INTRODUCTION
In a recent prospective study, Qin et al[1] discussed the cumulative effects of stress-sensitive factors on depressive symptoms and suicide risk. In this editorial, we analyse the potential role of stress in the diagnosis and prognostic monitoring of depression through the existing literature, aiming to provide new perspectives on the prevention, diagnosis and treatment of depression. This article will further emphasise the importance of personal stress management in the management of depression.
Depression is a pervasive mental disorder with a multifactorial etiology involving genetic, biochemical, environmental and psychosocial factors. However, the intricacy of depression's pathogenesis, an absence of specific diagnostic markers, and the insidious nature of psychosocial changes in mood pose difficulties in diagnosis and treatment. Early screening and subsequent intervention can significantly impact depression treatment and prognosis.
Stress is thought to be one of the main causes of depression. Short-term stress can even be good for survival. However, excessive or prolonged stress may disrupt mood regulation and lead to depression. Studies have found that stressful events in life can be a sign that depression might start or get worse. Stress that comes from relationships or other problems you face each day is a common cause of depression.
A cross-sectional study of Chinese college students revealed that those experiencing high perceived stress were more prone to subthreshold depressive symptoms compared to those with low perceived stress[2]. The high perceived stress population accounted for over 34.5% of the student population[3], a figure that may be underestimated due to the limited sample size[4]. A plethora of studies have confirmed a positive correlation between perceived stress and depression, and that mood disorders such as depression can be considered stress-responsive disorders. The initial impact of elevated perceived stress on the physiological homeostasis of the organism has been demonstrated to increase the likelihood of developing mental disorders, including depression. Consequently, interventions targeting individuals with elevated perceived stress levels are of paramount clinical significance in the prevention of stress-related mental disorders, including depression[5].
STRESS IS THE SCIENTIFIC BASIS FOR MOOD DISORDERS SUCH AS DEPRESSION
Cognitive and biological responses to stressors are central to understanding the relationship between stress and depression[6], with cognitive control, cognitive bias and emotional control, neurological, inflammatory, and neuroendocrine being important components[7]. In the context of stressor exposure, individuals with elevated perceived stress demonstrate heightened cognitive and biological stress responses, resulting in augmented depressive symptoms. Concurrently, depression engenders a heightened propensity for stressful life events, which are autonomous from each other and interact with each other, thereby establishing a cyclical relationship of 'stress-depression'[8]. Under stressor exposure, individuals at risk of depression or those with existing symptoms often exhibit a negative cognitive bias. This bias is characterized by heightened emotional reactivity, persistent distress, and may even contribute to the onset of mood disorders[9]. Researchers have utilised the regulatory mechanisms of emotions in response to stressors, such as rumination, suppression, and other stressors, to predict the onset and severity of depressive episodes[10].
The stress response is influenced by various stressors, including physical, physiological, and social (psychological) factors, which can trigger varying degrees of response intensity and duration. While individual differences and personal experiences shape the response, the hypothalamic-pituitary-adrenal (HPA) axis has been identified as a key pathway involved in the physiological responses to stress[11].
GOOD AND BAD STRESS: RELATIONSHIP TO ENDOCRINE, NEUROLOGICAL AND IMMUNE
Stress is not inherently detrimental; rather, a moderate amount of healthy stress can have beneficial effects in coping with environmental demands, physiological demands, energy demands, and cognitive demands. However, it is widely accepted that chronic, repetitive and persistent stress stimuli result in abnormal stress system responses, which are often endocrine, neurological and immune-related. These factors, in turn, have been demonstrated to exacerbate the risk of depression. Eustress, a form of positive psychological stress, has been shown to enhance resilience and mitigate depressive symptoms by modulating epigenetic mechanisms such as histone acetylation and DNA methylation. For instance, stress-induced activation of histone deacetylases (HDACs) has been linked to altered expression of depression-related genes, while interventions targeting these pathways (e.g., HDAC inhibitors) show therapeutic potential.
The release of monoamines, such as dopamine and norepinephrine, in response to stressors, has been demonstrated to be accelerated. The release of corticotropin-releasing hormone (CRH) from the anterior pituitary gland, in turn, has been shown to bind to CRH1 and CRH2 receptors, activating adrenocorticotropic hormone (ACTH) secretion and contributing to the synthesis and secretion of adrenocorticotropic hormones [glucocorticoids (GCs)], including cortisol[12]. The intracellular GC receptor (GR) has been shown to better recognise the high cortisol concentrations that occur during the response to stress[13]. Therefore, abnormal GR levels may explain the hyperactivity of the HPA axis in depression, and studies have confirmed the therapeutic effect of GR antagonists and inhibitors on depressive symptoms[14].
