An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

Serotonin signaling suppresses generation of amyloid-beta (A beta) in vitro and in animal models of Alzheimer's disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor, decreased A beta in brain interstitial fluid in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of preexisting plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram's effects on A beta production and A beta concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable isotope labeling kinetics, with CSF sampling during acute dosing of citalopram. A beta production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF A beta concentrations in the drug-treated group. The ability to safely decrease A beta concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials.