Effects of escitalopram on synaptic density in the healthy human brain: 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 hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in...
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| Veröffentlicht in: | Molecular psychiatry 2023-10, Vol.28 (10), p.4272-4279 |
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| creator | Johansen, Annette Armand, Sophia Plavén-Sigray, Pontus Nasser, Arafat Ozenne, Brice Petersen, Ida N. Keller, Sune H. Madsen, Jacob Beliveau, Vincent Møller, Kirsten Vassilieva, Alexandra Langley, Christelle Svarer, Claus Stenbæk, Dea S. Sahakian, Barbara J. Knudsen, Gitte M. |
| description | 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 [
11
C]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 [
11
C]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. |
| doi_str_mv | 10.1038/s41380-023-02285-8 |
| format | Article |
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n
= 17) or a placebo (
n
= 15). After an intervention period of 3–5 weeks, participants underwent a [
11
C]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 [
11
C]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.</description><identifier>ISSN: 1359-4184</identifier><identifier>ISSN: 1476-5578</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/s41380-023-02285-8</identifier><identifier>PMID: 37814129</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>59/57 ; 59/78 ; 631/337 ; 631/378 ; 692/53 ; 692/699/476 ; Antidepressants ; Behavioral Sciences ; Biological Psychology ; Brain ; Citalopram ; Citalopram - pharmacology ; Citalopram - therapeutic use ; Clinical trials ; Cognitive ability ; Cognitive Dysfunction - drug therapy ; Escitalopram ; Humans ; Hypotheses ; Medicine ; Medicine & Public Health ; Mental disorders ; Neocortex ; Neuroplasticity ; Neurosciences ; Pharmacotherapy ; Placebos ; Psychiatry ; Selective Serotonin Reuptake Inhibitors - pharmacology ; Serotonin uptake inhibitors ; Statistical analysis ; Synapses ; Synaptic density ; Synaptic plasticity</subject><ispartof>Molecular psychiatry, 2023-10, Vol.28 (10), p.4272-4279</ispartof><rights>The Author(s) 2023</rights><rights>2023. The Author(s).</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-f83a405253e6f4da93acbad352398680e186bef8060bf129dee7188f58d399fa3</citedby><cites>FETCH-LOGICAL-c513t-f83a405253e6f4da93acbad352398680e186bef8060bf129dee7188f58d399fa3</cites><orcidid>0000-0001-7352-1745 ; 0000-0003-1508-6866 ; 0000-0003-0264-2368 ; 0000-0001-5061-2820 ; 0000-0003-3058-1072 ; 0000-0001-7805-279X ; 0000-0001-7811-1825</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41380-023-02285-8$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41380-023-02285-8$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37814129$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:153880329$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Johansen, Annette</creatorcontrib><creatorcontrib>Armand, Sophia</creatorcontrib><creatorcontrib>Plavén-Sigray, Pontus</creatorcontrib><creatorcontrib>Nasser, Arafat</creatorcontrib><creatorcontrib>Ozenne, Brice</creatorcontrib><creatorcontrib>Petersen, Ida N.</creatorcontrib><creatorcontrib>Keller, Sune H.</creatorcontrib><creatorcontrib>Madsen, Jacob</creatorcontrib><creatorcontrib>Beliveau, Vincent</creatorcontrib><creatorcontrib>Møller, Kirsten</creatorcontrib><creatorcontrib>Vassilieva, Alexandra</creatorcontrib><creatorcontrib>Langley, Christelle</creatorcontrib><creatorcontrib>Svarer, Claus</creatorcontrib><creatorcontrib>Stenbæk, Dea S.</creatorcontrib><creatorcontrib>Sahakian, Barbara J.</creatorcontrib><creatorcontrib>Knudsen, Gitte M.</creatorcontrib><title>Effects of escitalopram on synaptic density in the healthy human brain: a randomized controlled trial</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><addtitle>Mol Psychiatry</addtitle><description>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 [
11
C]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 [
11
C]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.</description><subject>59/57</subject><subject>59/78</subject><subject>631/337</subject><subject>631/378</subject><subject>692/53</subject><subject>692/699/476</subject><subject>Antidepressants</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Brain</subject><subject>Citalopram</subject><subject>Citalopram - pharmacology</subject><subject>Citalopram - therapeutic use</subject><subject>Clinical trials</subject><subject>Cognitive ability</subject><subject>Cognitive Dysfunction - drug therapy</subject><subject>Escitalopram</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mental disorders</subject><subject>Neocortex</subject><subject>Neuroplasticity</subject><subject>Neurosciences</subject><subject>Pharmacotherapy</subject><subject>Placebos</subject><subject>Psychiatry</subject><subject>Selective Serotonin Reuptake Inhibitors - 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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 (
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n
= 15). After an intervention period of 3–5 weeks, participants underwent a [
11
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11
C]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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>37814129</pmid><doi>10.1038/s41380-023-02285-8</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-7352-1745</orcidid><orcidid>https://orcid.org/0000-0003-1508-6866</orcidid><orcidid>https://orcid.org/0000-0003-0264-2368</orcidid><orcidid>https://orcid.org/0000-0001-5061-2820</orcidid><orcidid>https://orcid.org/0000-0003-3058-1072</orcidid><orcidid>https://orcid.org/0000-0001-7805-279X</orcidid><orcidid>https://orcid.org/0000-0001-7811-1825</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1359-4184 |
| ispartof | Molecular psychiatry, 2023-10, Vol.28 (10), p.4272-4279 |
| issn | 1359-4184 1476-5578 1476-5578 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_867941 |
| source | MEDLINE; SpringerLink Journals; SWEPUB Freely available online |
| subjects | 59/57 59/78 631/337 631/378 692/53 692/699/476 Antidepressants Behavioral Sciences Biological Psychology Brain Citalopram Citalopram - pharmacology Citalopram - therapeutic use Clinical trials Cognitive ability Cognitive Dysfunction - drug therapy Escitalopram Humans Hypotheses Medicine Medicine & Public Health Mental disorders Neocortex Neuroplasticity Neurosciences Pharmacotherapy Placebos Psychiatry Selective Serotonin Reuptake Inhibitors - pharmacology Serotonin uptake inhibitors Statistical analysis Synapses Synaptic density Synaptic plasticity |
| title | Effects of escitalopram on synaptic density in the healthy human brain: a randomized controlled trial |
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