Clozapine for psychotic disorders in adults with intellectual disabilities

  • Review
  • Intervention

Authors


Abstract

Background

Psychosis is three times more common in people with an intellectual disability than in those without an intellectual disability. A low intelligence quotient (IQ) is a defining characteristic for intellectual disability and a risk factor for poor outcome in psychosis. Clozapine is recommended for treatment-resistant psychosis. The effect of psychotropic medication can be different in people with intellectual disability; for example, they may be more prone to side effects. People with an intellectual disability and psychosis form a special subgroup and we wanted to examine if there is randomised controlled trial (RCT) data in this population to support the use of clozapine.

Objectives

To determine the effects of clozapine for treating adults with a dual diagnosis of intellectual disability and psychosis.

Search methods

We searched CENTRAL, Ovid MEDLINE, Embase and eight other databases up to December 2014. We also searched two trials registers, the Cochrane Schizophrenia Group's Register of Trials, and contacted the manufacturers of clozapine.

Selection criteria

RCTs that assessed the effects of clozapine, at any dose, for treating adults (aged 18 years and over) with a dual diagnosis of intellectual disability and psychotic disorder, compared with placebo or another antipsychotic medication.

Data collection and analysis

Three review authors independently screened all titles, abstracts and any relevant full-text reports against the inclusion criteria.

Main results

Of the 1224 titles and abstracts screened, we shortlisted 38 full-text articles, which we subsequently excluded as they did not meet the inclusion criteria. These studies were not RCTs. Consequently, no studies are included in this Cochrane review.

Authors' conclusions

There are currently no RCTs that assess the efficacy and side effects of clozapine in people with intellectual disabilities and psychoses. Given the use of clozapine in this vulnerable population, there is an urgent need for a RCT of clozapine in people with a dual diagnosis of intellectual disability and psychosis to fill the evidence gap.

Resumen

Clozapina para los trastornos psicóticos en adultos con discapacidades intelectuales

Antecedentes

La psicosis es tres veces más frecuente en las personas con una discapacidad intelectual que en las que no presentan una discapacidad intelectual. Un coeficiente de inteligencia (CI) bajo es una característica definitiva de discapacidad intelectual y un factor de riesgo de resultado deficiente en la psicosis. La clozapina se recomienda para la psicosis resistente al tratamiento. El efecto de la medicación psicotrópica puede ser diferente en los pacientes con discapacidad intelectual; por ejemplo, pueden ser más propensos a los efectos secundarios. Los pacientes con una discapacidad intelectual y psicosis forman un subgrupo especial y se deseó examinar si hay datos de ensayos controlados aleatorios (ECA) en esta población para apoyar la administración de clozapina.

Objetivos

Determinar los efectos de la clozapina para tratar a adultos con un diagnóstico dual de discapacidad intelectual y psicosis.

Métodos de búsqueda

Se hicieron búsquedas en CENTRAL, Ovid MEDLINE, Embase y en otras ocho bases de datos hasta diciembre 2014. También se buscó en dos registros de ensayos, el registro de ensayos del Grupo Cochrane de Esquizofrenia y se estableció contacto con los fabricantes de la clozapina.

Criterios de selección

ECA que evaluaran los efectos de la clozapina a cualquier dosis para tratar a adultos (18 años de edad y más) con un diagnóstico dual de discapacidad intelectual y trastorno psicótico, en comparación con placebo u otro antipsicótico.

Obtención y análisis de los datos

Tres revisores examinaron de forma independiente todos los títulos, resúmenes y el texto completo de cualquier informe relevante contra los criterios de inclusión.

Resultados principales

De los 1224 títulos y resúmenes revisados, se preseleccionaron 38 artículos a texto completo que posteriormente se excluyeron porque no cumplieron los criterios de inclusión. Estos estudios no eran ECA. Por lo tanto, no se ha incluido ningún estudio en esta revisión Cochrane.

Conclusiones de los autores

Actualmente no hay ECA que evalúen la eficacia y los efectos secundarios de la clozapina en los pacientes con discapacidades intelectuales y psicosis. Debido a la administración de clozapina en esta población vulnerable, hay una necesidad urgente de un ECA de clozapina en pacientes con un diagnóstico dual de discapacidad intelectual y psicosis para completar las brechas en las pruebas.

Résumé scientifique

Clozapine pour le traitement des troubles psychotiques chez les adultes souffrant de déficiences intellectuelles

Contexte

La psychose est trois fois plus fréquente chez les personnes présentant une déficience intellectuelle que chez celles sans déficience intellectuelle. Un faible quotient intellectuel (QI) est une caractéristique distinctive pour la déficience intellectuelle et un facteur de risque de mauvais résultats de la psychose. La clozapine est recommandée pour la psychose résistante au traitement. L'effet d'un médicament psychotrope peut être différent chez les personnes souffrant de déficience intellectuelle ; par exemple, elles pourraient être plus sujettes à des effets secondaires. Les personnes présentant une déficience intellectuelle et une psychose forment un sous-groupe spécifique et nous voulions examiner s'il existe pour cette population des données d'essais contrôlés randomisés (ECR) permettant de soutenir l'utilisation de la clozapine.

Objectifs

Déterminer les effets de la clozapine pour le traitement des adultes présentant un diagnostic mixte de déficience intellectuelle et de psychose.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL, Ovid MEDLINE, Embase et huit autres bases de données jusqu'en décembre 2014. Nous avons également effectué des recherches dans deux registres d'essais, le registre d'essais du groupe Cochrane sur la schizophrénie, et contacté les fabricants de la clozapine.

Critères de sélection

ECR ayant évalué les effets de la clozapine, à n'importe quelle dose, pour le traitement des adultes (âgés de 18 ans et plus) présentant un diagnostic mixte de déficience intellectuelle et de troubles psychotiques, par rapport à un placebo ou à un autre traitement antipsychotique.

Recueil et analyse des données

Trois auteurs de la revue ont indépendamment examiné tous les titres, les résumés et les rapports complets pertinents selon les critères d'inclusion.

Résultats principaux

Sur les 1224 titres et extraits examinés, nous avons sélectionné 38 articles complets, que nous avons finalement exclus car ils ne répondaient pas aux critères d'inclusion. Ces études n'étaient pas des ECR. Par conséquent, aucune étude n'a été incluse dans cette revue Cochrane.

Conclusions des auteurs

Il n'existe actuellement aucun ECR évaluant l'efficacité et les effets secondaires de la clozapine chez les patients atteints de déficience intellectuelle et de psychoses. Compte tenu de l'utilisation de la clozapine chez cette population vulnérable, il est urgent de réaliser un ECR pour l'utilisation de la clozapine chez des patients présentant un diagnostic mixte de déficience intellectuelle et de psychose pour combler le manque de preuves.

Plain language summary

Use of clozapine in people with intellectual disabilities and psychoses

Review question

What is the evidence that clozapine can be helpful for adults with intellectual disabilities who have psychoses?

Background

People with intellectual disability have a low score on intelligence tests. They have problems in areas like self-care, social relationships, work, education and dealing with the challenges of daily life. To make a diagnosis of intellectual disability, we use tests in which we compare the performance of an individual person on certain tasks with other people of his or her age. People with intellectual disabilities are unable to process information as efficiently as people without intellectual disability. Depending on the severity of their condition, they need varying degrees of support to cope with the demands and expectations of life. Those who have a mild intellectual disability are able to manage their affairs with some additional support. Those who have a severe intellectual disability, most of the time are unable to live independently and require support on a daily basis.

Psychosis is a disorder of the mind in which people hear voices when there is no external source of the voices and they harbour unfounded beliefs called delusions. Psychosis affects their behaviour, relationships, performance at work, and other spheres of daily life. Psychosis is three times more common in people with an intellectual disability than those without an intellectual disability. Psychosis is treated with a group of drugs called antipsychotics. These drugs can have different desired and undesired (i.e. side effects) effects in different people. When at least two antipsychotics are not effective in treating the symptoms of psychosis, it is labelled as treatment-resistant psychosis. Clozapine is recommended for treatment-resistant psychosis.

People who have an intellectual disability and who also suffer from psychosis are at a higher risk of developing treatment-resistant psychosis. We systematically reviewed all available evidence which examined the effects of clozapine in people with intellectual disabilities and psychoses.

Study characteristics

The evidence is current to 15 December 2014. Although there were reports on studies involving only one person or groups of small numbers of people, we did not find any trial that compared groups of people with intellectual disabilities and psychoses who were prescribed clozapine, with other groups of people prescribed other drugs or who took no drugs at all.

Key results

Current research provides no evidence to support the use of clozapine in adults with intellectual disabilities and psychoses. Clinicians working with these individuals often rely on evidence from the general population (i.e. those without an intellectual disability) to prescribe clozapine. There is an urgent need for further research in this area.

Резюме на простом языке

Использование клозапина у людей с ограниченными умственными возможностями и психозами

Вопрос обзора

Каковы доказательства того, что клозапин может быть полезен для взрослых с интеллектуальными нарушениями, страдающими психозами?

Актуальность

Люди с умственными нарушениями имеют низкий балл по интеллектуальным тестам. Они имеют проблемы в таких областях, как уход за собой, социальные отношения, работа, образование и решения проблем повседневной жизни. Для того, чтобы поставить диагноз умственной отсталости, мы используем тесты, в которых мы сравниваем показатели отдельного человека при выполнении определенных задач с показателями других людей этого же возраста. Люди с ограниченными интеллектуальными возможностями не в состоянии обрабатывать информацию так эффективно, как люди без интеллектуальной нарушений. В зависимости от тяжести их состояния, они должны получать различную степень поддержки, чтобы справиться с требованиями и ожиданиями общества. Те, кто имеют незначительные интеллектуальные нарушения, способны управлять своими делами с некоторой дополнительной поддержкой. Те, кто имеют серьезные интеллектуальные отклонения, большую часть времени не в состоянии жить самостоятельно и нуждаются в поддержке ежедневно.

Психоз - это расстройство сознания, при котором люди слышат голоса при отсутствии внешнего источника голосов, и они полны необоснованными убеждениями, называемыми бредом. Психоз влияет на их поведение, отношения, производительность на работе, и в других сферах повседневной жизни. Психоз в три раза чаще встречается у людей с умственной недостаточностью, чем у лиц, без интеллектуальных отклонений. Психоз лечится группой лекарственных средств, называемых антипсихотиками (нейролептиками). Эти препараты могут иметь разные желательные и нежелательные (то есть побочные) эффекты у разных людей. В случае, если, по меньшей мере, два нейролептика не эффективны в лечении симптомов психоза, это называется резистентным психозом. Клозапин рекомендуется для лечения резистентного психоза.

