PII-043 - ANTIDEPRESSANT EXPOSURE IN THE ADOLESCENT BRAIN: FLUOXETINE AND PHARMACOGENETIC INFLUENCES ON BRAIN DISPOSITION

S. Stancil¹, I. Choi², P. Lee², W. Brooks², J. Tumberger¹, M. Bartkoski¹, J. Leeder¹; ¹Children's Mercy Kansas City, ²University of Kansas School of Medicine.

Background: Antidepressant response is variable which leads to delays in clinical improvement. Understanding individual factors that impact response may inform treatment decisions and shorten time to recovery. This study evaluates fluoxetine exposure in the blood and brain in adolescents and explores the relationship between brain-blood exposure, response, and the impact of pharmacogenetics.

Methods: Youth aged 12-21 years on fluoxetine at steady state completed fluorine magnetic resonance spectroscopy (19F-MRS) at 3T to detect fluoxetine concentration in the brain (Cb). Total fluoxetine+norfluoxetine plasma concentrations (Cp) were measured and ABCB1 (rs1045642, rs4148739, rs28401781, rs2032582) and CYP2D6 genotyped with Illumina array with ddPCR copy number confirmation. Participants with PHQ9 scores ≥ 11 or Promis Anxiety t-scores ≥ 60 (moderate anxiety) were considered non-responders. Correlation (Spearman’s rho, ρ), ANOVA & linear and logistic regression were done in SPSS.

Results: In 52 youth [16 ± 2.0 yr (12-21 yr), 69% female, 19% gender diverse], Cb and Cp (ρ = 0.901, p< 0.001) had a stronger correlation than Cb and dose (ρ = 0.770, p< 0.001). In a linear regression model predicting Cb, dose and Cp yielded R2adj = 0.844, p< 0.001 (Dose alone R2adj = 0.644; Cp alone R2adj = 0.808). Age, sex, BMI, CYP2D6 activity score or ABCB1 variants did not improve the model. Cb, Cp or brain:plasma ratio were not associated with depressive or anxiety symptom scores (ρ = -0.12 to 0.13) and mean Cb, Cp, or brain:plasma ratio did not differ in responders vs. non-responders (Table 1). In a logistic regression model, Cb, Cp, brain:plasma ratio, CYP2D6 activity score or ABCB1 variants did not predict response in anxiety or depression.

Conclusion: 19F-MRS quantified fluoxetine brain concentrations in adolescents, correlated strongly with plasma concentrations, and enabled inquiry into pharmacogenetic influences on brain-blood disposition. In this pilot study, we did not detect a relationship between brain or plasma concentrations and symptoms of anxiety or depression. Further work is needed to identify non-exposure-related factors that contribute to response and facilitate precision therapeutics.