Abstract
Fluoxetine therapy has been approved for children with major depressive disorder and obsessive compulsive disorder for over 14 years and has expanded to other childhood behavior disorders. As use increases, more detail on fluoxetine effects during juvenile brain development can help maintain safe and effective use of this therapy. Here, a narrative review is provided of previously published findings from a large nonhuman primate project. Fluoxetine was administered to juvenile male rhesus monkeys for an extended period (2 years) prior to puberty. Compared to controls, treated monkeys showed sleep disruption, facilitated social interaction, greater impulsivity, and impaired sustained attention during treatment. No effects on growth were seen. Metabolomics assays characterized a distinctive response to fluoxetine and demonstrated individual differences that were related to the impulsivity measure. Fluoxetine interactions with monoamine oxidase A polymorphisms that influenced behavior and metabolomics markers were an important, previously unrecognized finding of our studies. After treatment was discontinued, some behavioral effects persisted, but short-term memory and cognitive flexibility testing did not show drug effects. This detailed experimental work can contribute to clinical research and continued safe and effective fluoxetine pharmacotherapy in children.
Highlights
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that was approved for use in adults for depression in 1987 and for use in children for depression (MDD) and obsessive compulsive disorder (OCD) in 2003
The available literature did allow some expectations about the consequences of fluoxetine treatment in the juvenile monkeys
Most of the endpoints targeted for evaluation as potentially sensitive to fluoxetine were identified from clinical and experimental studies of SSRIs in human adults and children and from a small number of juvenile animal studies in the literature
Summary
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that was approved (as Prozac®) for use in adults for depression in 1987 and for use in children for depression (MDD) and obsessive compulsive disorder (OCD) in 2003. Plasma levels (fluoxetine + norfluoxetine) in the monkeys after 2 years of dosing were 273 ± 31 ng/mL [5], compared to 241 ± 91 ng/mL in children with MDD who showed a therapeutic response at the recommended dosage of 20 mg/day [12]. Fluoxetine interactions with MAOA polymorphisms influenced several of the behavioral assessments, most prominently emotional response (Table S2 in Supplementary Material).
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