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A novel peripheral biomarker for depression and antidepressant response

Molecular Psychiatry volume 27, pages 1640–1646 (2022)Cite this article

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Abstract

In contrast to healthy controls, the heterotrimeric G protein, Gsalpha (Gsα) is ensconced predominantly in lipid rafts in subjects with major depressive disorder (MDD) resulting in impaired stimulation of adenylyl cyclase. In this small proof-of-concept study, we examined the hypothesis that translocation of Gsα from lipid rafts toward a more facile activation of adenylyl cyclase is a biomarker for clinical response to antidepressants. There were 49 subjects with MDD (HamD17 score ≥15) and 59 healthy controls at the screen visit. The AlphaScreen (PerkinElmer) assay measured both basal activity and prostaglandin E1 (PGE1) stimulation of Gsα-adenylyl cyclase to assess the extent of coupling of Gsα with adenylyl cyclase. At screen, platelet samples obtained from MDD subjects revealed significantly lower PGE1 activation of adenylyl cyclase activity than controls (p = 0.02). Subsequently, 19 consenting MDD subjects completed a 6-week open label antidepressant treatment trial. The 11 antidepressant responders (HamD17 improvement ≥50% from screen) revealed significant increase in PGE1-stimulated adenylyl cyclase compared to non-responders (p = 0.05) with an effect size of 0.83 for the PGE1/Gsα lipid-raft biomarker. PGE1 stimulation increased by ≥30% from screen assessment in eight responders (72.7%) and two non-responders (25.0%) [Fisher exact = 0.07] with a positive predictive value for response of 80.0%. In this small, pilot study, increased PGE1 stimulated adenylyl cyclase was associated with antidepressant response in MDD subjects. These data suggest that a simple, high-throughput-capable assay for depression and antidepressant response can be developed. Future studies are needed to evaluate the utility of this biomarker for the treatment of MDD.

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Fig. 1: PGE-1 stimulated cAMP signaling response in platelets is significantly lower in subjects with MDD than healthy controls.
Fig. 2: Change from screen values of PGE-1 stimulated cAMP signaling response in platelets from MDD antidepressant treatment responders and non-responders.
Fig. 3: Antidepressant response to PGE1 stimulated adenylyl cyclase activity: changes in individual subjects from screen visit to 6-weeks of antidepressant treatment.
Fig. 4: Effects of depression and antidepressant treatment on Gsα plasma membrane localization.

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Acknowledgements

This research was supported by R43MH097370 and R41MH113398 to Pax Neuroscience and VA Merit BX00149 (MMR). MMR is a VA Research Career Scientist BX004475.

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Authors and Affiliations

  1. Signant Health, Boston, MA, USA

    Steven D. Targum

  2. Pax Neuroscience, Glenview, IL, USA

    Steven D. Targum, Jeffrey Schappi & Mark M. Rasenick

  3. University of Illinois College of Medicine, Chicago, IL, USA

    Jeffrey Schappi, Athanasia Koutsouris, Runa Bhaumik & Mark M. Rasenick

  4. Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, USA

    Mark H. Rapaport

  5. Stanford University School of Medicine, Stanford, CA, USA

    Natalie Rasgon

  6. Jesse Brown VAMC, Chicago, IL, USA

    Mark M. Rasenick

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Contributions

MMR and MHR designed original study. AK and JS collected data. RB, NR, and SDT did statistical analysis. SDT, JS, NR, MHR, and MMR interpreted data. SDT, NR, MHR, JS, and MMR wrote the paper.

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Correspondence to Steven D. Targum or Mark M. Rasenick.

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Competing interests

Dr. Targum is an employee of Signant Health and has received vendor grants and/or consulting fees from Acadia Pharmaceuticals Inc., Alkermes Inc., BioXcel Therapeutics Inc., Denovo Biopharma, EMA Wellness LLC, Epiodyne, Frequency Therapeutics, Functional Neuromodulation, Intra Cellular Therapies, Johnson and Johnson PRD, Karuna Therapeutics, Merck Inc., Methylation Sciences Inc., Navitor Pharmaceuticals Inc., and Sunovion Inc. during the past 3 years. Drs Schappi, Bhaumik, Rapaport and Rasgon, and Ms. Koutsouris report no conflicts of interest. Dr. Rasenick is co-founder and chief scientific officer of Pax Neuroscience. In the past three years he has consulted for Otsuka, Inc and has received research support from Lundbeck SA. He is also supported by grants from the Veterans Administration and is a research career scientist of the VA.

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Targum, S.D., Schappi, J., Koutsouris, A. et al. A novel peripheral biomarker for depression and antidepressant response. Mol Psychiatry 27, 1640–1646 (2022). https://doi.org/10.1038/s41380-021-01399-1

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