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The Alpha 2A-Adrenergic Receptor Gene Polymorphism Modifies Antidepressant Responses to Milnacipran

Wakeno, Masataka MD*; Kato, Masaki MD, PhD*†; Okugawa, Gaku MD, PhD*; Fukuda, Tsuyoshi PhD; Hosoi, Yuka BS; Takekita, Yoshiteru MD*; Yamashita, Megumi MSc; Nonen, Shinpei PhD; Azuma, Junichi MD; Kinoshita, Toshihiko MD, PhD*

Journal of Clinical Psychopharmacology: October 2008 - Volume 28 - Issue 5 - p 518-524
doi: 10.1097/JCP.0b013e31818455fc
Original Contributions

Objective: The alpha 2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity. Recently, the functional defect of ADRA2A has been implicated as a cause of depression, attention deficit hyperactivity disorder, and Tourette syndrome. In this study, the effect of genetic variants of the ADRA2A gene on the response to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) was examined in depressed patients.

Method: Ninety-three Japanese depressed patients were recruited in the present study, assigned randomly to paroxetine or milnacipran, and assessed by the Hamilton Rating Scale for Depression (HAM-D) scoring every 2 weeks before and after drug administration. The ADRA2A C-1297G polymorphism was considered in the association analysis with the efficacy of antidepressants.

Results: There were significant differences in the HAM-D percent score change over time (P = 0.019) among C/C, C/G, and G/G of the ADRA2A C-1297G polymorphism in the total subjects. The C allele carriers of the ADRA2A C-1297G polymorphism showed a significantly better improvement than G/G subjects at weeks 2, 4, and over time (P = 0.037) in the milnacipran group.

Discussion: Our findings suggest that ADRA2A plays an important role in depression therapy. The level of ADRA2A expression could be associated with the efficacy of SSRIs/SNRIs, especially milnacipran, although the functional change brought about by C-1297G polymorphism has not yet been fully identified in vivo and in vitro.

Conclusions: The ADRA2A polymorphism could be a reasonable candidate to predict the response to milnacipran. Our results are still preliminary, and a large sample size will be required to confirm our findings. However, to the best of our knowledge, this study is the first to suggest a possible association of ADRA2A variants with the SNRI response.

*Department of Neuropsychiatry, Kansai Medical University, Osaka, Japan; †Institute of Psychiatry, University of Bologna, Bologna, Italy; and ‡Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Received December 16, 2007; accepted after revision May 27, 2008.

This study was supported by GlaxoSmithKline, Asahi Kasei Pharma Corporation, and Santec Inc. This work was also supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Address correspondence and reprint requests to Masataka Wakeno, MD, Department of Neuropsychiatry, Kansai Medical University, 10-15 Fumizonocho, Moriguchi, Osaka 570-8506, Japan. Email:

© 2008 Lippincott Williams & Wilkins, Inc.