of 29.0 years (interquartile range [IQR] = 22.0-38.0). The median length of DUP in the sample was 10.1 weeks (IQR = 3.8-30.8). One SD increases in SZ-PGS, BD-PGS, MDD-PGS or IQ-PGS were not significantly associated with the length of DUP. Our results suggest that genetic variation does not contribute to the DUP in patients with a diagnosis of FEP disorders.

Guía práctica clínica para el tratamiento farmacológico y psicológico de los pacientes adultos con un trastorno mental grave y un trastorno por uso de sustancias / A clinical guideline for the pharmacological and psychological treatment of adult patients with a serious mental disorder and substance use disorder

Objetivos: El objetivo principal de esta Guía es recoger recomendaciones concretas basadas en los resultados de la literatura científica para tratar a pacientes con un trastorno mental grave y un consumo de sustancias atendidos en centros de tratamiento hospitalarios y ambulatorios. Incluye: 1) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno depresivo mayor y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 2) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con trastorno del espectro esquizofrénico y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 3) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno de ansiedad y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 4) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno bipolar y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina). 5) Recomendaciones farmacológicas y psicológicas para el tratamiento de los pacientes con un un trastorno por déficit de atención e hiperactividad y un trastorno por uso de sustancias (cocaína, cannabis, alcohol, nicotina).

Caffeine consumption in a long-term psychiatric hospital: Tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use.

This study further explores the association between schizophrenia and caffeine use by combining two prior published Spanish samples (250 schizophrenia outpatients and 290 controls from the general population) with two Spanish long-term inpatient samples from the same hospital (145 with schizophrenia and 64 with other severe mental illnesses). The specific aims were to establish whether or not, after controlling for confounders including tobacco smoking, the association between schizophrenia and caffeine is consistent across schizophrenia samples and across different definitions of caffeine use. The frequency of caffeine use in schizophrenia inpatients was not significantly higher than that in non-schizophrenia inpatients (77%, 111/145 vs. 75%, 48/64) or controls but was significantly higher than in schizophrenia outpatients. The frequency of high caffeine users among caffeine users in schizophrenia inpatients was not significantly higher than in non-schizophrenia inpatients (45%, 50/111 vs. 52%, 25/48) or controls, but was significantly lower than in schizophrenia outpatients. Smoking was significantly associated with caffeine use across all samples and definitions. Between 2 and 3% of schizophrenia inpatients, schizophrenia outpatients and non-schizophrenia inpatients showed caffeinism (>700 mg/day in smokers). Several of these smoking patients with caffeinism were also taking other inducers, particularly omeprazole. The lack of consistent association between schizophrenia and caffeine use is surprising when compared with the very consistent association between tobacco smoking and caffeine use across all of our analyses (use and high use in users) and all our samples. The confounding effects of tobacco smoking may explain in large part the apparent association between schizophrenia and caffeine use.

Lamotrigine augmentation of serotonin reuptake inhibitors in severe and long-term treatment-resistant obsessive-compulsive disorder.

The treatment recommendations in obsessive-compulsive disorder (OCD) after lack of response to selective serotonin reuptake inhibitors (SSRIs) include augmentation with other drugs, particularly clomipramine, a more potent serotonin reuptake inhibitor (SRI), or antipsychotics. We present two cases of response to lamotrigine augmentation in treatment-refractory OCD; each received multiple SRI trials over a >10-year period. The first patient had eleven years of treatment with multiple combinations including clomipramine and SSRIs. She had a >50% decrease of Y-BOCS (from 29 to 14) by augmenting paroxetine (60 mg/day) with lamotrigine (100 mg/day). The second patient had 22 years of treatment with multiple combinations, including combinations of SSRIs with clomipramine and risperidone. She had an almost 50% decrease of Y-BOCS (from 30 to 16) and disappearance of tics by augmenting clomipramine (225 mg/d) with lamotrigine (200 mg/day). These two patients were characterized by lack of response to multiple treatments, making a placebo response to lamotrigine augmentation unlikely. Prospective randomized trials in treatment-resistant OCD patients who do not respond to combinations of SSRIs with clomipramine and/or antipsychotics are needed, including augmentation with lamotrigine. Until these trials are available, our cases suggest that clinicians may consider lamotrigine augmentation in such treatment-resistant OCD patients.

