Recently, there has been a renewed focus on elucidating the intricate interplay between metabolic disorders and mental health, providing a more integrated framework for understanding systemic physiological regulation. Liraglutide, originally developed as glucagon-like peptide-1 (GLP-1) receptor agonist, was designed to address dysregulation in metabolic homeostasis [1, 2]. GLP-1, an endogenous incretin hormone, is secreted from enteroendocrine L cells, predominantly located in the distal part of the ileum and proximal colon, in response to postprandial glucose and carbohydrate intake, while present at lower levels during fasting. GLP-1 receptors, classified as members of the G-protein-coupled receptor (GPCR) superfamily, are primarily expressed in the pancreas, central nervous system, and gastrointestinal tract, with more limited expression in the heart, kidneys, vasculature, and peripheral nervous system [3]. Upon GLP-1 exerts its effects on pancreatic β-cells, inducing glucose-dependent insulin secretion via elevation of intracellular cyclic adenosine monophosphate (cAMP) concentrations [4]. Additionally, it promotes the survival and proliferation of pancreatic β-cells [5, 6]. GLP-1 also inhibits glucagon release from pancreatic α-cells, leading to reduced hepatic glucose output [7].

Liraglutide (also known commercially as Saxenda®, Victoza®, and Xultophy®) has transcended its original purpose as a GLP-1 receptor analog, initially developed for the treatment of type 2 diabetes mellitus and the prevention of diabetes-related cardiovascular complications [8,9,10]. Recent investigations have proposed a mechanistic linkage between GLP-1 signaling and mood regulation, thereby suggesting a potential connection between liraglutide and the pathophysiology of depressive symptoms. This positions liraglutide as a promising candidate in the emerging interface of metabolic and psychiatric medicine [11]. As researchers and clinicians continue to investigate novel therapeutic avenues for addressing mood disorders, liraglutide has emerged as a therapeutically relevant compound, with observed benefits extending beyond glycemic regulation into domains of neuropsychological health [12, 13].

This review aimed to elucidate the intricate effects of liraglutide on depressive symptoms by exploring its biological foundations and clinical applications. When administered, glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists reach the cerebrospinal fluid (CSF) and brain in the central nervous system, as evidenced in rodent models [14]. Increased GLP-1 concentrations in the brain have been postulated to affect hippocampal function [15]. The maintenance of glucose-insulin metabolic homeostasis plays a pivotal role in the gut-brain axis, given that glucose serves as the primary energy source for the brain [16]. Key incretins such as GLP-1 and GIP contribute to appetite regulation by diminishing hunger and enhancing satiety [16]. Additionally, they play a role in regulating glucose homeostasis by reducing blood glucose levels and modulating insulin release [17]. Figure 1 summarizes the role of GLP-1 in neurotransmission.

Liraglutide exerts its influence through multifaceted mechanisms, including neurotransmission modulation, neuronal survival enhancement, inflammation suppression, neurogenesis improvement, insulin sensitivity enhancement, energy consumption boost, glucose metabolism enhancement, insulin secretion promotion, and body weight reduction. The pivotal role of GLP-1, released from intestinal L-cells and originating from neurons in the nucleus tractus solitarius, serves as a linchpin in mediating the diverse effects of liraglutide

Liraglutide, which functions as a GLP-1 receptor agonist, exhibits considerable promise in alleviating depressive symptoms. Numerous preclinical and mechanistic studies have suggested that liraglutide may improve cognitive function and alleviate mood-related pathological changes. However, direct clinical evidence in human populations remains limited, and current insights primarily reflect theoretical and preclinical findings [18]. Behavioral studies in mouse models have further illuminated the impact of liraglutide on reducing depressive- and anxiety-like behaviors while enhancing cognition [19]. A systematic review and meta-analysis have suggested that GLP-1 receptor agonists, including liraglutide, may serve as potential treatments for depressive symptoms in humans [19]. While affirming the potential of liraglutide in the treatment of depression, these findings underscore the need for additional research and clinical trials to establish its efficacy and safety in human patients [18].

Activation of hippocampal GLP-1 receptors via mitogen-activated protein kinases (MAPKs) enhances learning and memory [20]. GLP-1 also plays a role in enhancing hippocampal synaptic plasticity and synapse formation [20]. These findings provide evidence of GLP-1’s potential to generate new neurons, which can enhance cognitive function and reduce depressive behavior. Further research is required to understand the precise mechanisms by which GLP-1 influences the generation of new neuronal cells [21]. The ability to improve learning and memory, reduce inflammation, decrease apoptosis, modulate reward behavior, and reduce food intake are some of the functions that have been proven for GLP-1. GLP-1 and its analogs have been shown to offer future promise in the treatment of many diseases associated with cognitive impairment, including Alzheimer’s disease [22, 23]. The availability of liraglutide therapy for the treatment of depression is a novel advancement in a vast area of psychiatric studies. Traditionally accepted for the treatment of type 2 diabetes, liraglutide is emerging as a new beacon for mental health therapeutics [24].

