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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-Juncá12, Adriana Symon1, Pamela López1, Jenny L Fiedler4, Graciela Rojas3, Cristóbal Heskia1, Pamela Lara3, Felipe Marín3, Viviana Guajardo3, A Verónica Araya5, Jaime Sasso6 and Luisa Herrera1*

Author Affiliations

1 Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Independencia, Santiago, Chile

2 Escuela de Psicología, Universidad de Los Andes, San Carlos de Apoquindo 2200, Las Condes, Santiago, Chile

3 Clínica Psiquiátrica Universitaria, Hospital Clínico Universidad de Chile, Av. La Paz 1003, Recoleta, Santiago, Chile

4 Laboratorio de Neuroplasticidad y Neurogenética, Departamento de Bioquímica y Biología Molecular, Universidad de Chile, Calle Sergio Livingstone Pohlhammer 1007 (ex Olivos), Independencia, Santiago, Chile

5 Departamento de Endocrinología, Universidad de Chile, Santos Dumont 999, Independencia, Santiago, Chile

6 Instituto de Investigaciones Farmacológicas y Toxicológicas (IFT), Facultad de Medicina, Universidad de Chile, Santiago, Chile

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BMC Psychiatry 2014, 14:220  doi:10.1186/s12888-014-0220-0

Published: 3 August 2014



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.


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.


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.


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.

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