Introduction
The mechanism of action of antidepressants is not fully ascertained. It is hypothesized that antidepressant agents alleviate symptoms in depressive disorders by triggering molecular cascades integral to neuroplasticity, neuroprotection, and anti-apoptosis (NNA).Reference Rădulescu, Drăgoi, Trifu and Cristea 1 , Reference Hunsberger, Austin, Henter and Chen 2 The aforementioned molecular and cellular effects collectively modulate synaptic connection and strength as well as resting-state functional connectivity (RSFC) in discrete neural circuits and networks subserving the phenomenology of depressive disorders (eg, default mode network).Reference McIntyre 3 –Reference Wang 6
Glucagon-like peptide-1 (GLP-1 RA) and glucose-dependent insulinotropic polypeptide receptor agonists (GIP RA), herein referred to as incretin receptor agonists (IRAs), mimic naturally occurring GLP-1 and GIP and are highly effective antidiabetic and anti-obesity agents.Reference Drucker 7 In addition to their robust acute and long-term effects on weight, metabolism, and blood pressure, these agents also reduce cardiovascular mortality as well as stroke risk and associated consequences.Reference Drucker 7 –Reference Vergès 9 During the past decade, a replicated and convergent body of preclinical evidence also indicates that IRAs activate molecular effectors critical to NNA.
Herein, we propose that IRAs are promising treatments for mental disorders that engage brain targets critical to NNA known to subserve transdiagnostic phenomenology, notably general cognitive, reward, and motivation systems. We succinctly synthesize extant evidence but do not intend a review of the topic as multiple comprehensive reviews have been previously published.Reference Hölscher 10 –Reference Drucker 19 Instead, we attempt to provide a mechanistic framework for considering IRAs as putative mechanistically informed therapeutics for disparate mental disorders. Articles selected for citation are articles that were determined by authors to be most impactful either as original research or as a synthesis of available research.
GLP-1 and GIP physiology and pharmacology
Glucagon-like peptide-1 is the product of preproglucagon encoded in intestinal L-cells as well as in neurons of the nucleus tractus solitarius (NTS). GLP-1 receptors are G-protein-coupled receptors (GPCRs) and are expressed in many human tissues, including the central nervous system (CNS; eg, hippocampus, hypothalamus, and cortex).Reference Muscogiuri, DeFronzo, Gastaldelli and Holst 20 GLP-1 receptors are expressed on endothelial cells, neurons, astrocytes, and microglia.Reference Fukuda 21 –Reference Wang 23
Neuronal projections from the NTS to the paraventricular nucleus (PVN) of the hypothalamus facilitate reductions in food intake and behavior.Reference López-Ferreras 24 , Reference Liu 25 GLP-1-producing neurons in the NTS also project to mesolimbic nuclei [eg, ventral tegmental area (VTA) and nucleus accumbens (NAcc)] and cortical structures.Reference Muscogiuri, DeFronzo, Gastaldelli and Holst 20 The aforementioned provides the basis for targeting these systems in the treatment and prevention of mental disorders.Reference Cooper 26
GIP is secreted by enteroendocrine K-cells, whose cognate receptor is also a GPCR.Reference Lennox 27 , Reference Campbell 28 Whether GIP is synthesized in the CNS remains uncertain. Mixed evidence suggests that mRNA for GIP may be detected in select brain regions (eg, hippocampus).Reference Adriaenssens, Gribble and Reimann 29 Notwithstanding, GIP receptors are expressed across disparate brain regions (eg, cortex, hippocampus, striatum).Reference Lennox 27 , Reference Nyberg, Jacobsson, Anderson and Eriksson 30 GIP receptor gene knockout results in reduced hippocampal NNA and impairs learning and memory in murine models.Reference Lennox 27 , Reference Fontanella 31
GLP-1 and GIP effects on neuro-genesis, -differentiation, - plasticity (Neuro-GDP) (Figure 1)(Figure 2)
Glucagon-like peptide-1 receptor agonists activate multiple signal transduction pathways relevant to neuro-genesis, -differentiation, -plasticity (Neuro-GDP).Reference Li, Li and Li 32 For example, endogenous GLP-1, GIP, and GLP-1 RAs (eg, liraglutide) increase synthesis of cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) via PI3K-Akt activation.Reference Cheng 33 –Reference Yang 35 Moreover, GLP-1 promotes neuronal progenitor cell differentiation and neurite outgrowth.Reference Perry, Haughey, Mattson, Egan and Greig 36 , Reference Cui, Stein, Fortin and Hayes 37
Figure 1. Distribution of GLP-1 receptors in the human central nervous system. Relevant structures that express GLP-1 receptors are highlighted.
