title: 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.
  
  
  METHODS
  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.
authors.affiliation: 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.
authors.forename: Ma-Li
authors.initials: ML
authors.lastname: Wong
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Dong
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Flores
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.forename: Stefan
authors.initials: S
authors.lastname: Bornstein
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
authors.forename: Julio
authors.initials: J
authors.lastname: Licinio
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D003891:Desipramine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D044127:Epigenesis, Genetic; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D017058:Mexican Americans; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D012107:Research Design; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D019208:Brain-Derived Neurotrophic Factor; D003891:Desipramine; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; C579455:BDNF protein, human