Люди, имеющие интеллектуальную нарушения и также страдающие психозом, имеют более высокий риск развития фармакорезистентного психоза. Мы сделали систематический обзор всех имеющиеся доказательств, изучавших эффекты клозапина у людей с ограниченными интеллектуальными возможностями и психозами.

Характеристика исследований

Доказательства актуальны по 15 декабря 2014 года. Несмотря на то,что были сообщения об исследованиях с участием только одного человека или группы из небольшого числа людей, мы не нашли ни одного испытания, сравнивающего группы людей с умственными расстройствами и психозами, которым назначали бы клозапин, с другими группами людей, которым назначали бы другие лекарственные средства или группами, которые не принимали бы никаких лекарств.

Основные результаты

Современные исследования не дают никаких доказательств в поддержку использования клозапина у взрослых с ограниченными умственными возможностями и психозами. Врачи, работающие с этими лицами, часто полагаются на доказательства из общей популяции (т.е. лица, без интеллектуальных отклонений) при назначении клозапина. Существует настоятельная необходимость в дальнейших исследованиях в этой области.

Заметки по переводу

Перевод: Низамова Чулпан Ильдаровна. Редактирование: Гамирова Римма Габдульбаровна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Laički sažetak

Klozapin za liječenje psihotičnih poremećaja u odraslih s intelektualnim poteškoćama

Pitanje koje postavlja sustavni pregled

Postoje li dokazi da klozapin može pomoći odraslima s intelektualnim poteškoćama koji imaju psihoze?

Dosadašnje spoznaje

Osobe s intelektualnim teškoćama ostvaruju niske rezultate na testovima inteligencije Imaju problema u područjima života kao što su briga o sebi, društveni odnosi, obrazovanje i snalaženje u svakodnevnom životu. Kako bi se dijagnosticirale intelektualne poteškoće, koriste se testovi u kojima se uspoređuje izvedba pojedinca u određenim zadacima s ostalim osobama te dobi. Osobe s intelektualnim poteškoćama nisu u mogućnosti obraditi informacije jednako učinkovito kao osobe bez intelektualnih poteškoća. Ovisno o težini stanja, takvim su pojedincima potrebne različite razine podrške kako bi se nosile sa zahtjevima i očekivanjima života. Osobe koje imaju blage intelektualne poteškoće mogu obavljati svoje svakodnevne zadatke uz određenu količinu dodatne pomoći. Osobe koje imaju teške intelektualne teškoće većinu vremena nisu sposobne samostalno živjeti i zahtijevaju podršku na dnevnoj bazi.

Psihoza je poremećaj uma u kojem osobe čuju glasove kada nema vanjskog izvora i imaju neutemeljena vjerovanja koja se nazivaju deluzije. Psihoza pogađa njihovo ponašanje, odnose, uspjeh u radu i druge sfere svakodnevnog života. Psihoze su tri puta češće u osoba s intelektualnim poteškoćama nego kod osoba bez intelektualnih teškoća. Psihoza se liječi skupinom lijekova koji se nazivaju antipsihotici. Ti lijekovi mogu imati različite željene i neželjene učinke ( nuspojave) kod različitih osoba. Kada barem dva antipsihotika nisu učinkoviti u liječenju simptoma psihoze, smatra se da je to psihoza rezistentna (otporna) na terapiju. Klozapin se preporučuje za liječenje psihoze rezistentne na liječenje.

Osobe koje imaju intelektualne poteškoće i koje pate od psihoza imaju veći rizik od razvoja psihoze rezistentne na terapiju. U ovom Cochrane sustavnom pregledu detaljno su pregledani svi dostupni dokazi o učinku klozapina u osoba s intelektualnim poteškoćama i psihozom.

Karakteristike studija

Dokazi se odnose na literaturu dostupnu do 15. prosinca 2014. godine. Iako je bilo znnastvenih radova o studijama koje su uključivale samo jednu osobu ili skupine s malim brojem osoba, nije pronađena niti jedna studija koja je uspoređivala skupine osoba s intelektualnim poteškoćama i psihozama kojima je propisan klozapin s drugim skupinama osoba kojima je propisan neki drugi lijek ili koje nisu uopće uzimale lijekove.

Ključni rezultati

Trenutno dostupna istraživanja ne pružaju dokaze koji bi poduprli korištenje klozapina u odraslih s intelektualnim teškoćama i psihozama. Kliničari koji rade s tim osobama često se oslanjaju na dokaze iz opće populacije (npr. onih bez intelektualnih teškoća) kako bi propisali klozapin. Postoji velika potreba za daljnjim istraživanjem u tom području.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Resumen en términos sencillos

Administración de clozapina en pacientes con discapacidades intelectuales y psicosis

Pregunta de la revisión

¿Cuáles son las pruebas de que la clozapina puede ser útil en los adultos con discapacidades intelectuales que presentan psicosis?

Antecedentes

Las personas con discapacidad intelectual tienen una puntuación baja en las pruebas de inteligencia. Tienen problemas en áreas como el autocuidado, las relaciones sociales, el trabajo, la educación y para hacer frente a los desafíos de la vida cotidiana. Para hacer un diagnóstico de discapacidad intelectual se utilizan pruebas en las cuales se compara el rendimiento de un paciente individual en ciertas tareas con otras personas de su edad. Las personas con discapacidades intelectuales no pueden procesar la información tan eficientemente como las personas sin discapacidad intelectual. Según la gravedad de la condición, necesitan grados variables de apoyo para hacer frente a las exigencias y las expectativas de la vida. Las que presentan una discapacidad intelectual leve pueden enfrentar sus asuntos con algún apoyo adicional. Las que presentan una discapacidad intelectual grave por lo general no pueden vivir de forma independiente y requieren un apoyo cotidiano.

La psicosis es un trastorno de la mente en el cual los pacientes oyen voces cuando no hay una fuente externa de voces y albergan creencias infundadas llamadas delirios. La psicosis afecta el comportamiento, las relaciones, el rendimiento en el trabajo y otras esferas de la vida cotidiana. La psicosis es tres veces más frecuentes en las personas con una discapacidad intelectual que en las que no tienen una discapacidad intelectual. La psicosis se trata con un grupo de fármacos llamados antipsicóticos. Estos fármacos pueden tener diferentes efectos deseados y no deseados (es decir, efectos secundarios) en diferentes pacientes. Cuando al menos dos antipsicóticos no son eficaces para tratar los síntomas de la psicosis, se le denomina psicosis resistente al tratamiento. La clozapina se recomienda para la psicosis resistente al tratamiento.

Los pacientes que tienen una discapacidad intelectual y también presentan psicosis tienen un riesgo mayor de desarrollar psicosis resistente al tratamiento. Se revisaron sistemáticamente todas las pruebas disponibles que examinaron los efectos de la clozapina en pacientes con discapacidades intelectuales y psicosis.

Características de los estudios

Las pruebas están actualizadas hasta el 15 de diciembre de 2014. Aunque hubo informes de estudios que incluyeron solamente un paciente o grupos con un escaso número de pacientes, no se encontraron ensayos que compararan grupos de pacientes con discapacidades intelectuales y psicosis a los que se les prescribiera clozapina, con otros grupos de pacientes a los que se les prescribieran otros fármacos o que no recibieran fármacos.

Resultados clave

Los estudios de investigación actuales no proporcionan pruebas para apoyar la administración de clozapina en adultos con discapacidades intelectuales y psicosis. Los clínicos que trabajan con estos pacientes a menudo dependen de las pruebas de la población general (es decir, pacientes sin discapacidad intelectual) para prescribir la clozapina. Hay una necesidad urgente de más investigación en esta área.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

Résumé simplifié

Utilisation de la clozapine chez les patients atteints de déficiences intellectuelles et de psychoses

Question de la revue

Quelles sont les preuves montrant que la clozapine peut aider les adultes atteints de déficiences intellectuelles et souffrant de psychoses ?

Contexte

Les personnes souffrant de déficience intellectuelle ont un score faible aux tests d'intelligence. Ils rencontrent des problèmes avec les soins personnels, les relations sociales, le travail, l'éducation, et ont du mal à affronter les défis de la vie quotidienne. Pour établir un diagnostic de déficience intellectuelle, nous utilisons des tests dans lesquels nous comparons la performance d'un individu pour une tâche particulière avec la performance d'autres personnes de son âge. Les personnes souffrant de déficience intellectuelle sont incapables de traiter les informations avec autant d'efficacité que les personnes sans déficience intellectuelle. Selon la gravité de leur condition, ils ont besoin de divers degrés de soutien pour faire face aux demandes et aux attentes de la vie. Les personnes qui ont une légère déficience intellectuelle peuvent gérer leurs affaires avec un soutien supplémentaire. Les personnes qui ont une déficience intellectuelle sévère sont la plupart du temps incapables de vivre de façon indépendante et ont besoin d'un soutien quotidien.

La psychose est un trouble de l'esprit dans lequel les patients entendent des voix alors qu'il n'y a pas de source externe de voix, et ils présentent des croyances infondées appelées délires. La psychose affecte leur comportement, leurs relations, leurs performances au travail, et d'autres sphères de leur vie quotidienne. La psychose est trois fois plus fréquente chez les personnes présentant une déficience intellectuelle que chez celles sans déficience intellectuelle. La psychose est traitée au moyen d'un groupe de médicaments appelés antipsychotiques. Ces médicaments peuvent avoir différents effets désirés et non-désirés (c.-à-d. effets secondaires) chez différentes personnes. Lorsqu'au moins deux antipsychotiques ne sont pas efficaces pour traiter les symptômes d'une psychose, celle-ci est qualifiée de psychose résistante au traitement. La clozapine est recommandée pour la psychose résistante au traitement.

Les personnes qui ont une déficience intellectuelle et souffrent également de psychose sont exposées à un risque plus élevé de développer une psychose résistante au traitement. Nous avons systématiquement examiné toutes les preuves disponibles qui ont examiné les effets de la clozapine chez les patients atteints de déficience intellectuelle et de psychoses.

