Comparison of pharmacogenomic associations with clinical change in olanzapine/fluoxetine combination treatment of patients with treatment resistant depression vs. bipolar is depression

Abstract

Background: Four single nucleotide polymorphisms (SNPs) in 3 genes have been reported to be associated with symptom change during 7-week olanzapine/fluoxetine combination (OFC) treatment in bipolar I depressed (BPD) patients. Genotyping samples from a second study allowed assessment of association of these SNPs with 8-week change in treatment-resistant depression (TRD) during OFC or olanzapine (OLZ) treatment. Methods: Mixed-effect models for repeated measures, adjusted for baseline Montgomery-Asberg Depression Rating Scale (MADRS), were used to assess association between 8-week change in MADRS and SNPs in genes coding for dopamine-3 receptor D3 (DRD3), histamine H1 receptor (HRH1), and melanocortin 2 receptor (MC2R) in Caucasian patients with TRD treated with OFC (N=63) or OLZ (N=52) after nonresponse following SSRI treatment. Results: Two-sided p-values for OFC treatment were: HRH1 rs346070, p=.0356; MC2CR rs4464147, p=.1884; DRD3 rs6280, p=.0972; and DRD3 rs16770, p=.0232. Previously reported greater depressive symptom improvement during OFC treatment of BPD was found for TRD with HRH1 rs346070(C), but not for OLZ although the direction of the effect was the same (p=.1228). Improvement was in opposite directions for BPD vs. TRD for DRD3 rs16770. Conclusions: HRH1 rs346070 may be a relatively non-specific predictor of symptom improvement with pharmacological treatment in both BPD and TRD. Discordant results with the other 3 SNPs may represent either failure to replicate due to lack of statistical power or a fundamental difference in the nature of treatment response in bipolar depression vs. TRD.