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
Bibliographic record
Abstract
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, 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). 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 connectivity following administration of glutamatergic agents with known or proposed antidepressant effects in persons with MDD or HC. 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. 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. • Glutamatergic modulators may benefit persons experiencing anhedonia and/or disrupted reward function. • Preliminary evidence suggests that intravenous ketamine affects striatal functional connectivity, which may potentially improve reward function or hedonic tone in persons with MDD or treatment-resistant depression. • Future research should prioritize task-based neuroimaging to investigate the effect of glutamatergic modulators on striatal reactivity, functional connectivity, and associated change in anhedonia and reward function. • Future studies should also primarily aim to evaluate the impact of glutamatergic modulators on reward-related brain structures and the temporality of the effect, as select glutamatergic modulators have a rapid onset of action.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.015 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.004 |
| Bibliometrics | 0.008 | 0.007 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".