Caractéristiques de l'étude

Les preuves sont à jour le 15 décembre 2014. Bien qu'il y ait eu des rapports sur des études portant sur une seule personne ou sur des groupes d'un petit nombre de personnes, nous n'avons trouvé aucun essai comparant des groupes de patients atteints de déficience intellectuelle et de psychoses à qui avait été prescrit de la clozapine, et d'autres groupes de personnes à qui d'autres médicaments avaient été prescrits ou ne prenant aucun médicament.

Résultats principaux

Les recherches actuelles n'apportent aucune preuve permettant de recommander l'utilisation de la clozapine chez les adultes atteints de déficience intellectuelle et de psychoses. Les cliniciens travaillant avec ces personnes s'appuient souvent sur des preuves provenant de la population générale (c'est-à-dire sans déficience intellectuelle) pour prescrire la clozapine. Il est urgent de réaliser d'autres recherches dans ce domaine.

Notes de traduction

Post-édition : Alice Baert (M2 ILTS, Université Paris Diderot)

Background

Description of the condition

Intellectual disability describes a significant impairment in a person's intelligence and social functioning, which presents initially during the developmental years from birth to 18 years of age. There is wide variation in the manifestation of intellectual disability, which partly depends on its severity. People who suffer from intellectual disabilities have a significantly reduced ability to understand new or complex information and to learn and apply new skills. This results in a diminished capacity to cope independently with the demands and expectations of life. The areas affected include:

  • Conceptual skills such as language and literacy, handling money, understanding the concept of time and number, and self-direction;

  • Social skills such as interpersonal skills, social responsibility, self-esteem, social problem solving, the ability to follow rules and obey laws, and to avoid being victimised; and

  • Practical skills such as activities of daily living (personal care), occupational skills, accessing healthcare, travelling and using transport, following schedules and routines, assuring one's safety, use of money and of the telephone (Schalock 2010).

Psychiatrists use two main systems of classifications: the International Classification of Mental and Behavioural Disorders, 10th Revision (ICD-10) (WHO 1992) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (APA 2013). Intellectual disability is described as "mental retardation" in the ICD-10 but as "intellectual disability" in the DSM-5.

In a meta-analysis of 52 studies, Maulik 2011 reported the overall prevalence of intellectual disability across all age groups as 10.37 per 1000 population (95% confidence interval (CI) 9.55 to 11.18). The paper also reported a decreasing trend in prevalence with the increasing affluence of countries. The highest prevalence was seen in low-income countries where the prevalence per 1000 population was 16.41 (95% CI 11.14 to 21.68). The prevalence rate per 1000 population in middle-income countries was 15.94 (95% CI 13.56 to 18.32) and in high-income countries it was 9.21 (95% CI 8.46 to 9.96).

Estimates of the prevalence of psychiatric and behavioural disorders in the intellectually disabled population have varied widely from 14.4% to 40.9% (Meltzer 1995; Deb 2001; Cooper 2007). This variation is related to the different methodologies and diagnostic criteria used in the studies. For example, in populations with severe intellectual disabilities, diagnosis of psychiatric disorders is relatively difficult because people have more difficulty describing their symptoms. Studies have suggested a lifetime prevalence of psychotic illness in individuals with intellectual disability as ranging from 0.4% to 7.8% (Meltzer 1995; Deb 2001; Cooper 2007), while the lifetime prevalence of schizophrenia in the general population is 0.27 to 0.83% (Messias 2007).

People suffering from psychosis experience hallucinations, delusions and disturbed behavior (agitation or withdrawal). Schizophrenia is characterised by disorganised speech and behaviour, delusions and hallucinations, and can be associated with abnormalities in brain structure and function (WHO 1997; Smieskova 2010). The typical manifestations of schizophrenia are positive symptoms such as fixed false beliefs (delusions) and perceptions without cause (hallucinations); negative symptoms such as apathy and lack of drive, disorganisation of behaviour and thought; and catatonic symptoms such as mannerisms and bizarre posturing (Carpenter 1994). The description of schizophrenia and psychosis somewhat differs between the two main diagnostic classification systems and has also evolved over time (WHO 1979; WHO 1992; DSM IV-TR 2000).

Schizophrenia is a serious mental illness that has variable outcomes. About 40% of people with schizophrenia achieve functional recovery. Outcome is poor in about 25% who have a relatively chronic course (Menezes 2006; Lambert 2008; Zipursky 2013). Schizophrenia leads to high levels of social burden and financial cost, as well as the huge emotional cost of individual suffering (WHO 1997; Mangalore 2007; Awad 2008). Studies indicate that people with comorbid intellectual disabilities and schizophrenia exhibit higher levels of observable psychopathology, more negative symptoms, and have a greater functional disability (Bouras 2004). Resistance to antipsychotics is a manifestation of poor outcome in schizophrenia. There is an association between low intelligence quotient (IQ) and poor outcome in schizophrenia (McGlashan 1988). It can be inferred that people with a dual diagnosis of intellectual disability and psychosis are at higher risk of being resistant to treatment.

Description of the intervention

Pharmacological treatment for psychotic disorders includes first generation antipsychotic and second generation antipsychotic medication. First generation antipsychotic medications, such as haloperidol, are effective in reducing symptoms; however, they can produce unpleasant side effects, such as drowsiness, and extrapyramidal side effects of dystonia, parkinsonism and akathisia, which can lead to discontinuation of medication and relapse. Second generation antipsychotic medications refer to a new group of medications, which differ from first generation antipsychotics in that they do not cause significant extrapyramidal side effects (Leucht 2009).

Manufactured by Sandoz in 1959, clozapine was the first of the second generation antipsychotics to be produced. However, it was later discontinued and withdrawn in several countries following reports of severe blood reactions (i.e. neutropenia) and the subsequent death of eight patients (Hippius 1999; Crilly 2007). Clozapine was later re-introduced with a rigid monitoring protocol after several studies showed its efficacy and safety in treatment-resistant schizophrenia. Currently, it is used in the United Kingdom as second-line treatment for schizophrenia after a failed trial with two antipsychotic medications for an adequate time period (Farooq 2011); though in some countries it is routinely used as first-line treatment (Tang 2008; Wang 2012). The extent of treatment-resistance in this population is unclear. Much of the evidence for treatment-resistant psychosis in the intellectually disabled population is based on the fact that low IQ is a predictor of poor prognosis in psychosis and one manifestation of poor prognosis is treatment resistance. Additionally, however, our clinical experience and case reports suggest that clozapine is required in this population.

Clozapine, like other drugs, has many side effects. Haemotological side effects include agranulocytosis, leukopenia, neutropenia and eosinophilia. Anaemia and leukocytosis have been reported in less than 1% of patients. Other important side effects are: tremor (6%), syncope (6%), disturbed sleep or nightmares (4%), restlessness (4%), hypokinesia or akinesia (4%), agitation (4%), seizures (3%), rigidity (3%), akathisia (3%), confusion (3%), fatigue (2%), insomnia (2%) and hyperkinesia (1%) (Safferman 1991; Millar 2000; Novartis Pharmaceuticals Corporation 2014). Drowsiness is quite common and can be troublesome. Hypersalivation is also common while constipation is relatively common. Orthostatic hypotension and tachycardia are important cardiovascular side effects (Safferman 1991; Millar 2000 ; Novartis Pharmaceuticals Corporation 2014). Clozapine treatment is also associated with weight gain and an increased risk for development or exacerbation of diabetes mellitus (Leucht 2009). Parkinsonism and irritability have been reported in less than 1% of patients (Safferman 1991). Dyskinesia, coma, dystonia and neuroleptic malignant syndrome are reported rarely.

Other second generation antipsychotics which do not cause significant extrapyramidal side effects include olanzapine, aripiprazole, risperidone and olanzapine (Leucht 2007; Leucht 2009). The main advantage of clozapine over these other antipsychotic medications is its effectiveness in the group of people who have not responded to other medication (Chakos 2001). This distinguishes clozapine from newer antipsychotic drugs (Farooq 2011).

There are many case reports and observational studies which demonstrate that clozapine is prescribed for adults with intellectual disability and psychotic disorders (Thalayasingam 2004; Singh 2010). There is no literature that provides information about the frequency of its use.

How the intervention might work

Clozapine is used as the second-line of treatment of people with schizophrenia. Clozapine acts on dopaminergic, serotonergic, cholinergic and histaminergic receptors. It has high affinity for D4 and 5HT2A receptors and low affinity for D1, D2 and D3 receptors (Meltzer 2008). Its low affinity for D1, D2 and D3 receptors explains the low chance of extrapyramidal side effects. It has greater efficacy than other antipsychotics in controlling positive symptoms in treatment-resistant illness (Chakos 2001). The underlying mechanism for its higher efficacy and low propensity for extrapyramidal side effects is not fully understood. It has been hypothesised that through its effect on different receptors, including 5HT2A, it increases the efflux of dopamine in the cerebral cortex and hippocampus, which is important in symptom control while its weaker effect on D2 receptors produces a weaker efflux of dopamine in striatum. The dopamine efflux in striatum is important for extrapyramidal side effects.

Why it is important to do this review

There is no robust evidence about the use of clozapine for psychotic disorders in the intellectually disabled population. By systematically searching for all relevant RCTs, this Cochrane review has the potential to provide robust and useful data, or to identify gaps in evidence and make recommendations for future research, or both. Due to differences in the side effect profile of antipsychotics, it will be useful to explore differences in health-related outcomes when clozapine is compared with other antipsychotics. It is likely that the dropout rate will be different in the comparison group depending on which other drug is used for comparison, as typical antipsychotics generally have a higher rate of dropout (Bagnall 2003). Duration of treatment with clozapine has a significant positive correlation with outcome in terms of treatment response and side effects (Wheeler 2009).

Objectives

To determine the effects of clozapine for treating adults with a dual diagnosis of intellectual disability and psychosis.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs), irrespective of design.

Types of participants

People aged 18 years and above with a dual diagnosis of intellectual disability and psychotic disorder (e.g. schizophrenia, schizophreniform or schizoaffective disorders) diagnosed by any criteria, such as ICD-10 (WHO 1992), DSM-5 (APA 2013), Diagnostic Criteria for Psychiatric Disorders for Use with Adults with Learning Disabilities/Mental Retardation (DC-LD) (Cooper 2003), or a diagnosis made by clinicians.

Types of interventions

Clozapine, at any dosage, compared with placebo or compared with another antipsychotic medication.

Types of outcome measures

Primary outcomes
  1. Global outcomes* - measures such as the Global Assessment of Functioning (GAF) scale (Jones 1995), or others, as defined by individual studies.

