ABCB1 variants and sex affect serotonin transporter occupancy in the brain
© 2022. The Author(s)..
Strategies to personalize psychopharmacological treatment promise to improve efficacy and tolerability. We measured serotonin transporter occupancy immediately after infusion of the widely prescribed P-glycoprotein substrate citalopram and assessed to what extent variants of the ABCB1 gene affect drug target engagement in the brain in vivo. A total of 79 participants (39 female) including 31 patients with major depression and 48 healthy volunteers underwent two PET/MRI scans with the tracer [11C]DASB and placebo-controlled infusion of citalopram (8 mg) in a cross-over design. We tested the effect of six ABCB1 single nucleotide polymorphisms and found lower SERT occupancy in ABCB1 rs2235015 minor allele carriers (n = 26, MAF = 0.18) compared to major allele homozygotes (t73 = 2.73, pFWE < 0.05) as well as in men compared to women (t73 = 3.33, pFWE < 0.05). These effects were robust to correction for citalopram plasma concentration, age and diagnosis. From occupancy we derived the ratio of occupied to unoccupied SERT, because in theory this measure is equal to the product of drug affinity and concentration at target sites. A model combining genotype with basic clinical variables, predicted that, at the same dosage, occupied to unoccupied SERT ratio was -14.48 ± 5.38% lower in rs2235015 minor allele carriers, +19.10 ± 6.95% higher in women, -4.83 ± 2.70% lower per 10 kg bodyweight, and -2.68 ± 3.07% lower per 10 years of age. Our results support the exploration of clinical algorithms with adjustment of initial citalopram dosing and highlight the potential of imaging-genetics for precision pharmacotherapy in psychiatry.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Molecular psychiatry - 27(2022), 11 vom: 07. Nov., Seite 4502-4509 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Silberbauer, Leo R [VerfasserIn] |
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| Links: |
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| Themen: |
0DHU5B8D6V |
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| Anmerkungen: |
Date Completed 19.12.2022 Date Revised 12.04.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41380-022-01733-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM345882369 |
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| 520 | |a © 2022. The Author(s). | ||
| 520 | |a Strategies to personalize psychopharmacological treatment promise to improve efficacy and tolerability. We measured serotonin transporter occupancy immediately after infusion of the widely prescribed P-glycoprotein substrate citalopram and assessed to what extent variants of the ABCB1 gene affect drug target engagement in the brain in vivo. A total of 79 participants (39 female) including 31 patients with major depression and 48 healthy volunteers underwent two PET/MRI scans with the tracer [11C]DASB and placebo-controlled infusion of citalopram (8 mg) in a cross-over design. We tested the effect of six ABCB1 single nucleotide polymorphisms and found lower SERT occupancy in ABCB1 rs2235015 minor allele carriers (n = 26, MAF = 0.18) compared to major allele homozygotes (t73 = 2.73, pFWE < 0.05) as well as in men compared to women (t73 = 3.33, pFWE < 0.05). These effects were robust to correction for citalopram plasma concentration, age and diagnosis. From occupancy we derived the ratio of occupied to unoccupied SERT, because in theory this measure is equal to the product of drug affinity and concentration at target sites. A model combining genotype with basic clinical variables, predicted that, at the same dosage, occupied to unoccupied SERT ratio was -14.48 ± 5.38% lower in rs2235015 minor allele carriers, +19.10 ± 6.95% higher in women, -4.83 ± 2.70% lower per 10 kg bodyweight, and -2.68 ± 3.07% lower per 10 years of age. Our results support the exploration of clinical algorithms with adjustment of initial citalopram dosing and highlight the potential of imaging-genetics for precision pharmacotherapy in psychiatry | ||
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| 700 | 1 | |a Vraka, Chrysoula |e verfasserin |4 aut | |
| 700 | 1 | |a Hartmann, Annette M |e verfasserin |4 aut | |
| 700 | 1 | |a Godbersen, Godber Mathis |e verfasserin |4 aut | |
| 700 | 1 | |a Philippe, Cécile |e verfasserin |4 aut | |
| 700 | 1 | |a Pacher, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Nics, Lukas |e verfasserin |4 aut | |
| 700 | 1 | |a Klöbl, Manfred |e verfasserin |4 aut | |
| 700 | 1 | |a Unterholzner, Jakob |e verfasserin |4 aut | |
| 700 | 1 | |a Stimpfl, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Wadsak, Wolfgang |e verfasserin |4 aut | |
| 700 | 1 | |a Hahn, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Hacker, Marcus |e verfasserin |4 aut | |
| 700 | 1 | |a Rujescu, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Kasper, Siegfried |e verfasserin |4 aut | |
| 700 | 1 | |a Lanzenberger, Rupert |e verfasserin |4 aut | |
| 700 | 1 | |a Gryglewski, Gregor |e verfasserin |4 aut | |
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