Long-Term Fluoxetine Administration Causes Substantial Lipidome Alteration of the Juvenile Macaque Brain.

Anna Tkachev,Nickolay Anikanov,Christoph W Turck,Ekaterina Khrameeva,Daniil M Bobrovskiy,Philipp Khaitovich,Dong Ik Park,Elena Stekolshchikova,Polina Ogurtsova,Daria Petrova,Mari S Golub,Anja K E Horn

doi:10.3390/ijms22158089

Abstract

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites. Here, we built upon this work by assessing residual effects of fluoxetine administration on the expression of genes and abundance of lipids and polar metabolites in the prelimbic cortex of 10 treated and 11 control macaques representing two monoamine oxidase A (MAOA) genotypes. Analysis of 8871 mRNA transcripts, 3608 lipids, and 1829 polar metabolites revealed substantial alterations of the brain lipid content, including significant abundance changes of 106 lipid features, accompanied by subtle changes in gene expression. Lipid alterations in the drug-treated animals were most evident for polyunsaturated fatty acids (PUFAs). A decrease in PUFAs levels was observed in all quantified lipid classes excluding sphingolipids, which do not usually contain PUFAs, suggesting systemic changes in fatty acid metabolism. Furthermore, the residual effect of the drug on lipid abundances was more pronounced in macaques carrying the MAOA-L genotype, mirroring reported behavioral effects of the treatment. We speculate that a decrease in PUFAs may be associated with adverse effects in depressive patients and could potentially account for the variation in individual response to fluoxetine in young people.

Highlights

Psychiatric disorders in young people, including depression, attention deficit hyperactivity disorder, autism, mental retardation, and obsessive-compulsive disorder, are commonly treated with antidepressant medications
We assessed alterations of gene expression, polar metabolite, and lipid abundance in the prelimbic cortex (PLC) of macaques treated with fluoxetine using RNA-sequencing (RNA-seq), Fouriertransform ion cyclotron resonance mass spectrometry (FT-ICR-MS), and high precision mass spectrometry coupled with liquid chromatography (LC-MS), respectively (Figure 1A)
The fluoxetine and vehicle administration began at one year of age, which is equivalent to 4–6 years of age in humans, and continued uninterrupted for two years, followed by a one year post-dosing period that ended at four years of age, just before puberty [35]

Summary

Introduction

Psychiatric disorders in young people, including depression, attention deficit hyperactivity disorder, autism, mental retardation, and obsessive-compulsive disorder, are commonly treated with antidepressant medications. One such drug is fluoxetine, a selective serotonin reuptake inhibitor (SSRI) that is used to manage behavioral symptoms in children and young adolescents. Treatment efficacy of fluoxetine in children has been demonstrated [1,2,3,4,5,6,7,8,9,10,11,12], individual variability in response, including potential long-term adverse effects observed in adolescents [13,14,15], has highlighted the need to examine the effects of this drug on the developing brain. Of relevance to our studies, nonhuman primates exhibit polymorphisms in genes that are related to psychiatric phenotypes and the psychoactive drug response

Methods

Results

Conclusion