COPD and Depression—The Vicious Mental Cycle

1. Introduction

COPD is considered one of the primary causes of morbidity and mortality worldwide and at the same time, creating a growing social and economic burden. [1]. The prevalence, morbidity, and mortality of COPD may vary between countries depending on the risk factors populations are exposed to. [2]. According to the World Health Organization (WHO), COPD is the fourth leading cause of death worldwide, causing 3.5 million deaths in 2021, which represent approximately 5% of all global deaths [3]. In addition, according to disability-adjusted life years, COPD is the eighth leading cause of poor health worldwide [3].

It is estimated that 80% of COPD patients are likely to have at least one comorbidity [4]. The relationship between COPD and mental health has recently gained significant research interest due to its impact on quality of life [5]. COPD significantly impacts mental health, pacients experiencing higher rates of depression compared to the general population. According to Atlantis et al., the relative risk of developing depression among COPD patients is 1.69 times higher than in the general population. [6]. The prevalence of depression among patients with stable COPD in primary care settings varies significantly, with a range of 10% to 57% [7]. Among patients with severe COPD (FEV1 <50% predicted), the prevalence of depression was 25.0%, compared to 17.5% in controls and 19.6% in persons with mild to moderate COPD [8].

Quality of life in COPD is significantly impacted by the progressive charactere of the disease. Moreover, depression in subjects with COPD worsens this impact and has been found to have the strongest correlation with self-reported health status and reduced HRQoL[9].

COPD is a chronic condition that typically requires the ongoing use of pharmacotherapy [10,11]. Nonadherence to treatment is a significant issue in COPD, with adherence rates estimated to be below 50% [12]. A meta-analysis has revealed that patients with symptoms of depression are three times more likely to be non-adherent to their prescribed medications [13]. Nonadherence to COPD treatments results in higher hospitalization rates, increased costs, and more frequent emergency department visits [14,15] .

Exacerbations of chronic obstructive pulmonary disease (COPD) represent a significant challenge for worldwide health-care systems; they are a major cause of morbidity, mortality, and reduced health status[16]. A recent study identified depression as an independent factor for acute exacerbations of COPD (AECOPD), associated with a higher risk of readmission for AECOPD (OR 2.06, 95% CI 1.28 - 3.31), regardless of lung function or previous severe exacerbations in the prior year [17].

2. Risk Factors

Several studies have identified risk factors for depression in patients with COPD including smoking, severe dyspnea, poor HRQoL, lower education levels and socio-economic status, as well as association with non-psychological comorbidities [18,19].

2.1. Smoking

Psychiatrists have observed that cigarette smoke seems to have an antidepressant effect [20], potentially providing temporary relief for symptoms of depression. This may explain why studies consistently reported that patients with COPD who also suffer from depression or anxiety are significantly more likely to be smokers [21,22]. The relationship between smoking and depression is, however, bidirectional. Young adults with a history of depression are more likely to start smoking compared with healthy counterparts who have no symptoms of depression. On the other hand, long-term cigarette use has been proven to heighten susceptibility to developing depression due to nicotine-induced changes in neurophysiology, including disruptions in neurotransmitter systems essential for mood regulation [23,24]. In addition, the prevalence of depression and anxiety tends to rise with the increasing duration of smoking (in years) and the number of cigarette pack-years [25].

Depression as a comorbidity has been shown to have a statistically significant relationship with patients’ HRQoL and smoking status [26].

2.2. Pulmonary Function

Spirometry is widely regarded as the gold standard for assessing lung function in patients with chronic lung diseases Several  studies have  proven  a significant association between reduced lung function and  symptoms  of  depression  in  subjects  with  respiratory   disease  [27] . Specifically, parameters such as FEV1 (P<0.001), FVC (P<0.001), and the FEV1/FVC ratio (P=0.022) were markedly lower in the group of subjects diagnosed with depression compared  with   subjects   with   no  symptoms  of depression [28] . Moderate-to-severe symptoms of depression have actually been proven  to  have   a   significant  and  independent   correlation with the progression of lung function decline in young adults [29] .

2.3. Socio-Economic Factors

Several studies suggest that younger persons with COPD may be more susceptible to depression [18,30,31], possibly as a result of early onset of the disease, which affects their work productivity, social engagement and quality of life. However, other research presents the opposite, that older adults are more vulnerable to depression, possibly due to the cumulative effects of chronic illness and age-related comorbidities [19,32]. A recent study showed that people with higher educational qualifications had a 40% lower risk of experiencing depression than those with less educational background. Additionally, the study reported younger age and a psychological history as significant risk factors for depression in COPD patients [33]. It’s important to recognize that studies exploring the relationship between depression and COPD vary widely, influenced by factors such as sample size, geographic location, and cultural differences [34].

3. Pathogenesis and Pathophysiology

The relationship between COPD and depression can be bidirectional [6], meaning that depression can aggravate the condition of patients suffering from COPD, leading to an increased risk of exacerbation and can indirectly lead to death. The pathophysiologic mechanisms for the development of depression in patients with COPD are complex and include the following: the anxiogenic effects of hyperventilation [35,36,37], misinterpretation of respiratory symptoms [35,38,39,40,41,42], neurobiologic sensitivity to CO2, lactate and other signals of suffocation [35,38,43,44], smoking [45,46,47,48,49,50,51,52,53], hypoxia [54,55,56,57,58] and inflammation [59,60,61,62,63,64,65,66,67,68,69,70].