Figure 2. GLP-1 and GIP effects on neuro-genesis, -differentiation, - plasticity (GDP), neuroprotection and anti-apoptosis.
In rodent models and humans, GLP-1-mediated secretion of BDNF increases synaptic density in the hippocampus.Reference Belsham 38 –Reference Diz-Chaves, Herrera-Pérez, González-Matías and Mallo 41 It is hypothesized that trophic and plasticity effectors triggered by GLP-1 RAs mediate effects on cognition and/or motor function reported in Alzheimer’s and Parkinson’s Disease rodent models.Reference Sharma and Sharma 42 –Reference Liu 48
Preclinical evidence indicates that liraglutide prevents reductions in phosphorylation levels of mTORC1 and BDNF expression in rat hippocampal structures exposed to neurotoxic levels of dexamethasone.Reference Park 49 The effect of liraglutide on BDNF expression and hippocampal dendrite length and spine density is blocked by rapamycin or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX).Reference Park 49
Reduced long-term potentiation (LTP), increased long-term depression (LTD), and alterations in RSFC within and between brain circuits and networks are replicated findings in persons with depressive disorders.Reference Reyes-Lizaola, Luna-Zarate, Tendilla-Beltrán, Morales-Medina and Flores 50 –Reference Coveleskie 52 Glucagon-like peptide-1 receptor agonists rapidly increase excitatory postsynaptic currents and LTP.Reference McClean, Gault, Harriott and Hölscher 53 Glutamatergic availability and function are integral to LTP and synaptic strength.Reference Lüscher and Malenka 54
Glucagon-like peptide-1 receptor agonism modulates glutamatergic signaling by increasing AMPA trafficking, mTOR activation, and the transcription of synaptic proteins.Reference Hölscher 55 –Reference Zanos 57 In addition to the direct effects of GLP-1 RAs on molecular systems relevant to GDP, it is also observed that liraglutide increases intrinsic connectivity in bilateral hippocampal, medial-frontal, and lateral occipital regions, which inversely correlated with measures of insulin resistance in persons at genetic risk for Alzheimer’s Disease.Reference Watson 58
Similar to the aforementioned effects of GLP-1 RAs on NNA, it is separately reported that GIP independently activates NNA systems. For example, GIP receptor knockout reduces neurogenesis and neurodifferentiation in the dentate gyrus of the hippocampus.Reference Nyberg 59 In addition, GIP increases hippocampal synaptic number and plasticity effects in murine models.Reference Faivre and Hölscher 60 , Reference Faivre, Hamilton and Hölscher 61
GLP-1 and GIP neuroprotective effects: anti-inflammatory and antioxidant
It is further reported that GLP-1 RAs exert neuroprotective effects via modulating immune-inflammatory processes and redox balance.Reference Athauda 43 , Reference Baggio and Drucker 62 –Reference Diz-Chaves, Mastoor, Spuch, González-Matías and Mallo 66 Pro-inflammatory processes and redox imbalance are implicated in the pathogenesis and progression of depressive disorders.Reference Bhatt, Nagappa and Patil 67 Glucagon-like peptide-1 receptors are expressed on myeloid cells including monocytes, macrophages and glia (eg, microglia) where they modulate immune-inflammatory and redox balance systems.Reference Timper 68 , Reference Diz-Chaves, Mastoor, Spuch, González-Matías and Mallo 69 It is known that GLP-1 RAs decrease circulating C-reactive peptide (CRP), matrix metalloproteinase-9, monocyte chemoattractant protein-1, toll-like receptor 4 (TLR4), JNK-1 expression, nuclear factor-B as well as pro-inflammatory cytokines (eg, interleukin-6; IL-6) in human subjects.Reference Chaudhuri 70
Glucagon-like peptide-1 is also synthesized and released in response to exposure to lipopolysaccharide.Reference Wong 71 Glucagon-like peptide-1 receptor agonists also affect glial homeostasis and reactivity insofar as they induce less transcription of pro-inflammatory markers.Reference Paolicelli 72 , Reference Qian 73 Finally, it has been observed that GLP-1 RAs decrease blood-brain barrier (BBB) permeability under toxic conditions.Reference Diz-Chaves, Mastoor, Spuch, González-Matías and Mallo 69 , Reference Shan 74 , Reference Gault and Hölscher 75
The brain is especially susceptible to redox imbalance (ie, reactive oxygen species; ROS) due to its high oxygen utilization, lipid content, and relatively low endogenous antioxidant capacity.Reference Bhatt, Nagappa and Patil 67 Oxidative stress compromises neuronal and glial integrity, viability, and function and is hypothesized to be integral to the pathoetiology of depressive and other mental disorders.Reference Liu 76 , Reference Black, Bot, Scheffer, Cuijpers and BWJH 77
