Article website: https://link.springer.com/article/10.1007/s40501-024-00331-y

Citation: Tempia Valenta, S., Nicastri, A., Perazza, F. et al. The Impact of GLP-1 Receptor Agonists (GLP-1 RAs) on Mental Health: A Systematic Review. Curr Treat Options Psych 11, 310–357 (2024). https://doi.org/10.1007/s40501-024-00331-y

Article Overview and Purpose

The article is a systematic review published in Current Treatment Options in Psychiatry. GLP-1 RAs are increasingly used for managing metabolic disorders like type 2 diabetes mellitus (T2DM) and obesity. Beyond metabolic benefits, GLP-1 RAs show neuroprotective and psychotropic effects. The review aims to synthesize evidence on the effects of GLP-1 RAs on mental health outcomes, including both potential benefits and risks.

What is GLP-1?

  • Glucagon-like peptide-1 (GLP-1) is a peptide hormoneprimarily synthesized in the intestinal L-cells of the gut and secreted into the blood. It plays a critical role in the regulation of glucose metabolism in the gut-brain axis. GLP-1 is also secreted by a small population of neurons in the hindbrain and by microglia.
  • In the central nervous system (CNS), GLP-1 can diffuse into the cerebrospinal fluid (CSF) and the brain. In the brain, GLP-1 can control thesecretion of various neurotransmitters, the progression of neuroinflammation, and increase insulin sensitivity. It is also thought to play an important role in glucose metabolism and neuronal function, including synaptic plasticity.

Potential Benefits of GLP-1 RAs on Mental Health

  • GLP-1 RAs exhibit potential beneficial effects on depressive symptoms. They may improve cognitive function. GLP-1 RAs are associated with a reduced risk of suicidal ideation in animal and human models. These potential benefits are suggested to occur through antioxidative, anti-inflammatory mechanisms, and modulation of neurotransmitter pathways.
  • GLP-1 RAs were effective in reducing alcohol and substance use. They were also effective in reducing binge eating behaviors. GLP-1 RAs hold promise for addressing psychiatric conditions such as depression, anxiety, alcohol and substance use disorders.

Potential Psychiatric Adverse Effects of GLP-1 RAs

  • Adverse psychiatric effects associated with GLP-1 RAs, including depression, anxiety, and suicidal ideation, are noted in pharmacovigilance analyses. There are variations in adverse effects among different GLP-1 RAs. Despite potential benefits, the risk of psychiatric adverse effects requires cautious administration.

Mechanisms and Specific Conditions Explored

GLP-1 may be both anxiogenic and antidepressant, with divergent effects from acute versus chronic administration. Some of the findings extracted from the article:

Semaglutide:

  • reduced alcohol drinking and modulated central GABA neurotransmission.
  • was successful in treating binge eating disorder and reduced alcohol use disorder symptoms in a case series.
  • had short-term effects on emotional eating and other abnormal eating patterns in subjects with obesity.
  • reduced alcohol consumption in individuals with obesity.

Liraglutide:

  • improved ouabain-induced mania and depressive state via the GSK-3β pathway in rats.
  • showed an antipsychotic-like effect in a mouse model for psychosis.
  • attenuated nicotine self-administration and seeking in rats.
  • reduced alcohol consumption, anxiety, and memory impairment in alcohol-dependent mice.
  • promoted improvements in objective measures of cognitive dysfunction in individuals with mood disorders in a pilot study.
  • showed effects on depressive behavior and cognition in a mouse depression model.
  • reversed atypical antipsychotic-associated behavioral depression and metabolic abnormalities in rats.
  • reduced fentanyl seeking in rats.
  • attenuated depressive- and anxiety-like behavior in a corticosterone-induced depression model via hippocampal neural plasticity.

 

Dulaglutide:

  • reduced binge episodes in type 2 diabetic patients with binge eating disorder.
  • impeded depressive-like behavior in a chronic social defeat stress model in mice.
  • reversed depression-like behavior in mice exposed to chronic mild stress.
  • was studied for promoting abstinence during smoking cessation and effects on alcohol consumption during smoking cessation.

 

Exenatide:

  • has shown sex-dependent effects on alcohol reinforcement.
  • attenuated rewarding properties of psychostimulants, nicotine-induced behaviors, and alcohol-mediated behaviors in rodents.
  • reduced cocaine self-administration in mice and relapse-like drinking in mice.
  • A case report noted exenatide worsening depression and causing suicidal ideation relapse.

GLP-1 RAs:

  • GLP-1 RAs prevented tolerance to ethanol’s anti-anxiety effect and withdrawal-induced anxiety in rats. GLP-1 and its analogue, exendin-4, decreased alcohol intake and reward in rodents.
  • Genetic association studies and a mouse model suggested the GLP-1 receptor as a potential treatment target in alcohol use disorder. A nationwide cohort study found a decreased risk of anxiety in diabetic patients receiving GLP-1 RAs.

Conclusion

GLP-1 RAs show promise for treating psychiatric conditions like depression, anxiety, and substance use disorders. However, their administration requires caution due to the risk of psychiatric adverse effects.