Abstract
IntroductionThe mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD).MethodsEighty healthy first-degree relatives to patients with MDD were randomized to escitalopram 10 mg versus matching placebo daily for four weeks. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUCtotal) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention.ResultsChange in CorAUCtotal showed no statistically significant difference between the escitalopram and the placebo group, p = 0.47. There were large intra- and inter-individual differences in the results of the DEX-CRH test. There was statistically significant negative correlation between the plasma escitalopram concentration and change in CorAUCtotal, rho = −0.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUCtotal.ConclusionThe present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age.Trial RegistrationClinicalTrials.gov [NCT00386841
Highlights
The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown
Depression is associated with an altered function of the neuroendocrine feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis, including cortisol escape from dexamethasone suppression and increased cortisol responses to the dexamethasone corticotropin releasing hormone (DEX-CRH) test [1]
Previous studies have shown that even healthy first-degree relatives to patients with major depressive disorder (MDD) have an abnormal HPA response to the dexamethasone corticotropin-releasing hormone (DEX-CRH) test, with an intermediary response when compared to healthy controls and patients with major depression [2]
Summary
The mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. Intervention with a single dose of a selective serotonin re-uptake inhibitor (SSRI) has been found to increase serum corticosterone levels in rats [6,7] and plasma corticosteroid levels in healthy humans [8,9,10,11,12]. Studies of depressed patients have suggested that improved hypothalamic-pituitary-adrenal (HPA) system regulation (decreased DEX-CRH test response) is associated with beneficial treatment response [16]. Whether this is a direct effect of treatment with antidepressants or a consequence of improvement in depressive symptoms is unclear
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