CLINICAL HANDBOOK OF SCHIZOPHRENIA

46. Children and Adolescents 487Also, the therapeutic benefits of the second-generation medications relative to conventionalantipsychotics appeared much smaller than what would have been assumed fromthe initial industry-sponsored studies.To date, most of the clinical data to support the use of second-generation antipsychoticsin children and adolescents with schizophrenia have been derived from studies ofclozapine, olanzapine, and risperidone. In comparison, no systematically collected dataregarding the use of ziprasidone, aripiprazole, and quetiapine in children and adolescentswith schizophrenia spectrum disorders have demonstrated either the safety or efficacy ofthese medications in this population.The best of the available published data supporting the use of second-generationantipsychotics are for clozapine, the first drug with convincing data that show it is superiorto other conventional (e.g., haloperidol) and second-generation antipsychotics (e.g.,high-dose olanzapine) in the treatment of adolescents with treatment-refractory schizophrenia.In accord with these data, naturalistic studies have found that clozapine is effectivein reducing the frequency of aggressive behaviors in youth with schizophrenia, andthat the rate of serious hematological disturbances, such as agranulocytosis, does not appearto be higher in children and adolescents compared to adults.In addition to clozapine, risperidone and olanzapine have demonstrated efficacycomparable to, if not exceeding, that of haloperidol in a recent randomized, double-blindtrial with adolescents. Unfortunately, recent evidence suggests that weight gain andextrapyramidal side effects may be more prevalent and severe for youth than for adultstreated with risperidone and olanzapine.Despite the lack of evidence supporting the use of the other second-generationantipsychotic agents, based on expert opinion and current community standards, aripiprazole,olanzapine, quetiapine, and risperidone are all considered acceptable first-lineagents for pediatric patients with psychoses. If patients fail to respond to an adequatetrial (dose and duration) of an initial atypical antipsychotic, physicians should first reassessthe diagnosis to rule out the presence of a comorbid condition that may be contributingto the poor clinical response. For example, after the resolution of psychotic symptoms,underlying affective symptoms and/or attentional impairments that may becomeevident might be effectively treated with a mood stabilizer or antidepressant. If failure torespond to an initial treatment does not appear to be due to a secondary or comorbidcondition, monotherapy with a different atypical antipsychotic should be tried (Pappadopuloset al., 2003); however, a clozapine trial should be attempted only after two adequateantipsychotic drug trials. Due to the comparative lack of published safety data, limiteduse of clozapine in pediatric populations, and risk for agranulocytosis, clozapineshould be considered as a second-line agent at the present time.Polypharmacy in young children, particularly in those who are poor treatment responders,has become a major problem. It has been suggested that if patients have notshown meaningful responses to multiple psychotropic medications administered in combination,then physicians should reexamine the diagnoses and consider tapering and discontinuingone or more medications.Weight gain has emerged as the major adverse side effect associated with secondgenerationantipsychotics in adolescents, particularly for clozapine, olanzapine, andrisperidone. Although diet, exercise, and behavioral treatments are the most commonlyrecommended strategies for preventing and treating atypical antipsychotic–inducedweight gain in adults with schizophrenia, the use of these strategies has not been systematicallyexamined in controlled studies of youth with schizophrenia, and such strategiesmay not be feasible during the acute phase of treatment, when a substantial portionof weight gain is likely to occur. Also, there has been increasing recognition that