Review
Second generation antipsychotics (SGAs) for non-psychotic disorders in children and adolescents: A review of the randomized controlled studies

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Abstract

In children and adolescents the Second Generation Antipsychotics (SGAs) represent the class of psychotropic drugs whose use has grown more significantly in recent years: they are primarily used for treatment of patients with disruptive behavior disorders, mood disorders and pervasive developmental disorders or mental retardation. In order to compare the efficacy and tolerability of antipsychotics against placebo or each other, a systematic Medline/PubMed search for randomized, double blind studies on SGA in patients younger than 18 years of age at enrolment, was conducted. Papers on schizophrenia, discussed in another article of this specific issue, were excluded by the efficacy analysis. A set of standard efficacy and safety indices, such as treatment effect sizes (ES), the Numbers Needed to Treat (NNT) and Numbers Needed to Harm (NNH), was used to compare medications. 32 studies analyzing efficacy and/or tolerability of SGAs in children and adolescents with bipolar, autistic or disruptive behavior disorders, and Tourette syndrome were identified. SGAs efficacy on mania, extreme mood variability, irritability, aggression and disruptive behavior appears to be greater than for psychotic symptoms in schizophrenia: average NNT was 2–5, whereas for schizophrenia it varies between 3 for risperidone and 10 for olanzapine, quetiapine, and aripiprazole.

As for schizophrenia, different SGAs show a similar efficacy for specific non-psychotic disorders, but they significantly differ in their safety profile. In randomized studies, adverse effects were usually relatively minor, easily predictable and manageable, whereas long-term open-label studies have indicated that some adverse event, such as the metabolic effects, may be severe and potentially life threatening on the long-term. Taken together, these findings suggest that the choice of a specific treatment should be guided primarily by the safety profile of specific antipsychotics, considering specific risk factors (i.e. obesity and BMI, family history of diabetes or cardiovascular disorder, etc) for the single patient.

Introduction

Starting from the 70s, typical antipsychotics (FGA, First-Generation Antipsychotic) had shown a moderate efficacy in the treatment of children and adolescents suffering from various symptoms and disorders, including not only schizophrenia and other psychotic disorders, but also pervasive developmental disorders, bipolar disorder, Tourette syndrome and other tic disorders, conduct disorder and impulsive and aggressive behaviors. Although effective in ameliorating positive symptoms of schizophrenia, these drugs show a modest efficacy on negative symptoms such as apathy, abulia, social withdrawal and affective flattening, also related to the fact that antipsychotic drugs themselves can cause or worsen negative symptoms, especially when used at high dose for long periods of time. Medication-induced tardive dyskinesia has been another reason of concern.

The definition of the medical model for the pathogenesis of emotional and behavioral disorders in childhood and adolescence, as opposed to psychosocial interpretation of mental illness, and the evidence that most of the psychiatric disorders in adulthood, including depression, bipolar disorder, anxiety and obsessive–compulsive disorders, often begin during childhood (Paus, et al., 2008), contributed to the expansion of pediatric use of psychotropic medication. The perception of a higher safety profile for Second Generation Antipsychotics (SGA) compared to FGAs and the expectation of a greater efficacy, especially in improving negative symptoms of schizophrenia, have been important factors for the expansion of their pediatric use (Vitiello et al., 2009). The perceived better safety and efficacy and the putative ease of use, made the treatment with SGAs more accepted also for non-psychotic conditions, including mood disorders, aggression and conduct disorders, as well as for disruptive behaviors in children and adolescents with pervasive developmental disorders and/or mental retardation (Olfson et al., 2006).

In the last 15 years, the prescription of psychotropic medication has consistently increased, taking a major role in the integrated program of therapeutic intervention for many psychiatric disorders diagnosed in children and adolescents. SGAs are the class of psychotropic drugs whose use has grown more significantly in recent years. Data from U.S. indicate that antipsychotics prescription in children and adolescents has increased six-fold between 1993 and 2002 (Olfson et al., 2006). Between 2000 and 2002, 9.2% of all visits to children and adolescents referred to psychiatrists were accompanied by the prescription of an antipsychotic medication: in the 92.3% of the cases it was a SGA (Moreno et al., 2007). This trend was further increased in subsequent years (Aparasu and Bhatara, 2007, Pathak et al., 2010).

Similar prevalence data have been reported, on average, in several European countries (Zito et al., 2008, Acquaviva et al., 2009, Koelch et al., 2009, Verdoux et al., 2010). In UK the prescriptions of antipsychotics for patients aged between 7 and 12 years have tripled between 1992 and 2005 and the prescription of SGA increased by 60 times between 1994 and 2005 (Rani et al., 2008). In the Netherlands the prevalence of prescriptions of antipsychotic drugs has doubled between 1997 and 2002, with the highest increase observed mainly in males in the age group between 10 and 14 years (Kalverdijk et al., 2008).

