Implications of marked weight gain associated with atypical antipsychotic medications in children and adolescents.

THE FINDINGS REPORTED BY CORRELL AND COLleagues in this issue of JAMA are both timely and sobering. Prior treatment-naive youth (N=272), aged 4 to 19 years, gained substantial weight during a 12week period of clinician’s choice treatment with atypical antipsychotic medications aripiprazole, olanzapine, quetiapine, or risperidone. The mean weight gain across treatment groups ranged from 8.5 kg with olanzapine to 4.4 kg with aripiprazole. More than half gained more than 7% of their total body weight. Significant abnormalities in lipid profiles and other metabolic parameters were also noted, especially with olanzapine. Comparison patients had minimal changes in body weight and lipid levels over the same period. These data confirm prior findings that children and adolescents are highly vulnerable to antipsychotic medication– induced weight gain and metabolic adverse effects. The magnitude of weight gain is particularly concerning, as is the implication that metabolic adverse events may be underestimated in studies in which participants have had prior atypical antipsychotic medication exposure. Furthermore, the development of clinically significant hyperlipidemias and insulin resistance after only 12 weeks of treatment portends severe long-term metabolic and cardiovascular sequelae. These results challenge the widespread use of atypical antipsychotic medications in youth. During the past decade, the use of antipsychotic medications in children and adolescents increased substantially in the United States. From 2003 to 2004, approximately 1% of outpatient pediatric visits resulted in the prescription of an atypical antipsychotic medication. All the atypical antipsychotic medications, with the exception of clozapine, are commonly prescribed to youth for a variety of problems. Only 2 have current approval from the US Food and Drug Administration (FDA) for pediatric use: risperidone for irritability associated with autistic disorder, schizophrenia, and bipolar disorder; and aripiprazole for schizophrenia and bipolar disorder. In June 2009, the FDA Psychopharmacologic Drugs Advisory Committee voted to approve quetiapine, ziprasidone, and olanzapine for schizophrenia and/or bipolar mania, but no formal action has been taken yet. Studies support the use of these medications for autism, schizophrenia, bipolar disorder, aggression, and tics. However, most of the trials in children and adolescents are short-term and have methodological limitations. Schizophrenia is the best-supported indication for use of atypical antipsychotic medications. Atypical antipsychotic medications have been widely viewed as superior to traditional agents and are now almost universally used as antipsychotic medications of first choice. Yet, recent research challenges these assumptions. Large clinical trials in adults do not support the superiority of atypical antipsychotic agents over traditional neuroleptics for schizophrenia. Moreover, regardless of medication choice, many patients do not continue the same treatment long-term due lack of efficacy, adverse effects, or nonadherence. In the Treatment of Early-Onset Schizophrenia Spectrum Disorder (TEOSS) study risperidone and olanzapine were not superior to molindone, a traditional neuroleptic, in the acute treatment (8 weeks) of youth with schizophrenia spectrum disorders (N=119). Overall, less than 50% of participants achieved an adequate response to treatment. Weight gain was significantly greater with the atypical antipsychotic agents, so much so that the study’s safety monitoring board stopped the olanzapine treatment group (mean [SD] weight gain, 6.1 [3.6] kg). The sharp increase in atypical antipsychotic medication prescriptions coincides with the controversial increase in the number of children and adolescents diagnosed with bipolar disorder, including children younger than 5 years old. Atypical antipsychotic medication use in pediatric bipolar disorder is justified primarily based on the adult literature. However, the continuity between childhood and adolescent forms and adult-onset forms has not been established, especially for younger children. Pediatric mania overlaps significantly with disruptive behavior disorders. Medication treatment of bipolar disorder in youth often targets aggression and explosive behavior, raising questions of speci-