The effect of selctive serotonin receptor inhibitors (SSRIs) on healthy individuals remains unclear. The aim of the trial was to evaluate the effect of the SSRI escitalopram on cognitive function in healthy first-degree relatives of patients with major depressive disorder (FDRs). A total of 80 FDRs were randomized to escitalopram (10mg/day) (N=41) versus placebo (n=39) for 4 weeks. Neuropsychological tests and ratings of mood were applied at entry (T0) and at 4 weeks (T4). The main outcome measure was calculated as the change (T4-T0) in a general cognition score, which was the standardized mean of 13 test measures. Mean change in the general cognition score was not significantly increased with escitalopram compared with placebo (p=0.37) or for any of the specific tests. In univariate analyses no statistically significant correlations were found between change in the general cognitive score and the variables age, sex, Hamilton depression score 17 items, Danish Adult Reading Test-45, and plasma escitalopram levels, respectively. These results suggest that treatment with escitalopram does not improve or impair cogntive function in FDRs. Improvement in cognitive function following treatment of depressed patients with SSRIs seems to be related to the effects on depressive symptoms rather than to a direct effect of the SSRI.TRIAL REGISTRATION: Clinicaltrials.gov NCT00386841Psychiatric Centre Copenhagen, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. ulla.knorr@regionh.dk