Abstract
The antidepressant drug fluoxetine (Prozac) has been increasingly prescribed to children and adolescents with depressive disorders despite a lack of thorough understanding of its therapeutic effects in the paediatric population and of its putative neurodevelopmental effects. Within the framework of PRIOMEDCHILD ERA-NET, we investigated; a) effects of chronic fluoxetine treatment on adult hippocampal neurogenesis, a structural readout relevant for antidepressant action and hippocampal development; b) effects on tryptophan hydroxylase (TPH) expression, a measure of serotonin synthesis; c) whether treatment effects during adolescence differed from treatment at an adult age, and d) whether they were subregion-specific. Stereological quantification of the number of proliferating (Ki-67+) cells and of the number of young migratory neurons (doublecortin+), revealed a significant age-by-treatment interaction effect, indicating that fluoxetine affects both proliferation and neurogenesis in adolescent-treated rats differently than it does in adult-treated rats. In terms of subregional differences, fluoxetine enhanced proliferation mainly in the dorsal parts of the hippocampus, and neurogenesis in both the suprapyramidal and infrapyramidal blades of the dentate gyrus in adolescent-treated rats, while no such differences were seen in adult-treated rats. Fluoxetine exerted similar age-by-treatment interaction effects on TPH cells mainly in the ventral portion of the dorsal raphe nucleus. We conclude that fluoxetine exerts divergent effects on structural plasticity and serotonin synthesis in adolescent versus adult-treated rats. These preliminary data indicate a differential sensitivity of the adolescent brain to this drug and thus warrant further research into their behavioural and translational aspects. Together with recent related findings, they further call for caution in prescribing these drugs to the adolescent population.
Highlights
Major depressive disorder (MDD) is an intractable mental disorder with a lifetime prevalence of 10–20% in adult life, but childhood and especially adolescent forms of depression are common [1]
Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-HT, and the neuronal form, TPH2, is predominantly expressed in the dorsal raphe nucleus (DRN) of the midbrain from where 5-HT projections extend to various brain regions
Its mRNA levels have been found to be increased in postmortem tissue of non-medicated suicide victims, implicating its involvement in a possible stimulatory response to compensate for low 5-HT levels in depression [8], depression has not been proven to be solely attributable to reductions in 5-HT per se [9]
Summary
Major depressive disorder (MDD) is an intractable mental disorder with a lifetime prevalence of 10–20% in adult life, but childhood and especially adolescent forms of depression are common [1]. The early onset forms of depression are associated with a more chronic and severe nature than adult onset depression [2]. The SSRI fluoxetine (FLX; Prozac) is currently the only approved drug available for treatment of paediatric depression, despite ongoing debate over its efficacy in this age category [3,4] and concerns of increased risk for suicidal thinking in the paediatric population [5]. Upon chronic SSRI treatment, 5-HT receptor desensitisation is believed to be instrumental in alleviating depressive symptoms [6,7]. Its mRNA levels have been found to be increased in postmortem tissue of non-medicated suicide victims, implicating its involvement in a possible stimulatory response to compensate for low 5-HT levels in depression [8], depression has not been proven to be solely attributable to reductions in 5-HT per se [9]
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