Neuroinflammation is a key contributor to the pathophysiology and symptomatology of schizophrenia spectrum disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), clinically approved anti-diabetic and -obesity medication, have been associated with anti-inflammatory properties. It remains unclear whether GLP-1RA treatment can improve neuroinflammation within psychiatric disorders, including schizophrenia. This scoping review synthesizes evidence from clinical and preclinical studies on the anti-inflammatory effects of GLP-1RAs in psychiatric, neurodegenerative and neurological disease models, identifying crucial research gaps and providing future recommendations to guide potential clinical translation. The literature search was conducted in PubMed, Embase and PsycINFO and included outcomes of cytokine levels within blood and brain samples. Within the 40 included studies, two were clinical (schizophrenia and alcohol-use disorder) and 38 were preclinical models of psychiatric diseases, Alzheimer's -, Parkinson's Disease, Multiple Sclerosis, Epilepsy and lipopolysaccharide (LPS)-induced neuroinflammation. Preclinical studies showed anti-(neuro)inflammatory effects of GLP-1RAs, whereas the two available clinical studies found no significant changes in peripheral inflammatory markers. As these trials were not primarily designed or powered to test neuroinflammatory effects, the clinical findings remain inconclusive. Differences in study design, inflammatory measurements, pharmacokinetics and dosing may have contributed to the discrepancy between preclinical and clinical findings. Future research should prioritize early-phase dose-finding trials in non-diabetic, or -overweight patients diagnosed with schizophrenia spectrum disorders, evaluating the effects of alternative GLP-1RA regimens on neuroinflammatory markers, safety and clinical symptomatology. This is an essential step to determine their potential mental health-enhancing effects through the modulation of neuroinflammation within schizophrenia spectrum disorders.
