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For a More Targeted and Safer Use of Antipsychotics in Youth


Benedetto Vitiello, M.D.
Division of Services and Intervention Research


The goal of this initiative is to develop and test for effectiveness a treatment algorithm to manage severe mood and behavior dysregulation in non-psychotic children and adolescents for whom antipsychotics are commonly prescribed in the community.


There is concern about the increasing use of antipsychotics in youth. Most of this use is not to treat psychosis, but rather to manage mood and behavior dysregulation such as extreme irritability, impulsive aggression, and temper outbursts. Due to their low incidence of neurological adverse effects, second generation antipsychotics have a much better tolerability than first generation antipsychotics (neuroleptics), but their use involves a high risk for metabolic adverse effects. Youths are especially sensitive to these metabolic effects, with consequent risk for obesity, diabetes, and hyperlipidemias. Another safety concern is that long-term use of antipsychotics is associated with cortical gray matter loss in rodents, non-human primates, and patients with schizophrenia.

The Food and Drug Administration has approved several antipsychotics for use in children and adolescents to treat bipolar mania, schizophrenia, or autism-associated irritability. Although antipsychotics may be the most rapidly effective treatment to manage extreme manifestations of mood instability and impulsive behavior, other therapeutic interventions--both psychosocial and pharmacological--are available, and may offer a more favorable risk/benefit balance, at least for certain groups of patients.

A few NIMH-funded studies have investigated the effects of behavior therapy, stimulant medications, valproate, and lithium for the management of children and adolescents with mood dysregulation and recurrent impulsive aggression. However, no systematic, multiple-step treatment approach has been developed and evaluated for effectiveness and safety. An evidence-based algorithm that would limit the use of antipsychotic to those youths who are non-responsive to alternative interventions would be useful to clinicians, families, and policy makers.

Building on data from recent trials on the efficacy of different treatment modalities for children with impulsive aggression and mood dysregulation, a contract or cooperative agreement will support the development of a stepped-care approach to the treatment of non-psychotic youths in the community who are currently prescribed antipsychotics. The algorithm will first involve the use of psychosocial intervention; then, if needed, the use of non-antipsychotic medications; and, if necessary, targeted use of antipsychotic medication, with attention to preventing metabolic adverse effects and limiting the duration of use. The algorithm will be pilot-tested for feasibility in practice settings, using existing mental health research networks. Finally, a pragmatic trial of the algorithm vs. care as usual will be conducted to determine the effectiveness of this approach. Outcomes will include measures of symptoms, levels of functioning, and metabolic parameters. Moderators, predictors, and mediators of outcome will be examined.

This initiative aims to develop a treatment algorithm with empirically-derived estimates of effectiveness at the various steps, and potential predictors, moderators, and mediators of treatment outcome.

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