The effect of selective serotonin reuptake inhibitors in healthy subjects revisited: A systematic review of the literature.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line drugs in the treatment of depression. Investigations of the effects of SSRIs in healthy individuals is a useful model to understand the mechanisms of SSRI action and potentially the underlying pathophysiology of depression. We conducted an updated systematic review of all randomized multiple-dose, placebo-controlled trials on the effect of intervention with SSRI for >= 7 days in healthy nonpsychiatric subjects. Tables were drawn for characteristics of the trial, quality assessment, outcome measures, and the effect of intervention with SSRI. The search strategy identified a total of 51 placebo-controlled randomized trials investigating seven different SSRIs and 249 different outcome measures. Among trials, using the same outcome measure, most associations were either contradictory or statistically nonsignificant. Replication of statistically significant findings in two or more trials showed that SSRIs compared with placebo decreased divided attention, sustained attention network, negative affects, hostility, sleep quality, and platelet 5-HT content and further increased activity in the amygdala in relation to happy faces. Factors such as age, gender, family history of psychiatric disorder, and drug level influenced the findings but were rarely systematically investigated. The newly published retrieved trials fulfilled more criteria according to the CONSORT statement. This systematic review points to effects of SSRIs increasing positive emotional processing and decreasing divided and sustained attention besides physiological effects decreasing sleep quality and platelet 5-HT content in healthy subjects. Larger studies with a translational medicines approach with improved methodology are needed on the effects of SSRIs in healthy subjects.