1 Department of Forensic Medicine - Retskemisk, Department of Forensic Medicine, Health, Aarhus University2 Centre for Psychiatric Research, Faculty of Health Sciences, Aarhus University, Aarhus University3 Institut for Neuro- og Sansefag4 Studienævn for den Sundhedsfaglige supplerings- og5 Department of Psychiatry Copenhagen, Rigshospitalet, Copenhagen University Hospital, Copenhagen6 Kliniske Institutter7 Institut for Ortopædi og Intern Medicin8 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital,9 Institut for Neurovidenskab og Farmakologi10 Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital11 Department of Forensic Medicine - Retskemisk, Department of Forensic Medicine, Health, Aarhus University
Abstract Introduction: The 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). Methods: Eighty 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. Results: Change 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 =20.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUCtotal. Conclusion: The present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPAaxis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPAresponse in the DEX-CRH test and this effect increased with age.