3.1. The Anxiogenic Effects of Hyperventilation. Misinterpretation of Respiratory Symptoms

Anxiety in COPD patients manifests as dyspnea, sweating, and tachycardia; these symptoms are often linked to fear of dyspnea attacks and death [35,36]. A complex relationship exists between dyspnea, hyperventilation, and anxiety [35], as anxiety increases respiratory rate, worsening dyspnea through shallow breathing [38]. COPD exacerbates this with increased ventilatory load, reduced capacity, and neural respiratory drive [39]. When perceived respiratory effort exceeds a threshold, it triggers emotional reactions, leading to avoidance behaviors that may temporarily reduce anxiety [40,41], but can activate a 'dyspnea-anxiety-dyspnea cycle,' exacerbating breathlessness and impairing quality of life [42].

3.2. Neurobiological Sensitivity to CO2, Lactate, and Other Suffocation Signals in COPD and Depression

Hyperventilation that exceeds the metabolic demands of the body leads to a reduction in CO₂ levels and in consequence, induces respiratory alkalosis. This, in turn, induces vasoconstriction and characteristic symptoms of panic, including feelings of numbness, breathlessness, dizziness, and tingling sensations—symptoms that can occur in healthy persons [38]. In patients with COPD, an increased respiratory rate contributes to dynamic hyperinflation. This hyperinflation, in turn, increases elastic load and the work of breathing and decreases inspiratory reserve capacity, thereby exacerbating dyspnea [43]. In severe cases of COPD, chronic hypoventilation leads to hypercapnia [38]. The resulting elevation in pCO₂ levels stimulates the medullary chemoreceptors, which excites noradrenergic neurons and precipitates a panic response [44]. Furthermore, hypoxia is associated with the generation of lactic acid, which is strongly implicated in the provocation of panic attacks. In addition, patients with COPD and comorbid anxiety are more sensitive to both hyperventilation and lactic acid buildup [35].

3.3. The Role of Nicotine Dependence and Smoking in COPD and Depression

The characteristic symptoms of depression in COPD patients include sleep disturbances, difficulty with concentration, loss of appetite, feelings of hopelessness, functional impairment in daily activities, difficulties with self-management during exacerbations, widespread negativity, and social withdrawal [47,48,49]. In COPD patients, depressive symptomatology is often exacerbated by guilt, stemming from the belief that they are a burden to others or responsible for the onset of their illness [50].

Adolescents with a genetic predisposition for depression or with a history of depressive episodes have an increased risk of developing COPD through nicotine addiction [51,52]. This creates a vicious cycle: depression leads to smoking, and smoking, as a major risk factor, contributes to the development of COPD. In turn, COPD exacerbates depression through various pathophysiological mechanisms [53]. Several studies [71,72], support a strong association between tobacco consumption and mental disorders.

3.4. The Impact of Hypoxia on COPD and Depression

Chronic, subclinical hypoxemia is a common finding in patients with COPD. Low arterial oxygen saturation has been linked to the presence of periventricular white matter lesions [54], which are similarly observed in older adults with depression[55]. Several studies have also indicated a relation between neuropsychologic impairment and persistent hypoxemia, with manifestations that include both cognitive impairments and depressive symptoms [56,57].

Research on sleep apnea has provided key insights into the relationship between hypoxemia and depression, suggesting that intermittent nocturnal hypoxemia is considered a significant cause for developing depressive states [58].

3.5. The Role of Inflammation in COPD and Depression

Various studies have found that pro-inflammatory cytokines, such as IL-6, affect the brain, contributing to depressive symptoms in COPD patients [58]. Elevated IL-6 levels are found in both COPD and depression, with IL-6, IFN-γ, and IL-2 involved in producing symptoms of depression [61].

IL-6 is produced at sites of inflammation and plays a key role in the acute phase response. It amplifies chronic inflammation by stimulating T- and B-cells [62]; therefore high concentrations of IL-6 suggest a relation between depression and COPD. Additionally, IL-6 modulates monocyte and macrophage differentiation [64], which is a key component of the immune system. When activated by pro-inflammatory signals such as IFN-γ or lipopolysaccharides, macrophages release nitric oxide (NO) [64]. Activated macrophages, in addition to producing NO, also secrete neopterin, a molecule that serves as a biomarker for T helper cell activation [65]. Elevated neopterin levels have been consistently identified in both COPD patients [62] and in subjects with depression [66], and thus underline the interconnected nature of chronic inflammation, COPD, and mood disorders. In humans, the administration of IFN-γ has been shown to induce various depression-like symptoms, such as headache, weight loss, fatigue, anorexia, irritability, and difficulties in concentration [73]. Similarly, IL-2 can cross the blood-brain barrier, causing cognitive and motor impairments [74].

