Fluoxetine Response Associated with Enantiomer Abundance in Adolescents

Introduction.Only 3-in-5 adolescents respond to antidepressants the first time.Identifying individual factors that influence response can guide treatment and expedite recovery.FLX is administered in racemic form (S and R).The S-enantiomer of norFLX is 20 times more active than R-enantiomer and thought to contribute meaningfully to drug response.Methods.Youth (12-21yr) 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.Participant PHQ9 scores 11 or Promis Anxiety t-scores 60 were considered nonresponders.Results.In 56 youth (161.9yr(12-21yr), 70% female), average norFLX S/R was higher in responders compared to non-responders (depression: 1.340.84vs 0.840.45,p = 0.001, Cohen's d = 0.73; anxiety: 1.560.98vs 0.970.55,p = 0.006, Cohen's d = 0.74).Participant symptom scores were 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). Conclusions.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 small sample size and 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.