title: The Impact of Sertraline Co-Administration on the Pharmacokinetics of Olanzapine: A Population Pharmacokinetic Analysis of the STOP-PD.
abstract: OBJECTIVE
  Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods.
  
  
  METHODS
  The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration.
  
  
  RESULTS
  Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p < 0.005) by 25-35 % depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance.
  
  
  CONCLUSIONS
  Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.
authors.affiliation: Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J 1H4, Canada. simon_davies@camh.net.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada. simon_davies@camh.net.
authors.forename: Simon J C
authors.initials: SJ
authors.lastname: Davies
authors.affiliation: Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J 1H4, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Mulsant
authors.affiliation: Department of Psychiatry, University of Toronto, Toronto, ON, Canada.|Department of Psychiatry, University Health Network, Toronto, ON, Canada.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Flint
authors.affiliation: Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Barnett S
authors.initials: BS
authors.lastname: Meyers
authors.affiliation: University of Massachusetts Medical School and University of Massachusetts Memorial Health Care, Worcester, MA, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Rothschild
authors.affiliation: Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Whyte
authors.affiliation: Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Kirshner
authors.affiliation: Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Sorisio
authors.affiliation: Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J 1H4, Canada.|Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Pollock
authors.affiliation: Centre for Addiction and Mental Health, 1001 Queen Street West, Toronto, ON, M6J 1H4, Canada.|Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.|Indiana Clinical and Translational Sciences Institute, Indianapolis, IN, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Bies
mesh_terms: D000328:Adult; D000368:Aged; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000077152:Olanzapine; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000378:metabolism*; D020280:Sertraline / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012737:Sex Factors
chemical_list: D001569:Benzodiazepines; D000077152:Olanzapine; D020280:Sertraline