TY - JOUR
T1 - Effects of escitalopram on synaptic density in the healthy human brain
T2 - a randomized controlled trial
AU - Johansen, Annette
AU - Armand, Sophia
AU - Plavén-Sigray, Pontus
AU - Nasser, Arafat
AU - Ozenne, Brice
AU - Petersen, Ida N
AU - Keller, Sune H
AU - Madsen, Jacob
AU - Beliveau, Vincent
AU - Møller, Kirsten
AU - Vassilieva, Alexandra
AU - Langley, Christelle
AU - Svarer, Claus
AU - Stenbæk, Dea S
AU - Sahakian, Barbara J
AU - Knudsen, Gitte M
N1 - © 2023. The Author(s).
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
KW - Brain
KW - Citalopram/pharmacology
KW - Cognitive Dysfunction/drug therapy
KW - Escitalopram
KW - Humans
KW - Selective Serotonin Reuptake Inhibitors/pharmacology
KW - Synapses
UR - http://www.scopus.com/inward/record.url?scp=85173943376&partnerID=8YFLogxK
U2 - 10.1038/s41380-023-02285-8
DO - 10.1038/s41380-023-02285-8
M3 - Journal article
C2 - 37814129
SN - 1359-4184
VL - 28
SP - 4272
EP - 4279
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 10
ER -