  2. Mental state* - clinically important response as defined by individual studies, for example, changes in score on the Positive and Negative Syndrome Scale (PANSS) (Kay 1987).

  3. Behaviour - clinical improvement as defined by individual studies.

  4. Seizures*.

Secondary outcomes
  1. Death.

    1. Suicide.

    2. Other causes.

  2. Extrapyramidal side effects.*

    1. Incidence of use of anti-Parkinson drugs.

    2. Clinically significant extrapyramidal side effects as defined by individual studies.

    3. Average score or change in extrapyramidal side effects.

  3. Other adverse effects.*

    1. Other clinically important side effects (cardiac effects, metabolic side effects, effects on white cell count).

  4. Quality of life.

    1. Average score or change in quality of life.

    2. Change in quality of life as defined by individual studies.

  5. Cognitive function.

    1. No clinically important change in cognitive function.

    2. Average score or change in cognitive function.

    3. Any change in cognitive function as defined by individual studies.

  6. Discontinuation as a result of drop in blood cell count.

Search methods for identification of studies

Electronic searches

We searched the following databases on 13 October 2013 and again on 15 December 2014 with no limit on the date, language or publication status.

  1. Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 11), part of the Cochrane Library (which includes the Cochrane Developmental, Psychosocial and Learning Problems Group's Specialised Register).

  2. Ovid MEDLINE (1946 to November Week 03 2014).

  3. Embase (Ovid) (1980 to 2014 Week 50).

  4. PsycINFO (Ovid) (1806 to December Week 02 2014).

  5. CINAHL (EBSCOhost) (1936 to current).

  6. Science Citation Index (SSI) (Web of Science) (1970 to 12 December 2014).

  7. Social Sciences Citation Index (SSCI) (Web of Science) (1970 to 12 December 2014).

  8. Conference Proceedings Citation Index - Science (CPCI-S) (Web of Science) (1990 to 12 December 2014).

  9. Conference Proceedings Citation Index - Social Sciences & Humanities (CPCI-SSH) (Web of Science) (1990 to 12 December 2014).

  10. Cochrane Database of Systematic Reviews (CDSR) (2014 Issue 12), part of the Cochrane Library.

  11. Database of Abstracts of Reviews of Effects (DARE) (2014 Issue 4), part of the Cochrane Library.

  12. ClinicalTrials.gov (clinicaltrials.gov/), all available years.

  13. World Health Organization (WHO) International Controlled Trials Registry Platform (ICTRP) (who.int/ictrp/), all available years.

The Cochrane Schizophrenia Group's Register of Trials was searched on 26 May 2015, but no relevant studies were found. Our search strategies, which were developed in Ovid MEDLINE and adapted for other databases, are reported in Appendix 1. We have reported additional search details in Appendix 2.

Searching other resources

  1. We wrote to the manufacturers of clozapine (Novartis Pharmaceuticals Canada Incorporated) to request information on any additional studies. We received a list of references from them, but we had already identified all the publications they mentioned through our search strategy.

  2. We searched the Internet using Google Scholar for any relevant studies and did not find any.

Data collection and analysis

Selection of studies

Three review authors (FN, TM, KS) independently screened all titles yielded by the search against our inclusion criteria and excluded those which were irrelevant. For all other studies, all review authors (FN, TM, KS, MA) screened abstracts. We obtained the full text of all relevant papers or those for which we needed more information. All review authors independently screened full-text papers to see if they met the inclusion criteria. There were no disagreements over eligibility, although we had planned to resolve these by discussions. We recorded the reasons for excluding trials (see Characteristics of excluded studies). None of the review authors were blinded to the study authors, institutions or publishing journals relating to each publication.

Data extraction and management

No studies met the inclusion criteria of this Cochrane review. For more information on the methods that we will use in future updates of this review, please see Appendix 3 and our protocol (Paul 2013).

Results

Description of studies

Results of the search

We initially found 1614 reports. After merging and removing duplicates, our database search identified 1195 unique reports. We identified 29 additional records from other sources, including searches of citations from selected papers. Three review authors (TM, KS, FN) screened the 1224 titles and all authors screened abstracts. We excluded 1186 articles. None of these articles described treatment with clozapine in individuals with intellectual disabilities and psychoses.

We shortlisted and evaluated 38 full-text articles for inclusion in the review. However, we did not find any RCTs. The articles were mainly case reports, audits and reviews, including literature reviews, case series and retrospective observational studies. Figure 1 shows our selection process.

Figure 1.

Study flow diagram of selection process.

Included studies

None of the papers met the inclusion criteria of this Cochrane review.

Excluded studies

We excluded 38 full-text publications. We excluded nine case reports (Towbin 1994; Kamal 1999; Reznik 2002; Shedlack 2003; Gladston 2005; Rajagopal 2007; Amann 2009; White 2010; Tufan 2013), and eight audits or chart reviews (Buzan 1998; Antonacci 2000; Friedlander 2001; Dalvi 2003; Thalayasingam 2004; Shedlack 2005; Dhumad 2007; Griffiths 2012). We also excluded seven case series (Vvncke 1974; Cohen 1994; Pary 1994; Sajatovic 1994; Schroeder 1995; Hammock 2001; Wehmeier 2005); seven observational studies (Buck 1989; Aman 1995; Advokat 2000; Tin 2008; De Kuijper 2010; Frighi 2011; Frighi 2012); and seven literature reviews (Aman 1986; Sajatovic 1995; Aman 1999; La Malfa 2006; Singh 2010; Unwin 2011; Zuddas 2011).

Risk of bias in included studies

We did not undertake any 'Risk of bias' assessments as no study met the inclusion criteria.

Effects of interventions

We were unable to assess the effects of the intervention as no study met the inclusion criteria.

Discussion

Summary of main results

This Cochrane review aimed to determine the effectiveness of clozapine and its adverse effects in treating adults with a dual diagnosis of intellectual disability and psychosis. The rate of psychosis is higher in the intellectually disabled population than in the general population (Deb 2001; Cooper 2007). Clozapine is an effective treatment for patients who are resistant to other antipsychotics in the general population (Chakos 2001). We did not find any RCTs of clozapine in adults with a dual diagnosis of intellectual disability and psychotic disorder. There is a major gap in evidence for use of clozapine in people suffering from intellectual disabilities and psychoses. At present, the use of clozapine in people with both an intellectual disability and psychosis, who are found to be treatment-resistant and require clozapine, is dictated by extrapolation of evidence from the general adult population with psychosis but without intellectual disability. There is evidence to support the effectiveness of clozapine in people with treatment-resistant schizophrenia and without intellectual disability (Lally 2015).

Overall completeness and applicability of evidence

We are unable to assess the overall completeness and applicability of the evidence as no trial met the inclusion criteria of this Cochrane review. We used broad categories in the selection of outcome measures. We believed that because of diversity within the intellectual disability population, researchers would have used a variety of different measures; a narrow definition of measures had a risk of losing clinically meaningful data. However, we found no information to populate the 'Summary of findings' table.

Quality of the evidence

As no study met the inclusion criteria, we were unable to assess the quality of the evidence.

Potential biases in the review process

We believe that our search was comprehensive and it is unlikely that we failed to identify any relevant evidence. We used broad search criteria and tried to search all potential sources of studies, including the grey literature. We wrote to the drug manufacturers and handsearched reference lists of the studies identified. This topic has been reviewed by other authors and they too did not identify any RCTs.

Agreements and disagreements with other studies or reviews

Buzan 1998 reviewed the literature on the use of clozapine and identified a total of 74 people with an intellectual disability who had been treated with clozapine. In 59 of these patients, clozapine was prescribed for behaviour difficulties and 15 people had treatment-resistant psychiatric disorders. Three of the 74 patients did not benefit from treatment with clozapine and experienced adverse effects. Since then there have been further reports on the prescription of clozapine in people with intellectual disabilities and psychoses as well as those with intellectual disabilities and behaviour disorders. We found 35 observational studies, case reports and case series that described the effectiveness of clozapine and its side effects (Vvncke 1974; Ratey 1993; Cohen 1994; Pary 1994; Sajatovic 1994; Towbin 1994; Rubin 1995; Sajatovic 1995; Schroeder 1995; Boachie 1997; Buzan 1998; Aman 1999; Kamal 1999; Antonacci 2000; Friedlander 2001; Hammock 2001; Reznik 2002; Dalvi 2003; Shedlack 2003; Thalayasingam 2004; Gladston 2005; Shedlack 2005; Wehmeier 2005; La Malfa 2006; Rajagopal 2007; Tin 2008; Amann 2009; De Kuijper 2010; Singh 2010; White 2010; Frighi 2011; Zuddas 2011; Frighi 2012; Tufan 2013; Butcher 2015). There is evidence from non-randomised trials indicating the potential effectiveness of clozapine in people with intellectual disabilities and psychoses (Ratey 1993; Rubin 1995; Boachie 1997; Buzan 1998; Antonacci 2000). For example, Thalayasingam 2004 described 24 patients who were treated with clozapine and reported that more than 70% (n = 17) reported an improvement on the Clinical Global Impression (CGI) scale. However, such evidence is only suggestive as it rests solely on studies in which there was no comparison group (see Pocock 2000).

Authors' conclusions

Implications for practice

At present, there is no direct evidence for the use of clozapine in patients with a dual diagnosis of intellectual disability and psychosis. The only available studies are those conducted in the general population. There is some preliminary evidence from observational studies that, at least in terms of their vulnerability to side effects, people with intellectual disability differ from those without intellectual disability (Butcher 2015).

Although the intellectually disabled population is heterogeneous, there is evidence that their life expectancy is different and that their physical health profiles may be different to that of the general population (Glover 2010). Thus, it is likely that the side effect profile of clozapine is different in those who are intellectually disabled; for example, this population may be more prone to seizures (Morgan 2003). At present, therefore, the prescription of clozapine for people with a dual diagnosis of intellectual disability and psychosis is based on insufficient evidence.

Implications for the patients with intellectual disability and their caregivers

There is evidence to suggest that clozapine is prescribed to people with intellectual disabilities and psychosis (Towbin 1994; Thalayasingam 2004; Tin 2008; Singh 2010). At present this is based on evidence extrapolated from studies in people without intellectual disabilities. There is no systematic evidence to support its use in this population. Given the lack of evidence, clinicians may wish to have an open dialogue with people with intellectual disabilities and their caregivers as part of the discussion about informed consent for this treatment.

