The genome-wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume and antidepressant response

TY - JOUR

T1 - The genome-wide expression effects of escitalopram and its relationship to neurogenesis, hippocampal volume and antidepressant response

AU - Powell, Timothy

AU - Murphy, Tytus Amadeusz

AU - De Jong, Simone

AU - Lee, Sang Hyuck

AU - Tansey, Katherine

AU - Hodgson, Karen

AU - Uher, Rudolf

AU - Price, Jack

AU - Thuret, Sandrine

AU - Breen, Gerome Daniel

N1 - Corresponding Author: Dr Sandrine Thuret, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 125 Coldharbour Lane, London, SE5 9NU, UK Telephone number: +44 (0)20 7848 5405 Email: [email protected]

PY - 2017/4/10

Y1 - 2017/4/10

N2 - Antidepressant-induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long-term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome-wide expression changes associated with AHN in human cells. We identify gene expression networks significantly activated during AHN, and we perform gene set analyses to probe the molecular relationship between AHN, hippocampal volume, and antidepressant response. The latter were achieved using genome-wide association summary data collected from 30,717 individuals as part of the ENIGMA Consortium (genetic predictors of hippocampal volume dataset), and data collected from 1,222 major depressed patients as part of the NEWMEDS Project (genetic predictors of response to antidepressants dataset). Our results showed that the selective serotonin reuptake inhibitor, escitalopram evoked AHN in human cells; dose-dependently increasing the differentiation of cells into neuroblasts, as well as increasing gliogenesis. Activated genome-wide expression networks relate to axon and microtubule formation, and ribosomal biogenesis. Gene set analysis revealed that gene expression changes associated with AHN were nominally enriched for genes predictive of hippocampal volume, but not for genes predictive of therapeutic response.

AB - Antidepressant-induced hippocampal neurogenesis (AHN) is hypothesized to contribute to increases in hippocampal volume among major depressive disorder patients after long-term treatment. Furthermore, rodent studies suggest AHN may be the cellular mechanism mediating the therapeutic benefits of antidepressants. Here, we perform the first investigation of genome-wide expression changes associated with AHN in human cells. We identify gene expression networks significantly activated during AHN, and we perform gene set analyses to probe the molecular relationship between AHN, hippocampal volume, and antidepressant response. The latter were achieved using genome-wide association summary data collected from 30,717 individuals as part of the ENIGMA Consortium (genetic predictors of hippocampal volume dataset), and data collected from 1,222 major depressed patients as part of the NEWMEDS Project (genetic predictors of response to antidepressants dataset). Our results showed that the selective serotonin reuptake inhibitor, escitalopram evoked AHN in human cells; dose-dependently increasing the differentiation of cells into neuroblasts, as well as increasing gliogenesis. Activated genome-wide expression networks relate to axon and microtubule formation, and ribosomal biogenesis. Gene set analysis revealed that gene expression changes associated with AHN were nominally enriched for genes predictive of hippocampal volume, but not for genes predictive of therapeutic response.

U2 - 10.1002/ajmg.b.32532

DO - 10.1002/ajmg.b.32532

M3 - Article

SN - 1552-4841

JO - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

JF - American Journal of Medical Genetics. Part B: Neuropsychiatric Genetics

ER -