Effects of escitalopram on synaptic density in the healthy human brain: a randomized controlled trial.

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Armand, Sophia 
Plavén-Sigray, Pontus 
Nasser, Arafat 
Ozenne, Brice 

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 hypothesis of neuroplasticity 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 with no history of psychiatric or cognitive disorders 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 [11C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24-38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [11C]UCB-J binding and duration of escitalopram intervention. 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. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.


Acknowledgements: Assistance from Lone Freyr, Anna Søndergaard, Elisabeth Pedersen, Dorthe Givard, Peter Steen Jensen, Lucas Andreasen, Oliver Overgaard-Hansen, Caroline Lund, Ida Likaj, Anton Lund, Ida Møller Larsen, Christina Schulze, and Vibeke Jensen, is greatly acknowledged. The John and Birthe Meyer Foundation is gratefully acknowledged for donating the Cyclotron and PET scanner. The Kirsten and Freddy Johansen Foundation is gratefully acknowledged for donating the MRI scanner. The Toyota Foundation is gratefully acknowledged for the donation of the HPLC equipment.

Humans, Selective Serotonin Reuptake Inhibitors, Escitalopram, Brain, Synapses, Cognitive Dysfunction, Citalopram
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Mol Psychiatry
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Springer Science and Business Media LLC
Lundbeckfonden (Lundbeck Foundation) (R281-2018-131, R281-2018-131, R281-2018-131, R281-2018-131, R281-2018-131)
Det Frie Forskningsråd (Danish Council for Independent Research) (8020-00414B, 8020-00414B)
Rigshospitalet (R216-A9684, R216-A9684)
Vetenskapsrådet (Swedish Research Council) (2021-00462)