Brazilian guidelines for the management of psychomotor agitation. Part 2. Pharmacological approach

Objective: To present the essential guidelines for pharmacological management of patients with psychomotor agitation in Brazil. Methods: This is a systematic review of articles retrieved from the MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and SciELO databases published from 1997 to 2017. Other relevant articles in the literature were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools. Results: Of 5,362 articles retrieved, 1,731 abstracts were selected for further reading. The final sample included 74 articles that met all inclusion criteria. The evidence shows that pharmacologic treatment is indicated only after non-pharmacologic approaches have failed. The cause of the agitation, side effects of the medications, and contraindications must guide the medication choice. The oral route should be preferred for drug administration; IV administration must be avoided. All subjects must be monitored before and after medication administration. Conclusion: If non-pharmacological strategies fail, medications are needed to control agitation and violent behavior. Once medicated, the patient should be monitored until a tranquil state is possible without excessive sedation. Systematic review registry number: CRD42017054440.

Recent evidence and potential mechanisms underlying weight gain and insulin resistance due to atypical antipsychotics

Objective: Atypical antipsychotics (AAPs) promote obesity and insulin resistance. In this regard, the main objective of this study was to present potential mechanisms and evidence concerning side effects of atypical antipsychotics in humans and rodents. Method: A systematic review of the literature was performed using the MEDLINE database. We checked the references of selected articles, review articles, and books on the subject. Results: This review provides consistent results concerning the side effects of olanzapine (OL) and clozapine (CLZ), whereas we found conflicting results related to other AAPs. Most studies involving humans describe the effects on body weight, adiposity, lipid profile, and blood glucose levels. However, it seems difficult to identify an animal model replicating the wide range of changes observed in humans. Animal lineage, route of administration, dose, and duration of treatment should be carefully chosen for the replication of the findings in humans. Conclusions: Patients undergoing treatment with AAPs are at higher risk of developing adverse metabolic changes. This increased risk must be taken into account when making decisions about treatment. The influence of AAPs on multiple systems is certainly the cause of such effects. Specifically, muscarinic and histaminergic pathways seem to play important roles. .

Comparación del efecto de la terapia prolongada con antipsicóticos atípicos o convencionales en la incidencia de diabetes mellitus 2: Revisión sistemática y metaanálisis / Risk of type 2 diabetes mellitus among users of atypical antipsychotic drugs or conventional treatment: Systematic review

Atypical antipsychotic drugs have less extra pyramidal side effects and are more effective to control the clinical manifestations of schizophrenia. However, their use may be associated to a higher incidence of weight gain, dyslipidemia, metabolic syndrome, glucose intolerance and type 2 diabetes mellitus. We performed a systematic literature search to evaluate the risk of type 2 diabetes mellitus incidence associated to the use of atypical antipsychotic drugs, compared to conventional treatment. If users of all types of atypical antipsychotic drugs are compared with users of conventional treatment, no significant differences in the incidence of type 2 diabetes mellitus were observed. If individual drugs are evaluated, clozapine and risperidone are associated with a higher risk of diabetes than haloperidol. Quetiapine is associated with a lower risk of diabetes than conventional treatment. The quality of the evidence found was low; therefore, new studies should been performed.

Cataract occurrence in patients treated with antipsychotic drugs / Ocorrência de catarata em pacientes tratados com antipsicóticos

OBJECTIVE: Typical antipsychotic drugs, mainly phenothiazines, have been associated with cataract formation for over forty years. Recently, there has been a concern about atypical antipsychotic drugs' potential for inducing this lenticular pathology. Accordingly, we sought to determine the cataract rate and other ocular side effects in patients on long-term therapy with antipsychotic drugs. METHOD: Eighty outpatients with DSM-IV diagnosis of schizophrenia from two settings who met pre determined inclusion criteria were submitted to an ophthalmological evaluation for ocular abnormalities with emphasis in the lens and cornea. They were divided into two groups: group 1 (n = 52) comprised patients who had been predominantly on typical antipsychotics for at least two years and group 2 (n = 28) patients who had been predominantly on atypical antipsychotics for at least two years. RESULTS: Cataract was found in 26 patients (33 percent) with predominance of anterior capsular cataract. The cataract rate among patients from group 1 (40 percent) was higher than among those from group 2 (18 percent). Visual acuity was reduced in 21 patients (26 percent). No changes were observed neither in the cornea nor in the retina. CONCLUSIONS: Patients using antipsychotic drugs should be submitted to a periodic ophthalmological evaluation.

