Mind over metabolism: a systematic review of GLP-1 receptor agonists in the treatment of stress-related disorders

Depression and post-traumatic stress disorder (PTSD) are highly prevalent and debilitating stress-related psychiatric disorders, yet current pharmacological treatments fail to provide meaningful benefit for approximately half of patients. Converging evidence implicates metabolic dysregulation across psychiatric disorders, highlighting metabolic pathways as novel therapeutic targets. Given their established clinical safety in type 2 diabetes, glucagon-like peptide-1 receptor (GLP-1R) agonists represent promising candidates for repurposing in psychiatric treatment.

Consequently, we sought to examine data from preclinical and experimental medicine studies to establish the translational rationale for repurposing GLP-1R agonists in psychiatric disorders. Using PubMed, Scopus and Web of Science, we conducted a search for peer-reviewed manuscripts exploring the use of GLP-1R agonists to treat depression and/or PTSD/relevant symptoms. Our search yielded 43 studies assessed as of at least medium quality using the Hawker tool, including 28 rodent models and 15 experimental medicine studies.

Evidence across GLP-1R agonists was highly heterogeneous resulting in each drug being assessed separately. Some clinical studies reported improvements in depressive or anxiety-related symptoms, whereas others found minimal or inconsistent effects. Evidence for exenatide was particularly variable, with mood-related outcomes appearing dependent on neurobiological context and concomitant treatment.

No studies directly evaluated GLP-1R agonists for the treatment of PTSD, with data limited to broader anxiety- and stress-related outcomes. Current evidence does not provide consistent support for GLP-1R agonists as treatments for depression or PTSD. However, evidence suggests that therapeutic effects (if any) may be most relevant in individuals with comorbid metabolic dysfunction.

Further research using validated models of trauma-related pathology and targeted clinical studies is required to determine whether GLP-1 receptor agonism represents a viable therapeutic strategy. CSR is jointly supported by a Machin studentship and Q550 studentship from Queens’ College, University of Cambridge. ALM is the Ferreras-Willetts Fellow in Neuroscience at Downing College, University of Cambridge.

For the purpose of open access, the authors have applied a Creative Commons Attribution (CCBY) licence to any Author Accepted Manuscript version arising from this submission. This systematic review was supported by the UK Research and Innovation’s Biological and Biotechnology Research Council under grant number BB/W001195/1. Although no direct financial costs were incurred during the course of this review, the grant provided administrative and research support.