OBJECTIVE: An initial pharmacogenetic study of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial reported an association between genetic variation in the HTR2A gene and outcome of citalopram treatment. By design, the study analyzed only those markers that showed reproducible association in the first wave of genotypes (comprising 1,297 patients) in the complete cohort of patients. The purpose of the present study was to utilize a second wave of genotype results, for a more powerful analysis, in the complete cohort of patients with available deoxyribonucleic acid (DNA) samples. METHOD: The authors tested the association between treatment response and 768 markers that were genotyped in the full set of 1,816 eligible patients from the STAR*D cohort. In order to control for multiple testing, the subjects were divided into two study groups: discovery and replication. RESULTS: In addition to the previously identified marker in the HTR2A gene, a new marker (rs1954787) in the GRIK4 gene, which codes for the kainic acid-type glutamate receptor KA1, was observed. The effect size of the GRIK4 marker alone was modest, but homozygote carriers of the treatment-response-associated marker alleles of both the GRIK4 and HTR2A genes were 23% less likely to experience nonresponse to treatment relative to participants who did not carry any of these marker alleles. CONCLUSIONS: The findings demonstrate that genetic variation in a kainic acid-type glutamate receptor is reproducibly associated with response to the antidepressant citalopram. This finding suggests that the glutamate system plays an important role in modulating response to selective serotonin reuptake inhibitors (SSRIs).
RCT Entities:
OBJECTIVE: An initial pharmacogenetic study of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial reported an association between genetic variation in the HTR2A gene and outcome of citalopram treatment. By design, the study analyzed only those markers that showed reproducible association in the first wave of genotypes (comprising 1,297 patients) in the complete cohort of patients. The purpose of the present study was to utilize a second wave of genotype results, for a more powerful analysis, in the complete cohort of patients with available deoxyribonucleic acid (DNA) samples. METHOD: The authors tested the association between treatment response and 768 markers that were genotyped in the full set of 1,816 eligible patients from the STAR*D cohort. In order to control for multiple testing, the subjects were divided into two study groups: discovery and replication. RESULTS: In addition to the previously identified marker in the HTR2A gene, a new marker (rs1954787) in the GRIK4 gene, which codes for the kainic acid-type glutamate receptor KA1, was observed. The effect size of the GRIK4 marker alone was modest, but homozygote carriers of the treatment-response-associated marker alleles of both the GRIK4 and HTR2A genes were 23% less likely to experience nonresponse to treatment relative to participants who did not carry any of these marker alleles. CONCLUSIONS: The findings demonstrate that genetic variation in a kainic acid-type glutamate receptor is reproducibly associated with response to the antidepressant citalopram. This finding suggests that the glutamate system plays an important role in modulating response to selective serotonin reuptake inhibitors (SSRIs).
Authors: Thomas G Schulze; Martin Alda; Mazda Adli; Nirmala Akula; Raffaella Ardau; Elise T Bui; Caterina Chillotti; Sven Cichon; Piotr Czerski; Maria Del Zompo; Sevilla D Detera-Wadleigh; Paul Grof; Oliver Gruber; Ryota Hashimoto; Joanna Hauser; Rebecca Hoban; Nakao Iwata; Layla Kassem; Tadafumi Kato; Sarah Kittel-Schneider; Sebastian Kliwicki; John R Kelsoe; Ichiro Kusumi; Gonzalo Laje; Susan G Leckband; Mirko Manchia; Glenda Macqueen; Takuya Masui; Norio Ozaki; Roy H Perlis; Andrea Pfennig; Paola Piccardi; Sara Richardson; Guy Rouleau; Andreas Reif; Janusz K Rybakowski; Johanna Sasse; Johannes Schumacher; Giovanni Severino; Jordan W Smoller; Alessio Squassina; Gustavo Turecki; L Trevor Young; Takeo Yoshikawa; Michael Bauer; Francis J McMahon Journal: Neuropsychobiology Date: 2010-05-08 Impact factor: 2.328
Authors: Eric J Peters; Susan L Slager; Greg D Jenkins; Megan S Reinalda; Holly A Garriock; Stanley I Shyn; Jeffrey B Kraft; Patrick J McGrath; Steven P Hamilton Journal: Pharmacogenet Genomics Date: 2009-01 Impact factor: 2.089
Authors: Michele L Pergadia; Arpana Agrawal; Anu Loukola; Grant W Montgomery; Ulla Broms; Scott F Saccone; Jen C Wang; Alexandre A Todorov; Kauko Heikkilä; Dixie J Statham; Anjali K Henders; Megan J Campbell; John P Rice; Richard D Todd; Andrew C Heath; Alison M Goate; Leena Peltonen; Jaakko Kaprio; Nicholas G Martin; Pamela A F Madden Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2009-10-05 Impact factor: 3.568