Glucagon-like peptide-1 receptor agonists exert direct and indirect regulatory effects on redox imbalance.Reference Wang, Liu, Xu, Hou and Hong 78 The antioxidant effects of GLP-1 RAs are observed whether oxidative stress is activated by glutamate or arachidonic acid.Reference Wang, Liu, Xu, Hou and Hong 78 A replicated finding is that the antioxidant effects of GLP-1 RAs are mediated via their effect on ERK5/CREB signaling.Reference Wang, Liu, Xu, Hou and Hong 78
Similar to GLP-1, disparate local and systemic anti-inflammatory effects are reported following GIP receptor activation. For example, GIP receptor activation results in decreased mRNA expression of macrophage chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM) as well as decreased circulating levels of interleukin IL-1β and TNFα.Reference He 79 GIP knockout models report decrease in circulating monocytes and neutrophils, suggesting direct effects on hematopoietic lines.Reference Morrow, Morissette and Mulvihill 80 Neuroprotective effects of GIP are hypothesized to be mediated via their anti-inflammatory effects.Reference Ji, Xue, Li, Li and Hölscher 81 The effect of GIP on redox balance is also replicated with observations of increases in glutathione peroxidase (GPX) and superoxide dismutase (SOD1) levels as well as decreased reactive oxygen species and release of nitric oxide.Reference Spielman, Gibson and Klegeris 82
Beneficial effects of IRAs against post-stroke excitotoxicity as well as prevention involve many of the effectors previously covered.Reference Vergès 9 IRAs affect glutamatergic signaling via ionotropic receptor modulation. For example, it is separately reported that N-Methyl-D-Aspartate (NMDA) receptor antagonism increases GLP-1 synthesis and release improving glucose-insulin homeostasis in persons treated with NMDA antagonists (eg, dextromethorphan).Reference Liu 83 –Reference Cyranka 85 Glucagon-like peptide-1 receptor agonists also modulate RSFC within and between circuits relevant to salience and cognitive control in persons with obesity and/or type 2 diabetes mellitus (T2DM).Reference Farr 86
Anti-apoptotic effects of GLP-1 and GIP
The pro-apoptotic BAX proteins are regulated by caspases and countered by the increased availability of SOD1, catalase (CAT), and GPX.Reference Yaribeygi, Maleki, Sathyapalan, Jamialahmadi and Sahebkar 87 Indirectly, GLP-1 receptor agonism modulates redox imbalance by reducing advanced glycation endproducts (AGE), malondialdehyde (MDA), and thiobarbituric acid reactive substances (TBARS).Reference Yaribeygi, Maleki, Sathyapalan, Jamialahmadi and Sahebkar 87 , Reference Lambadiari 88. Glucagon-like peptide-1 receptor agonists, as well as dual GLP-1 agonists, reduce caspase-3 and BAX activity while simultaneously increasing Bcl-2 activity.Reference Fontanella 31 , Reference Chen 89
Clinical corollaries
Glucagon-like peptide-1 receptor agonists (eg, exenatide, liraglutide, semaglutide) and GLP-1/GIP co-agonists (eg, tirzepatide) are detectable in the brain and have differential CNS penetrance when using murine models.Reference Salameh, Rhea, Talbot and Banks 90 , Reference Rhea 91 It remains uncertain the extent to which IRAs meaningfully penetrate (ie, target engagement) the BBB in human subjects and whether differential pharmacokinetics exist among the IRAs with respect to brain concentration.Reference Christensen 92 Preliminary evidence also suggests the benefit of IRAs in the treatment and/or prevention of alcohol-use, major neurocognitive (eg, Alzheimer’s Disease), Parkinson’s Disease, traumatic brain injury, and nicotine use.Reference McIntyre 12 , Reference Cooper 26 , Reference Svenningsson 93 –Reference Tang 111 A critical issue bridging preclinical study results to critical translation is posology and route of administration. Doses implemented in many of the preclinical models approximate comparable human doses but are not identical. Moreover, the route of administration in animals is similar to (eg, parenteral) human administration of IRAs, although it is recognized that there is a growing interest in the oral administration of IRAs in humans. In addition, it is unknown whether the dosing of IRAs that are effective in the prevention and treatment of mental disorders is similar to anti-diabetic and anti-obesity dosing.
