Related Experiment Video
Updated: May 28, 2026

Developing a Rat Model for Bipolar Disorder
Published on: May 2, 2025
Polymorphisms within the metabotropic glutamate receptor 1 gene are associated with depression phenotypes
Andreas Menke1, Philipp Sämann, Stefan Kloiber
1Max Planck Institute of Psychiatry, Kraepelinstr. 10, D-80804 Munich, Germany. menke@mpipsykl.mpg.de
Objectives:
Glutamate has been implicated in the pathophysiology and treatment of mood disorders possibly by affecting the regulation of the hypothalamus-pituitary-adrenocortical (HPA) axis. Growing evidence suggests an important role of the metabotropic glutamate receptor 1 (mGlu1) in depression-related phenotypes. To test whether these findings can also be supported by human genetics data, we explored polymorphisms within the metabotropic glutamate receptor 1 gene (GRM1) for their association with unipolar depression (UPD) as well as with biological phenotypes of this disorder.
Methods:
We first tested the association of 43 tag-SNPs covering the GRM1 locus with UPD in 350 patients and 370 matched controls. We then investigated the effects of the associated SNPs on hippocampal glutamate levels estimated using ¹H-MR-spectroscopy (¹H-MRS) and on endocrine measures from the combined dexamethasone-suppression/CRH stimulation (dex/CRH) test.
Results:
Within the GRM1 locus, 22 SNPs showed nominally significant association with UPD, of which 6 withstood corrections for multiple testing (rs2268666 with best allelic p=7.0×10⁻⁵). Supportive evidence for an association with UPD was gained from a second independent sample with 904 patients and 1012 controls. Furthermore, patients homozygous for the non-risk genotypes showed reduced hippocampal glutamate levels as measured by ¹H-MRS, a more pronounced normalization of HPA-axis hyperactivity as well as a better antidepressant treatment outcome.
Conclusions:
These results suggest that the combination of genetic and biological markers may allow to subgroup patients into etiopathogenetically more relevant subcategories which could guide clinicians in their antidepressant treatment choices.
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