Vida recreativa y consumo de cocaína y éxtasis en jóvenes / Recreational night life and cocaine and ecstasy consumption in youths

Uno de los fenómenos más recientes y que mayor interés está suscitando es el consumo de drogas por parte de los jóvenes, como elemento central del ocio nocturno y del botellón en España. El objetivo del presente estudio es evaluar las diferencias que hay en hábitos de salir de marcha y participación en el botellón entre jóvenes que han consumido psicoestimulantes (cocaína y éxtasis) y los que no los han consumido. La muestra está formada por 1214 jóvenes entre 16 y 25 años que fueron entrevistados siguiendo un muestreo aleatorio en sus domicilios y en lugares de ocio y diversión. Los resultados indican que hay importantes diferencias en cuanto a los hábitos de salir de marcha y participación en el botellón entre ambos grupos. Además, algunas de estas variables (p. ej., frecuencia de salir de marcha, dinero que gasta, consumo de drogas en el botellón) predicen los consumos de psicoestimulantes. Por lo tanto, el consumo o no de drogas se explica también en función de los hábitos que tienen los jóvenes al salir de marcha (AU)

A recent phenomenon with a special interest for research is drug consumption among youths, which is an important aspect of night life and "botellon" (street drinking) in Spain. The aim of the present study is to analyze the differences between stimulant users (cocaine and ecstasy) and non-users in their nightlife recreational habits. The sample consisted of 1214 youths between 16 and 25 years old who were interviewed at home or in recreational nightlife places following a random procedure. Results indicated that there are important differences in recreational night life and street drinking characteristics between stimulant users and non-users. Stimulant consumption is predicted by several variables (e.g., frequency of going out at night, money spent when going out, drug use during street drinking, etc.). Therefore, the habits of youths in recreational nightlife partly explain drug consumption

Borracheras, conducción de vehículos y relaciones sexuales en jóvenes consumidores de cocaína y éxtasis / Drunkenness, driving and sexual relations in young cocaine and ecstasy users

Los accidentes de tráfico, las enfermedades de transmisión sexual y embarazos no deseados, las borracheras y el consumo de drogas(fundamentalmente psicoestimulantes) son algunos de los aspectos más negativos asociados al reciente fenómeno de salir de marcha. El objetivo del presente estudio es analizar en una muestra de 1214 jóvenes de 14 a 25 años (49.7% varones y 50.3% mujeres) si los consumidores de psicoestimulantes (cocaína y éxtasis) tienen mayor frecuencia de borracheras y de realización de conductas de riesgo en el ámbito de las relaciones sexuales y la conducción de vehículos y analizar el peso que estas conductas tienen para predecir los consumos de psicoestimulantes en el último año. Los resultados indican que los consumidores de psicoestimulantes se emborrachan con más frecuencia, es más probable que hayan visto a un familiar ebrio y tienen más conductas de riesgo relacionadas con la conducción y el mantenimiento de relaciones sexuales completas. Por lo tanto, los consumidores de cocaína y éxtasis son una población de riesgo a la que deben de ir dirigidas campañas de prevención específicas por el alto riesgo de las conductas que realizan (AU)

