Treatment-resistant depression (TRD) poses a significant challenge within the field of mental health (McIntyre et al., 2023). As a particularly resistant subset of major depressive disorder (MDD), TRD is defined by the lack of response to two or more adequate trials of antidepressant medications (Zhdanava et al., 2021). It is estimated that up to 30 % of individuals with depression may experience TRD, making it a major global concern from both clinical and socioeconomic perspectives. TRD contributes to reduced productivity, increased healthcare costs, and diminished quality of life for both patients and their families (Wajs et al., 2020). Unlike typical depressive episodes, which are often managed effectively with first-line treatments, TRD is characterized by symptoms that persist despite various therapeutic interventions (Voineskos et al., 2020). The failure of standard treatments significantly exacerbates the overall burden of the disorder, creating a vicious cycle of poor mental health and increased demand for healthcare services (Benson et al., 2020). High rates of comorbid conditions such as anxiety disorders, substance use disorders, and chronic physical illnesses further complicate TRD management. A comprehensive understanding of the biological and environmental contributors to TRD is therefore essential for the development of more effective therapeutic strategies (Patrick et al., 2024).

Despite the availability of pharmacological and non-pharmacological treatments, many individuals with TRD continue to show limited or no improvement compared to long-term remitters (Boylan et al., 2020). This can be attributed to several treatment limitations, including delayed onset of therapeutic action, partial remission, and intolerable side effects (Kverno and Mangano, 2021). Traditional antidepressants primarily target the monoaminergic systems serotonin, norepinephrine, and dopamine (D. Rosenblat et al., 2015). Although these are effective for some, the complex and heterogeneous nature of depressive disorders renders them insufficient for many patients (Amasi-Hartoonian et al., 2022).

Numerous studies and meta-analyses published over the past decade suggest that depression is the result of a multifactorial interplay between genetic, neurochemical, and environmental factors (Rădulescu et al., 2021). In TRD specifically, dysregulation of the stress response, neuroinflammation, and impaired neuroplasticity play critical roles. Additionally, adverse effects of current medications such as weight gain, sexual dysfunction, and emotional blunting can further diminish patients' quality of life and highlight the urgent need for safer and more targeted treatment options (Pitsillou et al., 2020) (Borbély et al., 2022). Non-pharmacological treatments such as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) have shown promise in treating TRD. However, their effectiveness is not universal, and they are often limited by delayed onset, suboptimal response rates, adverse effects, and psychological stigma that may discourage patients from seeking care (Schroder et al., 2022). Psychotherapeutic interventions, such as cognitive-behavioral therapy (CBT), also play a role but may not yield sufficient results in severe or resistant forms of depression. These challenges underscore the urgent need for novel therapeutic approaches that can more effectively address the complexities of TRD (Wilkinson et al., 2021).

One emerging candidate in this context is neuropeptide Y (NPY), which is gaining attention for its mechanistic relevance in TRD due to its roles in stress modulation, neuroinflammation, and synaptic plasticity (Mathé et al., 2020; Serova et al., 2014). NPY, a 36-amino acid peptide, is widespread in the central and peripheral nervous systems, with especially high levels in brain regions of interest regarding emotional processing and psychiatric regulation, including the hypothalamus, amygdala, and prefrontal cortex (Sah and Geracioti, 2012). As one of the most widespread neuropeptides in the mammalian brain, NPY is involved in the regulation of mood, stress, and homeostasis. Its actions are mediated through five receptor subtypes: Y1, Y2, Y4, Y5, and Y6, though it should be noted that the Y6 receptor is non-functional in humans. Of these receptors, Y1, Y2, and Y5 are of most relevance to psychiatric disorders like depression, anxiety, and TRD (Farzi et al., 2015). NPY is also involved in regulating stress responses, appetite, and circadian rhythms (Wu et al., 2011). It has been shown to alleviate chronic stress-induced anxiety by inhibiting hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, a process modulated through neural remodeling (McGuire et al., 2011; Reichmann and Holzer, 2015). It has been shown to alleviate chronic stress-induced anxiety by inhibiting hyperactivation of the HPA axis, a process modulated through neural remodeling (Heilig, 2004; Hidese et al., 2023). For example, in preclinical models of depression, NPY administration has been associated with reduced stress-related behaviors and normalization of HPA axis function (Antunes et al., 2015; Serova et al., 2014; Tural and Iosifescu, 2020). Among NPY receptors, Y1 is associated with anxiolytic and antidepressant effects and is known to reverse stress-induced neurobiological changes, thereby enhancing emotional resilience. Y2 functions primarily as an autoreceptor and heteroreceptor, modulating neurotransmitter release and contributing to the regulation of chronic stress. Y5 has also been implicated in emotional modulation and feeding behaviors. There is a growing body of preclinical evidence supporting the antidepressant and anxiolytic effects of NPY and its receptor-specific ligands. Studies have shown that targeting these receptors can improve depressive-like behaviors in rodent models (Domin, 2021; Domin et al., 2016; Morales-Medina et al., 2012; Sharma et al., 2022).

This accumulating evidence supports the hypothesis that dysregulated NPY signaling plays a role in the pathophysiology of TRD (Antunes et al., 2015; Serova et al., 2014). Beyond its central nervous system effects, NPY also influences immune responses and tissue repair following injury or infection. Chronic depressive symptoms often accompanied by psychosocial dysfunction and neuro-immuno-endocrine disturbances may impair NPY signaling, complicating recovery. Furthermore, research on NPY pathways has revealed associations with hyperadrenocorticism, maladaptive stress responses, social and affective deficits, impaired self-regulation, and metabolic abnormalities all clinically relevant features of TRD, as illustrated in Table 1 and Fig. 1 (Reichmann and Holzer, 2015; Zukowska-Grojec, Z., 1995).

This review aims to explore the therapeutic potential of NPY as a target, focusing on its role in the interplay between stress, neuroinflammation, and neuroplasticity. It also examines how NPY-based strategies can be integrated into existing treatment frameworks to address the unmet clinical needs of TRD patients.