Genome-wide association studies of placebo and duloxetine response in major depressive disorder

Pharmacogenomics J. 2018 May 22;18(3):406-412. doi: 10.1038/tpj.2017.29. Epub 2017 Jul 11.

Abstract

We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18-75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery-Åsberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points. In the placebo-treated subsample (N=205), we observed a genome-wide association with rs76767803 (β=0.69, P=1.25 × 10-8) upstream of STAC1. STAC1 rs76767803 was also associated with response using mixed model analysis (χ2=3.95; P=0.001). In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; β=-0.46, P=1.55 × 10-5), NCAM1 (rs2303377; β=0.45, P=1.76 × 10-5) and MLL5 (rs117986340; β=0.91, P=3.04 × 10-5). Our findings suggest that a variant upstream of STAC1 is associated with placebo response, which might have implications for treatment optimization, clinical trial design and drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / adverse effects
  • CD56 Antigen / genetics
  • DNA-Binding Proteins / genetics*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / genetics
  • Depressive Disorder, Major / pathology
  • Double-Blind Method
  • Duloxetine Hydrochloride / administration & dosage
  • Duloxetine Hydrochloride / adverse effects
  • Female
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Placebos
  • Transcription Factors / genetics
  • Young Adult

Substances

  • Antidepressive Agents
  • CD56 Antigen
  • DNA-Binding Proteins
  • KMT2E protein, human
  • NCAM1 protein, human
  • Nerve Tissue Proteins
  • Placebos
  • Transcription Factors
  • ZNF385D protein, human
  • STAC protein, human
  • Duloxetine Hydrochloride

Grants and funding