title: Relationship of cortisol levels and genetic polymorphisms to antidepressant response to placebo and fluoxetine in patients with major depressive disorder: a prospective study.
abstract: BACKGROUND
  Increased cortisol levels and genetic polymorphisms have been related to both major depressive disorder and antidepressant treatment outcome. The aim of this study is to evaluate the relationship between circadian salivary cortisol levels, cortisol suppression by dexamethasone and genetic polymorphisms in some HPA axis-related genes to the response to placebo and fluoxetine in depressed patients.
  
  
  METHODS
  The diagnosis and severity of depression were performed using the Mini International Neuropsychiatric Interview (M.I.N.I.) and Hamilton depression scale (HAM-D17), respectively. Euthyroid patients were treated with placebo (one week) followed by fluoxetine (20 mg) (two months). Severity of depression was re-evaluated after placebo, three weeks and two months of fluoxetine treatments. Placebo response was defined as HAM-D17 score reductions of at least 25% and to < 15. Early response and response were reductions of at least 50% after three weeks and two months, and remission with ≤ 7 after two months. Plasma TSH, free-T4, circadian salivary cortisol levels and cortisol suppression by dexamethasone were evaluated. Seven genetic polymorphisms located in the Corticotrophin-releasing-hormone-receptor-1 (rs242939, rs242941, rs1876828), Corticotrophin-releasing-hormone-receptor-2 (rs2270007), Glucocorticoid-receptor (rs41423247), FK506-binding-protein-5 (rs1360780), and Arginine-vasopressin (rs3729965) genes were determined. Association analyses between response to placebo/fluoxetine and polymorphism were performed by chi-square or Fisher exact test. Cortisol levels were compared by t-test, ANOVA and the general linear model for repeated measures.
  
  
  RESULTS
  208 depressed patients were recruited, 187 of whom were euthyroid. Placebo responders, fluoxetine responders and remitters exhibited significantly lower circadian cortisol levels than those who did not respond (p-values of 0.014, 0.008 and 0.021 respectively). Patients who abandoned treatment before the third week also exhibited a trend to low cortisol levels (p = 0.057). The polymorphisms rs242939 (CRHR1) and rs2270007 (CRHR2) were not in Hardy-Weinberg equilibrium. Only the rs242939 polymorphism (CRHR1) exhibited association with early response (three weeks) to fluoxetine (p-value = 0.043). No other association between outcomes and polymorphisms was observed.
  
  
  CONCLUSIONS
  These results support the clinical relevance of low salivary cortisol levels as a predictor of antidepressant response, either to placebo or to fluoxetine. Only one polymorphism in the CRHR1 gene was associated with the early response. Other factors may be involved in antidepressant response, although further studies are needed to identify them.
authors.forename: Raúl
authors.initials: R
authors.lastname: Ventura-Juncá
authors.forename: Adriana
authors.initials: A
authors.lastname: Symon
authors.forename: Pamela
authors.initials: P
authors.lastname: López
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Fiedler
authors.forename: Graciela
authors.initials: G
authors.lastname: Rojas
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Heskia
authors.forename: Pamela
authors.initials: P
authors.lastname: Lara
authors.forename: Felipe
authors.initials: F
authors.lastname: Marín
authors.forename: Viviana
authors.initials: V
authors.lastname: Guajardo
authors.forename: A Verónica
authors.initials: AV
authors.lastname: Araya
authors.forename: Jaime
authors.initials: J
authors.lastname: Sasso
authors.forename: Luisa
authors.initials: L
authors.lastname: Herrera
mesh_terms: D000293:Adolescent; D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001127:Arginine Vasopressin / Q000235:genetics; D003865:Major Depressive Disorder / Q000097:blood / Q000188:drug therapy*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics; D022021:Tacrolimus Binding Proteins / Q000235:genetics; D016896:Treatment Outcome; D055815:Young Adult; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001127:Arginine Vasopressin; D005473:Fluoxetine; D006854:Hydrocortisone; D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099052:CRF Receptor, Type 1; D000099159:Tacrolimus Binding Protein 5; C101531:CRF receptor type 2
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