Escitalopram increases synaptic density in the human brain over weeks: A randomized controlled trial

Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The neuroplasticity hypothesis is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3-5 weeks, participants underwent a [ 11 C]UCB-J PET scan to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Group means were compared using t-tests, and effect of intervention duration was assessed with linear models. Whereas there was only a small difference in [ 11 C]UCB-J binding between the escitalopram and placebo groups after an average of 29 (range: 24-38) days of intervention (Cohen’s d of 0.31-0.42, p values > 0.26), we identified time-dependent group effects (neocortex: p = 0.020; hippocampus: p = 0.058). Linear models showed positive associations between [ 11 C]UCB-J binding and duration of escitalopram intervention: p Neocortex = 0.016; p Hippocampus = 0.11). Our findings suggest that brain synaptic plasticity evolves over 3-5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans, and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs.