Paradoxical anxiogenic response of juvenile mice to fluoxetine

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.