The activation of negative feedback mechanisms has been demonstrated to balance the stress response of the organism. The regulation of these negative feedback loops is crucial for the adaptive stress response[15]. Through the adaptive stress response, the organism can often successfully terminate the stress response caused by general stressors. GCs have been identified as being key to the initiation of this process. Specifically, the organism rapidly mediates the process of GC elevation and the termination of the endocrine stress response by refining negative feedback mechanisms[16,17].
Stressor signals, such as those associated with life-threatening risks, social stressors, and stimuli to physical harm, are initially transmitted by the sensory nervous system and subsequently processed by emotional circuits in the brain[18]. Neurological abnormalities induced by stressors have been demonstrated to prolong periods of distress and elevate the risk of depressive episodes. This phenomenon is evidenced by abnormalities in brain regions associated with emotional responses, including the prefrontal cortex, the ventral tegmental area, and the hippocampus. In depressed states, stressors result in elevated activation of brain regions responsible for emotional responses, while negative feedback regulates reduced activation of brain regions involved in emotional responses to the stressor. Furthermore, a decrease in the connectivity between these two types of brain regions has been observed, which collectively contribute to a reduction in the body's capacity to regulate negative emotions, thereby increasing the risk of depression.
Stressor-induced neuro-immune dysregulation is also closely related to depression; immune mediators such as cytokines are important regulators of brain-organism interactions. Mediators in the immune system, such as interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), are consistently elevated in patients with depression. By affecting mood-related central nervous system (CNS) functions, immune mediators such as IL-1β and TNF-α regulate cognitive, sleep and metabolic processes[19]. In addition, it is evident from the existing literature that heightened inflammatory responses are associated with the onset of depressive symptoms, including sadness, anxiety, and fatigue, and can serve as predictors for clinically significant depressive episodes[20]. Moreover, the presence of peripheral inducers of immune cytokines within both the CNS and peripheral organs has been demonstrated to play a contributory role in the development of depressive symptoms within an organism. This observation serves to corroborate the immune-depressive correlation, thereby elucidating the consistency of psychiatric and somatic symptoms in depressed patients[21].
In animal models where rodents are continuously exposed to stress, levels of inflammatory factors such as IL-1β and TNF-α are consistently increased, and these immune changes may precede the development of behavioural depressive symptoms, suggesting that immune activation may precede clinical symptoms. Healthy humans also exhibit specific manifestations in stress, and the Trier Social Stress Test has also flanked the relationship between cytokine changes in the immune response and stress. Interestingly, we believe that the relationship between the immune response and stress and depression is a complex interaction, where the immune response may lead to depressive episodes, stress may induce the immune response, and the immune response may be exacerbated after depressive episodes. In other words, their relationship may not be a simple causal one.
BIOMARKERS FOR STRESS QUANTIFICATION
Previous stress response quantification has predominantly relied on surveys and questionnaires, which lack objective quantification. Researchers have developed an electronic skin sensor for stress detection, which can be used to differentiate between stressors and assess stress response by detecting molecular biomarkers in the patient's vital signs (pulse waveform, galvanic skin response, and skin temperature) and in sweat (glucose, lactate, uric acid, sodium ions, potassium ions, and ammonium ions)[22].
As previously mentioned, cortisol hormones are secreted by the body in response to stress. Increased secretion of cortisol is one of the potential biomarkers of increased stress in the body. In this context, researchers have developed a wearable and implantable cortisol-sensing electronic device with microsensors that can monitor and measure cortisol concentrations in real time, thereby enabling the sensing and measurement of stress levels[23,24].
Furthermore, electrophysiological signals and sweat can also be used as potential markers to indirectly measure stress. Conversely, salivary α-amylase (sAA) has been identified as a sensitive indicator for assessing stress with non-pharmacological interventions[25]. However, salivary biomarkers have received comparatively less study in stressed populations, despite the evidence that alpha amylase levels vary in response to physical and psychological stress[26,27]. In contrast, alpha amylase-cortisol association testing has become a paradigm for measuring stress in various groups[28-30].
Acute stress has been demonstrated to exert a significant effect on ACTH levels in humans. ACTH, in turn, has been shown to stimulate the adrenal glands to secrete GCs, which are essential for stress coping, stress resilience, and homeostasis in vivo. In a rat model of chronic unpredictable stress[31], ACTH analogues have been shown to possess antidepressant properties and to alleviate the markers of chronic stress load, thus suggesting that ACTH levels can be utilised as a biomarker for the general acute stress response[32,33].
