Creer en la clozapina: fe y evidencias / Believing in clozapine: faith and evidence

Muchos investigadores y profesionales creen que la clozapina es el tratamiento más eficaz para los pacientes con esquizofrenia. La clozapina se propone como el tratamiento de elección para la esquizofrenia resistente al tratamiento (TRS) en muchas guías clínicas. Sin embargo, los estudios cada vez apoyan menos esta percepción y cuestionan que haya una verdadera diferencia entre distintos antipsicóticos en cuanto a mejoría funcional y recuperación. En este artículo se muestran y discuten las pruebas a favor de la clozapina y se analiza el estudio de Kane et al. (1988), el ensayo en el que la clozapina obtiene sus mejores resultados. Se concluye que, según la investigación actual, no hay pruebas para defender una superioridad relevante de la clozapina sobre otros antipsicóticos. El estudio de Kane muestra una diferencia a su favor pequeña y poco relevante, teniendo además un diseño sesgado que induce los resultados obtenidos. No obstante, nada de esto parece hacer cambiar la opinión y la práctica de investigadores y clínicos. Se reflexiona acerca del porqué de este estado de cosas y se proponen cambios significativos en la clínica e investigación actual en psiquiatría dirigidos al desarrollo de una clínica colaborativa que incorpore las psicoterapias y el apoyo en la comunidad, y se oriente hacia la funcionalidad, la recuperación y la calidad de vida

Many researchers and clinicians think that clozapine is the most effective treatment for patients with schizophrenia. Clozapine is proposed as the treatment of choice for Treatment-Resistant Schizophrenia (TRS) in many clinical guidelines. However, most of the studies do not support this conviction and put into question a real difference among antipsychotics in terms of functional improvement and recovery. In this article, we examine and discuss the evidence of clozapine’s higher efficacy; especially, the study of Kane et al. (1988), the trial that found best results for clozapine. According to current research in the field, we conclude that there is no evidence to support clozapine’s superiority over other antipsychotics. The study of Kane only shows a small, but not relevant, advantage for clozapine. In addition, its design is biased, somehow inducing the results achieved. Despite this, the beliefs and practices of researchers and clinicians have not changed. We discuss the reasons for this state of things and suggest some significant changes in the clinical practice and in research. These changes are aimed at the development of a collaborative clinical practice that integrates psychotherapies and support in the community, and is oriented towards functionality, recovery, and quality of life

[A current view on the history of atypical antipsychotics]. / Sovremennyi vzgliad na istoriiu atipichnykh antipsikhoticheskikh sredstv.

Based on the analysis of the original literature, the author for the first time systemizes the data on the story of atypical antipsychotic drugs. The history of introduction of the first atypical neuroleptics - clozapine and sulpiride, which launched the dichotomic development of psychopharmacology of atypical antipsychotics, is described. Historical facts on the introduction into practice of different sulpiride- and clozapine-like neuroleptics as well as the relationship of their history with the elaboration of dopamine and serotonin hypotheses of mechanisms of action of antipsychotics are presented. The author analyzes the efficacy and tolerability of treatment with different atypical neuroleptics. An importance of evidence-based medicine principles in the history of atypical antipsychotics is described. A significance of the history of some atypical and typical (pericyazine) neuroleptics in the evolution of conceptions on the validity of evidence-based medicine in psychiatry is evaluated. Main stages in the history of typical and atypical antipsychotics are determined.

Determining Whether a Definitive Causal Relationship Exists Between Aripiprazole and Tardive Dyskinesia and/or Dystonia in Patients With Major Depressive Disorder, Part 2: Preclinical and Early Phase Human Proof of Concept Studies.

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20 mg/d for 2 wk followed by 10 mg/d for 4 wk instead of the intended dose of 2 mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential--if any--to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and "real-world" data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an example and discussing why such studies are rarely done.

Quo Vadis Clozapine? A Bibliometric Study of 45 Years of Research in International Context.