Semaglutide, another GLP-1 receptor agonist with an extended half-life and similar central mechanisms, also crosses the blood-brain barrier and exhibits neuroprotective properties. Preliminary data suggest that semaglutide may exert antidepressant effects via modulation of neuroinflammation and hippocampal plasticity [25]. Although the current review centers on liraglutide due to its broader psychiatric characterization in preclinical and clinical settings, future comparative analyses that incorporate semaglutide are essential to delineate the nuanced roles of long-acting GLP-1 analogues in mood regulation.

Major depressive disorder (MDD) is a common mood disorder characterized by chronic painful symptoms of ruminative thoughts, impaired cognition, anhedonia, and deficiencies in attentional control [26, 27]. Depression is a complicated, multifaceted ailment that arises from a combination of genetic vulnerability and exposure to environmental stressors [28]. In addition to the personal toll, MDD significantly impacts family dynamics and contributes to substantial societal and healthcare costs [26, 27]. Beyond individual suffering, depression significantly diminishes the quality of life of patients and their families, imposing considerable economic and mental health burdens [27]. Research indicates that over 50% of those grappling with depression face chronic and recurrent challenges, with symptoms escalating to the risk of suicide without timely intervention [18]. This underscores the urgent need for timely diagnosis and intervention, reinforcing the importance of developing more effective therapeutic options and preventive strategies.

Depression intricately intertwines with various neurobiological factors, including neuroinflammation, neurotransmitter imbalances,, increased permeability of the blood-brain barrier, deficits in neurogenesis, and synaptic dysfunction [28]. Studies reveal that individuals with depression display impaired neurogenesis, delayed neural growth, and reduced synaptic plasticity [29]. Brain regions such as the prefrontal cortex (PFC), amygdala, and hippocampus critical for emotional regulation, cognitive processing, and stress response exhibit functional disruptions in depressive states. Diminished activity in the PFC and hippocampus, alongside increased activation of the amygdala, reflects core neuropathological changes observed in major depressive disorder [30]. Understanding these neurobiological foundations is essential for guiding the development of more targeted therapeutic strategies and early preventive interventions [12].

What sets liraglutide apart is its novel approach to address depressive symptoms. Operating as a GLP-1 receptor agonist, it transcends conventional neurotransmitter modulation, engaging in the domains of neuroplasticity and synaptic function [31]. Evidence suggests that liraglutide regulates mood through distinct pathways not shared by traditional antidepressants [32]. The fact that hippocampal neural plasticity is induced by liraglutide treatment in a manner that correlates with the relief of depressive and anxiety-like behaviors [19] suggests its potential to exert antidepressant effects and enhance cognitive function. Moreover, short- and long-acting GLP-1 receptor agonists, including liraglutide, effectively pass through the blood-brain barrier,, indicating their capacity to act directly within the central nervous system [33].

The neurobiological pathways through which liraglutide acts in depression are yet to be identified, but the results imply that it modulates several pathways [27, 34]. The mechanisms by which liraglutide exerts its antidepressant effects demand rigorous clarification, particularly through well-designed clinical studies [35, 36]. Liraglutide’s potential spans from molecular targets to real-world clinical implications, challenging the traditional separation between psychiatric and metabolic medicine. Its ability to improve both glycemic control and depressive symptoms reflects a dual therapeutic potential, advancing an integrated approach for comorbid conditions [36]. The emerging evidence base surrounding liraglutide’s neuropsychiatric mechanisms underscores a compelling opportunity for future investigation, inviting researchers to refine existing paradigms of psychiatric care [9, 35, 37]. Therefore, in a field characterized by innovation, liraglutide represents the face change of scientific inquiry and an opening into the future when metabolic agents might be key players in defining the face of mental health therapeutics [38].

Liraglutide, classified as a lipopeptide, serves as a human GLP-1 analog [8, 10, 21]. Its characteristic structural changes as shown in Fig. 2, include the substitution of lysine at position 27 with arginine and the linkage of a hexadecanoyl group to the remaining lysine through a glutamic acid spacer, determine its activity [20]. Liraglutide, in its major use, is used in combination with diet and exercise to help control glycemia in adults with type 2 diabetes mellitus [3, 9, 39]. Beyond its established metabolic applications, emerging evidence suggests that liraglutide may confer neuroprotective and mood-stabilizing effects. Understanding its pharmacological foundations, particularly the central mechanisms linked to its neuropsychiatric benefits, is increasingly recognized as essential [19].

