The field of neuropsychiatric disorders encompasses a variety of conditions that affect both the central and peripheral systems. A prominent category within this domain is depression, marked by persistent feelings of sadness accompanied by cognitive and physical alterations that disrupt regular functioning over the course of a lifetime, potentially culminating in suicide (de Aguiar Neto & Rosa, 2019; Monroe & Harkness, 2022). Crucially, depression stands as a primary contributor to the worldwide burden of disease, exerting a substantial influence on social and economic well-being (Malhi & Mann, 2018). According to the Global Burden of Disease 2016 study, depressive disorders, including major depressive disorder (MDD) and dysthymia, represent the third-largest contributor to the global burden of disease in terms of years lost to disability (Disease, Injury, & Prevalence, 2017; Nerurkar, Siebert, McInnes, & Cavanagh, 2019). In practice, diagnosing and treating depression frequently present challenges for clinicians (Kupfer, Frank, & Phillips, 2012). Because of its unpredictable course, complex progression, and variable response. Scientists are trying to understand the prediction, etiology and treatment of depression. To clarify, the pathogenesis of depression encompasses various factors, including the nervous, immune, and endocrine systems, with inflammatory processes considered a crucial element in the pathophysiology of depression. Rapid advances in the understanding of immunology and neuroimmunology in the process of depression have provided a promising focus for research and action (Drevets, Wittenberg, Bullmore, & Manji, 2022). Continual immune investigations contribute to the updates of novel theories regarding depression, suggesting that individuals with MDD who exhibit an immune response may display more effective responses to treatments that specifically target immune pathways.

Presently, a variety of treatments for depression are available, including antidepressant drugs (e.g., selective serotonin reuptake inhibitors (SSRIs)), transcranial magnetic stimulation (TMS), transcranial direct-current stimulation (tDCS), deep brain stimulation (DBS), and dietary interventions (e.g., high-fiber diets) (Fig. 1). Notably, immunotherapies have transformed the treatment landscape for central nervous system (CNS) pathology, presenting distinct profiles of immune response linked to specific mechanisms and dictated by the form of immunotherapy (Sampson, Gunn, Fecci, & Ashley, 2020; Tan et al., 2020). Clinical trials are underway to expand the indications for these therapies and to explore new ways of harnessing the immune system. The increasing use of immunotherapy in the clinic highlights the importance of the immune system in the pathological condition of depression. Further studies focusing on the different stages of depression would improve current treatments. In this review, we will mainly discuss immune researches of depression because they are most relevant to the development of immunotherapies for MDD.

Narrative review based on literature searches of PubMed up to October 2023 with no date limits imposed. Search included terms such as “depression”, “central nervous system”, “emotional disorder”, “mental disorder”, “inflammation”, “immune system”, “immunotherapy”, “immune response”, “immunity”, “T cell”, “cytokines”, “clinical trials” and “intervention.”