title: 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.
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: California National Primate Research Center, University of California, Davis, Davis, CA, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Hogrefe
authors.affiliation: NIH West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Grapov
authors.affiliation: NIH West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Palazoglu
authors.affiliation: NIH West Coast Metabolomics Center, University of California, Davis, Davis, CA, USA.
authors.forename: O
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: C W
authors.initials: CW
authors.lastname: Turck
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, Davis, CA, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Golub
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D065786:Delay Discounting / Q000187:drug effects*; D005473:Fluoxetine / Q000378:metabolism* / Q000494:pharmacology; D007175:Impulsive Behavior / Q000187:drug effects*; D007206:Individuality; D008253:Macaca mulatta / Q000378:metabolism*; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D005473:Fluoxetine; D008995:Monoamine Oxidase; D017367:Selective Serotonin Reuptake Inhibitors