Genetic Association Study of Treatment Response With Olanzapine/Fluoxetine Combination or Lamotrigine in Bipolar I Depression

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 D3 receptor and histamine H1 receptor (HRH1) genes were significantly associated with response to OFC. SNPs within the dopamine D2 receptor, HRH1, dopamine β-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.

Submitted: August 22, 2008; accepted January 2, 2009.

Online ahead of print: December 15, 2009.

Corresponding author: Roy H. Perlis, MD, MSc, Bipolar Clinic and Research Program, 50 Staniford St, 5th Floor, Boston, MA 02114 ([email protected]).