مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
The Role of Neuroimmunological Factors, Oxidative Stress, HPA Axis, Neurogenesis, Decision-Making, Chronic Pain, and EEG in Depression: A Comprehensive Review
The Role of Neuroimmunological Factors, Oxidative Stress, HPA Axis, Neurogenesis, Decision-Making, Chronic Pain, and EEG in Depression: A Comprehensive Review
Introduction: Major Depressive Disorder (MDD) is recognized as a serious and common neurological disorder worldwide, characterized by symptoms such as persistent sadness, loss of interest and pleasure in usual activities, decreased energy, difficulties in thinking and decision-making, appetite and sleep disturbances, psychomotor changes, and in severe cases, suicidal thoughts [3]. The World Health Organization (WHO) ranks major depression as one of the leading causes of disability globally and predicts it will be the second leading cause of disease burden worldwide by 2030 [3,6,9,11]. The lifetime prevalence of Major Depressive Disorder is significant [5], and this disorder not only negatively impacts individuals' overall functioning and quality of life but is also associated with increased rates of physical illnesses and mortality [7, 8]. Various factors contribute to the onset and progression of depression, including genetic structure, and psychological, environmental, and biological factors [5]. Recent research has shown that more complex mechanisms are involved in the onset of depression that go beyond traditional theories of monoamine neurotransmitters [6]. Specifically, the role of oxidative stress and inflammation in the pathophysiology of major depression has increasingly gained attention [6,10]. An imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses can lead to damage to vital molecules and activation of pro-inflammatory signaling pathways, ultimately resulting in neuronal cell death [10]. The brain is particularly vulnerable to oxidative stress due to its high oxygen consumption, high-fat content, and weaker antioxidant defenses [10]. In addition to oxidative stress, neuroinflammatory mediators such as interleukins (IL-1β, IL-6, TNF-α) also play a significant role in the pathophysiology of mood disorders, including major depression and bipolar disorder [3, 10,12]. Increased levels of these pro-inflammatory cytokines have been observed in the blood and cerebrospinal fluid of depressed individuals, and there is evidence suggesting that immune system activation can lead to the emergence of depressive symptoms [2,3,4,6,12]. Moreover, research in the field of genetics has shown that hereditary factors play a significant role in the risk of developing depression [12]. Although several studies have identified different candidate genes, many of these findings have not been confirmed in subsequent studies, indicating the complex and multifactorial nature of this disorder [12]. Epigenetic changes that alter gene functionality without changing the DNA sequence have also been highlighted in the onset and progression of depression [12].
Studies indicate that women experience a higher prevalence of depression compared to men [1,4,11]. Hormonal changes during puberty, premenstrual periods, postpartum, and perimenopause may play a significant role in this gender difference [11]. However, the precise mechanisms of this relationship have not yet been fully elucidated. Additionally, depression can manifest as a side effect or co-occur with other medical conditions such as chronic pain, cardiovascular diseases, diabetes, obesity, and cognitive disorders, negatively impacting the treatment and recovery processes for these conditions [1,2,5,9]. For instance, chronic pain can act as a stressor leading to depression, and the coexistence of these two conditions can exacerbate the severity of both disorders [5]. Given the complexity of depression and the limitations of questionnaire-based diagnostic methods, considerable efforts have been made to find objective biomarkers for diagnosing and predicting treatment responses through non-invasive methods such as electroencephalography (EEG) [7]. EEG, due to its high temporal resolution, is a powerful tool for examining brain electrical activity and identifying patterns associated with depression [7]. In conclusion, major depression is a complex disorder with multiple risk factors that require a deep understanding of the interactions between genetic, biological, psychological, and environmental factors. Recent research emphasizes the critical roles of oxidative stress, inflammation, hormonal changes, genetic and epigenetic factors, as well as their interactions with other medical conditions in the pathophysiology of this disorder. The search for objective biomarkers and the development of more effective therapeutic strategies that address the various mechanisms involved in depression remain research priorities in this field.
