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

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.

Socioeconomic and environmental contexts of suicidal rates in a latitudinal gradient: Understanding interactions to inform public health interventions.

Suicide results from complex interactions between biological, psychological, and socioeconomic factors. At the population level, the study of suicide rates and their environmental and social determinants allows us to disentangle some of these complexities and provides support for policy design and preventive actions. In this study we aim to evaluate the associations between environmental and socioeconomic factors and demographically stratified suicide rates on large temporal and spatial scales. Our dataset contains information about yearly suicides rates by sex and age from 2000 through 2017 along a 4000 km latitudinal gradient. We used zero-inflated negative binomial models to evaluate the spatio-temporal influence of each environmental and socioeconomic variable on suicide rates at each sex/age combination. Overall, we found differential patterns of associations between suicide rates and explanatory variables by age and sex. Suicide rates in men increases in middle and high latitude regions and intermediate age classes. For adolescent and adult women, we found a similar pattern with an increase in suicide rates at middle and high latitudes. Sex differences measured by the male/female suicide ratio shows a marked increase with age. We found that cloudiness has a positive effect on suicide rates in both men and women 24 years old or younger. Regional poverty shows a major impact on men in age classes above 35 years old, an effect that was absent in women. Alcohol and marijuana consumption showed no significant effect sizes. Our findings support high spatio-temporal variability in suicide rates in interaction with extrinsic factors. Several strong differential impacts of environmental and socioeconomic variables on suicide rates depending on sex and age were detected. These results suggest that the design of public policies and interventions to reduce suicide prevalence need to consider the local social and environmental contexts of target populations.