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1.
Expert Opin Drug Saf ; 19(1): 43-57, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31770500

RESUMO

Introduction: Clozapine remains the most effective antipsychotic for treatment-refractory schizophrenia. However, ~40% of the patients respond insufficiently to clozapine. Clozapine's effects, both beneficial and adverse, have been proposed to be partially attributable to its main metabolite, N-desmethylclozapine (NDMC). However, the relation of the clozapine to norclozapine ratio (CLZ:NDMC; optimally defined as ~2) to clinical response and metabolic outcomes is not clear.Areas covered: This narrative review comprehensively examines the clinical utility of the CLZ:NDMC ratio to reduce metabolic risk and increase treatment efficacy. The association of the CLZ:NDMC ratio with changes in psychopathology, cognitive functioning, and cardiometabolic burden will be explored, as well as adjunctive treatments and their effects.Expert opinion: The literature suggests a positive association between the CLZ:NDMC ratio and better cardiometabolic outcomes. Conversely, the CLZ:NDMC ratio appears inversely associated with better cognitive functioning but less consistently with other psychiatric domains. The CLZ:NDMC ratio may be useful for predicting and monitoring cardiometabolic adverse effects and optimizing potential cognitive benefits of clozapine. Future studies are required to replicate these findings, which if substantiated, would encourage examination of adjunctive treatments aiming to alter the CLZ:NDMC ratio to best meet the needs of the individual patient, thereby broadening clozapine's clinical utility.


Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Esquizofrenia/tratamento farmacológico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Clozapina/efeitos adversos , Clozapina/análogos & derivados , Clozapina/sangue , Clozapina/farmacocinética , Cognição/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Humanos
2.
Tidsskr Nor Laegeforen ; 139(13)2019 Sep 24.
Artigo em Norueguês, Inglês | MEDLINE | ID: mdl-31556524

RESUMO

BACKGROUND: Norwegian national guidelines recommend that clozapine be offered to patients with schizophrenia after two failed attempts with other antipsychotic drugs. One of the main objectives for the introduction of clinical pathways in mental health care is to provide an equal service to patients irrespective of where in the country they live. We wished to investigate the prescribing level of clozapine in various Norwegian counties. MATERIAL AND METHOD: We retrieved aggregated data from the Norwegian Prescription Database, the Norwegian Patient Registry and Statistics Norway on prescribing of clozapine, number of patients in contact with the specialist health service with the diagnosis schizophrenia, and population figures for 2016. RESULTS: Nationwide in 2016, there were 50 users of clozapine per 100 000 inhabitants (95 % confidence interval (CI) 48-52). The number of users was highest in Troms county (76 (95 % CI 63-89) per 100 000 inhabitants) and lowest in Akershus county (38 (95 % CI 33-43) per 100 000 inhabitants). We found no significant correlation between the prescribing rate for clozapine and the proportion of the population in the county who were undergoing treatment for schizophrenia in the specialist health service. INTERPRETATION: Prescribing of clozapine varies among Norwegian counties and is not correlated with the proportion of the population who are undergoing treatment for schizophrenia in the specialist health service. Different levels of implementation of the national guidelines constitute a possible explanation for the geographic differences.


Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Esquizofrenia/tratamento farmacológico , Adulto , Idoso , Antipsicóticos/uso terapêutico , Clozapina/uso terapêutico , Bases de Dados Factuais , Feminino , Fidelidade a Diretrizes , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Guias de Prática Clínica como Assunto , Sistema de Registros , Adulto Jovem
3.
Psychiatr Danub ; 31(Suppl 3): 543-548, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488788

RESUMO

BACKGROUND: The attitudes of schizophrenic patients toward medications directly impact the treatment compliance. Although noncompliance represents a serious concern in long-term schizophrenia treatment, a detailed information on the factors that impair compliance is still limited. The present study aims to assess the factors related to noncompliance with antipsychotics agents, in long-term treated chronic paranoid schizophrenia patients. SUBJECTS AND METHODS: Two groups of such patients (total number n=162) were analyzed and compared: 1). patients with symptomatic remission on haloperidol (n=32), clozapine (n=40) or olanzapine (n=45), and 2). drug resistant patients (n=45). The mean duration of the disease was 19.3 years. RESULTS: Altogether, in our patient sample, a better drug attitude was found in the olanzapine and clozapine groups. Our findings have also revealed that worse attitude toward antipsychotics correlated with an earlier onset of schizophrenia, younger patient age, shorter duration of the disease, higher burden of symptoms, treatment with a typical antipsychotics, and higher severity of akathisia. CONCLUSION: Our results suggest that detecting factors that influence the patient's attitude toward medications might be helpful for designing targeted educational strategies in chronic schizophrenia patients (particularly those with the high risk of noncompliance), and further trials are warranted to explore this topic.


Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/uso terapêutico , Cooperação do Paciente , Esquizofrenia/tratamento farmacológico , Psicologia do Esquizofrênico , Clozapina/administração & dosagem , Clozapina/uso terapêutico , Haloperidol/administração & dosagem , Haloperidol/uso terapêutico , Humanos , Olanzapina/administração & dosagem , Olanzapina/uso terapêutico , Cooperação do Paciente/psicologia , Cooperação do Paciente/estatística & dados numéricos , Fatores de Risco
8.
Am J Ther ; 26(3): e406-e416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31082865

RESUMO

BACKGROUND: Clozapine is a second-generation antipsychotic typically used for refractory schizophrenia or otherwise psychotic pathology. There are no FDA or manufacturer guidelines for use of clozapine in pediatric population. We investigated the current state of research concerning the use of clozapine in pediatric patients. AREAS OF UNCERTAINTY: We describe consistent calls for more research into the long-term and short-term effects of clozapine use in a young patient population. Despite the strongly supported efficacy, questions concerning clear indications for use and risk-benefit analysis persist. We acknowledge that a more comprehensive meta-analysis would greatly benefit the field. However, this is the first article of its kind for clozapine in recent history, and therefore, serves as a focus and reference point for future, more in-depth analyses. DATA SOURCES: We conducted a search of PubMed, ClinicalKey, PsycINFO, and MEDLINE databases. Keywords used included, in varying combinations: clozapine, off-label, indications, children and adolescent, pediatric, behavioral, suicidality, psychosis, early and very-early onset schizophrenia, side-effect profile, and long-term use. Further criteria and selection are described in Methods below. RESULTS: We describe the documented efficacy of clozapine for the management of refractory psychotic and nonpsychotic symptoms in the pediatric population. The authors highlight the risk of unmanaged early-onset schizophrenia, aggressive or suicidal behavior, and severe nonpsychotic pathology. Unfortunately, these studies are generally small. There is little consistency in when clozapine is prescribed, how long it is administered, and how long patients are followed. Despite the lack of FDA and manufacturer guidelines, clozapine continues to be used for the benefit of young patients. CONCLUSIONS: Indications for prescription of clozapine should be revisited, given the data presented in this manuscript of a low risk-benefit ratio for properly chosen patients. Larger studies should be conducted to provide more statistical power and determine clear guidelines for use, risk of side effects, and long-term adverse events that may arise.


Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Uso Off-Label/normas , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adolescente , Fatores Etários , Agranulocitose/induzido quimicamente , Agranulocitose/epidemiologia , Antipsicóticos/efeitos adversos , Criança , Clozapina/efeitos adversos , Humanos , Seleção de Pacientes , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento
9.
Biomed Res Int ; 2019: 3163502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30956977

RESUMO

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.


Assuntos
Clozapina/análogos & derivados , Modelos Biológicos , Esquizofrenia , Adulto , Idoso , Clozapina/administração & dosagem , Clozapina/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Uruguai
12.
J Mol Neurosci ; 68(2): 311-317, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968339

RESUMO

Antipsychotic drugs, known as the antagonists of dopaminergic receptors, may also affect a large spectrum of other molecular signaling pathways in the brain. Despite the numerous ongoing studies on neurosteroid action and regulation, there are no reports regarding the influence of extended treatment with typical and atypical neuroleptics on brain aromatase (CYP19A1) expression. In the present study, we assessed for the first time aromatase mRNA and protein levels in the brain of rats chronically (28 days) treated with olanzapine, clozapine, and haloperidol using quantitative real-time PCR, end-point RT-PCR, and Western blotting. Both clozapine and haloperidol, but not olanzapine treatment, led to an increase of aromatase mRNA expression in the rat brain. On the other hand, aromatase protein level remained unchanged after drug administration. These results cast a new light on the pharmacology of examined antipsychotics and contribute to a better understanding of the mechanisms responsible for their action. The present report also underlines the complex nature of potential interactions between neuroleptic pharmacological effects and physiology of brain neurosteroid pathways.


