INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is the leading cause of disability and mortality worldwide. Its pathophysiology involves chronic inflammation of the airways and lung parenchyma, with significant links to the metrics for assessing COPD severity: Body mass index, airflow obstruction, dyspnea, and exercise capacity and frailty indices (encompassing comorbidities, anxiety, depression, and cognitive decline)[1]. A meta-analysis incorporating 79 studies across 25 countries reveals a 34.5% pooled prevalence of depression in patients with COPD - a significantly higher odds of depression than in non-COPD individuals[2]. Patients with COPD typically exhibit elevated levels of depression and anxiety, poorer quality of life (QoL), and reduced pulmonary function parameters (e.g., spirometry values and peripheral oxygen saturation); depression especially has a significant correlation with lung function decline[3,4]. Patients with COPD also exhibit reduced heart rate variability (HRV), an indicator of cardiac autonomic function; a low HRV correlates with an increased risk of COPD exacerbation, suggesting its potential as a biomarker for high-risk COPD[5]. Depression is independently linked to HRV alterations that may function as a predictive marker of depression[6]. However, whether HRV reduction occurs specifically in COPD patients with comorbid depression or universally across all COPD cases remains unclear. The mechanistic interplay between COPD, depression, and HRV requires further investigation.
Yang et al[7] examined 120 patients with COPD. The cohort demonstrated significantly higher depression levels than the healthy controls. Gradual deterioration of depressive symptoms correlated with declines in both pulmonary function parameters and HRV metrics - markers of autonomic nervous system activity - with HRV values significantly lower than those in the control group. Negative correlations emerged between depression scores and HRV indices, whereas positive correlations linked HRV to lung function metrics.
These findings suggest that the HRV reduction in patients with COPD may stem from a higher depression burden, wherein severe depression impairs pulmonary function via HRV suppression. This study provides a critical theoretical groundwork for unraveling the psychopathological and pathophysiological mechanisms by which depression exacerbates the decline in lung function and it informs future therapeutic strategies. The present editorial synthesizes recent advances in psychopathological and physiological research on depression-COPD comorbidities, offering evidence to guide personalized intervention approaches.
PATHOPHYSIOLOGICAL MECHANISMS RELATED TO DEPRESSION AND AUTONOMIC DYSFUNCTION IN COPD
Autonomic dysfunction and HRV reduction
Yang et al[7] provide direct evidence for the pathway between autonomic dysfunction and HRV reduction, demonstrating that the severity of depressive symptoms was quantitatively linked to reduced HRV (a marker of autonomic dysfunction), which, in turn, was associated with worse lung function. This mechanistic chain highlights the role of autonomic dysfunction as a critical mediator[7]. HRV indices progressively decrease with COPD severity, correlating with depression and anxiety[8]. Autonomic symptoms (measured by the COMPASS 31: Autonomic Symptom Scale) are also linked to worse QoL[9]. In at least one study, compared with the control group, depressed patients showed significantly lower 24-hour HRV indices. Levels of inflammatory markers [i.e., C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α)] were also significantly elevated, and the 24-hour HRV index exhibited a strong negative correlation with IL-6[10].
Inflammatory cytokine imbalance
COPD patients with depression normally show elevated levels of IL-1β, IL-2, IL-6, IL-8, IL-10, and TNF-α[11]. As inflammatory markers, the monocyte-to-lymphocyte ratio, red cell distribution width, and IL-6 are also correlated with depression and cor pulmonale in COPD patients[12]. CRP, a marker of inflammation, is associated with fatigue in COPD; management of depression and pain may serve as an effective therapeutic strategy for COPD-related fatigue[13].
Impact of respiratory therapy on mood
Bi-level positive airway pressure improves lung function and reduces depressive symptoms by modulating serotonin and IL-6[14]. These findings suggest that comorbid depression in COPD may exacerbate lung function impairment through multi-pathway psychophysiological interactions.
