Glutamatergic modulation of brain function in psychosis: A systematic review of neuroimaging studies.

Background: Aberrant dopamine and glutamate signalling 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 if such changes map onto clinical outcomes.

Methods: Following 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, employing functional neuroimaging (1H-MRS, fMRI, ASL, PET, EEG, or MEG). Twenty-seven articles met inclusion criteria, encompassing 841 participants.

Results: Evidence from ¹H-MRS suggests that sarcosine, N-Acetylcysteine, and Riluzole reduce glutamate concentrations in frontal and hippocampal regions, but no clinical outcomes investigated. Resting-state and task-based fMRI studies suggest that NMDAR modulators may normalise measures of functional dysconnectivity, though effects were often short-lived and did not always correspond to sustained symptom improvements. Similarly, EEG studies consistently identified normalisation of mismatch negativity and gamma oscillations, but correlations with symptom or cognitive outcomes were inconsistent.

Conclusions: While glutamatergic modulators show measurable effects on brain chemistry and electrophysiology, the relationship to robust, durable clinical benefits remains elusive. Future work should employ larger, longer duration, and multimodal imaging studies to clarify the precise mechanisms, optimal dosing, and patient subgroups most likely to benefit from glutamatergic interventions in psychosis.