The ratio of tryptophan (TRP) to tyrosine (KYN) in tissues (KTR) has also been identified as an acute stress biomarker. Research has demonstrated that cortisol, KYN and TRP levels in Oncorhynchus mykiss exhibit rapid changes in response to acute stress induction, suggesting that KTR may have potential as an acute stress diagnostic biomarker in fish.
CONCLUSION
It is imperative that future research continues to explore the multifaceted relationship between stress and depression, with a view to developing more precise biomarkers to quantify the stress response. A more in-depth analysis of the biological mechanisms underpinning stress is expected to facilitate the creation of more targeted interventions for the prevention and treatment of depression and other mood disorders. Concurrently, given the heterogeneity of the stress response across diverse populations, there is a necessity for more sophisticated studies to develop more personalised stress management programmes. Interdisciplinary collaboration will be instrumental to the development of this field. A close collaboration among psychologists, biologists, neuroscientists, and clinicians will facilitate a more comprehensive understanding of the biological basis of stress and its interactions with mood disorders such as depression. Such collaboration will also promote the emergence of new theories, encourage technological innovations, and accelerate the translation of research results into clinical practice.
We believe that there is a multidimensional correlation mechanism between the breakthrough application of biomarker technology, the in-depth analysis of gene-environment interactions and the integrated socio-bio-psychological intervention model. Based on the potential of wearable devices in stress monitoring, multimodal biomarker co-detection can be further explored in the future. Integrating the dynamic changes of cortisol, sAA, inflammatory factors (e.g., IL-1β, TNF-α) and neurotransmitters (e.g., 5-hydroxytryptophan), a comprehensive stress assessment model can be constructed to improve the sensitivity and specificity of diagnosis. The role of epigenetic mechanisms (e.g. DNA methylation) in stress response was mentioned in the paper, and future studies can combine genome-wide association analysis and single-cell sequencing technologies to locate the regulatory loci of stress-sensitive genes (e.g. FK506 binding protein 5, CRH receptor 1) and reveal the differences in their expression under different stress patterns. This could provide a theoretical basis for the development of gene-targeted therapies (e.g., CRH receptor antagonists). While existing interventions focus on the individual level, this paper suggests the need to pay attention to the influence of socio-cultural factors. In the future, we can design community-based intervention programmes, group stress management programmes based on digital platforms, simulate stress reduction scenarios with virtual reality technology, and collect environmental stress data (e.g., economic fluctuations, natural disasters) through social media to establish a social stress early warning system. Such research will contribute to the paradigm shift from ‘individual treatment’ to ‘socio-ecological intervention’.
So what are the potential prospective studies ideas? Exploring and optimising the mechanisms of non-pharmacological therapies: Although cognitive behavioural therapy and meditation have been shown to be effective, their biological mechanisms still need to be elucidated in depth. The effects of non-pharmacological interventions on neuroplasticity in brain regions such as prefrontal cortex and hippocampus can be quantified using functional magnetic resonance imaging and electroencephalography techniques. Developing ‘hybrid therapies’ to enhance therapeutic effects through neuromodulation, and using machine learning to predict patient response to specific therapies.
Translational value of cross-species research: Although animal models can mimic some human depression phenotypes, species differences limit their clinical translation. We need to establish organoid or humanized mouse models that mimic the genetic and immune characteristics of human stress responses, or collect data on stress behaviours of humans and animals synchronously in their natural environments, which can reveal the evolutionary conservatism and uniqueness of stress responses.
Differences in global health perspectives: Current research has mostly focused on high-income countries, while the effects of cultural background and socioeconomic level on stress perception have not been fully explored. Future cross-cultural cohort studies are needed to compare differences in biological markers of stress in populations from different regions and to design culturally adapted intervention strategies.
Dynamic regulation of immune-neuroendocrine network: It is pointed out in the paper that immune activation may precede depressive symptoms, but the temporal relationship among the three (immune, neurological, and endocrine) is still unclear. In the future, longitudinal multi-omics data can be used to construct dynamic network models to identify key nodes in the transition from stress to depression. The development of drugs targeting immune-metabolic pathways may break the vicious cycle of ‘stress-inflammation-depression’.
Furthermore, a focus on the social influences of mood disorders, such as stress and depression, including the social environment, cultural background and education level, may have an impact on an individual's stress response and mood state. When developing intervention strategies, it is essential to consider these social factors to ensure the effectiveness and sustainability of the interventions. Through these efforts, it is expected to make a significant contribution to the improvement of mental health on a global scale.
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Psychiatry
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade C
Novelty: Grade B, Grade C
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade B, Grade B
P-Reviewer: Huang L; Norman TR S-Editor: Luo ML L-Editor: A P-Editor: Yu HG