Implications for the clinicians

In the absence of evidence to support the effectiveness of clozapine for intellectually disabled adults with psychoses, clinicians face a clinical and ethical dilemma. If they cease prescribing clozapine, they may be depriving their patients of a potentially effective treatment. They may wish to have an open dialogue with their patients and families about the lack of evidence to support the prescribing of clozapine. It is likely that clinicians already using clozapine are doing so as a last resort. In such circumstances, when clinicians are considering prescribing untested treatments, they may wish to discuss it with the patient and his or her family in order to reach consensus about appropriateness and acceptability.

Implications for policymakers

Policymakers may wish to discuss the need for guidance on the use of clozapine in people with intellectual disability, including whether or not there is need for extra caution and monitoring of side effects.

Implications for research

General suggestion

Maintaining a register of RCTs of psychotropic medication for people with intellectual disability will be extremely helpful. This will be a ready source of easily searchable information to help clinicians and researchers.

Specific suggestions

This Cochrane review highlights the need to develop the evidence base for the use of clozapine in people with intellectual disabilities and psychoses. RCTs of clozapine in this population are urgently required. We recommend a multi-centre RCT of clozapine for patients with intellectual disability and psychosis. We provide an outline of an appropriate design in Table 1.

Table 1. Suggested trial design
  1. Abbreviations: DC-LD: Diagnostic Criteria for Psychiatric Disorders for Use with Adults with Learning Disabilities/Mental Retardation; CGI: Clinical Global Impression.

MethodsAllocation will be randomised with full and explicit description of methods of randomisation and allocation concealment
Blinding: Open
Setting: Intellectual disabilities psychiatry services
Duration: 1 year
ParticipantsDiagnosis: Intellectual disability and schizophrenia (diagnosed using DC-LD criteria (Cooper 2003)) and after treatment with two antipsychotics has failed
Number of participants: 300a
Age: Adults
Gender: Both male and female
Interventions

Clozapine dose: Range from 100 to 750 mg, number of participants 150

Any other antipsychotic: Dose as recommended by the clinical team, number of participants 150

Outcomes
  1. Global state: CGI scaleb

  2. Leaving the study early

  3. Mental state: CGI

  4. Service use

  5. Quality of life: CGI

  6. Satisfaction with treatment: CGI

  7. Economic outcomes

  8. Barnes Scale for Akathisia (Barnes 1989)

  9. Abnormal Involuntary Movement Scale (AIMS) for tardive dyskinesia (Guy 1976)

  10. Simpson-Angus scale for extrapyramidal side effects (SAEPS) (Simpson 1970)

  11. Seizures

  12. Blood count monitoring

Notes aPowered to be able to identify a difference of ˜ 20% between groups for primary outcome with adequate degree of certainty.
bThis simple measure can be used to target specific aspects of functioning, symptoms or attitudes.

The proposed trials should be led by researchers or clinicians skilled in dealing with this population. When planning these trials, they should consider (1) the challenges of making a sound diagnosis of psychosis in this population, (2) issues of informed consent, and (3) mechanisms for recruitment. There are valid instruments that can be used to gather information about psychopathology in this population, and reliable diagnostic criteria are available (Moss 1996; Cooper 2003). In clinical practice, the patients in this population either give informed consent for any intervention or, when they do not have the capacity to consent, a substitute decision maker is involved. There are different mechanisms for this process in different jurisdictions; any proposed trial should have the flexibility to use substitute decision makers when required and within the legal and ethical framework. Multi-centre trials will ensure studies have sufficient power to elucidate clinically relevant results of efficacy. Funding bodies can play an important role in this by bringing together research groups to address this issue; this has happened in other areas, such as the genetics of psychiatric disorders.

Acknowledgements

This Cochrane review was produced within the Cochrane Developmental, Psychosocial and Learning Problems Group. We thank Margaret Anderson for undertaking the database searches, and Farhad Shokanreh for searching the Cochrane Schizophrenia Group's Register of Trials. We appreciate the help and support from Dr Joanne Wilson (Managing Editor) and Professor Geraldine Macdonald at every stage of the review process.

Appendices

Appendix 1. Search strategies

CENTRAL, part of the Cochrane Library (and which includes the Specialized Register of the Cochrane Developmental, Psychosocial and Learning Problems Group)

#1[mh "Intellectual disability"]
#2[mh "Mentally Disabled Persons"]
#3[mh "Developmental Disabilities"]
#4((mental* or intell*) near/3 (impair* or retard* or disab* or defici* or handicap* or subnormal* or sub-normal* or "below normal" or "below average"))
#5(learning* near/3 (impair* or disab*))
#6feeble-minded*
#7moron*
#8imbecil*
#9(de next lange*)
#10Cri near chat
#11(Wagr near/3 syndrome)
#12(down* near/3 syndrome*)
#13(Rubinstein near/3 Taybi)
#14(prader near/3 willi)
#15(williams near/3 syndrome)
#16 (fragile next X) or FRAXE or FRAXA
#17(Martin next Bell)
#18(les*h near/3 Nyhan*)
#19Adrenoleukodystrophy
#20(Coffin near/1 Lowry)
#21Menkes
#22Glycogen next Storage next Disease
#23Mucopolysaccharidosis
#24Rett*
#25Pyruvate Dehydrogenase
#26{or #1-#25}
#27[mh Clozapine]
#28[mh ^"antipsychotic agents"]
#29clozapine
#30(Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or Denzapine or Zaponex or Klozapol or Clopine)
#31(atypical next (antipsychotic or anti-psychotic))
#32{or #27-#31}
#33#26 and #32

Cochrane Schizophrenia Group's Register of Trials

*intel* or *retard* in Healthcare Condition of STUDY

MEDLINE (Ovid)

1 exp Intellectual disability/
2 exp Mentally Disabled Persons/
3 Developmental Disabilities/
4 ((mental$ or intell$) adj3 (impair$ or retard$ or disab$ or defici$ or handicap$ or subnormal$ or sub-normal$ or "below normal" or "below average")).tw.
5 (learning$ adj3 (impair$ or disab$)).tw.
6 feeble-mind$.tw.
7 moron$.tw.
8 imbecil$.tw.
9 de lange$.tw.
10 Cri-du-chat.tw.
11 (Wagr adj3 syndrome).tw.
12 (down$ adj3 syndrome$).tw.
13 (Rubinstein adj3 Taybi).tw.
14 (prader adj3 willi).tw.
15 (williams adj3 syndrome).tw.
16 fragile X.tw.
17 ((Martin Bell or FRAXE or FRAXA) adj3 syndrome$).tw.
18 (les?h adj3 nyhan$).tw.
19 Adrenoleukodystrophy.tw.
20 (Coffin adj Lowry).tw.
21 Menkes.tw.
22 Glycogen Storage Disease.tw.
23 Mucopolysaccharidosis.tw.
24 Rett$.tw.
25 Pyruvate Dehydrogenase.tw.
26 or/1-25
27 antipsychotic agents/
28 Clozapine/
29 clozapine.mp.)
30 (Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or Denzapine or Zaponex or Klozapol or Clopine).mp.
31 (atypical adj (antipsychotic or anti-psychotic)).tw.
32 or/27-31
33 randomized controlled trial.pt.
34 controlled clinical trial.pt.
35 randomi#ed.ab.
36 placebo$.ab.
37 drug therapy.fs.
38 randomly.ab.
39 trial.ab.
40 groups.ab.
41 or/33-40
42 exp animals/ not humans.sh.
43 41 not 42
44 26 and 32 and 43

Embase (Ovid)

1 intellectual impairment/
2 exp mental deficiency/
3 developmental disorder/
4 ((mental$ or intell$) adj3 (impair$ or retard$ or disab$ or defici$ or handicap$ or subnormal$ or sub-normal$ or "below normal" or "below average")).tw.
5 (learning$ adj3 (impair$ or disab$)).tw.
6 feeble-mind$.tw.
7 imbecil$.tw.
8 de lange$.tw.
9 Cri-du-chat.tw.
10 (Wagr adj3 syndrome).tw.
11 (down$ adj3 syndrome$).tw.
12 (Rubinstein adj3 Taybi).tw.
13 (prader adj3 willi).tw.
14 (williams adj3 syndrome).tw.
15 fragile X.tw.
16 ((Martin Bell or FRAXE or FRAXA) adj3 syndrome$).tw.
17 (les?h adj3 nyhan$).tw.
18 Adrenoleukodystrophy.tw.
19 (Coffin adj Lowry).tw.
20 Menkes.tw.
21 Glycogen Storage Disease.tw.
22 Mucopolysaccharidosis.tw.
23 Rett$.tw.
24 Pyruvate Dehydrogenase.tw.
25 moron$.tw.
26 or/1-25
27 neuroleptic agent/
28 clozapine/
29 clozapine.mp.
30 (Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or Denzapine or Zaponex or Klozapol or Clopine).mp.
31 (atypical adj (antipsychotic or anti-psychotic)).tw.
32 or/27-31
33 26 and 32
34 exp Clinical trial/
35 Randomized controlled trial/
36 Randomization/
37 Single blind procedure/
38 Double blind procedure/
39 triple blind procedure/
40 Crossover procedure/
41 Placebo/
42 Randomi#ed.tw.
43 RCT.tw.
44 (random$ adj3 (allocat$ or assign$)).tw.
45 randomly.ab.
46 groups.ab.
47 trial.ab.
48 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
49 Placebo$.tw.
50 Prospective study/
51 (crossover or cross-over).tw.
52 prospective.tw.
53 or/34-52
54 33 and 53

PsycINFO (Ovid)