A) chemical structure of liraglutide (HAEGTFTSDVSSYLEGQAAKEEFIAWLVRGRG). B) schematic peptide illustration of liraglutide structure showing in pink the alpha-helix orientation. Image was generated by PyMol

The abundantly expressed GLP-1 receptor in the brain assumes a crucial role in modulating neurotransmission and synaptic plasticity [16, 29, 37]. Recent investigations have elucidated the impact of liraglutide on neuroplasticity, establishing a mechanistic basis for its putative antidepressant properties [1, 10, 18, 21, 40, 41]. Clinical trials not only reveal enhancements in glycemic control, but also clinically meaningful reductions in depressive symptoms, thereby prompting a re-evaluation of liraglutide’s therapeutic scope. This dual effect suggests liraglutide may represent a valuable adjunctive option in patients experiencing metabolic-psychiatric comorbidity [36, 42].

A comprehensive study on liraglutide exhibited significant analgesic effects in an extended murine model of osteoarthritis induced by sodium monoiodoacetate [43, 44]. This was also emphasized by the progressive recovery from mechanical allodynia over time when compared to the vehicle-treated group. Such findings, in which improvements in pain-related behavior were demonstrated in a sodium monoiodoacetate osteoarthritis mouse model, are due to the anti-inflammatory activity mediated by GLP-1 receptor activation, as observed after intra-articular administration of liraglutide [24, 45].

Liraglutide treatment also significantly suppressed the secretion of inflammatory mediators such as IL-6, PGE2, and nitric oxide [46]. A dose-dependent reduction in the expression of inflammatory genes was also observed in chondrocytes and macrophages [43]. It has also been shown that liraglutide can reverse the inflammatory in vitro polarized macrophage phenotype from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, indicating its anti-inflammatory potential [47]. In addition to its anti-inflammatory effects, liraglutide displays potent anti-catabolic activity by significantly diminishing the activities of metalloproteinases and aggrecanases, pivotal enzymes implicated in cartilage breakdown [39, 48]. Taken together, these findings suggest that liraglutide exhibits therapeutic potential in treating osteoarthritis, not only by mitigating pain, but also by reducing inflammation and safeguarding against cartilage degradation.

The bidirectional interplay between metabolic disorders and mental health is a multifaceted line of scientific research that includes complex pathways and shared molecular cascades [49]. This interplay has revealed a multifactorial association between insulin resistance, inflammation, and neurotransmitter dysregulation as the focus of research. Recent comprehensive reviews, such as the work by Jones and Brown, offer mechanistic crosstalk between metabolic disturbances and depressive symptomatology; such reviews are important in providing foundational context for understanding the potential implications of liraglutide [50].

However, in the complex terrain of the potential of liraglutide to alleviate depressive symptoms, substantial progress has been made, yet critical questions remain unanswered. Neuroimaging techniques, specifically fMRI, can reveal the neural correlates underlying the antidepressant effects of liraglutide [47]. Knowledge of the sources of inter-individual variance in treatment responses and possible biomarkers is for advancing clinical translation. However, the view of liraglutide as a novel antidepressant is not entirely free of scientific controversy and debate [51].

Other researchers feel that the available evidence is still limited and urge cautious interpretation, emphasizing the need for large-scale well-controlled clinical trials. Such questions about the overlap of metabolic and antidepressant effects give rise to the potential problem of whether liraglutide’s mood-related effects are direct or secondary to metabolic improvements. However, answers to these concerns are imperative for defining the exact clinical niche and the population of patients most likely to benifit.

However, the association between liraglutide use and depression remains unclear. Clarifying this relationship is essential for advancing evidence-based psychiatric applications of metabolic agents [38, 52]. Rather than being purely theoretical, this question is increasingly informed by emerging molecular evidence suggesting that liraglutide’s neurobiological targets may overlap with pathways implicated in mood regulation. Recent studies have provided a basis for further investigation as they have synthesized the results of many clinical trials. Despite encouraging leads, this field remains scientifically immature, complicated by conflicting data and methodological variability [53,54,55,56]. These studies emphasize a clear gap in understanding how liraglutide—originally approved for metabolic indications such as obesity might influence neuropsychiatric outcomes, particularly depression. Preliminary insights suggest a potential inverse association between anxiety symptoms and treatment adherence, though the underlying mechanisms remain undefined. Further mechanistic and clinical research is required to determine whether liraglutide exerts a direct therapeutic effect on depressive symptoms.

Liraglutide targets metabolic aberrations and may also alleviate depressive symptoms. However, like other pharmacological strategies, there are certain limitations. Its benefits, such as a relatively good side-effect profile and reported absence of weight gain, in particular, have been documented [