OBJETIVO: Os antipsicóticos típicos, principalmente as fenotiazinas, têm sido associados à formação de catarata há mais de quarenta anos. Nos últimos anos, tem existido um questionamento acerca do potencial dos antipsicóticos atípicos de induzir essa patologia lenticular. Neste estudo, buscamos determinar a taxa de catarata e de outros efeitos oculares adversos em pacientes em uso de antipsicóticos a longo prazo. MÉTODO: Oitenta pacientes tratados ambulatorialmente com diagnóstico de esquizofrenia segundo o DSM-IV, de dois centros, que preencheram os critérios de inclusão pré determinados foram submetidos a uma avaliação oftalmológica para pesquisa de alterações oculares com ênfase no cristalino e na córnea. Eles foram divididos em dois grupos: o grupo 1 (n = 52) era formado por pacientes que tinham usado predominantemente antipsicóticos típicos por pelo menos dois anos e o grupo 2 (n = 28) por pacientes que tinham usado predominantemente antipsicóticos atípicos por pelo menos dois anos. RESULTADOS: Catarata foi encontrada em 26 pacientes (33 por cento) com predomínio de catarata capsular anterior. A taxa de catarata entre os pacientes do grupo 1 (40 por cento) foi maior do que naqueles do grupo 2 (18 por cento). A acuidade visual estava reduzida em 21 pacientes (26 por cento). Não foram encontradas alterações nem na córnea nem na retina. CONCLUSÕES: Pessoas em uso de antipsicóticos devem ser submetidas à avaliação oftalmológica periódica.

Cost analysis of the treatment of schizophrenia in Thailand: a simulation model comparing olanzapine, risperidone, quetiapine, ziprasidone and haloperidol.

OBJECTIVES: To compare the annual costs of treating schizophrenia with four atypical antipsychotics-olanzapine, risperidone, quetiapine and ziprasidone and one typical antipsychotic: haloperidol in Thailand MATERIAL AND METHOD: The present study used a cost analysis model. The model simulated treatment of schizophrenics for 12 months with the data from international literature review. A comprehensive search of pharmacoeconomic literature was carried out in order to identify studies to be included in the present review. Model parameter used data from the searches of 1175 publications but merely 31 of them were relevant to the objectives of the present study. Costs associated with olanzapine, risperidone, quetiapine, ziprasidone and haloperidol therapy were calculated over a period of 12-months. This analysis included health care costs and costs associated with productivity losses. RESULTS: The total cost from the cost analysis was as follows: Haloperidol gives the lowest annual cost of THB 86,004, within the atypical antipsychotics, Olanzapine produces an annual cost of THB 103,225 compared to THB 104,564 with risperidone, 118,314 with ziprazidone. The cost ranges up to THB 146,526 for quetiapine therapy. CONCLUSION: Treatment with olanzapine appears to be more cost-effective than that with the other atypical antipsychotics in Thai schizophrenic patients.

A importância dos antipsicóticos de segunda geração na prática clínica / The importance of the second genetation of antipsychotics in the clinical practice

Os antipsicóticos foram introduzidos na década de 50. A maioria das classes disponíveis, naquele momento, apresentava grandes taxas de efeitos extrapiramidais. Com isso houve a necessidade do desenvolvimento de compostos que reduzissem esse efeito colateral. A clozapina éo primeiro composto da segunda geração, e apesar de apresentar pequena probabilidade d desenvolvimento de sintomas extrapiramidais, o risco de agranulicitose acaba limitando muito o seu uso. Outras drogas de segunda geração como risperidona, olanzapina, quetiapina e mais recentemente riprasidona encontram-se disponíveis na prática clínica, sem causar os efeitos hematológicos indesejáveis da clozapina. Esse artigo os autores discutem o perfil desses compostos e sua aplicação na prática clínica.