Methods: For this literature review, a comprehensive search was conducted across several databases, including Google Scholar, PubMed, and Elsevier, to identify relevant articles. The search focused on the period from 2010 to 2019 and primarily included original research articles, review papers, systematic reviews, and retrospective studies. Key search terms employed included Major Depressive Disorder, Neuroinflammation, Cytokines, Microglia and Anti-Inflammatory Drugs. This selection aimed to capture a broad range of evidence related to the topic.
Articles were selected based on their relevance to the interplay between neuroinflammation and Major Depressive Disorder. Titles and abstracts were screened, and full-text articles were retrieved for further evaluation if they addressed the research question. This review did not involve the collection of primary data or statistical analysis; instead, it synthesized information and findings from the identified literature to provide an overview of the current understanding of the subject. The review was conducted by the sole author, who was responsible for the literature search, article screening, data extraction, synthesis, and writing of the manuscript. The focus was on critically examining the existing literature and identifying key concepts, findings, and potential gaps in understanding the role of neuroinflammation in Major Depressive Disorder.
Results: The literature reveals a significant association between major depressive disorder (MDD) and alterations in inflammatory and neurobiological pathways. Major depression is characterized by immune dysregulation and the activation of inflammatory responses, where chronic stress and the release of pro-inflammatory cytokines lead to neuroinflammation, contributing to depressive symptoms. Key factors in this pathophysiology include elevated pro-inflammatory cytokines and glucocorticoid receptor (GR) resistance, creating a feedback loop that exacerbates inflammation and impairs GR function. Cytokines such as TNFα, IL-1β, and IL-6 are linked to stress-induced depression-like behaviors and inhibited neurogenesis. Additionally, neuroinflammation disrupts the balance between oxidative stress and antioxidant defenses, with the kynurenine pathway playing a crucial role in this process.
Research on anti-inflammatory treatments for depression has shown mixed but encouraging results. A meta-analysis of 14 trials involving 6,262 participants demonstrated a reduction in depressive symptoms with anti-inflammatory treatments, including NSAIDs and cytokine inhibitors. Notably, the COX-2 inhibitor celecoxib showed significant antidepressant effects. However, many studies exhibited high bias risks, affecting their validity. While cytokine inhibitors indicated a trend toward superiority over placebo, results varied. A study using infliximab in treatment-resistant MDD found benefits for patients with elevated baseline hs-CRP levels, while those with lower levels responded better to placebo. Elevated hs-CRP was associated with reduced placebo response, and infliximab significantly lowered hs-CRP concentrations.
These findings highlight the heterogeneous nature of MDD, suggesting that immune dysregulation may not be present in all patients but rather in specific subpopulations. Higher pro-inflammatory cytokine levels correlate with poorer responses to conventional antidepressants. Identifying patients with elevated inflammatory biomarkers is crucial for targeted interventions. The interplay between inflammation and neurobiological factors, including neurotransmitter imbalances, underscores the need for tailored therapeutic strategies.
Conclusion: The available evidence suggests that depression is associated with alterations in neuroplasticity, brain electrical activity, and neuroinflammation [4,6,7,16,18]. Reduced BDNF can lead to impaired neural plasticity and the development of depressive symptoms [5,12]. Abnormal activity in EEG frequency bands, particularly increased alpha power and changes in gamma, may indicate disturbed brain function in depressed individuals [7]. Neuroinflammation, which is initiated through pathways such as the P2X7-NLRP3 inflammasome, plays a significant role in the pathophysiology of depression [3,4,10]. Stress and environmental factors can influence these neurobiological processes [5,10]. Furthermore, the bidirectional communication between systemic and neuroinflammation and the role of the HPA axis in regulating inflammatory responses indicate that depression is a complex disorder involving multiple body systems [4,6,9,10]. Ultimately, further research is essential to fully understand these mechanisms and develop more effective treatments that target these neurobiological changes [6,10].