An emerging literature has also examined antidepressant efficacy associated with GLP-1 RAs. Chen et al.Reference Chen, Zhao, Wang, Guo and Pan 112 identified 5 randomized controlled trials in diabetic and/or Parkinson’s Disease patients (n = 2071) prescribed exenatide or liraglutide and reported a small but significant reduction in associated depressive symptoms in secondary analyses as compared to placebo or other antidiabetics such as insulin, sulfonylureas or pioglitazone. The presence of subthreshold depressive symptoms in the included samples may account for the small observed effect sizes (SMD = −0.12, 95% CI = −0.21 to −0.03). A separate meta-analysis, focusing on GLP-1 RAs specifically to treat major depression (6 randomized trials, n = 399), reported a small effect size that just fell short of statistical significance (SMD = 0.25, 95% CI = −0.1 to 0.60).Reference Zhang 113 Exploratory subgroup analyses in the latter study suggested ethno-geographic variability as a moderator of GLP-1 RA antidepressant response.Reference Chen, Zhao, Wang, Guo and Pan 112 , Reference Zhang 113
Concluding remarks
We propose that IRAs, via their effect on, NNA hold tremendous promise as therapeutics across multiple mental disorders. In addition, extant evidence provides a rationale for potential preventative effects, especially as it relates to cognitive dysfunction and possibly depressive symptoms with these agents. There is a need for target engagement studies in human clinical populations with these agents to better characterize the NNA effects on circuit and network connectivity. There is also the need for large, adequate, well-controlled phase II and phase III studies with these agents in the disorders that are lead candidates (eg, Parkinson’s Disease, major neurocognitive, alcohol use, and depressive disorders). In addition, preliminary evidence suggests allelic variants for gene barriers so the GLP-1 receptor gene may be associated with risk for select mental disorders (eg, alcohol use disorders, Alzheimer’s Disease).Reference Farokhnia 114 , Reference Tang 115
Both the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have issued public statements that no causal evidence exists linking IRAs to suicidality.Reference McIntyre 116 –Reference Wang 120 Moreover, replicated results from cohort observational studies also suggest that GLP-1RAs are associated with no increase in suicidality and in some reports a decrease reporting in suicidality and/or conditions associated with suicide (eg, depressive disorders).Reference Wang 110 , Reference Wadden 121 –Reference Kerem and Stokar 128 In addition, there is a need for adequate well-controlled studies targeting psychotropic drug-related weight gain (PDWG) and metabolically associated comorbidity (eg, cardiovascular disease, metabolic dysfunction associated with steatotic liver disease; MASLD).Reference McIntyre, Kwan, Rosenblat, Teopiz and Mansur 129 , Reference Jawad 130 The greater effect size of GLP-1/GIP co-agonists when compared to GLP-1 RAs on body weight reduction and associated metabolic morbidity, along with the direct NNA effects documented with GIP, introduce the rationale that incretin co-agonists may have additional but different mechanistic effects on systems subserving psychopathological domains.Reference Frías 131
Author contribution
Writing – review & editing: J.F.G., R.B.M., S.M.S., G.H.L., K.T., N.R., S.W., R.S.M.; Conceptualization: R.S.M.; Data curation: R.S.M.; Investigation: R.S.M.; Methodology: R.S.M.; Project administration: R.S.M.; Supervision: R.S.M.; Writing – original draft: R.S.M.
Financial support
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.
Rodrigo B. Mansur has received research grant support from the Canadian Institute of Health Research; Physicians’ Services Incorporated Foundation; the Baszucki Brain Research Fund; and the Academic Scholar Awards, Department of Psychiatry, University of Toronto.
Kayla M. Teopiz has received fees from Braxia Scientific Corp.
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 and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion and COMPASS.
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