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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.
