A systematic review in effects of glucagon-like peptide-1 (GLP-1) mono-agonists on functional connectivity: Target engagement and rationale for the development in mental disorders

Hezekiah C T Au; Yang Jing Zheng; Gia Han Le; Sabrina Wong; Lee Phan; Kayla M Teopiz; Angela T H Kwan; Taeho Greg Rhee; Joshua D Rosenblat; Roger Ho; Roger S McIntyre

doi:10.1016/j.jad.2024.11.019

A systematic review in effects of glucagon-like peptide-1 (GLP-1) mono-agonists on functional connectivity: Target engagement and rationale for the development in mental disorders

J Affect Disord. 2025 Feb 1:370:321-327. doi: 10.1016/j.jad.2024.11.019. Epub 2024 Nov 7.

Authors

Hezekiah C T Au¹, Yang Jing Zheng², Gia Han Le³, Sabrina Wong⁴, Lee Phan⁵, Kayla M Teopiz⁶, Angela T H Kwan⁷, Taeho Greg Rhee⁸, Joshua D Rosenblat⁹, Roger Ho¹⁰, Roger S McIntyre¹¹

Affiliations

¹ Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: hezekiah.au@mail.utoronto.ca.
² Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: yangjing.zheng@mail.utoronto.ca.
³ Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada; Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: hanny.le@mail.utoronto.ca.
⁴ Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada; Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address: sabrinal.wong@mail.utoronto.ca.
⁵ Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada. Electronic address: lee.phan@mail.utoronto.ca.
⁶ Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada. Electronic address: kayla.teopiz@mail.utoronto.ca.
⁷ Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada; Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. Electronic address: angela.kwan@mail.utoronto.ca.
⁸ Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA. Electronic address: taeho.rhee@yale.edu.
⁹ Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address: joshua.rosenblat@uhn.ca.
¹⁰ Division of Life Science (LIFS), Faculty of Science, Hong Kong University of Science and Technology (HKUST), Hong Kong; Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: rogercmho@ust.hk.
¹¹ Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address: roger.mcintyre@bcdf.org.

PMID: 39515485
DOI: 10.1016/j.jad.2024.11.019

Abstract

Introduction: The mechanistic role of glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RAs) in modulating brain functional activity has been inadequately examined. Mental disorders are characterized by dysregulated functional connectivity in brain circuits that subserve phenomenology. We conducted a comprehensive synthesis of known effects of GLP-1 and GLP-1RAs on functional connectivity.

Methods: We conducted a systematic review examining studies that investigate changes in functional connectivity mediated by GLP-1 and GLP-1RAs in human adults. Relevant articles were retrieved from OVID (MedLine, Embase, AMED, PsychINFO, JBI EBP Database), PubMed, and Web of Science from database inception to April 26, 2024. Primary or secondary studies (n = 8) investigating the role of GLP-1 and GLP-1RAs on functional connectivity were included for analysis.

Results: GLP-1 and GLP-1RAs modulate functional connectivity within the dorsal default mode network (DMN), visuospatial network, right frontal parietal network, and the salience network. GLP-1 agonism is also associated with decreased functional connectivity within the hypothalamus, lateral orbitofrontal cortex, and amygdala. Contrastingly, some GLP-1RAs (e.g. exenatide) increase functional connectivity in the hypothalamus, nucleus tractus solitarius, and thalamus. Moreover, liraglutide is associated with increased functional connectivity within the hippocampus in healthy individuals suggesting that GLP-1RAs may have differential effects on brain functional connectivity.

Discussion: We observed that GLP-1 and GLP-1 RAs are associated with changes in functional connectivity known to subserve phenomenology of many mental disorders (e.g. anhedonia). Future research should aim to further examine neural circuits and networks affected by GLP-1 receptor activity and how they may affect cognitive and psychopathological domains in psychiatric disorders.

Keywords: Brain functional connectivity; Dulaglutide; Exenatide; Liraglutide; Lixisenatide; Psychiatric disorders; Semaglutide; Tirzepatide.

Publication types

Systematic Review
Review

MeSH terms

Adult
Brain* / drug effects
Brain* / physiopathology
Default Mode Network / diagnostic imaging
Default Mode Network / drug effects
Default Mode Network / physiopathology
Glucagon-Like Peptide 1* / pharmacology
Glucagon-Like Peptide-1 Receptor* / agonists
Humans
Mental Disorders* / drug therapy
Mental Disorders* / physiopathology
Nerve Net / drug effects
Nerve Net / physiopathology

Substances

Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor