Review
Antipsychotics in children and adolescents: Increasing use, evidence for efficacy and safety concerns

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Abstract

Second-generation antipsychotics (SGA) are increasingly used to treat children and adolescents. The European College of Neuro-psychopharmacology convened an expert panel to review relevant efficacy and safety data, and identify needs for further research. Controlled studies support the short-term efficacy of several SGA for treating psychosis, mania, and aggression within certain diagnostic categories. Except for clozapine, no clinically significant superiority in efficacy has been demonstrated for any specific antipsychotic, including both first- and second-generation agents, in children and adolescents. Major differences exist, however, with respect to type and severity of adverse effects; therefore the choice of treatment is primarily guided by tolerability and safety considerations. Children appear to be at higher risk than adults for a number of adverse effects, such as extrapyramidal symptoms and metabolic and endocrine abnormalities. While the safety profile during acute and intermediate treatment has been evaluated, the distal benefit/risk ratio during long-term treatment remains to be determined. Research is also needed to understand the mechanisms underlying antipsychotic-induced toxicities in order to develop effective preventive and treatment strategies.

Introduction

Since their introduction into clinical practice, antipsychotic medications have been used in the treatment of children and adolescents with a variety of psychiatric conditions, including psychosis, physical aggression, mania, irritable mood, and Tourette's disorder (Findling et al., 2005). In recent years, the pediatric use of antipsychotics has substantially increased, due to an increment in prescription of second-generation antipsychotics (SGA), despite a limited evidence base in support of their efficacy and safety.

Pharmacoepidemiological studies using databases from both the U.S.A and several European countries have documented that the use, although showing wide variability in absolute terms across countries (Zito et al., 2008), has at least doubled during the last ten years (Cooper et al., 2004, Olfson et al., 2006, Aparasu and Bhatara, 2007, Kalverdijk et al., 2008, Rani et al., 2008). In the U.S., pediatric use (i.e., by patients under 19 years of age) accounted for 15% of total use in 2004–2005, as compared with 7% in 1996–1997 (Domino and Swartz, 2008). Moreover, the duration of treatment with these agents has been increasing (Kalverdijk et al., 2008, Rani et al., 2008).

This rapid increase and the recognition that many antipsychotics induce metabolic adverse effects, thus increasing the risk for obesity, diabetes type II, and associated cardiovascular morbidity (Newcomer et al., 2002, Guo et al., 2006, Bobes et al., 2007), have raised concerns about the proper utilization of these agents and stirred controversy among both experts and the general public (Elias, 2006, Harris, 2008). After having been hailed as a safer alternative to first-generation antipsychotics because of their lower tendency to induce neurological effects, the SGA are now recognized to have a high propensity for causing other, equally problematic, adverse effects, thus triggering a reconsideration of their benefit/risk ratio, especially in children (Tyrer and Kendall, 2008, Correll et al., 2006, Correll, 2008a, Correll, 2008b, Sikich et al., 2008).

We report on the conclusions of an expert panel convened under the auspices of the European College of Neuro-psychopharmacology in Barcelona, Spain, in August 2008, with the task of reviewing the clinical implications of the available data on antipsychotic use in children and adolescents, and identifying critical knowledge gaps in need of further research. The focus of the review was primarily on data from controlled clinical investigations conducted in children and adolescents.

Section snippets

Factors contributing to the increased pediatric use of antipsychotics

Multiple factors have likely contributed to the increased pediatric use of antipsychotics. In general, the rising of a medical model for explaining emotional and behavioral disturbances of childhood, as opposed to the psychosocial interpretations of mental illness that had prevailed until the 1980s, has led to greater utilization of medical interventions such as pharmacology. In parallel, it has become apparent that psychiatric disorders often have their onset in childhood, so that conditions

Benefits and risks of antipsychotics in children and adolescents: clinical implications

A few short-term, placebo-controlled trials support the acute efficacy of risperidone, aripiprazole, olanzapine, and quetiapine in decreasing psychotic symptoms of schizophrenia in adolescents and manic symptoms of bipolar disorder in children and adolescents (Sikich, 2008, Chang, 2008, Findling et al., 2008, Kryzhanovskaya et al., 2009). Based on these studies, both risperidone and aripiprazole have recently been approved for the treatment of 13–17 year old adolescents with schizophrenia and

Research implications

The large and steep increase in pediatric use stands in stark contrast with the relative paucity of data from controlled investigations in this age group, especially when considering that most of the use is for the management of non-psychotic conditions, such as aggression, disruptive behavior and mood dysregulation (Olfson et al., 2006). The limitations of the current evidence base for efficacy and safety are particularly evident with respect to data informing on outcomes during chronic

Role of the funding source

ECNP as an organization was not involved in the actual content of this review.

Contributors

Drs. Vitiello, Correll, van Zwieten-Boot, Zuddas, Parellada, and Arango participated in the data review and discussions and at the ECNP TEM.

Dr. Vitiello prepared the manuscript, which was critically reviewed by the other authors.

All authors approved the final version of the manuscript, which is being submitted for publication.

Conflict of interest

Drs. Vitiello and van Zwieten-Boot have no potential conflicts of interest.

Dr. Correll has been a consultant to or has received honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Otsuka, Pfizer, Supernus and Vanda, has served on the speaker's bureau of AstraZeneca, Bristol-Myers Squibb/Otsuka and Pfizer, and has received grant/research support from the American Academy of Child and Adolescent Psychiatry, Bristol-Myers Squibb, The Feinstein Medical Research Center, NARSAD, the

Acknowledgments

This report is based on the discussion and conclusions at a Treatment Expert Meeting organized by the European College of Neuro-psychopharmacology in Barcelona, Spain, in August 2008. Disclaimer: The opinions and assertions contained in this report are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Health and Human Services, the National Institutes of Health, or the National Institute of Mental Health or the Medicines

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