Guías para el tratamiento farmacológico de la esquizofrenia / Guidelines for the pharmacological treatment of schizophrenia

En este trabajo se revisan las guías más recientes para el tratamiento farmacológico de la esquizofrenia. En el análisis de las tendencias terapéuticas actuales destacan el surgimiento de los antipsicóticos atípicos como tratamiento de primera línea, la consolidación del papel de la clozapina como tratamiento de elección de la esquizofrenia resistente, y la reevaluación de la utilidad de los antipsicóticos convencionales o neurolépticos. Se analiza el algoritmo de tratamiento de la esquizofrenia del Texas Medication Algorithm Project (TMAP) y se sugiere algunas variantes en su utilización práctica

Antipsicóticos atípicos / Atypical antipsychotics

Los antipsicóticos atípicos han representado un aporte para el tratamiento de las psicosis, particularmente de la esquizofrenia. En este artículo se discute el concepto de antipsicótico y se revisan las características clínicas y farmacológicas de estos medicamentos. El concepto de atipicidad puede ser considerado desde un punto de vista clínico o farmacológico. Desde el punto de vista clínico implica efectividad sobre los síntomas positivos, negativos, afectivos y cognitivos de la esquizofrenia, además de menores afectos colaterales. Desde el punto de vista farmacológico implica una acción diferencial sobre distintos receptores cerebrales. En la segunda parte del artículo se revisan las características clínica y farmacológicas de la clozapina, risperidona, olanzapina, quetiapina, amisulprida, ziprasidona, zotepina, loxapina y otros antipsicóticos en etapas avanzadas de investigación

Antipsicóticos, diabetes y control de peso / Antipsychotics, diabetes and body weight control

Los pacientes con esquizofrenia tienen una mayor prevalencia de obesidad, la que se puede acentuar con el uso de nuevos antipsicóticos. Esto puede disminuir la aceptación del tratamiento y favorecer el desarrollo de patologías relacionadas al síndrome de resistencia insulínica, como diabetes tipo 2, la hipertensión arterial y las dislipidemias, aumentando el riesgo de enfermedades cardiovasculares. Entre los fármacos antipsicóticos aquellos que más se relacionan al incremento de peso son la clozapina y la olanzapina, en menor grado la risperidona, la zotepina, sertindole y quetiapina, mientras la ziprasidona no lo modifica. Esta respuesta estaría relacionada al perfil farmacológico de las drogas. En consecuencia, es recomendable evaluar en estos pacientes el peso, la presión arterial, controlando también glicemias y perfiles de lípidos. para un diagnóstico y tratamiento precoz. En estos casos se debe indicar un consejo dietético y hábitos de vida saludables y, eventualmente, un cambio en el antipsicótico indicado

Pharmacology of new antipsychotic drugs

The research on antipsychotic drugs with more efficacy and tolerance was an important subject during the last years. Numerous drugs were studied. Some of them could be new treatment strategies compared with the classical dopaminergic antagonists. The limbic and frontal cortex specificity leads to a better tolerance as well as a better efficacy on negative symptoms with better quality of life for patients and at the end a decrease of the burden of schizophrenia. It was shown that new antipsychotic drugs decreased by 10% rehospitalisation of responders or non-responders. The profile of the new drugs leads to a better dopaminergic balance a decrease in spontaneous instability, and negative symptoms as well as limiting fluctuations between positive and negative symptoms. They seem to act as psychic stabilizers. The pharmacology of these new antipsychotic drugs is reviewed

El concepto de atipicidad en los antipsicóticos / The concept of atypicity in antipsychotics

En este trabajo se revisan algunos aspectos farmacológicos de los fármacos antipsicóticos y se describen las características de los antipsicóticos típicos y atípicos. Se define como un atipsicótico atípico a un fármaco de elevada potencia antipsicótica, que produce mínimos efectos extrapiramidales, que no causa disquinesia tardía y que solo produce discreta elevación de la prolactina sérica. Se discuten las hipótesis neuroquímicas que se han formulado para explicar la atipicidad de la nueva generación de antipsicóticos

