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Published Online: 31 October 2014

Clinical Outcomes and Genome-Wide Association for a Brain Methylation Site in an Antidepressant Pharmacogenetics Study in Mexican Americans

Abstract

Objective:

The authors compared the effectiveness of fluoxetine and desipramine treatment in a prospective double-blind pharmacogenetics study in first-generation Mexican Americans and examined the role of whole-exome functional gene variations in the patients’ antidepressant response.

Method:

A total of 232 Mexican Americans who met DSM-IV criteria for major depressive disorder were randomly assigned to receive 8 weeks of double-blind treatment with desipramine (50–200 mg/day) or fluoxetine (10–40 mg/day) after a 1-week placebo lead-in period. Outcome measures included the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale, and the Beck Depression Inventory. At week 8, whole-exome genotyping data were obtained for 36 participants who remitted and 29 who did not respond to treatment.

Results:

Compared with desipramine treatment, fluoxetine treatment was associated with a greater reduction in HAM-D score, higher response and remission rates, shorter time to response and remission, and lower incidences of anticholinergic and cardiovascular side effects. Pharmacogenetics analysis showed that exm-rs1321744 achieved exome-wide significance for treatment remission. This variant is located in a brain methylated DNA immunoprecipitation sequencing site, which suggests that it may be involved in epigenetic regulation of neuronal gene expression. This and two other common gene variants provided a highly accurate cross-validated predictive model for treatment remission of major depression (receiver operating characteristic integral=0.95).

Conclusions:

Compared with desipramine, fluoxetine treatment showed a more rapid reduction of HAM-D score and a lower incidence of side effects in a population comprising primarily first-generation Mexican Americans with major depression. This study’s pharmacogenetics approach strongly implicates the role of functional variants in antidepressant treatment response.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 1297 - 1309
PubMed: 25220861

History

Received: 5 September 2012
Revision received: 17 October 2013
Revision received: 2 May 2014
Accepted: 16 June 2014
Published ahead of print: 31 October 2014
Published online: 1 December 2014
Published in print: December 01, 2014

Authors

Details

Ma-Li Wong, M.D.
From the Mind and Brain Theme, South Australian Health and Medical Research Institute, and the Department of Psychiatry, Flinders University School of Medicine, Adelaide, Australia; the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami; the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, Calif.; Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany; and the John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Chuanhui Dong, M.D., Ph.D.
From the Mind and Brain Theme, South Australian Health and Medical Research Institute, and the Department of Psychiatry, Flinders University School of Medicine, Adelaide, Australia; the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami; the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, Calif.; Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany; and the John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Deborah L. Flores, M.D.
From the Mind and Brain Theme, South Australian Health and Medical Research Institute, and the Department of Psychiatry, Flinders University School of Medicine, Adelaide, Australia; the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami; the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, Calif.; Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany; and the John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Monika Ehrhart-Bornstein, Ph.D.
From the Mind and Brain Theme, South Australian Health and Medical Research Institute, and the Department of Psychiatry, Flinders University School of Medicine, Adelaide, Australia; the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami; the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, Calif.; Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany; and the John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Stefan Bornstein, M.D., Ph.D.
From the Mind and Brain Theme, South Australian Health and Medical Research Institute, and the Department of Psychiatry, Flinders University School of Medicine, Adelaide, Australia; the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami; the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, Calif.; Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany; and the John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Mauricio Arcos-Burgos, M.D., Ph.D.
From the Mind and Brain Theme, South Australian Health and Medical Research Institute, and the Department of Psychiatry, Flinders University School of Medicine, Adelaide, Australia; the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami; the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, Calif.; Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany; and the John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Julio Licinio, M.D.
From the Mind and Brain Theme, South Australian Health and Medical Research Institute, and the Department of Psychiatry, Flinders University School of Medicine, Adelaide, Australia; the Department of Neurology, Leonard M. Miller School of Medicine, University of Miami, Miami; the Department of Psychiatry, Harbor-UCLA Medical Center, Torrance, Calif.; Medical Clinic III, Carl Gustav Carus University Hospital, Dresden University of Technology, Dresden, Germany; and the John Curtin School of Medical Research, Australian National University, Canberra, Australia.

Notes

Address correspondence to Professor Licinio ([email protected]) or Professor Wong ([email protected]).

Author Contributions

The first two authors contributed equally to this work.

Funding Information

National Institutes of Health10.13039/100000002: GM61394, RR017365, MH062777, RR000865, RR16996, DK063240
The authors report no financial relationships with commercial interests. An intellectual property application has been prepared to include the pharmacogenetics findings of this work.Supported by NIH grants GM61394, RR017365, MH062777, RR000865, RR16996, and DK063240 and by grant APP1051931 from the National Health and Medical Research Council (Australia); the German-Australian Institute of Translational Medicine; and institutional funds from the Australian National University, Flinders University, and the South Australian Health and Medical Research Institute.

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