PT-017 - FLUOXETINE RESPONSE ASSOCIATED WITH ENANTIOMER ABUNDANCE IN ADOLESCENTS.

J. Tumberger^1,2, M. Bartkoski³, I. Choi⁴, P. Lee⁴, W. Brooks⁴, J. Leeder³, S. Stancil^3,2,5; ¹Children's Mercy Kansas City, Kansas City, MO, USA, ²University of Kansas School of Medicine, Kansas City, KS, USA, ³Children's Mercy Kansas City, Kansas City, MO, USA, ⁴University of Kansas Medical Center, Kansas City, KS, USA, ⁵University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

Background: Only 3 in 5 adolescents respond to antidepressants the first time. Identifying individual factors that influence response can guide treatment and expedite recovery. Our prior work demonstrated a strong correlation between brain and plasma fluoxetine (FLX) concentrations; however, no relationship between brain or plasma concentrations and response was detected. FLX is administered in racemic form (S and R) and bio-transformed into the primary metabolite, norfluoxetine (norFLX). The S-enantiomer of norFLX is ~20 times more active than the R-enantiomer and thought to contribute meaningfully to drug response. CYP2D6 is a highly polymorphic enzyme partially responsible for the stereospecific metabolism of FLX to norFLX. The S-enantiomer of norFLX has higher affinity for CYP2D6, suggesting the potential accumulation of S-Norflu as CYP2D6 activity decreases. This pilot study evaluated the relative abundance of FLX and norFLX S and R enantiomers as a potential contributor to response.

Methods: Youth aged 12-21 yr on FLX at steady state had plasma FLX and norFLX S/R measured by UPLC-MSMS and CYP2D6 genotyped by Illumina array with ddPCR copy number confirmation. Participants with PHQ9 scores ≥ 11 or Promis Anxiety t-scores ≥ 50 were considered non-responders. Descriptive statistics, Spearman’s rho (rs) and Cohen’s d (d) were performed in JMP v17 software.

Results: In 56 youth (16±1.9 yr (12-21 yr), 70% female), average norFLX S/R was higher in responders compared to non-responders (depression: 1.34±0.84 vs 0.84±0.45, p= 0.001, Cohen's d=0.73; anxiety: 1.56±0.98 vs 0.97±0.55, p=0.006, Cohen's d=0.74). Participant symptom scores were also negatively correlated with norFLX S/R (depression rs = -0.28; anxiety rs = -0.34), while FLX S/R was not associated with depression or anxiety response. Mean norFLX S/R was similar across CYP2D6 phenotypes (PM n=2, IM n=11, NM n=36, UM n=3).

Conclusion: In adolescents on FLX, norFLX S/R was significantly higher in responders compared to non-responders. No difference was detected in norFLX S/R across CYP2D6 phenotypes, a finding limited by a small sample size and is likely related to autoinhibition of CYP2D6 activity resulting in FLX-associated phenoconversion to poor metabolizer status in all participants. Further research is needed to evaluate the role of norFLX S/R as a predictor of FLX response.