PSYCHOPATHOLOGICAL MECHANISMS RELATED TO DEPRESSION AND AUTONOMIC DYSFUNCTION IN COPD
Negative emotions
Patients with COPD and comorbid depression typically experience higher levels of anxiety, greater social stress, and more significant impairment in their QoL[15]. Depression and anxiety in patients with COPD are closely associated with both symptom and physiological burden. Higher oxygen dependency correlates with more severe anxiety and depressive symptoms, as well as worse QoL[16].
Psychological perceptions
Patients with COPD holding “harmful smoke exposure beliefs” (81% vs 28% in controls) demonstrate aggravated somatic symptoms, poorer QoL and elevated anxiety, and depression levels, and increased inflammatory markers including neutrophils, red blood cell distribution width, and CRP[17]. Personality traits: Hospitalization frequency in patients with COPD is positively associated with neuroticism, while outpatient visits are linked to conscientiousness and emotional support utilization, suggesting that personality traits and emotional states impact healthcare-seeking behaviors[18].
Resilience, self-efficacy, social support and coping styles
COPD patients with poor mental health typically show reduced resilience, self-efficacy, and social support, whereas symptom burden and low income exacerbate psychological distress[19]. Lack of social support, maladaptive coping (e.g., avoidance), and low resilience directly elevate psychological distress and indirectly worsen disease outcomes by amplifying the symptom burden[20].
Clinical prognosis
Psychological distress (e.g., depression and anxiety) significantly increases the risk of COPD exacerbation, hospitalization, and mortality[21]. Depression and anxiety in patients with COPD result from multifactorial interactions including physiological symptoms, personality traits, social support, and psychological adaptability, which collectively exacerbate the disease burden and create a vicious cycle.
PHARMACOLOGICAL TREATMENT OF DEPRESSION COMORBID WITH COPD
Efficacy of antidepressant drug interventions
COPD is associated with high morbidity and mortality and is frequently comorbid with depression, anxiety, and other mental disorders[22]. A bidirectional interaction may exist between depression/anxiety and COPD. Depressive symptoms can exacerbate COPD progression, whereas COPD, as a chronic stressor, further aggravates anxiety and depressive symptoms. Therefore, antidepressant pharmacotherapy plays a crucial role in its clinical management.
The United Kingdom National Institute for Health and Care Excellence guidelines recommend antidepressant treatment for COPD patients with moderate-to-severe depression. Sertraline and fluoxetine significantly improve depression scores in COPD patients, while paroxetine shows minimal effects within 6 weeks but effectively alleviates depressive symptoms and enhances QoL after 3 months of treatment[23]. A United Kingdom epidemiological survey revealed that COPD patients with severe dyspnea have a 42% higher risk of depression and are 40% more likely to receive antidepressant prescriptions than other patients[24].
Current evidence indicates that interventions targeting anxiety and depression in COPD patients, such as antidepressants or cognitive behavioral therapy, can considerably reduce symptom burden while significantly improving QoL[25,26]. Long-term follow-up data as well confirm that patients with COPD receiving antidepressant treatment exhibit significantly lower acute exacerbation rates within 1 year compared with untreated patients. However, owing to their compromised health status, COPD patients exhibit heightened susceptibility to adverse drug reactions. Thus, clinical decision-making must carefully consider drug-related factors, including sedative effects, anticholinergic side effects, metabolic interactions, and other pharmacological impacts[27]. Clinical implications: Existing studies on antidepressant efficacy in patients with COPD with comorbid depression have demonstrated heterogeneity, possibly owing to variations in study populations. Further high-quality studies are required to confirm these findings. When formulating individualized treatment plans, clinicians should balance the therapeutic benefits against potential risks while closely monitoring the treatment response.
