Identifying individual differences of fluoxetine response in juvenile rhesus monkeys by metabolite profiling

Abstract

Fluoxetine is the only psychopharmacological agent approved for depression by the US Food and Drug Administration for children and is commonly used therapeutically in a variety of neurodevelopmental disorders. Therapeutic response shows high individual variability, and severe side effects have been observed. In the current study we set out to identify biomarkers of response to fluoxetine as well as biomarkers that correlate with impulsivity, a measure of reward delay behavior and potential side effect of the drug, in juvenile male rhesus monkeys. The study group was also genotyped for polymorphisms of monoamine oxidase A (MAOA), a gene that has been associated with psychiatric disorders. We used peripheral metabolite profiling of blood and cerebrospinal fluid (CSF) from animals treated daily with fluoxetine or vehicle for one year. Fluoxetine response metabolite profiles and metabolite/reward delay behavior associations were evaluated using multivariate analysis. Our analyses identified a set of plasma and CSF metabolites that distinguish fluoxetine- from vehicle-treated animals and metabolites that correlate with impulsivity. Some metabolites displayed an interaction between fluoxetine and MAOA genotype. The identified metabolite biomarkers belong to pathways that have important functions in central nervous system physiology. Biomarkers of response to fluoxetine in the normally functioning brain of juvenile nonhuman primates may aid in finding predictors of response to treatment in young psychiatric populations and in progress toward the realization of a precision medicine approach in the area of neurodevelopmental disorders.

Peripheral fibroblast metabolic pathway alterations in juvenile rhesus monkeys undergoing long-term fluoxetine administration

“…Impulsive behavior in macaques was previously shown to be a behavioral effect of fluoxetine treatment (He et al, 2014). For correlation with metabolomics data we carried out Beta regression to identify metabolites associated with impulsive behavior in the fluoxetine treated group.…”

“…The cohort of male rhesus monkeys ( Macaca mulatto ) that were sampled for this study has been described previously (He et al, 2014; Golub et al, 2015). At approximately 1 year of age animals were selected from the outdoor colony at the CNPRC, relocated to indoor caging, and assigned to treatment (fluoxetine) or control (vehicle) groups.…”

“…To compare fluoxetine’s metabolic profile and behavioral effects we used a reward delay test adapted for monkeys as described previously (He et al, 2014) from similar tests in children to measure impulsivity (Golub et al, 2005, 2007). The test was hand administered in the Wisconsin General Test Apparatus (WGTA) in one session of 40 trials.…”

Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine

“…Interestingly, fluoxetine can also directly inhibit MAOA activity (34). In metabolomics studies of juvenile rhesus we found that fluoxetine administration interacted with MAOA polymorphism genotype in influencing metabolites in plasma and cerebrospinal fluid (35) indicating a biological basis for an interaction between fluoxetine and MAOA.…”

Regulation of emotional response in juvenile monkeys treated with fluoxetine: MAOA interactions

“…The ages of the rhesus macaque subjects in the present study (one to four years of age) correspond roughly to four to twelve year-old children. Previous reports from this project have described dose selection (Golub and Hogrefe, 2014), metabolomic biomarkers of drug action (He et al, 2014), bone growth (Golub et al, 2015), sleep disturbance (Golub and Hogrefe, 2016), and social interaction (Golub et al, 2016). …”