ReviewAntipsychotics in children and adolescents: Increasing use, evidence for efficacy and safety concerns
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
References (68)
- et al.
Effects of short- and long-term risperidone treatment on prolactin levels in children with autism
Biol. Psychiatry
(2007) - et al.
Clinical effectiveness of new generation antipsychotics in adolescent patients
Eur. Neuropsychopharmacol.
(2004) - et al.
Cardiovascular and metabolic risk in outpatients with schizophrenia treated with antipsychotics: results of the CLAMORS Study
Schizophr. Res.
(2007) Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes
J. Am. Acad. Child Adolesc. Psychiatry
(2008)- et al.
Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents
J. Am. Acad. Child. Adolesc. Psychiatry
(2006) - et al.
Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents
Child Adolesc. Psychiatr. Clin. N. Am.
(2006) - et al.
Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomized clinical trial
Lancet
(2008) - et al.
Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial
J. Am. Acad. Child Adolesc. Psychiatry
(2009) - et al.
Clozapine and “high-dose” olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison
Biol. Psychiatry
(2008) - et al.
Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs
J. Am. Acad. Child. Adolesc. Psychiatry
(2002)
Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study
J. Am. Acad. Child Adolesc. Psychiatry
How can we improve the assessment of safety in child and adolescent psychopharmacology?
J. Am. Acad. Child Adolesc. Psychiatry
Cognitive effects of risperidone in children with autism and irritable behavior
J. Child Adolesc. Psychopharmacol.
Acute and long-term safety and tolerability of risperidone in children with autism
J. Child Adolesc. Psychopharmacol.
Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children with subaverage intelligence
Am. J. Psychiatry
Patterns and determinants of antipsychotic prescribing in children and adolescents, 2003–2004
Curr. Med. Res. Opin.
A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities
J. Clin. Psychiatry
Trends in the inpatient mental health treatment of children and adolescents in US community hospitals between 1990 and 2000
Arch. Gen. Psychiatry
Antipsychotic treatment in child and adolescent first-episode psychosis: a longitudinal naturalistic approach
J. Child Adolesc. Psychopharmacol.
Retrospective analysis of risk factors in patients with treatment-emergent diabetes during clinical trials of antipsychotic medications
Br. J. Psychiatry
The use of atypical antipsychotics in pediatric bipolar disorder
J. Clin. Psychiatry
New users of antipsychotic medications among children enrolled in TennCare
Arch. Ped. Adolesc. Med.
Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents
J. Clin. Psychiatry
Pharmacogenetics of antipsychotic-induced weight gain
Psychopharmacology (Berl.)
QTc changes after 6 months of second-generation antipsychotic treatment in children and adolescents
J. Child Adolesc. Psychopharmacol.
Effectiveness and tolerability of olanzapine in the treatment of adolescents with schizophrenia and related psychotic disorders: results from a large, prospective, open-label study
J. Child Adolesc. Psychopharmacol.
Who are the new users of antipsychotic medications?
Psychiatr. Serv.
New antipsychotic drugs carry risks for children
Prolactin levels during long-term risperidone treatment in children and adolescents
J. Clin. Psychiatry
Use of antipsychotics in children and adolescents
J. Clin. Psychiatry
A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia
Am. J. Psychiatry
Metabolic and hormonal side effects in children and adolescents treated with second-generation antipsychotics
J. Clin. Psychiatry
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