1 exp Intellectual Development Disorder/
2 exp Developmental Disabilities/
3 ((mental$ or intell$) adj3 (impair$ or retard$ or disab$ or defici$ or handicap$ or subnormal$ or sub-normal$ or "below normal" or "below average")).tw.
4 (learning$ adj3 (impair$ or disab$)).tw.
5 feeble-mind$.tw.
6 moron$.tw.
7 imbecil$.tw.
8 de lange$.tw.
9 Cri-du-chat.tw.
10 (Wagr adj3 syndrome).tw.
11 (down$ adj3 syndrome$).tw.
12 (Rubinstein adj3 Taybi).tw.
13 (prader adj3 willi).tw.
14 (williams adj3 syndrome).tw.
15 fragile X.tw.
16 ((Martin Bell or FRAXE or FRAXA) adj3 syndrome$).tw.
17 (les?h adj3 nyhan$).tw.
18 Adrenoleukodystrophy.tw.
19 (Coffin adj Lowry).tw.
20 Menkes.tw.
21 Glycogen Storage Disease.tw.
22 Mucopolysaccharidosis.tw.
23 Rett$.tw.
24 Pyruvate Dehydrogenase.tw.
25 or/1-24
26 Clozapine/
27 clozapine.tw.
28 (Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or Denzapine or Zaponex or Klozapol or Clopine).tw.
29 (atypical adj (antipsychotic or anti-psychotic)).tw.
30 Neuroleptic Drugs/
31 or/26-30
32 25 and 31
33 clinical trials/
34 (randomis$ or randomiz$).tw.
35 (random$ adj3 (allocat$ or assign$)).tw.
36 ((clinic$ or control$) adj trial$).tw.
37 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
38 (crossover$ or "cross over$").tw.
39 random sampling/
40 Experiment Controls/
41 Placebo/
42 placebo$.tw.
43 exp program evaluation/
44 treatment effectiveness evaluation/
45 ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw.
46 or/33-45
47 32 and 46

CINAHL Plus (EBSCOhost)

S33 S26 AND S32
S32 S27 OR S28 OR S29 OR S30 OR S31
S31 (atypical N1 (antipsychotic or anti-psychotic))
S30 (MH "Antipsychotic Agents")
S29 (Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or
Denzapine or Zaponex or Klozapol or Clopine)
S28 clozapine
S27 (MH "Clozapine")
S26 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25
S25 Pyruvate Dehydrogenase
S24 Rett*
S23 Mucopolysaccharidosis
S22 Glycogen Storage Disease
S21 Menkes S
S20 (Coffin N1 Lowry)
S19 Adrenoleukodystrophy
S18 (les#h N3 nyhan*)
S17 (Martin Bell or FRAXE or FRAXA)
S16 fragile X
S15 (williams N3 syndrome)
S14 (prader N3 willi)
S13 (Rubinstein N3 Taybi)
S12 (down* N3 syndrome*)
S11 (Wagr N3 syndrome)
S10 Cri-du-chat
S9 de lange*
S8 imbecil*
S7 moron*
S6 feeble-mind* y
S5 (learning* N3 (impair* or disab*))
S4 ((mental* or intell*) N3 (impair* or retard* or disab* or defici* or handicap* or subnormal* or sub-normal* or "below normal" or "below average"))
S3 (MH "Developmental Disabilities")
S2 (MH "Mentally Disabled Persons")
S1 (MH "Mental Retardation+")

Web of Science databases

Science Citation Index (SCI), Social Science Citation Index (SSCI), Conference Proceedings Citation Index- Science (CPCI-S), Conference Proceedings Citation Index - Social Sciences & Humanities (CPCI-SS&H)

#10 #9 AND #5
DocType=All document types; Language=All languages;
#9 #8 OR #7
DocType=All document types; Language=All languages;
#8 TS=(atypical NEAR/3 (antipsychotic or anti-psychotic))
DocType=All document types; Language=All languages;
#7 TS=(Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or Denzapine or Zaponex or Klozapol or Clopine)
DocType=All document types; Language=All languages;
#6 TS=(clozapine)
DocType=All document types; Language=All languages;
#5 #4 OR #3 OR #2 OR #1
DocType=All document types; Language=All languages;
#4 TS=("de lange" or "cris du chat" or "down* syndrome" or "prader willi*" or "fragile X" or FRAXE or FRAXA or "les*h nyhan" or rett* or "williams syndrome" or "rubenstein Taybi" or "wagr* syndrome" or "martin Bell" or "coffin lowry" or menkes)
DocType=All document types; Language=All languages;
#3 TS=("feeble minded" or moron* or imbecil*)
DocType=All document types; Language=All languages;
#2 TS=(learning* near/3 (impair* or disab*))
DocType=All document types; Language=All languages;
#1 TS=((mental* or intell*) near/3 (impair* or retard* or disab* or defici* or handicap* or subnormal* or sub-normal* or "below normal" or "below average"))
DocType=All document types; Language=All languages;

Cochrane Database of Systematic Reviews (CDSR), part of the Cochrane Library

#1[mh "Intellectual disability"]
#2[mh "Mentally Disabled Persons"]
#3[mh "Developmental Disabilities"]
#4((mental* or intell*) near/3 (impair* or retard* or disab* or defici* or handicap* or subnormal* or sub-normal* or "below normal" or "below average")):ti,ab
#5(learning* near/3 (impair* or disab*)):ti,ab
#6(feeble next minded*):ti,ab
#7moron*:ti,ab
#8imbecil*:ti,ab
#9(de next lange*):ti,ab
#10Cri near chat:ti,ab
#11(Wagr near/3 syndrome):ti,ab
#12(down* near/3 syndrome*):ti,ab
#13(Rubinstein near/3 Taybi):ti,ab
#14(prader near/3 willi):ti,ab
#15(williams near/3 syndrome):ti,ab
#16fragile next X:ti,ab
#17(Martin next Bell):ti,ab or FRAXE or FRAXA
#18(les*h near/3 Nyhan*):ti,ab
#19Adrenoleukodystrophy:ti,ab
#20(Coffin near/1 Lowry):ti,ab
#21Menkes:ti,ab
#22Glycogen next Storage next Disease:ti,ab
#23Mucopolysaccharidosis:ti,ab
#24Rett*:ti,ab 3
#25Pyruvate Dehydrogenase:ti,ab
#26{or #1-#25} 2
#27[mh Clozapine]
#28[mh ^"antipsychotic agents"]
#29clozapine:ti,ab 81
#30(Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or Denzapine or Zaponex or Klozapol or Clopine):ti,ab
#31(atypical next (antipsychotic or anti-psychotic)):ti,ab
#32{or #27-#31}
#33#26 and #32 in Cochrane Reviews (Reviews only)

Database of Abstracts of Reviews of Effects (DARE), part of the Cochrane Library

#1[mh "Intellectual disability"]
#2[mh "Mentally Disabled Persons"]
#3[mh "Developmental Disabilities"]
#4((mental* or intell*) near/3 (impair* or retard* or disab* or defici* or handicap* or subnormal* or sub-normal* or "below normal" or "below average"))
#5(learning* near/3 (impair* or disab*))
#6feeble-minded*
#7moron*
#8imbecil*
#9(de next lange*)
#10Cri near chat
#11(Wagr near/3 syndrome)
#12(down* near/3 syndrome*)
#13(Rubinstein near/3 Taybi)
#14(prader near/3 willi)
#15(williams near/3 syndrome)
#16fragile next X
#17(Martin next Bell):ti,ab or FRAXE or FRAXA 7
#18(les*h near/3 Nyhan*)
#19Adrenoleukodystrophy
#20(Coffin near/1 Lowry)
#21Menkes
#22Glycogen next Storage next Disease
#23Mucopolysaccharidosis
#24Rett*
#25Pyruvate Dehydrogenase
#26{or #1-#25}
#27[mh Clozapine]
#28[mh ^"antipsychotic agents"]
#29clozapine
#30(Clozaril or Azaleptin or Leponex or Fazaclo or Froidir or Denzapine or Zaponex or Klozapol or Clopine)
#31(atypical next (antipsychotic or anti-psychotic))
#32{or #27-#31}
#33#26 and #32

ClinicalTrials.gov

(clinicaltrials.gov/)

Intervention : clozapine
Condition: Intellectual disability
Limited to Adults and Seniors

WHO ICTRP

(who.int/ictrp/en)

Basic search: clozapine AND mental* OR clozapine AND retard* OR clozapine AND intellect*

Appendix 2. Summary of searches

Database Search date Date range or issue searched Number of records Limits applied
CENTRAL (Cochrane Library)16 October 20132013 Issue 956
CENTRAL (Cochrane Library)15 December 20142014 Issue 1112013-2014
MEDLINE (OVID)16 October 20131946 to October Week 01 2013565
MEDLINE (OVID)15 December 20141946 to November Week 03 201426ed=20131001-20141118
Embase (OVID)16 October 20131980 to 2013 Week 41501
Embase (OVID)15 December 20141980 to 2014 Week 5035em=201341-201450
PsycINFO (OVID)16 October 20131806 to October Week 02 201371
PsycINFO (OVID)15 December 20141806 to December Week 02 20142up=20131007-20141208
CINAHL Plus (EBSCOhost)16 October 20131937 to current208No RCT filter
CINAHL Plus (EBSCOhost)15 December 20141937 to current21EM 20131001-
Social Sciences Citation Index (Web of Science)16 October 20131970 to 11 October 201346No RCT filter
Social Sciences Citation Index (Web of Science)15 December 20141970 to 12 December 201432013-2014
Science Citation Index (Web of Science)16 October 20131970 to 11 October 201354No RCT filter
Science Citation Index (Web of Science)15 December 20141970 to 12 December 201442013-2014
Conference Proceedings Citation Index - Science (Web of Science)16 October 20131990 to 11 October 20136No RCT filter
Conference Proceedings Citation Index - Social Sciences & Humanities (Web of Science)15 December 20141990 to 12 December 201402013-2014
CDSR (Cochrane Library)16 October 20132013 Issue 106
CDSR (Cochrane Library)15 December 20142014 Issue 1202013-2014
DARE (Cochrane Library)16 October 20132013 Issue 39
DARE (Cochrane Library)15 December 20142014 Issue 402013-2014
ClinicalTrials.gov (clinicaltrials.gov/)16 October 2013All available years1
ClinicalTrials.gov15 December 2014All available yearsNo new records
WHO ICTRP (who.int/ictrp/)16 October 2013All available years28
WHO ICTRP15 December 2014All available yearsNo new records
Cochrane Schizophrenia Group's Register of Trials26 May 2015All available years0-

Abbreviations: CENTRAL - Cochrane Central Register of Controlled Trials; CINAHL - Cumulative Index to Nursing and Allied Health Literature; WHO ICTRP - World Health Organization International Clinical Trials Registry Platform; CDSR - Cochrane Database of Systematic Reviews; DARE - Database of Abstracts of Reviews of Effects.

Appendix 3. Methods for future review updates

Please see our Cochrane protocol (Paul 2013).

