Fluoxetine Administration in Juvenile Monkeys: Implications for Pharmacotherapy in Children

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.

Long-Term Fluoxetine Administration Causes Substantial Lipidome Alteration of the Juvenile Macaque Brain

“…Interaction between fluoxetine treatment and MAOA genotype has been shown not only for circulating metabolite levels in juvenile macaques, but for behavioral responses, as well [26,35]. In line with this observation, compared to the average, the 106 treatmentassociated lipids showed an increased number of treatment-by-genotype interactions identified using ANOVA (enrichment p < 10 −7 , Figure 3A; Table S6).…”

“…Additionally, in a previous study we detected a reduction of AA in the blood plasma of fluoxetine-treated macaques [26], further supporting the hypothesis that fluoxetine can introduce organism-wide fatty acid metabolism alterations. While we cannot make conclusions about causality, our previous studies including the same macaque individuals [24,29,35] demonstrated that these fluoxetine-related metabolic alterations were accompanied by behavioral alterations as well.…”

“…We assessed alterations of gene expression, polar metabolite, and lipid abundance in the PLC of macaques treated with fluoxetine using RNA-sequencing (RNA-seq), Fouriertransform ion cyclotron resonance mass spectrometry (FT-ICR-MS), and high precision mass spectrometry coupled with liquid chromatography (LC-MS), respectively (Figure 1A). The fluoxetine and vehicle administration began at one year of age, which is equivalent to 4-6 years of age in humans, and continued uninterrupted for two years, followed by a one year post-dosing period that ended at four years of age, just before puberty [35]. Our analysis included 10 monkeys treated with fluoxetine and 11 control monkeys administered with a vehicle (Table S1).…”

Selective serotonin reuptake inhibitor treatment retunes emotional valence in primate ventral striatum

“…This dosage has been shown to reduce anxiety-related symptoms such as self-injuries and stereotypic behaviors in monkeys [37,38]. Drug concentrations and metabolic profiles are reported to be consistent with those seen in humans [42]. Fluoxetine administration was initiated after completion of experimental sessions defined as control days in which data was collected without any injection.…”

Delineation of biomarkers and molecular pathways of residual effects of fluoxetine treatment in juvenile rhesus monkeys by proteomic profiling

“…Despite its significant pharmacological efficacy, there are no studies on the potential effects of fluoxetine on brain development in children. Notably, recent studies in nonhuman primates (NHPs) have documented persistent effects on sleep disturbance, sustained attention, and impulsivity after discontinuation of treatment ( Golub et al, 2017 ; Golub & Hogrefe, 2016 ; Golub et al, 2016a ; Golub et al, 2018 ; He et al, 2014 ). Furthermore, alterations in serotonin receptor binding and lipidomics have been detected in the brain one year after treatment cessation ( Golub et al, 2019 ; Tkachev et al, 2021 ).…”