We have carried out a bibliometric study about the international scientific publications on clozapine. We have used the EMBASE and MEDLINE databases, and we applied bibliometric indicators of production, as Price's Law on the increase of scientific literature. We also calculated the participation index (PI) of the different countries. The bibliometric data have also been correlated with some social and health data from the 12 most productive countries in biomedicine and health sciences. In addition, 5607 original documents dealing with clozapine, published between 1970 and 2013, were downloaded. Our results state non-fulfilment of Price's Law, with scientific production on clozapine showing linear growth (r=0.8691, vs. r=0.8478 after exponential adjustment). Seven of the 12 journals with the highest numbers of publications on clozapine have an Impact Factor>2. Among the countries generating clozapine research, the most prominent is the USA (PI=24.32), followed by the UK (PI=6.27) and Germany (PI=5.40). The differences among countries on clozapine research are significantly related to economic variables linked to research. The scientific interest in clozapine remains remarkable, although after the application of bibliometric indicators of production, a saturation point is evident in the growth of scientific literature on this topic.

Clozapine in China.

Clozapine remains one of the most commonly used antipsychotic medications in China. As China has the largest population internationally on clozapine treatment, its experience and research findings are of keen interest to Western psychiatrists. However, most of the related papers have hitherto been published only in Chinese language journals. Here we review mainly Chinese-language publications on the use of clozapine in China. A descriptive study based on literature identified from searches of Medline and the China National Knowledge Infrastructure (CNKI) databases (1979-2007), and other hand-picked references. Unlike the situation in other countries, clozapine is still widely used for a number of psychiatric disorders in China, though the prescription of other second-generation antipsychotics (SGAs) is also increasing. About 25-60% of all treated patients with schizophrenia receive clozapine; and clozapine is preferred by some as a first-line treatment for schizophrenia. Clozapine is also used for other conditions such as mania, treatment-resistant depression and drug abuse. The average daily dose is between 200 and 400 mg. The incidence of leukopenia is 3.92% and agranulocytosis 0.21% in China, with about one third of reported cases of patients with agranulocytosis dying. Weight gain and clozapine-associated diabetes are also commonly reported in the Chinese population. Clozapine is currently the most commonly used treatment for schizophrenia in China. Chinese psychiatrists need to pay more attention to its potential toxic side effects when they make drug choices.

The history of clozapine and its emergence in the US market: a review and analysis.

Clozapine is known as the first 'atypical' medication and is effective in people who have treatment-resistant schizophrenia. Its 1990 emergence in the USA was marked by considerable controversy over its high cost, due in large part to having been both the first new antipsychotic medication to come to market in over a decade and the need for comprehensive safety monitoring within a decentralized health system. This paper traces the history of clozapine's discovery and development in Europe, its part in the 1975 Finnish agranulocytosis scare, and its subsequent volatile emergence in the USA. Analyses examine peripheral forces at the time, particularly the influence of political, corporate, medical and societal forces which shaped its market course.

Starting clozapine in the community: a UK perspective.

Clozapine is the most effective antipsychotic available for the treatment of schizophrenia that has proved resistant to other medications and the only antipsychotic licensed for this indication. Although the drug is increasingly being used more widely in patients with schizophrenia and with other psychiatric and neurological disorders, it is still underused. The main reasons for this are that it can cause adverse effects such as weight gain and sedation, and the need for regular blood test monitoring because of the risk of agranulocytosis. While these hurdles are unavoidable, another problem in the UK has been the historical practice of admitting patients to hospital to initiate treatment with clozapine. However, protocols have now been developed for both home and day-hospital initiation. The experience of one assertive community treatment team of starting clozapine in patients' own homes has been positive, with no major adverse events reported. This approach is, however, extremely demanding of staff resources and for many services the use of day-hospitals to initiate treatment with clozapine is more appropriate. Research into staff and patients' views about community initiation of clozapine, and its economic costs, would be welcome.