Assuntos
Antipsicóticos/farmacologia , Aromatase/genética , Encéfalo/efeitos dos fármacos , Clozapina/farmacologia , Haloperidol/farmacologia , Olanzapina/farmacologia , Animais , Antipsicóticos/administração & dosagem , Aromatase/metabolismo , Encéfalo/metabolismo , Clozapina/administração & dosagem , Haloperidol/administração & dosagem , Masculino , Olanzapina/administração & dosagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Psychopharmacology (Berl) ; 236(6): 1949-1957, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30747254

RESUMO

OBJECTIVE: This study examined the effect of adjunctive telmisartan on body metabolism in clozapine- or olanzapine-treated patients with schizophrenia. METHOD: Each subject had been on stable dose of olanzapine or clozapine for at least 1 month. In a 12-week randomized, double-blind, placebo-controlled study, subjects received either telmisartan (80 mg once per day) or placebo. The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated based on fasting blood levels of insulin and glucose. Fasting blood levels of triglycerides and cholesterols, as well as serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were measured. The whole-body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline and repeated at week 12. RESULTS: Fifty-four subjects were randomized and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). There were no significant differences between the two groups in week 12 changes for HOMA-IR or fasting triglycerides (- 0.18 ± 1.24 vs 0.39 ± 1.39, p = 0.181; - 26 ± 76 vs - 10 ± 81 mg/dL, p = 0.679, respectively) (telmisartan vs placebo). Further, there were no significant between group differences in week 12 changes for other fasting lipids, body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's > 0.100). The DXA assessment showed no significant differences between the two groups in week 12 changes for fat mass, lean mass, or total mass (p's > 0.100). CONCLUSION: In the present study, adjunctive treatment of telmisartan did not seem to improve body metabolism in schizophrenia patients receiving olanzapine or clozapine. The implications for future studies were discussed. CLINICALTRIALS. GOV IDENTIFIER: NCT00981526.


Assuntos
Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Olanzapina/administração & dosagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Telmisartan/administração & dosagem , Adulto , Composição Corporal/efeitos dos fármacos , Composição Corporal/fisiologia , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucose/metabolismo , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Triglicerídeos/sangue
17.
Expert Rev Clin Pharmacol ; 12(3): 219-234, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30700161

RESUMO

INTRODUCTION: This is a comprehensive review of antipsychotic (AP)-induced dysphagia and its complications: choking and pneumonia. Areas covered: Four PubMed searches were completed in 2018. The limited literature includes: 1) 45 case reports of AP-induced dysphagia with pharmacological mechanisms, 2) a systematic review of APs as a risk factor for dysphagia, 3) reviews suggesting adult patients with intellectual disability (ID) and dementia are prone to dysphagia (APs are a risk factor among multiple others), 4) studies of the increased risk of choking in patients with mental illness (APs are a contributing factor), 5) naturalistic pneumonia studies suggesting that pneumonia may contribute to AP-increased death in dementia, and 6) naturalistic studies suggesting that pneumonia may be a major cause of morbidity and mortality in clozapine patients. Expert commentary: The 2005 Food and Drug Administration requirement that package inserts warn of AP-induced dysphagia jumpstarted this area, but current studies are limited by: 1) its naturalistic nature, 2) the lack of dysphagia studies of patients with IDs and dementia on APs, and 3) the assumed indirect association between dysphagia with choking and pneumonia. Future clozapine studies on pneumonia, if they lead to a package insert warning, may have high potential to save lives.


Assuntos
Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Transtornos de Deglutição/induzido quimicamente , Adulto , Obstrução das Vias Respiratórias/etiologia , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Transtornos de Deglutição/complicações , Transtornos de Deglutição/etiologia , Demência/complicações , Rotulagem de Medicamentos , Humanos , Deficiência Intelectual/complicações , Transtornos Mentais/complicações , Pneumonia/etiologia , Fatores de Risco
18.
Clin Drug Investig ; 39(3): 253-273, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30675684