Reports from both the US and the European countries show that this increase in prescription appears to be correlated to a more frequent use of SGAs for non-psychotic disorders and to a more prolonged use. According to both US and European data (Olfson et al., 2006, Acquaviva et al., 2009, Koelch et al., 2009), in children and adolescents these medicines are predominantly used not for the treatment of psychotic disorders (14.2% of prescribed cases) but for disruptive behavior disorders (37.8%), mood disorders (31.8%) and, in a lower percentage, for pervasive developmental disorders or mental retardation (17.3%). Despite their extensive use, until very recently, most of these drugs were not registered in Europe for such uses, or they have been approved only for a small minority of possible indications.

More recently a significant increase in antipsychotic medication has been observed also in very young (2–4 year old) children: between 1999–2001 and 2007, in a cohort of more than 400,000 privately insured children the annual rate of any antipsychotic use per 1000 very young children increased from 0.78 to 1.59 (Olfson et al., 2010); these children were mainly affected by pervasive developmental disorder or mental retardation (28.2%), attention deficit/hyperactivity disorder (ADHD) (23.7%) or other types of disruptive behavior disorder (12.9%).

The aim of this descriptive review is to compare the efficacy and safety of SGA in the treatment of psychiatric disorders different from schizophrenia in children and adolescents. For this purpose, studies on bipolar disorder, a disease with frequent but not consistent psychotic symptoms, were also considered when the primary outcome was the effects on affective symptoms as measured by the Young Mania Rating Scale (Young et al., 1978).

Section snippets

Search strategy and comparison of efficacy and safety

A systematic Medline/PubMed search of the papers published in English between 1990 and April 2010 (i.e. after the introduction of SGAs) focusing on randomized, double blind studies on SGA in patients younger than 18 years of age was conducted in order to compare the efficacy and tolerability of antipsychotics against placebo or each other. The following key words were used: “antipsychotic”; and “double blind”; and “child”. The search was then repeated replacing “antipsychotic” with “olanzapine”,

Efficacy in bipolar disorder

Bipolar disorder (BD) is a mood disorder characterized by depressive episodes and hypomania/mania (APA, 2000). BD in adulthood is a clearly defined entity (Judd and Akiskal, 2003): Although at least one third of adults claim early symptoms of the disorder in childhood or adolescence (Goodwin et al., 2008), only recently solid evidence on clinical presentation and outcome of disorders have been established (Birmaher, 2007, McClellan et al., 2007, Geller et al., 2008). Nevertheless, phenomenology

Safety and tolerability

The second-generation antipsychotics were introduced in the pharmacopeia with the expectation of greater safety and tolerability compared to first generation ones, particularly with respect to extrapyramidal symptoms including tardive dyskinesia. In recent years, several double-blind and open studies have been performed in order to compare adverse effects of SGA in childhood: they show that children and adolescents may experience a higher risk of adverse events compared to adults. Unlike the

Clinical and research implication

The randomized double blind studies analyzed in the present review show that SGA are effective in ameliorating non-psychotic psychiatric disorders in children and adolescents. As for schizophrenia, different SGAs show a similar efficacy for specific non-psychotic disorders, but significantly differ in their safety profile. In children and adolescents with bipolar, autistic or disruptive behavior disorders, SGA efficacy, on mania, extreme mood variability, irritability, aggression, measured as

Role of the funding source

Supported in part by Agenzia Italiana del Farmaco AIFA Grant “Monitoraggio dell'uso degli antidepressivi (N06A) e degli antipsicotici (N06A) in bambini ed adolescenti mediante Registro Elettronico Regionale”.

Contributors

Dr Zuddas designed the review, contributed to the search and selection of the articles and to the interpretation of data, and wrote the first draft of the paper including the discussion.

Dr. Zanni and Usala participated in the search and selection of the articles, and in the extraction and interpretation of data.

All authors contributed to and have approved the final manuscript. They declare that they are responsible for all the information contained in this manuscript.

Conflict of interest

Dr. Zuddas has received research grants from Eli Lilly and Shire Laboratories; has been a speaker or had an advisory or consulting relationship with Lilly, Shire, Bristol-Myer Squibb/Otsuka, Schering-Plough, Astra Zeneca.

Dr. Zanni and Dr. Usala have no conflict of interest to declare.

Acknowledgment

The study was supported in part by Agenzia Italiana del Farmaco — AIFA. Pharmacovigilance Grant Monitoraggio dell'uso degli antidepressivi (N06A) e degli antipsicotici (N06A) in bambini ed adolescenti mediante Registro Elettronico Regionale”. The authors wish to thank Dr. Enrica Mosca and Ms. Tricia Palmer for the editorial assistance.

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