Types of outcome measuresWe will present those primary and secondary outcomes marked with an asterisk (*) in a 'Summary of findings' table.
Trials of mixed age groupsWe will include trials aimed primarily at people aged 18 years or over. If we find a trial with mixed age groups we will include it. Where possible, we will obtain separate data for subgroups within the target age range.
Types of interventions We will perform an initial analysis by adding together all antipsychotics and then performing separate analyses of the data for each antipsychotic compared with clozapine.
'Risk of bias' assessment in included studies

Two review authors, working independently, will use the Cochrane 'Risk of bias' tool described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) to assess risk of bias across the following domains: sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome reporting, reporting bias and other potential sources of bias. For each included study, they will assign a rating of either low, high or unclear risk of bias for each domain. We will resolve potential disagreements by discussion and, if necessary, by involving a third review author.

Our criteria for assessing the risk of bias for each domain is described below.

Sequence generation

  • If randomisation is clearly described using valid techniques, such as simple randomisation or stratified randomisation, we will rate the study as being at low risk of bias. Adequate methods include use of a random number table, random number generation by a computer, coin tossing, shuffling cards or envelopes, throwing dice, drawing of lots and minimisation.

  • If the method of sequence generation is not adequately described we will rate the study as being at unclear risk of bias.

  • We will rate the study as being at high risk of bias when sequence generation is done by odd or even date of birth, date (or day) of admission, or hospital or clinic record number.

Allocation concealment

  • We will judge the study to be at low risk of bias when participants and trial authors enrolling the participants are unable to foresee assignment to intervention or control groups because one of the following (or an equivalent) techniques was employed:

    • Central allocation (including telephone, web-based and pharmacy-controlled randomisation);

    • Sequentially numbered drug containers of identical appearance; or

    • Sequentially numbered, opaque, sealed envelopes.

  • We will judge the study to be at high risk of bias if it is possible that participants or trial authors enrolling participants could have foreseen assignments and thus introduced selection bias such as allocation based on the following:

    • An open random allocation schedule (e.g. a list of random numbers);

    • Assignment envelopes used without appropriate safeguards (e.g. if envelopes are unsealed or non­opaque or not sequentially numbered);

    • Alternation or rotation;

    • Date of birth; or

    • Case record number.

  • If the allocation method is not adequately described, we will judge the study to be at unclear risk of bias.

Blinding of participants and personnel

  • We will consider the study to be at low risk of bias on this domain if participants and study personnel are adequately blinded.

  • We will consider the study to be at unclear risk of bias when there is not enough information about blinding.

  • We will consider the study to be at high risk of bias when participants and study personnel are not blinded.

Blinding of outcome assessors

  • If the outcome assessors are adequately blinded we will judge the study to be at low risk of bias. We will also judge the study to at low risk of bias if the outcome and measures assessing the outcome are unlikely to be influenced by the lack of blinding.

  • Where there is not enough information to make a judgement about blinding, we will classify the study as being at unclear risk of bias.

  • If the outcome assessors are not blinded we will rate the study as being at high risk of bias.

Incomplete outcome data

  • Where all participants are included in the outcome analyses, including those that withdrew, and where an intention-to-treat (ITT) analysis has been carried out, we will judge the study to be at low risk of bias.

  • When this is unclear we will judge the study to be at unclear risk of bias.

  • We will judge the study to be at high risk of bias when ITT analyses have not been performed and cannot be performed after acquiring information from trial authors.

  • When there are no missing outcome data we will judge the study to be at low risk of bias. We will also judge the study to be at low risk of bias if there are missing outcome data in the studies but they are balanced across the intervention groups and reasons for the missing data are similar; and when there is a relatively small proportion of missing outcome data (compared to the baseline risk) that is unlikely to have a clinical impact on the estimation of the effect size.

  • We will judge the study to be high risk of bias when there are different amounts of missing data in the intervention and control groups or the reasons for dropout are not clearly specified; and when the study has used a potentially inappropriate imputation (e.g. ITT analysis has been applied to the missing data, but not consistently).

  • If the study does not provide information about the missing data we will judge it to be at unclear risk of bias.

Selective reporting

  • We will try to access the protocols of all studies included in the review and compare the pre-specified outcomes with those that are reported. When a protocol is unavailable but it is clear that all of the collected data have been reported, we will rate the study as being at low risk of bias.

  • When some measures used in the trial are not reported (i.e. only a subset is reported, or there is a disagreement between the method and results section), we will rate the study as being at high risk of bias.

  • We will rate the study as being at unclear risk of bias when it is not possible to determine whether all the measures used in the trial have been reported.

Selective recruitment of cluster participants

  • For cluster-RCTs, we will assess the risk of bias associated with the selective recruitment of cluster participants. The knowledge of whether a cluster belongs to the 'intervention' group or the 'control' group can affect the types of participants recruited. If participants are identified before a cluster is randomised we will judge the study to be at low risk of bias. We will also judge the study to be at low risk of bias when clusters are randomised before the participants are identified but there are arrangements to mask the recruiters.

  • We will judge the study to be high risk of bias if, at the time of participant selection, recruiters were aware of the group to which the cluster belonged.

  • We will rate the study as being at unclear risk of bias if there is not enough information as regards when the clusters were randomised or if and when recruiters were masked.

Other potential sources of bias

  • We will explore other sources of bias, such as adherence to protocol. If the study adhered to the protocol we will judge it to be at low risk of bias.

  • If the study did not adhere to protocol we will judge it to be at high risk of bias.

  • We will judge the study to be at unclear risk of bias if the information provided was insufficient to determine whether the study had adhered to the protocol.

Measures of treatment effect

Binary data

We will calculate the odds ratio (OR) and its 95% CI. If the study does not provide 2 x 2 tables we will compute them from the data provided (numbers, percentages, or both, and sample sizes). We will transform other effect measures, such as the risk ratio (RR), to the OR.

Continuous data

For continuous data, we will calculate mean differences (MD) for studies using the same measurement scale and standardised mean differences (SMDs) for studies using different scales. If the standard deviation (SD) or standard error (SE) is unavailable, we will calculate them from P values provided or we will use the SDs from other studies. In some studies only change from baseline scores will be available. When studies provide only change scores, we will include the MD of the change score in the analysis. We will combine in a meta-analysis studies with change from baseline outcomes with studies with final measurement outcomes by using the (unstandardised) MD method in Review Manager 2014. Since the mean values and SDs for the two types of outcomes may differ substantially, we will place them in separate subgroups to avoid confusion for the reader, but will pool the results of the subgroups together.

If a trial presents both the change score as well as the endpoint score, we will include only one in the meta-analysis. The decision about which one to use will depend on their distribution. We will preferentially use the one that is normally distributed (i.e. not skewed). If both scores are normally distributed, we will prefer the change score as it removes a component of between-person variability from the analysis.

In the initial analysis, we will include all data irrespective of the distribution of the data (normal or skewed). We will check the data for skewness. Visual inspection of the histogram of the data can indicate skewness. Another method to check skew involves calculating the observed mean minus the lowest possible value (or the highest possible value minus the observed mean), and dividing this by the SD. A ratio less than two suggests skew. If the ratio is less than one, there is strong evidence of a skewed distribution (Altman 1996). We will use Kolmogorov-Smirnov test to assess normality if the sample size is more than 40. We will transform the skewed data for inclusion in the analysis. Data can be transformed in a number of ways (square root transformation, logarithmic transformation, reciprocal transformation). We will use the appropriate transformation after looking at the data (Bland 1996). We will present the results of the transformed and untransformed data separately. We will consider excluding studies with skewed data in a sensitivity analysis if the sample size is small (i.e. < 40).

Scale-derived data can be problematic if there is no information to support reliability and validity of the scales used. If any included study has used a scale we will find published information about its reliability and validity. If the scale used does not have any published data to support its reliability and validity then we will ask the trial authors for any such data. If there is no information to support the reliability and validity of the scale then we will use sensitivity analysis to explore the impact of using this scale.

Unit of analysis issues

Cluster-RCTs

Ignoring the interclass correlation coefficient (ICC) in cluster-randomised studies leads to a 'unit of analysis' error (Divine 1992) as it overestimates the significance level and increases the likelihood of a type 1 error (Bland 1997; Gulliford 1999). We will follow the guidance provided in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2008) for statistical analysis of cluster-RCTs. When clustering is not accounted for in primary studies, we will present the data in a table, with an asterisk (*) to indicate the presence of a probable unit of analysis error. If possible, we will seek to contact authors of such trials to obtain the ICC values for their clustered data and to adjust for this by using accepted methods (Gulliford 1999). Where clustering has been incorporated into the analysis of primary studies, we will adjust for the clustering effect. To achieve this the binary data should be divided by a 'design effect'. This is calculated using the mean number of participants per cluster (m) and the ICC (Design effect = 1 + (m - 1) * ICC) (Donner 2002). If the ICC is not reported we will assume it to be 0.1 (Ukoumunne 1999). If cluster studies have been analysed appropriately, taking the ICC and relevant data documented in the report into account, synthesis with other studies is possible using the generic inverse variance technique.

Cross-over trials

In cross-over trials the effect of the first phase can be carried over to the second phase. As a consequence, on entry to the second phase, the participants can differ systematically from their initial state despite a washout phase. Cross-over designs are inappropriate for unstable conditions like schizophrenia (Elbourne 2002). Therefore, we will only use data from the first phase of cross-over studies.

Studies with multiple treatment groups

We will mention all intervention groups in a multi-arm study in the 'Characteristics of included studies' tables. We will only describe in detail those groups relevant to our review. We may have more than one treatment group that satisfies our inclusion criteria and more than one control group. In this case, we will combine the experimental intervention groups to form a single group and similarly combine the control groups into one control group and enter the study only once in the review. In case all intervention groups are relevant to the review and the multiple interventions are completely different, then no 'grouping' will be applied. For example, there will be no grouping between antipsychotic interventions and placebo. We will not make any indirect comparisons.

Dealing with missing data

We will contact the corresponding author(s) of the included trial(s) to retrieve any missing data (incomplete assessments, dropouts, stopped treatment because of side effects or adverse events). We will contact the other trial authors if we receive no response from the corresponding author. If a trial only describes the results for participants who completed the trial or who followed the protocol, we will enquire about the participants who were randomised and did not complete the treatment. If we do not have enough information to determine whether the data is missing at random, we will assume that it is 'not missing at random'. In trials where it is clear that data are missing at random, and less than 20% of the participants are lost to follow-up, we will include completers in the graph. Where more than 20% are lost to follow-up, we will perform an ITT analysis and carry forward the last observation. For data that are not missing at random, we will perform an ITT analysis carrying forward the last observation.

