title: Association of common variations in the norepinephrine transporter gene with response to olanzapine-fluoxetine combination versus continued-fluoxetine treatment in patients with treatment-resistant depression: a candidate gene analysis.
abstract: OBJECTIVE
  To determine whether single-nucleotide polymorphisms (SNPs) in candidate genes are associated with response to olanzapine-fluoxetine combination.
  
  
  METHODS
  A post hoc analysis of a priori-selected SNPs used data from a clinical trial (dates: April 2002-July 2005) of olanzapine-fluoxetine combination, fluoxetine, and olanzapine in patients with major depressive disorder (DSM-IV criteria) and with nonresponse to prestudy antidepressant treatment and nonresponse to fluoxetine treatment during the study. Patients received open-label treatment with fluoxetine for 8 weeks (2 weeks, 25 mg/d; then 6 weeks, 50 mg/d), at the end of which nonresponders (< 25% decline in the 17-item Hamilton Depression Rating Scale score) were randomized to receive double-blind, monotherapy treatment with olanzapine-fluoxetine combination (6/50-18/50 mg/d, n = 71), fluoxetine (50 mg/d, n = 78), or olanzapine (6-18 mg/d, n = 56) for 8 weeks. Statistical significance was assessed at P < .05. The primary efficacy measure for within-study treatment was improvement on the Montgomery-Asberg Depression Rating Scale (MADRS).
  
  
  RESULTS
  Rs36024, an intronic SNP in the norepinephrine transporter (SLC6A2), as well as 3 SNPs in melanocortin 3 receptor (MC3R) and 2 SNPs in tryptophan hydroxylase 2 (TPH2), were associated with MADRS-defined response to treatment with olanzapine-fluoxetine combination (adjusted Li-Nyholt P < .05). Except for 1 SNP in TPH2, identified SNPs were not significantly associated with response to continued-fluoxetine or olanzapine treatments.
  
  
  CONCLUSIONS
  Our findings further support the hypothesis that the synergistic effect of olanzapine and fluoxetine on prefrontal cortical levels of norepinephrine and dopamine might be an underlying mechanism for the efficacy of olanzapine-fluoxetine combination in the treatment of treatment-resistant depression and, if replicated, may form a basis on which response to olanzapine-fluoxetine combination versus continued fluoxetine can be predicted based on variants in SLC6A2.
  
  
  BACKGROUND
  Parent study registered at ClinicalTrials.gov identifier: NCT00035321.
authors.affiliation: Lilly USA, LLC, Indianapolis, IN 46285, USA. Houston_John_P@lilly.com
authors.forename: John P
authors.initials: JP
authors.lastname: Houston
authors.forename: Kit
authors.initials: K
authors.lastname: Lau
authors.forename: Virginie
authors.initials: V
authors.lastname: Aris
authors.forename: Wenlei
authors.initials: W
authors.lastname: Liu
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Fijal
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Heinloth
authors.forename: Roy H
authors.initials: RH
authors.lastname: Perlis
mesh_terms: D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001569:Benzodiazepines / Q000627:therapeutic use*; D061218:Depressive Disorder, Treatment-Resistant / Q000188:drug therapy / Q000235:genetics*; D004311:Double-Blind Method; D004338:Drug Combinations; D005473:Fluoxetine / Q000627:therapeutic use*; D056726:Genetic Association Studies / Q000379:methods / Q000706:statistics & numerical data; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000235:genetics*; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D014365:Tryptophan Hydroxylase / Q000235:genetics
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001569:Benzodiazepines; D004338:Drug Combinations; D005473:Fluoxetine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D000077152:Olanzapine; D044104:Receptor, Melanocortin, Type 3; D017367:Selective Serotonin Reuptake Inhibitors; D014365:Tryptophan Hydroxylase; C505392:MC3R protein, human; C493227:SLC6A2 protein, human; C492572:olanzapine-fluoxetine combination; C494784:TPH2 protein, human