Traffic accidents, sexually-transmitted diseases, unwanted pregnancies, drunkenness, and drug use (especially psychostimulants) are negative aspects associated with recreational nightlife. The aim of the present study is to analyze in a sample of 1214 young people (aged 15-25; 49.7% males, 50.3% females) whether psychostimulant users (cocaine and ecstasy) have a higher frequency of drunkenness and risk behaviours related to sex and to driving. We also analyze the importance of these behaviours in the prediction of psychostimulant use in the last year. The results indicate that psychostimulant users get drunk more frequently,are more likely to have seen a relative drunk, and present more risk behaviours in the contexts of driving and full sexual relations. Therefore, cocaine and ecstasy users are a risk population who need specific preventive programs (AU)

[Drunkenness, driving and sexual relations in young cocaine and ecstasy users]. / Borracheras, conducción de vehículos y relaciones sexuales en jóvenes consumidores de cocaína y éxtasis.

Traffic accidents, sexually-transmitted diseases, unwanted pregnancies, drunkenness, and drug use (especially psychostimulants) are negative aspects associated with recreational nightlife. The aim of the present study is to analyze in a sample of 1214 young people (aged 15-25; 49.7% males, 50.3% females) whether psychostimulant users (cocaine and ecstasy) have a higher frequency of drunkenness and risk behaviours related to sex and to driving. We also analyze the importance of these behaviours in the prediction of psychostimulant use in the last year. The results indicate that psychostimulant users get drunk more frequently, are more likely to have seen a relative drunk, and present more risk behaviours in the contexts of driving and full sexual relations. Therefore, cocaine and ecstasy users are a risk population who need specific preventive programs.

QTc interval in a sample of long-term schizophrenia inpatients.

This naturalistic study attempted to determine the prevalence of prolonged QTc interval in a relatively large population of inpatients hospitalized with chronic schizophrenia, and to explore QTc relationship with demographic variables, metabolic parameters and prescribed treatments. All inpatients from a Spanish long-term psychiatric hospital were cross-sectionally investigated to determine the prevalence of QTc prolongation and metabolic syndrome. The sample with a DSM-IV diagnosis of schizophrenia included 171 Caucasian inpatients, all of Spanish origin. A prolonged QTc interval was defined as >450 ms in men and >470 ms in women. The relationships between QTc and other continuous variables were assessed using a linear regression model with QTc as the dependent variable. Only 10 patients (6%) had a prolonged QTc interval; one case was possibly explained by hypokalemia. Three patients (2%) had a QTc > 500 ms. Gender, old age (> or = 50 years old), current smoking, systolic blood pressure, HDL cholesterol and history of arrhythmia were found to have significant effects on QTc interval in a linear regression analysis. After controlling for significant variables, the mean QTc interval was not significantly influenced by antipsychotic dose, type of antipsychotic treatment, the use of depot antipsychotics, or the number of different antipsychotics prescribed. Our study focused on long-term schizophrenia inpatients with frequent antipsychotic polypharmacy and high antipsychotic doses, and suggested that after excluding the case with hypokalemia length of QTc was associated with history of arrhythmias and with metabolic factors, while the effects of antipsychotic compound or class were not so evident.

Quetiapina y enfermedad de Parkinson / Quetiapine and Parkinson’s disease

No disponible

Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene.

BACKGROUND: Pharmacological studies indicate a dysregulation of the serotonergic system in obsessive-compulsive disorder (OCD). A variable number tandem repeats (VNTR) polymorphism with three alleles (Stin2.9, Stin2.10, Stin2.12) has been described in intron 2 of the serotonin transporter (5-HTT) gene. This polymorphism has been associated with unipolar depression, bipolar disorder, schizophrenia, and anxiety disorders including OCD. METHODS: The association between OCD and the polymorphism is examined in 97 OCD patients, 578 psychiatric controls and 406 healthy controls, all Spanish Caucasians. RESULTS: Genotype frequencies for the polymorphism were significantly different in OCD patients, psychiatric patients and controls. There was a significant excess of 12/12 and 12/10 genotypes in OCD patients compared to psychiatric patients and controls. CONCLUSIONS: Our results indicate a possible association between the Stin2.12 allele of the VNTR polymorphism and OCD.