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.
Author(s): Houston JP, Lau K, Aris V, Liu W, Fijal BA, Heinloth AN, Perlis RH.
Affiliation(s): Lilly USA, LLC, Indianapolis, IN 46285, USA. Houston_John_P@lilly.com
Publication date & source: 2012, J Clin Psychiatry. , 73(6):878-85
OBJECTIVE: To determine whether single-nucleotide polymorphisms (SNPs) in
candidate genes are associated with response to olanzapine-fluoxetine
combination.
METHOD: 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.
TRIAL REGISTRATION: Parent study registered at ClinicalTrials.gov identifier:
NCT00035321.
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