Unraveling the interplay between stress, immune responses, and metabolic indicators in major depression

21 May 2023

The concept of allostatic load (AL) has been known to capture the long-term effects of fluctuating or heightening neural and neuroendocrine responses caused by repeated or chronic environmental stressors.1 Subsequent research elucidated the adaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis, which triggers the release of AL mediators into the bloodstream in response to unforeseen events.1 Therefore, the observed inflammatory disturbances in patients with major depressive disorder (MDD) may result from the hyperactivation of the HPA axis, which is regulated by the AL.1 During the recent EPA 2023: 31st European Congress of Psychiatry, Dr. Virginia Soria presented an illuminating review of a recent research that established a significant link among the AL, inflammation, and MDD.1 In addition, she presented a translational study conducted by her team, which shed additional light on these intriguing correlations.1 

The encounter with sudden or prolonged stressors and dangers cause different immune system reactions depending on their duration.1 Acute stress causes the immune system to adapt and respond appropriately, whereas chronic stress causes maladaptive responses.1 When confronting with a temporary threat, the immune system's response is carefully regulated by the glucocorticoid negative feedback, ensuring homeostasis.1 However, chronic stress can burden the body with an inflammatory disposition and disrupted neurotransmitter metabolism, known as allostasis mediators, which have been linked to stress-related mental health disorders such as depression and anxiety.1 For example, in the NESDA study, distinct patterns of allostasis mediators were identified in various depressive subtypes, immunometabolism dysregulation was observed in atypical depression, whereas melancholic depression was characterized by elevated HPA axis activity.1 In addition, atypical depression was associated with a prolonged unfavorable metabolic profile, even after 6 years of follow-up.1 

As introduced by Dr. Soria, a fascinating discovery was found regarding an AL index (ALi) comprising a variety of allostasis mediators associated with accumulated stress, revealing improved predictive capabilities regarding mortality, physical morbidity, and cognitive decline when compared with the use of independent markers.1 Higher ALi with increased levels of allostasis mediators and physiological stress indicators [i.e., elevated cortisol (CORT) levels, sympathetic tone, inflammation, and disturbed sleep] are associated with impaired cognitive performance, structural changes in the brain that impact memory, and an increase in amyloid accumulation.1  

MARIDE was a cross-sectional study designed to examine peripheral inflammatory markers and oxidative stress in MDD patients and healthy controls (HC).1 In a sub-project of MARIDE, Dr. Soria and her colleagues developed an ALi system and conducted tests to investigate its correlation not only with major depression, but also with cognitive deficits, which have not been previously documented in approximately two-thirds of MDD patients with significant functional impairment.1 This Ali system incorporated 17 robust allostasis mediators from the cardiovascular (CV) and autonomic nervous systems (ANS), the metabolic system, the neuroendocrine system, and the immune system.1 In this study, 74 patients, 38 with MDD and 36 HC were recruited.1 The collection of saliva and blood samples was repeated throughout the day and on 2 consecutive days.1 The weight of each biomarker in the ALi system was equal based on its position within the risk quartile of the sample.1 A clinical psychometric evaluation based on confirmatory factor analysis (CFA) was also performed to calculate the global cognition index for attention, processing speed, executive functions, and memory. 1 According to preliminary findings, the ALi was higher in MDD than in HC subjects (p=0.043).1 Analysis of linear regression revealed that the ALi was significantly associated with CFA in both populations.1 

To conclude, the study results demonstrated the association between changes in allostasis mediators and clinical features of MDD.1 However, the validation of biomarker sets that are both clinically relevant and cost-effective has yet to be completed.1 In addition, the lack of consensus regarding a standard ALi in MDD and its translation into robust predictive models for routine clinical practice necessitates additional research.1 Despite this, the implementation of personalized treatments guided by informative ALi systems represents the future of precision psychiatry.1 This may include dietary modifications, exercise regimens, psychobiotics, anti-diabetic medications, immunomodulators, HPA axis modulators, and a variety of psychotherapies.1 

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