Glutamatergic Modulation of Brain Function in Psychosis: A Systematic Review of Neuroimaging Studies

Aberrant dopamine and glutamate signaling are implicated in the pathophysiology of schizophrenia. Existing treatments primarily target dopamine pathways underlying positive symptoms but have relatively little effect on cognitive and negative symptoms. Glutamatergic modulators may treat the latter symptom domains, and neuroimaging studies have the potential to identify therapeutic mechanisms. We conducted a systematic review to examine functional neuroimaging studies of glutamatergic modulators in psychosis and determine whether these agents alter brain activity, chemistry, or functional connectivity and whether such changes map onto clinical outcomes. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO: CRD42024549120), MEDLINE, Embase, and PsycInfo were searched from inception to June 2024 for studies administering pharmacologic glutamate modulators to individuals with psychosis, using functional neuroimaging (proton magnetic resonance spectroscopy [¹H-MRS], functional magnetic resonance imaging [fMRI], arterial spin labeling, positron emission tomography, electroencephalography [EEG], or magnetoencephalography). Twenty-seven articles met inclusion criteria, encompassing 841 participants. Evidence from ¹H-MRS suggests that sarcosine, N-acetylcysteine, and riluzole reduce glutamate concentrations in frontal and hippocampal regions, but clinical outcomes have not been investigated. Resting-state and task-based fMRI studies suggest that NMDA receptor modulators may normalize measures of functional dysconnectivity, although effects were often short-lived and did not always correspond to sustained symptom improvements. Similarly, EEG studies consistently identified normalization of mismatch negativity and gamma oscillations, but correlations with symptom or cognitive outcomes were inconsistent. While glutamatergic modulators show measurable effects on brain chemistry and electrophysiology, the relationship to robust, durable clinical benefits remains elusive. Future work should use larger, longer-duration, and multimodal imaging studies to clarify the precise mechanisms, optimal dosing, and the patient subgroups most likely to benefit from glutamatergic interventions in psychosis.