RESUMO

BACKGROUND AND OBJECTIVE: Individuals with severe mental illness experience increased morbidity and mortality as a result of metabolic problems that may partly be related to the adverse effects of antipsychotics. Compared with first-generation antipsychotics, second-generation antipsychotics collectively are considered to have stronger associations with lipid abnormalities, but evidence for this specific claim has not been systematically reviewed. The objective of this review was to evaluate the risk of dyslipidaemia with second-generation versus first-generation antipsychotics amongst individuals with severe mental illness. METHODS: Major electronic databases were searched until November 2018. Studies were eligible if they were cross-sectional, cohort, case-control or interventional, where any individual second-generation antipsychotic was directly compared with first-generation antipsychotics in individuals with severe mental illness, and where lipid metabolism was a primary or secondary outcome. The evidence was reviewed and appraised according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: In total, 18 studies were eligible. The reported associations between second-generation antipsychotics vs. first-generation antipsychotics with dyslipidaemia were inconsistent, with high variability between studies and only a full qualitative synthesis was feasible. We had sufficient data, however, to undertake limited meta-analyses for clozapine, olanzapine and risperidone, all showing mildly elevated associations with dyslipidaemia "caseness" (clozapine, odds ratio 1.26, 95% confidence interval 1.16-1.38; olanzapine, odds ratio 1.29, 95% confidence interval 0.89-1.87; risperidone, odds ratio 1.05, 95% confidence interval 0.80-1.37) compared with first-generation antipsychotics, but heterogeneity was high (all I2 > 50%, p < 0.05). Clozapine was also associated with increased triglycerides (standardised mean difference = 0.51, 95% confidence interval 0.21-0.81, I2 = 5.74%), but not with cholesterol. Compared with haloperidol, neither olanzapine nor risperidone was associated with statistically significant increases in cholesterol or triglycerides. CONCLUSIONS: There was considerable variation in study design and methodologies. Determining the comparative risk of second-generation vs. first-generation antipsychotics as a group of antipsychotics for lipid dysregulation may be of limited clinical utility, as drugs from either group have the potential to cause such adversity to varying degrees. It is therefore more valuable to consider the metabolic risks of specific antipsychotics rather than focusing on collective metabolic effects belonging to either antipsychotic group.


Assuntos
Antipsicóticos/efeitos adversos , Lipídeos/sangue , Transtornos Mentais/tratamento farmacológico , Antipsicóticos/administração & dosagem , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Humanos , Olanzapina/administração & dosagem , Olanzapina/efeitos adversos , Risperidona/administração & dosagem , Risperidona/efeitos adversos
19.
Mol Psychiatry ; 24(3): 328-337, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30647433

RESUMO

Individuals of African ancestry in the United States and Europe are at increased risk of developing schizophrenia and have poorer clinical outcomes. The antipsychotic clozapine, the only licensed medication for treatment-resistant schizophrenia, is under-prescribed and has high rates of discontinuation in individuals of African ancestry, due in part to increased rates of neutropenia. The genetic basis of lower neutrophil levels in those of African ancestry has not previously been investigated in the context of clozapine treatment. We sought to identify risk alleles in the first genome-wide association study of neutrophil levels during clozapine treatment, in 552 individuals with treatment-resistant schizophrenia and robustly inferred African genetic ancestry. Two genome-wide significant loci were associated with low neutrophil counts during clozapine treatment. The most significantly associated locus was driven by rs2814778 (ß = -0.9, P = 4.21 × 10-21), a known regulatory variant in the atypical chemokine receptor 1 (ACKR1) gene. Individuals homozygous for the C allele at rs2814778 were significantly more likely to develop neutropenia and have to stop clozapine treatment (OR = 20.4, P = 3.44 × 10-7). This genotype, also termed "Duffy-null", has previously been shown to be associated with lower neutrophil levels in those of African ancestry. Our results indicate the relevance of the rs2814778 genotype for those taking clozapine and its potential as a pharmacogenetic test, dependent on the outcome of additional safety studies, to assist decision making in the initiation and on-going management of clozapine treatment.


Assuntos
Clozapina/efeitos adversos , Neutropenia/induzido quimicamente , Neutropenia/genética , Grupo com Ancestrais do Continente Africano/genética , Alelos , Antipsicóticos/uso terapêutico , Clozapina/administração & dosagem , Sistema do Grupo Sanguíneo Duffy/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Neutropenia/sangue , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/patologia , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Fatores de Risco , Esquizofrenia/genética
20.
Pharmacogenomics J ; 19(2): 211-218, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29298994

RESUMO

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.


Assuntos
Agranulocitose/epidemiologia , Agranulocitose/genética , Clozapina/efeitos adversos , Esquizofrenia/epidemiologia , Adulto , Agranulocitose/induzido quimicamente , Agranulocitose/patologia , Alelos , Clozapina/administração & dosagem , Estudos de Coortes , Análise Custo-Benefício , Feminino , Predisposição Genética para Doença , Genótipo , Antígenos HLA-B/genética , Cadeias beta de HLA-DQ/genética , Humanos , Masculino , Pessoa de Meia-Idade , Testes Farmacogenômicos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
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