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Glucagon-like Peptide-1 receptor agonists as emerging therapeutics in bipolar disorder: a narrative review of preclinical and clinical evidence

Molecular Psychiatry (2025)Cite this article

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Abstract

Bipolar disorder (BD) is a chronic and disabling psychiatric illness characterized by complex pathophysiological mechanisms. Traditional treatments often fail to address these multidimensional processes, highlighting the need for novel therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for metabolic disorders, have emerged as promising candidates for a range of neuropsychiatric conditions due to their broad neurobiological effects. This narrative review synthesizes preclinical, clinical, and real-world evidence evaluating the therapeutic potential of GLP-1RAs in BD. These agents modulate neurotransmission, reduce neuroinflammation and oxidative stress, enhance mitochondrial and neurotrophic function, and improve insulin sensitivity and hypothalamic-pituitary-adrenal (HPA) axis regulation. These mechanisms are implicated in the neurobiology of BD, and preliminary findings suggest benefits across core psychopathological domains and common comorbidities, including depression, anxiety, mania, cognitive dysfunction, weight gain, and substance use disorders. While human data—particularly in BD populations—remain limited, evidence points to potential adjunctive benefits, especially in individuals with metabolic or cognitive vulnerabilities. Given their pleiotropic actions and established safety profile, GLP-1RAs represent compelling candidates for drug repurposing in BD. Well-powered, controlled trials are needed to confirm efficacy and safety, identify optimal subgroups, and evaluate long-term outcomes.

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Acknowledgements

Cristian-Daniel Llach received the support of a fellowship from “la Caixa” Foundation (ID 100010434 - fellowship code LCF/BQ/EU22/11930062).

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Authors and Affiliations

  1. Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada

    Cristian-Daniel Llach, Sebastian Badulescu, Aniqa Tabassum, Hiya Shah, Hartej Gill, Gia Han Le, Joshua D. Rosenblat & Rodrigo B. Mansur

  2. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Cristian-Daniel Llach, Gia Han Le, Roger S. McIntyre, Joshua D. Rosenblat & Rodrigo B. Mansur

  3. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Sebastian Badulescu, Aniqa Tabassum, Hartej Gill, Joshua D. Rosenblat & Rodrigo B. Mansur

  4. Brain and Cognition Discovery Foundation, Toronto, ON, Canada

    Sebastian Badulescu

  5. Bipolar and Depressive Disorders Unit, Hospital Clínic de Barcelona, Barcelona, Spain

    Eduard Vieta

  6. Institute of Neurosciences (UBNeuro), Barcelona, Spain

    Eduard Vieta

  7. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

    Eduard Vieta

  8. Biomedical Research Networking Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III (ISCIII), University of Barcelona, Barcelona, Spain

    Eduard Vieta

  9. Department of Medicine, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

    Eduard Vieta

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  1. Cristian-Daniel Llach
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  2. Sebastian Badulescu
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Contributions

CDLL: Writing – review & editing, Writing – original draft, Methodology, Investigation, Conceptualization. SB: Writing – review & editing. AT: Writing – review & editing. HS: Writing – review & editing. HG: Writing – review & editing. GHL: Writing – review & editing. EV: Writing – review & editing. RSM: Writing – review & editing. JDR: Writing – review & editing, Supervision. RBM: Writing – review & editing, Supervision.

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Correspondence to Cristian-Daniel Llach.

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Competing interests

Cristian-Daniel Llach received financial support from the ‘La Caixa’ Foundation, which provided salary support during the fellowship through its fellowship programs. However, the foundation was not involved in any stage of this manuscript, including its design, writing, revision, or submission. There are no conflicts of interest between the author’s research and the ‘La Caixa’ Foundation. C.L. has also received CME-related honoraria or consulting fees from CASEN Recordati, Organon, Lundbeck, and the Academy for Continuing Medical Education (Akademijazakme), with no financial or other conflicts of interest relevant to the subject of this article. Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, AbbVie, Adamed, Alcediag, Angelini, Biogen, Beckley-Psytech, Biohaven, Boehringer-Ingelheim, Casen-Recordati, Celon Pharma, Clariane, Compass, Dainippon Sumitomo Pharma, Esteve, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Intra-Cellular therapies, Idorsia, Johnson & Johnson, Lundbeck, Luye Pharma, Medincell, Merck, Mitsubishi Tanabe Pharma, Newraxpharm, Newron, Novartis, Organon, Orion Corporation, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, Teva, and Viatris, outside the submitted work. Dr. Roger S. McIntyre has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Neurawell, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie and Atai Life Sciences. Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund, Inagene and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Abbvie, Braxia Health (Canadian Rapid Treatment Centre of Excellence), Braxia Scientific, Janssen, Allergan, Lundbeck, Sunovion and COMPASS.

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Llach, CD., Badulescu, S., Tabassum, A. et al. Glucagon-like Peptide-1 receptor agonists as emerging therapeutics in bipolar disorder: a narrative review of preclinical and clinical evidence. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03261-0

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