Abstract
The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine-induced neuroplasticity in the amygdala.
Highlights
Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed drugs in psychiatry
Repeated measures ANOVA revealed that fluoxetine had no effect on body weight in adolescent rats (F(1,18) = 0.826, NS), but significantly reduced adult body weight (F(1,18) = 9.218, p,0.01)
Since fluoxetine was undetectable in blood plasma 1 week after the last injection, we argue that these behavioral manifestations reflect neuroplastic changes
Summary
Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed drugs in psychiatry. The number of children for whom anti-depressants are prescribed has increased during the last decade [1]. Fluoxetine is the only SSRI registered for treatment of depression in the paediatric population. Some alarming studies have reported that children and adolescents may experience increases in suicidal ideation and behavior, as well as agitation, depression and anxiety [2,3,4,5,6]. Based on some of these reports, the Federal Drug Agency and European Medicines Agency stated in 2004 that SSRIs were contraindicated for treating depression in children and adolescents. In 2006 fluoxetine was approved in children aged 8 years and older for treatment of moderate to severe depression [8]
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