title: The effect of selective serotonin reuptake inhibitors in healthy first-degree relatives of patients with major depressive disorder - an experimental medicine blinded controlled trial.
abstract: The mechanisms of action for selective serotonin re-uptake in-hibitors (SSRI) in depressed patients remain widely unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. Further, the serotonergic neurotransmitter system seems closely linked to personality and cognition. It is not known if SSRIs have a direct effect on the HPA system, personality or cognition that is independent of their effect on depression. Thus, healthy individuals with a genetic liability for depression represent a group of particular interest when investigating if intervention with SSRIs affects these potential biomarkers. SSRIs may affect these potential biomarkers in depressed patients, but it is unclear if the effect is directly on the biomarkers or is secondary to the effect of SSRIs on depressive symptoms. It has newer been tested whether an intervention with a SSRI has a beneficial effect on these potential biomarkers in healthy individuals with a genetic liability for depression. The aim of the thesis was by an experimental medicine blinded controlled trial, to investigate if long-term intervention with SSRI versus placebo decreases cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD). Further, to test the hypothesis that a SSRI may reduce neuroticism in healthy first-degree relatives of patients with MDD. Finally, to test whether SSRI enhance cognitive function in healthy first-degree relatives of patients with MDD. Eighty healthy first-degree relatives to patients with MDD were randomised to receive escitalopram 10 mg versus matching pla-cebo daily for four weeks in a blinded trial. 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. The secondary outcomes were a) change in self-reported neuroticism scores on the 240-items Revised Neuroticism-Extroversion-Openness-Personality Inventory (NEO-PI-R) and the 101-items Eysenck Personality Inventory (EPQ) at entry to after four weeks of intervention and b) the change in the general cognition score, which was the standardised mean of 13 cognitive test measures. Change in CorAUCtotal showed no statically significant difference between the escitalopram and the placebo group, p = 0.47. Fur-ther, escitalopram did not significantly affect self-reported neu-roticism compared with placebo, NEO-PI-R (p = 0.09) and EPQ (p = 0.73). Finally, mean change in the general cognition score was not significantly increased with escitalopram compared with placebo, (p = 0.37). In univariate analyses, no statistically significant correlations were found between change in the primary and secondary outcomes, respectively, and the covariates age, sex, Hamilton depression score 17-items, and plasma escitalopram levels. In conclusion, the present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis, neuroticism and cognitive function in healthy first-degree relatives to patients with MDD.
authors.affiliation: Psychiatric Centre Copenhagen, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark. ulla.knorr@regionh.dk
authors.forename: Ulla Benedichte
authors.initials: UB
authors.lastname: Knorr
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D015283:Citalopram / Q000097:blood / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D003718:Denmark / Q000453:epidemiology; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010375:Pedigree; D010556:Personality Tests; D011594:Psychometrics; D057566:Self Report; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000627:therapeutic use*; D013223:Statistics as Topic; D055815:Young Adult
chemical_list: D015283:Citalopram; D006854:Hydrocortisone; D017367:Selective Serotonin Reuptake Inhibitors