The relationship between neuroinflammation and depression is a complex area of research that has garnered significant attention in recent years. Neuroinflammation, characterized by the activation of glial cells and the release of pro-inflammatory cytokines, has been implicated in the pathophysiology of depression. The relationship between neuroinflammation and depression is bidirectional; not only can inflammation contribute to the onset of depressive symptoms, but depression itself can also exacerbate inflammatory responses, creating a vicious cycle that complicates treatment and recovery. The present comprehensive review aimed to explore the current findings on the interplay between neuroinflammation and depression, as well as the mechanisms, risk factors, and therapeutic implications. The mechanisms by which neuroinflammation induces depressive-like behaviors are diverse. Neuroinflammation can increase pro-inflammatory cytokines, activate the hypothalamus-pituitary-adrenal (HPA) axis, and impair serotonin synthesis, all of which contribute to depressive symptoms. Furthermore, the activation of microglia has been linked to the release of inflammatory mediators that can disrupt neuronal function and contribute to mood disorders. Stress-induced neuroinflammatory responses can lead to the release of pro-inflammatory cytokines that not only affect brain function but also influence behavior and mood. Understanding these mechanisms is crucial for developing targeted therapies that can mitigate the effects of neuroinflammation on mood disorders.

Common psychiatric disorders (CPDs) and depression contribute significantly to the global epidemic of type 2 diabetes (T2D). We postulated a possible pathophysiological mechanism that through Bridge-Symptoms present in depression and CPDs, promotes the establishment of emotional eating, activation of the reward system, onset of overweight and obesity and, ultimately the increased risk of developing T2D. The plausibility of the proposed pathophysiological mechanism is supported by the mechanism of action of drugs such as naltrexone-bupropion currently approved for the treatment of both obesity/overweight with T2D and as separate active pharmaceutical ingredients in drug addiction, but also from initial evidence that is emerging regarding glucagon-like peptide 1 receptor agonists that appear to be effective in the treatment of drug addiction. We hope that our hypothesis may be useful in interpreting the higher prevalence of CPDs and depression in patients with T2D compared with the general population and may help refine the integrated psychiatric-diabetic therapy approach to improve the treatment and or remission of T2D.

Neuroinflammation triggers the production of inflammatory factors, influences neuron generation and synaptic plasticity, thus playing an important role in the pathogenesis of depression and becoming an important direction of depression prevention and treatment. Itaconate is a metabolite secreted by macrophages in immunomodulatory responses, that has potent immunomodulatory effects and has been proven to exert anti-inflammatory effects in a variety of diseases. Microglia are mononuclear macrophages that reside in the central nervous system (CNS), and may be the source of endogenous itaconate in the brain. Itaconate can directly inhibit succinate dehydrogenase (SDH), reduce the production of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), activate nuclear factor erythroid-2 related factor 2 (Nrf2), and block glycolysis, and thereby improving the depressive symptoms associated with the above mechanisms. Notably, itaconate also indirectly ameliorates the depressive symptoms associated with some inflammatory diseases. With the optimization of the structure and the development of new delivery systems, the application value and therapeutic potential of itaconate have been significantly improved. Dimethyl itaconate (DI) and 4-octyl itaconate (4-OI), cell-permeable derivatives of itaconate, are more suitable for crossing the blood-brain barrier (BBB), exhibiting therapeutic effects in the research of multiple diseases. This article provides an overview of the immunomodulatory effects of itaconate and its potential therapeutic efficacy in inflammatory depression, focusing on the promising application of itaconate as a precursor of antidepressants.

For a long time, Substance Use Disorders (SUDs) were not considered a component in the etiology of dementia. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders introduced substance-induced neurocognitive disorders, incorporating this notion to clinical practice. However, detection and monitoring of neurodegenerative processes in SUD patients remain a major clinical challenge, especially when early diagnosis is required. In the present study, we aimed to investigate new potential biomarkers of neurodegeneration that could predict cognitive impairment in SUD patients: the circulating concentrations of Neurofilament Light chain protein (NfL) and Brain-Derived Neurotrophic Factor (BDNF). Sixty SUD patients were compared with twenty-seven dementia patients and forty healthy controls. SUD patients were recruited and assessed using the Psychiatric Research Interview for Substance and Mental (PRISM) and a battery of neuropsychological tests, including the Montreal Cognitive Assessment test for evaluation of cognitive impairment. When compared to healthy control subjects, SUD patients showed increases in plasma NfL concentrations and NfL/BDNF ratio, as well as reduced plasma BDNF levels. These changes were remarkable in SUD patients with moderate-severe cognitive impairment, being comparable to those observed in dementia patients. NfL concentrations correlated with executive function and memory cognition in SUD patients. The parameters "age", "NfL/BDNF ratio", "first time alcohol use", "age of onset of alcohol use disorder", and "length of alcohol use disorder diagnosis" were able to stratify our SUD sample into patients with cognitive impairment from those without cognitive dysfunction with great specificity and sensibility. In conclusion, we propose the combined use of NfL and BDNF (NfL/BDNF ratio) to monitor substance-induced neurocognitive disorder.

Introduction: Obstructive sleep apnea (OSA) is a disorder that, apart from somatic sequelae, increases the risk of developing psychiatric conditions. Brain-derived neurotrophic factor (BDNF) signaling pathway is involved in the pathophysiology of depression and insomnia. Therefore, the study aimed to investigate differences in concentrations of BDNF and proBDNF in patients with OSA and healthy individuals, to evaluate diurnal changes of these proteins, and to assess the correlations with psychiatric symptoms. Methods: Sixty individuals following polysomnography (PSG) were divided into two groups based on the apnea-hypopnea index (AHI): OSA patients (AHI ≥ 30; n = 30) and control group (AHI < 5; n = 30). Participants filled out questionnaires: Beck Depression Inventory (BDI), Athens Insomnia Scale (AIS), and Pittsburgh Sleep Quality Index (PSQI). Peripheral blood was collected before and after PSG. Protein concentrations were measured using ELISA. OSA group was divided into subgroups: AIS (−)/AIS (+) (AIS > 5), PSQI (−)/PSQI (+) (PSQI > 5), and BDI (−)/BDI (+) (BDI > 19). Results: No differences in BDNF and proBDNF protein levels were observed between OSA and the control groups. However, BDNF and proBDNF evening protein concentrations were higher in the AIS (+) and PSQI (+) groups (p < 0.001 for all). The BDI (+) group was characterized by lower morning levels of both proteins (p = 0.047 and p = 0.003, respectively). Conclusions: BDNF signaling pathway might be involved in the pathophysiology of depression and insomnia in patients with OSA. BDNF and proBDNF protein levels might be useful in defining OSA phenotypes.