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

Abstract

Background Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children. Methods Male rhesus monkeys 1–3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n=16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA). Results Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitations and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors. Conclusions Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect.

Cognitive performance of juvenile monkeys after chronic fluoxetine treatment

“…We have previously reported that growth was not generally compromised by the treatment ( Golub et al, 2015a ). Fluoxetine effects on sleep ( Golub and Hogrefe, 2016 ), social interaction ( Golub et al, 2015b ), delay impulsivity ( He et al, 2014 ), and emotional response ( Golub et al, 2016 ), have also been reported from this study along with metabolomic biomarkers of fluoxetine action ( He et al, 2014 , Su et al, 2016 ).…”

Fluoxetine Administration in Juvenile Monkeys: Implications for Pharmacotherapy in Children

“…Facilitated social interaction was seen in our fluoxetine-treated monkeys ( 5 ). Monkeys were housed in pairs and were observed interacting with their longtime cagemate.…”

“…Because simple weight-based extrapolation from humans to monkeys is not appropriate ( 11 ), preliminary pharmacokinetic studies in juvenile rhesus were used to select an oral dose of 2 mg/kg relevant to children ( 1 ). Plasma levels (fluoxetine + norfluoxetine) in the monkeys after 2 years of dosing were 273 ± 31 ng/mL ( 5 ), compared to 241 ± 91 ng/mL in children with MDD who showed a therapeutic response at the recommended dosage of 20 mg/day ( 12 ).…”

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). …”