Happy birthday neuroleptics! 50 years later: la folie du doute.

Given that we are celebrating the 50th birthday of neuroleptics introduction in psychiatry, the author proposes to take a look at certain results related to therapeutic practice. After a brief chronological literature review of the clinical practices and theoretical models that have controlled drug treatment of schizophrenia, the author presents a critical review of four meta-analyses. Since Delay, Deniker and Harl's initial report, the story of neuroleptics comprises several periods. In 1963, the hyper-dopaminergic theory of psychoses was proposed. Another period began with models mainly based on the serotonin/dopamine relative blockade receptor hypothesis. More recently, a new framework to understand the differential effect of antipsychotics is related to the appropriate modulation (e.g., fast dissociation) of the D2 receptor alone. The concept of atypicality has become a new vista for research and to market new compounds. However, after 50 years of neuroleptic drugs, are we able to answer the following simple questions: Are neuroleptics effective in treating schizophrenia? Is there a difference between atypical and conventional neuroleptics? How do the efficacy and safety of newer antipsychotic drugs compare with those of clozapine? Actually, the answers yielded by these simple questions by meta-analysis should elicit in us a good deal of humility. If we wish to base psychiatry on evidence-based medicine, we run a genuine risk in taking a closer look at what has long been considered fact. Each psychiatrist must continue to be critical, sceptical, optimistic (not overoptimistic) and to learn in order to integrate the positive aspects of our growing knowledge base.

Cinqüenta anos de medicamentos antipsicóticos em psiquiatria: III. fenotiazinas piperidínicas / Fifty years of antipsychotic drugs in psychiatry: III. piperidine phenothiazines

Na iminência de uma nova era na terapêutica psiquiátrica com a redescoberta da clozapina e a introduçäo dos novos antipsicóticos atípicos, é tempo de um inventário das substâncias desenvolvidas nos últimos cinqüenta anos. É feito um breve histórico dos antecedentes dos antipsicóticos tradicionais na era que se encerra. As substâncias introduzidas até o presente poderiam ser reunidas nos grupos tradicionais - fenotiazinas (alifáticas, piperazínicas e piperidínicas), tioxantenos, butirofenonas, difenilbutilpiperidinas, benzaminas, indóis, dibenzoxazepinas - e nos grupos químicos mais recentes - diidroindolonas, dbenzodiazepinas, benzisoxazólicos -, além de compostos ainda em desenvolvimento. Neste artigo, o terceiro de uma série concebida com esta finalidade, säo examinados os derivados fenotiazínicos com cadeia lateral piperidínica que tenham demonstrado utilidade na prática clínica e ou guardem importância histórica: mepazina, mesoridazina, nortioridazina, piperacetazina, propericiazina, sulforidazina e toridazina. Com base em bibliografia básica específica, säo discutidos aspectos técnicos e revisado o conhecimento científico acumulado através da experimentaçäo e utilizaçäo clínica destes compostos, desde seu lançamento até a presente data, com informaçöes sistemáticas sobre fórmula estrutural, fórmula molecular, nomes químicos, nomes de fantasia e códigos de cada composto, além de dados sobre eventual comercializaçäo no país

A historical perspective of clozapine.

Having challenged the established view that extrapyramidal symptoms are an intrinsic feature of antipsychotic activity, clozapine was developed as the first atypical antipsychotic with activity against both the positive and negative symptoms of schizophrenia. Following its partial withdrawal due to concerns over agranulocytosis, clozapine was reintroduced in response to pressure from psychiatrists and is now used worldwide in patients with treatment-resistant schizophrenia, having demonstrated its superiority over typical antipsychotic agents. This, combined with its low propensity to cause tardive dyskinesia, has transformed the management of patients with schizophrenia. This article outlines the history of clozapine's development, from its discovery in 1958 to its current position as the "gold standard" therapy for treatment-resistant schizophrenia.