Genetic association study of treatment response with olanzapine/fluoxetine
combination or lamotrigine in bipolar I depression.
Author(s): Perlis RH, Adams DH, Fijal B, Sutton VK, Farmen M, Breier A, Houston JP.
Affiliation(s): Bipolar Clinic and Research Program, 50 Staniford St, 5th Floor, Boston, MA
02114, USA. rperlis@partners.org
Publication date & source: 2010, J Clin Psychiatry. , 71(5):599-605
OBJECTIVE: To evaluate common genetic variations for association with symptomatic
improvement in bipolar I depression following treatment with
olanzapine/fluoxetine combination (OFC) or lamotrigine.
METHOD: Symptom improvement was assessed in 88 OFC-treated and 85
lamotrigine-treated white patients with bipolar I depression in the 7-week acute
period of a randomized, double-blind study comparing OFC (6/25, 6/50, 12/25, or
12/50 mg/d [olanzapine/fluoxetine]) with lamotrigine (titrated to 200 mg/d). The
original study was conducted from November 2003 to August 2004. Single nucleotide
polymorphisms (SNPs) were genotyped in a set of 19 candidate genes corresponding
to known sites of activity for olanzapine and fluoxetine or previously associated
with antidepressant or antipsychotic response. Primary outcome was the reduction
in Montgomery-Asberg Depression Rating Scale (MADRS) total score as assessed by
the difference by genotype from baseline to week 7 from a mixed-effects repeated
measures analysis with terms for visit, genotype, genotype-by-visit interaction,
and baseline MADRS score as a covariate.
RESULTS: SNPs within the dopamine D(3) receptor and histamine H(1) receptor
(HRH1) genes were significantly associated with response to OFC. SNPs within the
dopamine D(2) receptor, HRH1, dopamine beta-hydroxylase, glucocorticoid receptor,
and melanocortin 2 receptor genes were significantly associated with response to
lamotrigine.
CONCLUSIONS: SNPs in specific candidate genes were associated with symptomatic
improvement in a treatment-specific fashion. These results suggest the importance
of dopaminergic effects in the treatment of patients with bipolar I depression
and the potential utility of genotyping in selection of pharmacologic treatments
for bipolar depression.
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