Therapeutic efficacy of traditional Chinese medicine and integrated traditional-conventional interventions
A combination of traditional Chinese medicine (TCM) and conventional medical treatment can significantly improve pulmonary function, inflammatory markers, and psychological status in patients with COPD. In one study, when treated with ipratropium bromide combined with TCM interventions - including psychological intervention, 50 minutes of daily physical activity training, and external application of Chinese herbal medicine on acupoints - the experimental group exhibited significant improvements in forced expiratory volume in 1 second (FEV1), percentage of predicted FEV1 (FEV1% pred), forced vital capacity, and peak expiratory flow after 1 month[28]. The experimental group showed significantly reduced serum levels of inflammatory cytokines, including TNF-α, IL-6, IL-8, and CRP, along with lower anxiety and depression scores and the lowest incidence of adverse reactions[28].
In another study, combining TCM health promotion (including breathing exercises, acupuncture, massage, etc.) with conventional treatment increased the 6-minute walking distance, patient satisfaction, and partial pressure of oxygen in arterial blood, while reducing the COPD Assessment Test score and partial pressure of carbon dioxide in arterial blood[29]. Similarly, a modified Xiaoyao Powder (a Chinese herbal formula) administered for 6 months to patients with COPD alleviated depressive symptoms and reduced acute exacerbations and hospitalizations[30]. The Qingfei Xuanxie decoction showed a higher overall effectiveness rate after 1 month of treatment (91.67% vs 72.92%) compared with conventional treatment. It also demonstrated superior improvements in the FEV1/forced vital capacity ratio, arterial oxygen saturation, and IL-6 levels, including significant enhancements in sleep quality and QoL[31]. These findings suggest that TCM, through a holistic regulatory approach (targeting pulmonary function, psychological status, and QoL), may provide novel perspectives for COPD management. Further high-quality studies are needed to validate these findings.
EFFICACY OF PSYCHOLOGICAL INTERVENTIONS AND INTEGRATED MANAGEMENT FOR PATIENTS WITH COPD
Various psychological interventions effectively alleviate symptoms and enhance QoL in patients with COPD. Art and psychotherapy, music therapy (particularly five-element music), expressive arts therapy, and hypnotherapy are known to reduce dyspnea and anxiety and improve sleep quality[32-36]. Cognitive behavioral therapy alleviates anxiety and depression, enhances treatment adherence, and improves pulmonary function[37].
Mindfulness-based therapy significantly reduces dyspnea and fatigue[38]. Specifically, HRV biofeedback training modulates autonomic function in COPD patients, demonstrating: (1) Improved exercise capacity (6-minute walking test) and reduced dyspnea (modified Medical Research Council dyspnoea scale)[38]; (2) Enhanced cardiac autonomic regulation (increased standard deviation of normal to normal R-R intervals/square root of the mean squared differences of successive R-R intervals)[38]; (3) Greater self-efficacy (COPD self-efficacy scale) and QoL (St George’s Respiratory Questionnaire)[39]; and (4) Accelerated autonomic recovery post-exertion[39]. These adjunctive benefits to standard care highlight its clinical utility[39,40].
The health belief model facilitates psychological adaptation in rehabilitation and lowers inflammatory markers[41]. A meta-analysis of integrated management benefits demonstrated that multidimensional interventions combining patient education, exercise training, cognitive behavioral therapy, and smoking cessation significantly improved QoL and exercise tolerance and reduce hospitalization duration[42]. Compared with pharmacotherapy alone, combined psychological and integrated approaches avoid drug-related side effects. When combined with antidepressants or TCM, synergistic effects may further enhance efficacy while reducing the required drug dosages and adverse reactions.
EFFICACY OF EXERCISE AND BIOFEEDBACK INTERVENTIONS FOR DEPRESSION COMORBID WITH COPD
Prevalence and risk factors
Sarcopenia affects 60.3% of the patients with COPD, and depressive symptoms further increase this risk. Regular exercise improves muscle function and psychological status[43].
Exercise interventions
Three months of consistent walking can significantly alleviate anxiety and depressive symptoms, reduced dyspnea, and enhanced QoL[44].
