2016 Gatlinburg Conference Poster
PS-94
Title: Fluoxetine (Prozac®) Effects in a Rhesus Monkey Model of Childhood Therapeutic Exposure
Authors: Mari S. Golub, Casey E. Hogrefe, Christoph W. Turck, John P. Capitanio
Introduction: Fluoxetine (Prozac®) is widely used during childhood in treating depression, autism, anxiety, ADHD, and conduct
disorder. Post-therapy consequences for brain development are difficult to study in children and require animal models.
Methods: Juvenile male rhesus (n=16 compared to 16 vehicle controls) were given fluoxetine daily for two years (1 to 3 years of
age), a period roughly equivalent to 4 to 12 years of age in children. The dose (2 mg/kg, oral) was determined in pilot studies to
produce blood levels in the range of treated children. They were evaluated for growth, health, activity, sleep patterns, social
interaction, emotional response, impulsivity and attention. After discontinuation of dosing they were evaluated for an additional
year prior to puberty with the same tests, plus additional tests of short term memory and cognitive flexibility. Assessments were
based on side effect reports in adults and children and serotonin system functions. Metabolomic profiles were used to look for
peripheral markers of central effects. The monkeys were genotyped for polymorphisms in serotonin-related genes monoamine
oxidase (MAOA) and serotonin transporter (SERT) that have homologous polymorphisms in humans. Data analysis included
potential interactions with these polymorphisms.
Results: Growth was normal with the exception of a delay in long bone growth in association with SERT polymorphisms. There
was no indication of hyperactivity during 48 h actimeter monitoring but increased sleep fragmentation was seen in the fluoxetine
group. Social interaction with their familiar cagemate was increased 30% by fluoxetine treatment, and MAOA genotype
influenced the types of behaviors affected. Impulsivity, evaluated with a reward delay task, was greater in the fluoxetine group,
and sustained attention, evaluated with the continuous performance test, was impaired. Emotional responses elicited by
pictures were lower specifically in the monkeys with the low transcription MAOA polymorphisms. Metabolomic profiles from
blood and cerebrospinal fluid samples reflected fluoxetine impact on neurotransmitter and purine/pyrimidine pathways, as well
as interaction with MAOA genotype. After dosing, effects on attention, impulsivity and emotional response persisted, and an
effect was also seen in the cognitive flexibility test. The occurrence of these effects was often modified by MAOA genotype. Low
transcription MAOA polymorphisms are known to interact with developmental experiences in both humans and monkeys to
influence later behavior.
Discussion: In the absence of psychopathology, fluoxetine influenced many brain regulated behavior domains in juvenile
monkeys as might be anticipated from its biological actions. After discontinuation of dosing, some of these effects persisted. A
striking interaction of polymorphisms in the MAOA gene with fluoxetine may be relevant to use of this pharmacological agent in
children.