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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.

SUBMITTER: He Y

PROVIDER: S-EPMC4259988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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

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| S-EPMC5557667 | biostudies-literature

Fluoxetine Administration in Juvenile Monkeys: Implications for Pharmacotherapy in Children.

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| S-EPMC5809484 | biostudies-literature

Fluoxetine administered to juvenile monkeys: effects on the serotonin transporter and behavior.

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Individual Differences in Infant Temperament Predict Social Relationships of Yearling Rhesus Monkeys (<i>Macaca mulatta</i>).

Project description:Affiliative relationship formation in nonhuman primates is known to be influenced by kinship, rank, and sex, but such factors do not fully explain observed variation in primate social relations. Individual differences in temperament have a number of important behavioural and physiological correlates that might influence relationship formation. We observed 57 yearling rhesus macaques at the California National Primate Research Center for 10 weeks to determine whether individual differences in temperament relate to the number and quality of affiliative relationships formed with peers. Subjects' temperament characteristics had previously been quantified during a colony-wide biobehavioural assessment at 90-120 days of age. Yearlings that had scored high on Equability (demonstrating calmness and low levels of physical activity) as infants had fewer peer relationships compared to animals low on this dimension. Additionally, yearlings preferentially affiliated with peers that were similar to themselves in Equability as well as in Adaptability (reflecting the degree of behavioural flexibility that subjects displayed during the biobehavioural assessment). Although kinship, rank, and sex influenced relationship formation as expected, temperament remained a significant predictor of affiliative preferences even after controlling for these variables. Our findings suggest that temperament is a proximate determinant of variation in affiliative relationship formation in group-living primates.

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Paradoxical anxiogenic response of juvenile mice to fluoxetine.

Project description:Depression, anxiety, and conduct disorders are common in children and adolescents, and selective serotonin reuptake inhibitors (SSRIs) are often used to treat these conditions. Fluoxetine (Prozac) is the first approved SSRI for the treatment of depression in this population. Although it is believed that overall, fluoxetine is effective in child and adolescent psychiatry, there have been reports of specific adverse drug effects, most prominently, suicidality and psychiatric symptoms such as agitation, worsening of depression, and anxiety. Chronic fluoxetine substantially increases brain extracellular 5-HT concentrations, and the juvenile developing brain may respond to supraphysiological 5-HT levels with specific adverse effects not seen or less prominent in adult brain. Using novelty-induced hypophagia, as well as open-field and elevated plus maze tests, we show that both Swiss Webster and C57Bl/6 mice, receiving fluoxetine in a clinically relevant dose and during their juvenile age corresponding to child-adolescent periods in humans, exhibit a paradoxical anxiogenic response. The adverse effects of juvenile fluoxetine disappeared upon drug discontinuation and no long-term behavioral consequences were apparent. No adverse effect to chronic fluoxetine was seen in adult mice and a dose-dependent anxiolytic effect developed. These data show that the age of the mice, independently of the strains and tests used in this study, is the determining factor of whether the response to chronic fluoxetine is anxiolytic or anxiogenic. Taken together, the response of the juvenile and adult brain to fluoxetine could be fundamentally different and the juvenile fluoxetine administration mouse model described here may help to identify the mechanism underlying this difference.

| S-EPMC2771172 | biostudies-literature

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Project description:The radioprotective effect of indralin in rhesus monkeys was examined over 60 d following gamma irradiation. Male and female rhesus macaques (Macaca mulatta) 2-3-years-old and weighing 2.1-3.5 kg were used. Animals were exposed to total-body gamma irradiation from (60)Co at a dose of 6.8 Gy (lethal dose, 100% lethality over 30 days). Indralin (40-120 mg kg(-1)) was administered intramuscularly 5 min prior to radiation exposure. Indralin taken at a dose of 120 mg kg(-1) protected five out of six monkeys (compared with the radiation control group, in which all 10 animals died). The average effective dose of indralin in the monkeys exposed to gamma irradiation for 30 min was equal to 77.3 (63.3-94.3) mg kg(-1), and the maximum tolerated dose of indralin administered to monkeys was 800 mg kg(-1). Indralin reduced radiation-induced injuries in macaques, thus resulting in a less severe course of acute radiation syndrome. Delayed and less pronounced manifestation of the haemorrhagic syndrome of the disease, and milder forms of both leukopenia and anaemia were also noted. The therapeutic index for indralin, expressed as the ratio of the maximum tolerated dose to the average effective dose, was equal to 10. Therefore, indralin has a significant radioprotective effect against radiation and has a high therapeutic index in rhesus monkeys.

| S-EPMC4229912 | biostudies-literature

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