Should glutamatergic modulators be considered preferential treatments for adults with major depressive disorder and a reported history of trauma? Conceptual and clinical implications.

Jennifer Swainson, Sabrina Wong, Melanie Zhang, Angela T H Kwan, Kayla M Teopiz, Roger Ho, Roger S McIntyre, Bing Cao, Heidi K Y Lo, Moiz Lakhani, Poh Khuen Lim, Gia Han Le, Christine Dri, Kyle Valentino

Journal: CNS spectrums 2025;30(1):e61

PMID: 40415673

Full Text on Cambridge University Press View on PubMed

Abstract

Major depressive disorder (MDD) is a chronic, highly prevalent, and debilitating mental disorder associated with significant illness and economic burden globally. Exposure to trauma (eg, physical, sexual, emotional abuse, and/or physical, and emotional neglect) is common among individuals with MDD. Persons with MDD and a history of trauma often exhibit an attenuated response to conventional serotonergic antidepressants compared to those with non-traumatized depression. Emerging evidence indicates that exposure to trauma is associated with increased inflammatory markers [eg, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)] as well as glutamatergic dysregulation in the central nervous system (CNS). It is hypothesized that individuals with MDD and a history of trauma may be conceptualized as a distinct bio-phenotype compared to non-traumatized depression. Furthermore, preliminary evidence positions select glutamatergic modulators as potential, novel, mechanistically-informed therapeutic strategies that may provide benefit to persons with elevated inflammation and glutamatergic dysregulation.

Address: Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.; Department of Psychiatry, University of Hong Kong, Hong Kong, China.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.; Department of Pharmacology, University of Toronto, Toronto, ON, Canada.; Department of Psychiatry, University of Alberta, Edmonton, AB, Canada.; Neuroscience and Mental Health Institute, Edmonton, AB, Canada.; Key Laboratory of Cognition and Personality, Faculty of Psychology, Ministry of Education, https://ror.org/01kj4z117Southwest University, Chongqing, P. R. China.; Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore.; Division of Life Science (LIFS), Hong Kong University of Science and Technology (HKUST), Hong Kong, China.

DOI: 10.1017/S1092852925100278