How does the SSRI fluoxetine work in adolescent depression?

The efficacy of the selective serotonin reuptake inhibitor (SSRI) fluoxetine has been well characterized in young people with depression. However, our understanding of how SSRIs work in this age group is still in its infancy. Developmental differences affect symptoms, diagnosis, and treatment response in depression, highlighting the need for age-specific development of experimental medicine models to understand treatment action. The current proposal will therefore take a developmental and interdisciplinary approach to analyse how fluoxetine affects neurocognitive function relevant to adolescents with depression. WP1 defines the measures used in this work together with our young advisors with lived experience and utilizing pilot data from our lab focused on anger/irritability, a core debilitating presentation of youth depression. We will perform detailed mechanistic studies in healthy volunteers to isolate markers of fluoxetine treatment (WP2) and apply these to adolescent depression to characterise mechanisms of clinical response (WP4) as well as withdrawal from treatment (WP5). We will also use complementary affective models in adolescent rodent models to refine our mechanistic model development (WP3). A better understanding of the mechanisms underpinning the effects of SSRIs in young people with depression will help formulate human experimental medicine models to optimize treatments of the future.