Traditional exercise therapies
Qigong improves pulmonary function, exercise capacity, and mental health as adjunct therapy[45]. Yoga enhances respiratory muscle function and exercise endurance while reducing anxiety/depression scores[46,47].
Tai Chi
A meta-analysis demonstrated that 53.4-minute sessions, four times weekly for four months, increased the 6-minute walk distance and optimized both lung function and psychological metrics (e.g., Hospital Anxiety and Depression Scale scores)[48].
Adaptive training for elderly patients
For those aged > 70 years with > 10-year disease duration, a 24-week qigong or yoga session (2-3 sessions/week, 30-60 minutes/session) can significantly alleviate anxiety and depression[49].
Biofeedback therapy
By regulating physiological parameters, such as breathing patterns and HRV, biofeedback effectively reduces dyspnea and negative emotions while improving the QoL[50].
Clinical implications
Exercise recommendations: Low-intensity activities such as qigong, yoga, and walking should be integrated into management plans.
Combined approach: Synergistic effects may be achieved by combining exercise with biofeedback to simultaneously improve physiological and psychological outcomes.
LIMITATIONS AND PROSPECTS
Current limitations
Mechanistic research gaps: While studies confirm that depression affects COPD lung function through psychopathological-pathophysiological interactions, the underlying biopsychological mechanisms (e.g., autonomic dysfunction and cytokine pathways) require further elucidation through basic research.
Pharmacological challenges: Certain antidepressants (e.g., mirtazapine) fail to alleviate dyspnea in COPD and may induce adverse effects[51,52]. Their primary role should be improving comorbid anxiety/depression and QoL, rather than directly targeting respiratory symptoms.
Prospects for integrated and personalized management
Given the heightened vulnerability of COPD patients to drug-related complications, antidepressant therapy (e.g., low-dose selective serotonin reuptake inhibitor) requires careful risk-benefit assessment. A combined regimen incorporating non-pharmacological interventions (psychotherapy, exercise training, and HRV biofeedback) and/or TCM is recommended to maximize pulmonary safety while addressing depressive symptoms.
Future research directions
Clinical research: Conduct rigorous randomized control trials to evaluate the efficacy/safety of diverse interventions (pharmacological, psychological, and TCM). Prioritize low-risk therapies (e.g., biofeedback, tailored exercise) to reduce pharmacological reliance.
Integrated care models: Develop personalized management through multidisciplinary collaboration (pulmonology, psychiatry, rehabilitation, TCM). Establish a “biopsychosocial” framework to address COPD-depression comorbidity holistically.
Basic science: Utilize animal/cell models to dissect molecular pathways linking depression-associated autonomic dysfunction and inflammation to COPD progression.
CONCLUSION
This editorial is based primarily on the key findings of Yang et al[7], which demonstrated that comorbid mood disorders may impair lung function in patients with COPD through multiple mechanisms, with depression-related autonomic dysfunction serving as a contributing factor to pulmonary decline. Conversely, the distress caused by COPD exacerbates depressive symptoms. We put forward the hypothesis/argument that bidirectional interaction significantly worsens the patients’ QoL and prognosis. Disruption of this vicious cycle remains the key therapeutic focus. Prioritizing screening and intervention for depression in COPD while adopting integrated approaches, including antidepressants, TCM, and non-pharmacological therapies, can substantially improve outcomes. The interplay between depression and the COPD pathophysiology presents challenges and opportunities for clinical management. By fostering multidisciplinary collaboration and utilizing innovative research into practice, this approach is beneficial for overcoming the limitations of conventional therapies and ultimately enhance both the QoL and long-term prognosis for patients with COPD.
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 B
Novelty: Grade B, Grade C
Creativity or Innovation: Grade B, Grade C
Scientific Significance: Grade B, Grade B
P-Reviewer: Xu HY, MD, PhD, Professor, China S-Editor: Wang JJ L-Editor: A P-Editor: Wang CH
