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

Abstract

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.

Genetic Risk for Psychiatric Disorders and Telomere Length

“…One possible explanation is that antidepressants are increasing the proliferation of blood cells in users, and the knock-on effect is telomere shortening. Indeed, research using lymphoblastoid cell lines (resembling white blood cells), hippocampal progenitor cell lines, and in vivo studies of the hippocampus, support the notion that antidepressants increase proliferation ( Manev et al, 2001 ; Breitfeld et al, 2017 ; Powell et al, 2017b ). However, some work indicates that antidepressants may additionally increase the activity of telomerase, which is an enzyme involved in telomere maintenance and elongation ( Bersani et al, 2015 ), therefore more work is needed to better understand the effects of antidepressants on telomere length and proliferation over time.…”

Abnormal Prefrontal Development in Pediatric Posttraumatic Stress Disorder: A Longitudinal Structural and Functional Magnetic Resonance Imaging Study

“…One possible explanation could be that medication exposure in youth with PTSD is masking these effects. Notably, SSRIs are known to increase hippocampal neurogenesis (28,29), and appear to increase hippocampal gray matter volume in adults with PTSD (38,39). Intriguingly, an exploratory analysis revealed an interaction effect with SSRI use in the right anterior hippocampus.…”

Inter-individual variation in genes governing human hippocampal progenitor differentiation in vitro is associated with hippocampal volume in adulthood

“…Each experiment consisted of a control, low, medium and high drug dose. In the context of all adequately detected (unfiltered) probes on the microarray, neither drug had significant effects on expression of individual genes 25 , 26 . The inclusion of untreated control conditions allowed us to regress out any minor effects of drug and drug dose within our conservative statistical models, in order to accurately compare proliferating versus differentiating cell gene expression profiles (see below).…”