GPR56/ADGRG1 is associated with response to antidepressant treatment

Nat Commun. 2020 Apr 2;11(1):1635. doi: 10.1038/s41467-020-15423-5.

Abstract

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

Trial registration: ClinicalTrials.gov NCT00635219 NCT00599911 NCT01140906 NCT02209142.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antidepressive Agents / administration & dosage*
  • Cohort Studies
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / genetics
  • Depressive Disorder, Major / metabolism
  • Female
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Serotonin Uptake Inhibitors / administration & dosage
  • Treatment Outcome

Substances

  • ADGRG1 protein, human
  • Antidepressive Agents
  • GPR56 protein, mouse
  • Receptors, G-Protein-Coupled
  • Serotonin Uptake Inhibitors
  • Glycogen Synthase Kinase 3

Associated data

  • ClinicalTrials.gov/NCT00635219
  • ClinicalTrials.gov/NCT00599911
  • ClinicalTrials.gov/NCT01140906
  • ClinicalTrials.gov/NCT02209142