Original Article

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

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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.

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Acknowledgements

This research was conducted with the support of the Ontario Brain Institute, an independent non-profit corporation, funded partially by the Ontario government. The opinions, results and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. This study was part of a Canadian Biomarker Integration Network in Depression (CAN-BIND) project. The authors wish to acknowledge the CAN-BIND team listed here: www.canbind.ca/our-team. MM is supported by a CIHR postdoctoral fellowship; VSM is supported by an OMHF doctoral studentship and a trainee fellowship from the CIHR-STAGE program, and DJM is supported by the Joanne Murphy Professorship.

Author information

Author notes

    • M Maciukiewicz
    •  & V S Marshe

    These authors contributed equally to the work.

Affiliations

  1. Pharmacogenetic Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    • M Maciukiewicz
    • , V S Marshe
    • , A K Tiwari
    • , T M Fonseka
    • , N Freeman
    • , J L Kennedy
    •  & D J Müller
  2. Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    • V S Marshe
    • , J L Kennedy
    •  & D J Müller
  3. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    • A K Tiwari
    • , J L Kennedy
    • , S Rotzinger
    • , S H Kennedy
    •  & D J Müller
  4. Department of Psychiatry, University Health Network, Toronto, ON, Canada

    • T M Fonseka
    • , S Rotzinger
    •  & S H Kennedy
  5. Department of Psychiatry, St. Michael’s Hospital, Toronto, ON, Canada

    • T M Fonseka
    •  & S H Kennedy
  6. Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada

    • J A Foster

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to D J Müller.

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