Decanoato de flupentixol versus otros neurolépticos en esquizofrénicos crónicos / Flupentixol decanoate versus other neuroleptics in chronic schizophrenia

El estudio fue realizado en 80 pacientes ambulatorios del Servicio de Psiquiatría del Hospital Salvador (Santiago, Chile) con diagnóstico de esquizofrenia crónica según los criterios del DSM-IV. 40 pacientes fueron tratados con decanoato de flupentixol (como monoterapia neuroléptica). Los 40 restantes (grupo control) fueron tratados con uno o más de los siguientes neurolépticos: clorpromazina, haloperidol, tioridazina, decanoato de flufenazina. Ambos grupos fueron evaluados en entrevistas psiquiátricas y psicológicas utilizando 7 escalas estandarizadas. El uso de decanoato de flupentixol redujo los síntomas positivos y negativos que caracterizan a la esquizofrenia, corroborado por escalas BPRS y CGI.La adhesión al tratamiento con decanoato de flupentixol fue mejor y los efectos colaterales fueron escasos. El grupo control requirió el uso de uno o más neurolépticos para lograr la estabilización o reducción de los síntomas, con la consecuente presentación de efectos colaterales en un mayor número de casos. Finalmente, los resultados positivos obtenidos con decanoato de flupentixol están relacionados con la intensidad de la sintomatología. La efectividad de la medicación fue interior en los pacientes que desarrollaron crisis psicóticas y/o en los pacientes resistentes al tratamiento neuroléptico

Associaçäo entre níveis sanguíneos dos antipsicóticos e resposta clínica: meta-análise sobre a questäo da janela terpêutica / Relationships among blood levels of the antipsychotics and clinical response: meta-analysis about the therapeutic windows

Existem, atualmente, cerca de 60 estudos sobre a associaçäo entre os níveis sanquineos dos neurolépticos e a resposta clínica. Haloperidol. o mais amplamente estudado, é o único antipsicótico que permite conclusöes mais decisivas. vários autores sugeriram que a acentuada falta de concordância entre os diferentes estudos resulta da heterogeneidade da qualidade metodológica desses estudos. Realizamos aqui uma meta-análise qualitativa e quantitativa. Na primeira, propusemos o sistema baseado em escores para avaliar a qualidade dos estudos. De acordo com este sistema, nenhum (0/19) dos estudos aos quais foi atribuído o escore < 0,60 foi capaz de demonstrar a ocorrência de janela terapêutica, em comparaçäo com 50 por cento (10/20) daqueles com escore > 0.60 (p=0.0003, teste exato de Fisher). Os estudos que demonstraram a janela terapêutica durante o tratamento com haloperidol foram aqueles com amostras > 20 casos - resultado com tendência à significância estatística (p=0.07)-, e aqueles cujos pacientes foram tratados com doses fixas ou faixas de concentraçäo fixas (p=0.001). O diagnóstico de esquizofrenia näo pareceu ser condiçäo exclusiva, em comparaçäo com aqueles que também incluíram pacientes com transtornos esquizofreniforme e esquizoafetivo (p=0.72). De acordo com a análise de regressäo logística, apenas o regime de dose fixa explicou significativamente a presença da janela terapêutica. Esta análise qualitativa das publicaçöes sobre os níveis sanguíneos de haloperidol e a resposta terapêutica parece indicar a ocorrência de um limite superior de eficácia. Após a análise qualitativa, realizamos a síntese quantitativa dos dados presentes nos estudos que forneceram, para cada paciente, as informaçöes sobre os níveis sanguíneos do haloperidol e a melhora clínica. Foram testadas todas as janelas terapêuticas sugeridas na literatura, por diferentes autores. Identificou-se, com base nesta análise, a faixa de concentraçäo terapêutica entre 4-26 ng/ml (OR= 1,84, p= 0.007). Aqui, novamente, os resultados foram confirmados pela análise de regressäo logística (OR= 2,21,p=0.0001), controlando as variáveis diagnóstico, regime posológico e presença de washout. Os níveis sanguíneos acima de 26 ng/ml parecem reduzir o efeito terapêutico do haloperidol, por mecanismo farmacodinâmico ainda näo compreendido