We will describe the missing data and dropouts/attrition of the included studies in 'Risk of bias' tables (beneath the 'Characteristics of included studies' tables). We will discuss the effect of the missing data on the results and conclusions of the review. We will undertake a sensitivity analysis to establish the extent to which primary outcomes change when 'completer' data only are compared to the ITT analysis.

When SDs are not reported for continuous variables, we will try to obtain the missing values from the trial authors. If this is not achievable, but an exact SE and CIs are available for group means and either the P value or t value is available for differences in mean, we will calculate them according to the rules described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When only the SE is reported we will calculate SDs using the formula SD = SE * square root (n). Sections 7.7.3 and 16.1.3 of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011) present detailed formulae for estimating SDs from P values, t values, F values, CIs, ranges or other statistics. If these formulae do not apply, we will calculate SDs according to a validated imputation method, which is based on the SDs of the other included studies (Furukawa 2006). Although some of these imputation strategies can introduce error, the alternative would be to exclude a given study's outcome and thus lose valuable information. Nevertheless, we will examine the validity of the imputations in a sensitivity analysis excluding imputed values.

Assessment of heterogeneity

Clinical heterogeneity

The main potential sources of clinical heterogeneity are diagnostic and outcome assessments and study settings. If we find significant variation in the results of different studies, then we will look at participant characteristics, study settings, and diagnostic and outcome assessment as possible sources of variation. We will describe any clinical heterogeneity in the review.

Methodological heterogeneity

The variation in methodology, for example, the method of randomisation, blinding and allocation concealment, can result in heterogeneity in outcome. If there is significant variation in the results of studies, then we will look at methodological variation as a possible explanation and describe it in the review.

Statistical heterogeneity

We will visually inspect graphs to investigate the possibility of statistical heterogeneity. We will describe statistical heterogeneity by calculating the I² statistic, a quantity that describes approximately the proportion of variation in point estimates that is due to heterogeneity rather than sampling error (Higgins 2002). We will also employ a Chi² test of homogeneity. The importance of the observed value of I² statistic depends on (1) the magnitude and direction of the effects and (2) the strength of evidence for heterogeneity (e.g. P value of Chi² test, or a CI for I² statistic). We will interpret the I² statistic according to guidance provided in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011). It advises against any rigid interpretation, but suggests potential meanings of various ranges of the estimate (Section 9.5.2, Higgins 2002). We will treat an I² statistic value above 50% as an indication of substantial heterogeneity.

Assessment of reporting biases

Funnel plots may be useful in investigating reporting biases, but are of limited power to detect small-study effects. We will draw funnel plots for outcomes where there are 10 or more trials, unless all trials are of similar sizes.

Asymmetry in the funnel plot can result from the following:

  • Publication bias;

  • Selective outcome reporting;

  • Poor methodological quality causing spurious inflated results in smaller studies;

  • Sampling variation leading to an association between the intervention effect and its SE; and

  • True heterogeneity, where the size of the effect differs according to the size of the study.

We will assess the individual studies to determine the reasons for asymmetry in the funnel plot. The methodological rigour of the trial, quality of reporting of results, and when the trial was conducted may help us to understand asymmetry.

We will endeavour to retrieve any unpublished data for comparison with the published trial to assess the potential for publication bias.

Data synthesisWe intend to combine the results of the studies in a meta-analysis for each outcome. We will use a random-effects meta-analysis to combine results. A fixed-effect meta-analysis produces misleading results when heterogeneity is present in the studies. Empirical evidence suggests that heterogeneity is very often present even when it is not detected (Kontopantelis 2013). The random-effects model is preferable for small to moderate heterogeneity. Its results are similar to the fixed-effect model when no heterogeneity is present.
Subgroup analysis and investigation

To investigate heterogeneity, we will check whether the data have been appropriately extracted and entered.

The choice of subgroup analysis or meta-regression will depend on the number of studies that we find. If there are fewer than 10 studies, we will conduct a subgroup analysis. If we find more than 10 studies, we will consider a meta-regression. To avoid false positive results, we will keep the number of subgroup analyses to a minimum and treat these analyses as exploratory. We will consider the following effect modifiers for subgroup analyses: choice of comparison treatment and length of follow-up. These are important because the side effect profile of the comparison drugs will affect compliance and attrition, and duration of treatment has implications for the outcome.

We will apply a random-effects subgroup and meta-regression analysis because of the possibility of heterogeneity. The sources of heterogeneity are participant characteristics, study settings, and diagnostic and outcome assessment and variation in methodology. Heterogeneity can be present even if it is not detected.

Sensitivity analyses

We will conduct the following sensitivity analyses to determine whether the findings are sensitive to restricting the analyses to studies judged to be at low risk of bias:

  • Only studies with a low risk of selection bias (associated with sequence generation, allocation concealment);

  • Only studies with a low risk of performance bias (associated with issues of blinding); and

  • Any studies with a low risk of attrition bias (associated with completeness of data).

Also, we will undertake a sensitivity analysis to assess the effects of including data from cluster-RCTs where we have used imputed ICC values in calculating the design effect. If substantial differences are noted in the effect estimates in any of the sensitivity analyses, we will not present the pooled data from the removed trials with the other trials contributing to the outcome, but will present them separately.

History

Protocol first published: Issue 6, 2013
Review first published: Issue 9, 2015

DateEventDescription
22 July 2013AmendedWe updated the review authors' contact details.

Contributions of authors

Dr Muhammad Ayub conceived and coordinated the review, and made a major contribution to the review write-up. Drs Khalid Saeed, Tariq A Munshi and Farooq Naeem reviewed the studies and prepared the manuscript.

Declarations of interest

Muhammad Ayub - none known.
Khalid Saeed - none known.
Tariq A Munshi - Dr Munshi is on the Advisory Boards of the following pharmaceutical companies: Lundbeck, Sunovion, Bristol Myers Squibb and Jansenn Cilag. He has been an invited speaker for Otsuka, Bristol Myers Squibb, Lunbeck and Astra Zeneca. He has received sponsorship from Lunbeck and Eli Lilly for educational activities; and Bristol Myers Squibb funded the development of a resource book for patients, caregivers and professionals involved in patient care. Tariq declares that no commercial funding was received for this review.
Farooq Naeem - none known.

Sources of support

Internal sources

  • Bracken Health Science Library, Queen's University, Kingston, Canada.

    Provided full-text reports

External sources

  • No sources of support supplied

Differences between protocol and review

We added the Cochrane Schizophrenia Group's Register of Trials to our original list of sources.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    Abbreviations: RCT - randomised controlled trial.

Advokat 2000Observational study of side effect profiles of atypical antipsychotics, typical antipsychotics or no psychotropic medications in people with intellectual disabilities.
Aman 1986Literature review. Not a RCT.
Aman 1995Observational study of use of psychotropic drugs in people with intellectual disabilities living in group homes.
Aman 1999Literature review. Not a RCT.
Amann 2009Case report of treatment-resistant schizoaffective disorder in a patient treated with clozapine.
Antonacci 2000Retrospective chart review of 33 cases who received clozapine.
Buck 1989Observational study of use of psychotropic medication in people with intellectual disabilities living in long-term care facilities.
Buzan 1998Chart review of 10 patients who received clozapine for treatment-resistant psychosis or mania. The report does not specify retrospective or prospective and it is difficult to determine this from the description provided in the publication.
Cohen 1994Case series of the use of clozapine in six patients with moderate to profound mental retardation.
Dalvi 2003Audit of case notes of 18 patients being treated with high dose antipsychotic medication.
De Kuijper 2010Cross-sectional, observational study of use of antipsychotic drugs in people with intellectual disabilities living in residential settings.
Dhumad 2007Chart review of 100 case notes on the use of antipsychotic medication in people with intellectual disabilities.
Friedlander 2001Retrospective chart review of patients with intellectual disabilities and comorbid psychiatric diagnoses who received atypical antipsychotics diagnoses.
Frighi 2011Observational study of 138 participants with intellectual disabilities treated with antipsychotic medication compared to 64 treatment-naive participants with intellectual disabilities.
Frighi 2012Observational study of atypical antipsychotics.
Gladston 2005Case report of a patient with velocardiofacial syndrome and treatment-resistant psychosis who was treated with clozapine.
Griffiths 2012Audit of prescribing practice of antipsychotics for people with intellectual disabilities.
Hammock 2001Case series describing two patients with self-injurious behaviour.
Kamal 1999Case report of a patient with moderate intellectual disability and treatment-resistant psychiatric disorder treated with clozapine.
La Malfa 2006Literature review. Not a RCT.
Pary 1994Case series of use of clozapine in three individuals with mild mental retardation and treatment-resistant psychosis.
Rajagopal 2007Case report of treatment-resistant schizophrenia in a patient with an intellectual disability and prevention of clozapine-induced granulocytopenia/granulocytosis with granulocyte-colony stimulating factor.
Reznik 2002Case report of a patient with an intellectual disability and schizoaffective disorder treated with clozapine.
Sajatovic 1994Case series of three females and two males with treatment-resistant schizophrenia or schizoaffective disorder and borderline intellectual disabilities treated with clozapine.
Sajatovic 1995Literature review. Not a RCT.
Schroeder 1995Case series of the use of clozapine to treat self-injurious behaviour in three patients with profound mental retardation.
Shedlack 2003Case report of a patient with an intellectual disability and schizoaffective disorder treated with clozapine. Clozapine restarted after neuroleptic malignant syndrome.
Shedlack 2005Retrospective chart review of 72 patients with mild mental retardation and comorbid illness treated with antipsychotic mediation.
Singh 2010Literature review. Not a RCT.
Thalayasingam 2004Retrospective chart review of 24 patients with intellectual disabilities and psychoses or behaviour disorder treated with clozapine.
Tin 2008Observational study of use of antipsychotics in people with intellectual disabilities accessing psychiatry services in Leicester, England.
Towbin 1994Case report of a 14 year-old male with an intellectual disability and treatment-resistant psychosis treated with clozapine.
Tufan 2013Case report of an adolescent patient with an intellectual disability and psychosis who developed tardive dyskinesia on olanzapine and was successfully treated with clozapine.
Unwin 2011Literature review. Not a RCT.
Vvncke 1974Case series of 40 patients with behaviour disorders treated with clozapine.
Wehmeier 2005Case report of a pair of twins.
White 2010Case report looking at the effect of polydrug therapy on white blood cell count and absolute neutrophil count.
Zuddas 2011Literature review. Not a RCT.

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