Relationship of cortisol levels and genetic polymorphisms to antidepressant response to placebo and fluoxetine in patients with major depressive disorder: A prospective study

Raúl Ventura-Juncá, Adriana Symon, Pamela López, Jenny L. Fiedler, Graciela Rojas, Cristóbal Heskia, Pamela Lara, Felipe Marín, Viviana Guajardo, A. V. Araya, Jaime Sasso, Luisa Herrera*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish
Article number220
JournalBMC Psychiatry
Volume14
Issue number1
DOIs
StatePublished - 3 Aug 2014
Externally publishedYes

Bibliographical note

Funding Information:
The authors are deeply grateful to the patients for their participation in this study. We also thank the personnel of the Departamento de Endocrinología of the José Joaquin Aguirre Hospital for extracting and analyzing blood samples. We also thank Miss Paola González for invaluable technical help in this project, Mr. Egardo Caamaño for the endocrinological evaluations and Dr Lafayette Eaton for revising the English of the manuscript. This research was supported by grant FONDECYT 1090219 (LH, AS, PL, JF, GR, CH, PL, FM, VG, JS, and VA), and Universidad de los Andes FAI-7, 2011 (RVJ). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2014 Ventura-Juncá et al., licensee BioMed Central Ltd.

Keywords

  • Antidepressants
  • Fluoxetine
  • Major depressive disorder
  • Placebo
  • Polymorphisms
  • Salivary cortisol

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