Effects of glutamatergic modulators on striatal activation, functional connectivity and reward in persons with major depressive disorder and healthy controls: A systematic review of fMRI studies

Introduction Convergent evidence suggests that disrupted reward processing may be associated with observed alterations in frontostriatal activity in persons with major depressive disorder (MDD). Replicated evidence suggests that glutamatergic modulators may benefit persons experiencing disrupted reward function compared to healthy controls (HC). Herein, we systematically reviewed functional magnetic resonance imaging (fMRI) studies that examined the effects of glutamatergic modulators on frontostriatal activity and/or reward function in persons with MDD or healthy controls (HC). Methods A systematic literature search of online databases (PubMed, OVID, Scopus, Web of Science) and manual search of reference lists and Google Scholar was conducted from inception to July 22, 2025. Studies were included if they employed fMRI to assess changes in frontostriatal activation or connectivity following administration of glutamatergic agents with known or proposed antidepressant effects in persons with MDD or HC. Results We identified 11 fMRI studies that investigated the effects of ketamine (n  = 9), nitrous oxide (n  = 1) or memantine (n = 1) on frontostriatal activity in persons with MDD or HCs. Preliminary evidence suggests that intravenous ketamine may affect functional connectivity in striatal regions that may be relevant to improved reward function in persons with TRD. Conclusion Future studies should evaluate the impact of glutamatergic modulators on brain structures subserving reward and the temporality of the effect, as select glutamatergic modulators have a rapid onset of action. Future studies should also compare the effects of glutamatergic modulators on frontostriatal connectivity between persons with TRD and HCs, and aim to identify baseline characteristics that may mediate/moderate antidepressant response.