title: Escitalopram pharmacogenetics: CYP2C19 relationships with dosing and clinical outcomes in autism spectrum disorder.
abstract: OBJECTIVE
  Selective serotonin reuptake inhibitors such as escitalopram are commonly used to treat patients with autism spectrum disorder (ASD), but there are individual differences in treatment response and tolerability. CYP2C19 encodes the primary enzyme responsible for escitalopram metabolism and we investigated whether polymorphisms in CYP2C19 were related to symptoms and dosing in a pharmacogenetic study of ASD.
  
  
  METHODS
  Participants completed the Aberrant Behavior Checklist--Community Version (ABC-CV) weekly for 6 weeks. Escitalopram was initiated at a dose of 2.5 mg per day, with weekly increases to 20 mg unless intolerable side-effects occurred. Three CYP2C19 metabolizer groups, including ultrarapid, extensive, and reduced metabolizers, were examined in relation to symptom improvement and tolerated dose.
  
  
  RESULTS
  ABC-CV scores improved over the course of treatment (P<0.0001). No differences were identified in the rate of improvement across metabolizer groups for the ABC-CV irritability subscale, which was the primary outcome for clinical symptoms. There was a trend for a metabolizer group by time interaction with respect to dose (P=0.10). This interaction was driven by the linear rate of change from week 1 to study endpoint between the reduced metabolizers and ultrarapid metabolizer groups (P=0.05). Post-hoc analyses identified significant differences in the rate of dose escalation between ultrarapid metabolizers and extensive metabolizers and for ultrarapid metabolizers compared with reduced metabolizers (P's<0.04), whereby ultrarapid metabolizers showed a slower rate of change in dose over time.
  
  
  CONCLUSIONS
  CYP2C19 ultrarapid metabolizers were associated with reduced tolerance to a fixed titration schedule of open-label escitalopram in this ASD study sample. Possible explanations may involve the altered kinetics of faster metabolizers or previously unknown activities of escitalopram metabolites.
authors: aDepartment of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy bDepartment of Psychiatry, University of Minnesota College of Medicine, Minneapolis, Minnesota cDepartment of Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, Illinois dDepartments of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Jeffrey R
authors: JR
authors: Bishop
authors: Fedra
authors: F
authors: Najjar
authors: Leah H
authors: LH
authors: Rubin
authors: Stephen J
authors: SJ
authors: Guter
authors: Thomas
authors: T
authors: Owley
authors: Matthew W
authors: MW
authors: Mosconi
authors: Suma
authors: S
authors: Jacob
authors: Edwin H
authors: EH
authors: Cook
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015283:Citalopram / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human