GLP-1 Receptor Agonist Effects on Neuronal Function and Cognition in Veterans with Schizophrenia

Schizophrenia and related psychotic disorders continue to be a leading cause of disability for Veterans. Among illness symptoms, cognitive dysfunction remains the least well-treated, despite being the most accurate predictor of psychosocial function and quality of life. Consequently, much effort has been devoted to developing novel treatments for cognitive deficits in schizophrenia, using a variety of pharmacologic targets. Nonetheless, no compound has yet earned a federal indication for improved cognition in schizophrenia. A potentially powerful approach to guide therapeutic development is to target specific aspects of neurobiology likely to be involved in disease pathology. Using human neuroimaging, studies have consistently shown that altered structure and function of the hippocampus is a fundamental characteristic of schizophrenia. Specifically, increased resting metabolism and neuronal activity of the hippocampus have been observed repeatedly. This hyperactivity is also associated with illness symptoms, including cognitive deficits. As such, using hippocampal hyperactivity as a target biomarker may be a useful strategy for therapeutic development. Multiple strategies have attempted to target this hyperactivity. For example, our group has used nicotinic cholinergic agonists with some success. Effects were limited, however, likely due to the complex pharmacology of nicotinic agonists. Recent work, including ours, has also attempted to target this hyperactivity with low-dose levetiracetam, an anti-epileptic agent. While our trial with this agent is not yet complete, very recent work from others suggests significant but still weak effects on cognition. Importantly, in both our prior work and in these recent studies, the modest nature of cognitive effects was accompanied by weak hippocampal effects. As such, while the success of novel pharmacological approaches to date remains limited, the utility of measuring hippocampal activity as an indicator of target engagement continues to show great promise. Given this, the proposed study will examine if an exciting new pharmacological treatment, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), may be able to improve cognitive function by targeting hippocampal hyperactivity in schizophrenia and related disorders. GLP-1 RAs have recently surged in popularity for use in the treatment of diabetes and obesity, contexts in which they seem to be tremendously effective. Recent animal and human studies have also shown, however, pro-cognitive effects of GLP-1 RAs. Mechanistically, GLP-1 receptors are present in the hippocampus, localized to glutamatergic and GABAergic neurons, with animal studies finding GLP-1 RAs to improve performance on hippocampal-dependent cognitive tasks. Beneficial effects of GLP-1 RAs on hippocampal structure and function, in tandem with associated cognitive improvements, have been observed in rodent models of alcohol use and Alzheimer’s disease, in addition to models of schizophrenia. Furthermore, recent clinical studies have observed GLP-1 RA-associated cognitive improvements in type 2 diabetes (T2D), mild Alzheimer’s dementia, depression, and bipolar disorder, with a study in T2D finding these effects to be hippocampally-mediated. Given the primacy of hippocampal dysfunction in schizophrenia, this is a fascinating and promising new avenue of investigation. As such, the proposed study aims to complete an important first step in this line of investigation, by determining if improved cognition and hippocampal activity are associated with GLP-1 RA treatment. The first aim will determine if Veterans with schizophrenia currently treated with GLP-1 RAs, compared to those currently not treated with the agents, show fewer cognitive symptoms, as measured with the MATRICS Consensus Cognitive Battery (MCCB). The second aim will determine if GLP-1 RA treatment is associated with reduced hippocampal activity, as measured by the resting fractional amplitude of low frequen Project Number: 1I01CX002834-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: JASON TREGELLAS | Institution: VA EASTERN COLORADO HEALTH CARE SYSTEM, Aurora, CO | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 MHBC-F (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11054481