Rationale-The selective serotonin reuptake inhibitor (SSRI) fluoxetine is the only psychopharmacological agent approved for use in children. While short-term studies of side effects have been performed, long-term consequences for brain development are not known. Such studies can be performed in appropriate animal models if doses modeling therapeutic use in children are known.Objectives-To identify a daily dose of fluoxetine in juvenile monkeys which would result in serum fluoxetine and norfluoxetine concentrations in the therapeutic range for children.Methods-Juvenile (2.5 year old rhesus monkeys, n=6) received single administration of doses of 1, 2 and 4 mg/kg-d fluoxetine on a background of chronic dosing at an intermediate level to provide steady state conditions to model therapeutic administration. Using nonlinear modeling, standard pharmacokinetic parameters were derived. Cerebrospinal fluid monoamine neurotransmitters were assayed to confirm the pharmacological effects.Results-Dose-dependent AUC and Cmax values were seen while Tmax and absorption/ elimination half-lives were minimally influenced by dose. A dosage of 2 mg/kg-d given over a 14 week period led to steady state serum concentrations of active agent (fluoxetine + norfluoxetine) similar to those recorded from drug monitoring studies in children. Cisternal cerebrospinal fluid concentrations of serotonin increased significantly over the 14 week period, while concentrations of the serotonin metabolite (5-HIAA) were lower but not significantly different.Conclusions-2 mg/kg/d fluoxetine in juvenile rhesus monkeys provides an internal dose similar to therapeutic use in children and will help establish a valuable animal model for understanding fluoxetine therapeutic and potential adverse effects in children.