Taken together, these findings highlight the significant role of inflammation, particularly mediated by cytokines like IL-2, IL-6, and IFN-γ, in the pathogenesis of both COPD and depression.

3.6. Oxidative Stress

Oxidative stress, resulting from an imbalance between reactive oxygen species (ROS), reactive nitrogen species (RNS), and antioxidant defenses, plays a key role in the pathogenesis of COPD. In the lungs, oxidants damage nucleic acids, lipids, and proteins, trigger redox-cycling reactions, deplete antioxidants (e.g., glutathione), initiate carcinogenesis, and inactivate protease inhibitors such as α1-antitrypsin [75]. Cigarette smoke is a major exogenous oxidant source and significantly contributes to COPD [76,77].

Air pollution, containing nitrogen dioxide (NO₂), ozone, polycyclic aromatic hydrocarbons (PAHs), and endotoxins, also induces oxidative stress and is a significant cause of COPD development [78].

Endogenous oxidant sources include mitochondria, which generate superoxide, a key ROS, along with membrane-bound oxidases like cytochrome P450 [79,80]. Increased plasma lipid peroxidation markers, such as malondialdehyde, and biomarkers like exhaled ethane and 8-isoprostanes, indicate oxidative damage in COPD patients [81,82,83,84,85].

Figure 1. Pathogenesis and pathophysiology of depression in COPD.

Figure 1. Pathogenesis and pathophysiology of depression in COPD.

4. Depression and COPD Exacerbations

The progression of COPD is largely influenced by the frequency of exacerbations and the presence of comorbidities, both of which significantly impact the disease course and worsen prognosis [86,87,88]. Depressive symptoms in COPD patients are associated with more frequent severe exacerbations, reduced physical activity, increased dyspnea, and a lower quality of life, suggesting that depression may contribute to faster disease progression [89].

A recent study found a high prevalence of depression in COPD patients with frequent exacerbations, with more severe depressive symptoms observed in advanced disease stages. [90]. The pathophysiological mechanisms involved in the impact of depression on acute AECOPD remain poorly understood [89]. Psychophysiological, behavioral, and psychosocial factors likely contribute to this association. Depression, marked by hopelessness and fear, can reduce self-care, treatment adherence, and increase smoking[91,92] all of which may contribute to AECOPD. Cognitive impairments may also amplify dyspnea perception, raising healthcare utilization and hospitalization risk [89].

5. Depression and COPD in the Elderly

Depression is a common problem for older people. According to reports, 80% of older adults with COPD suffer from depression [93,94]. Older adults with COPD are more likely to experience dyspnea after physical activity, leading to a long-term decline in activity levels, which in turn results in reduced muscle mass and function [95].

Patients with both COPD and comorbid depression tend to have a poorer prognosis, including lower exercise tolerance, greater functional limitations, more frequent acute exacerbations, and an increased risk of mortality compared to those without depression [96].

Depression in patients with COPD was associated with length of hospital stay and increases in both 30- and 60-day hospital readmission rates [97]. Older adults with COPD exhibit a higher prevalence of severe social disengagement (4.5% vs 2.1%; adjusted odds ratio [OR], 0.7; 95% confidence interval [CI], 0.1-4.8) and loneliness (57.7% vs 42.1%; unadjusted OR, 1.9; 95% CI, 1.4-2.5) compared to their counterparts without COPD [98].

6. COPD and Depression: Clinical Differences Between Men and Women

The global prevalence of COPD is estimated at approximately 12%, and its burden continues to rise worldwide [99,100], furthermore, COPD has become the leading cause of death among female smokers [98]. Biological differences between males and females include differences in airway development, inflammatory responses, and susceptibility to inhaled substances such as tobacco smoke [101]. One key distinction is that females tend to have smaller airways relative to lung volume compared to males [102]. This may partially explain why women experience more severe small airway disease than men, even with comparable tobacco smoke exposure [103].

Female sex is a significant risk factor for depression in COPD, along with lower BMI, living alone, smoking, and greater disease severity, particularly in GOLD stage III/IV. Risk factors for depression differ by sex: in males, they include low BMI, low income, living alone, and multiple comorbidities, while in females, they involve lower education, urban living, and smoking [104]. Women with COPD report higher levels of depression and reduced quality of life compared to males [105], even after adjusting for lung function, age, smoking history, and emphysema severity [106]. Additionally, female sex, depression, and anxiety are linked to increased exacerbations and mortality [103].

7. Screening for Depression in COPD

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends the use of the COPD Assessment Test (CAT) for evaluating patients with COPD [107]. Research suggests that the CAT Test may serve as a indicator of major depression in COPD patients with mild hypoxemia [108] . Although various screening tools are available to identify depression— such as the Beck Depression Inventory (second revision), the Center for Epidemiologic Studies Depression Scale (CES-D), the Geriatric Depression Scale (GDS), the Hospital Anxiety and Depression Scale (HADS), and the Patient Health Questionnaire-9 (PHQ-9) [109] , none of these instruments are routinely implemented in primary care practices [110,111].

8. Scales/Scores for Assessment of Depression in COPD

	BDI	GDS	CES-D	HADS
Number of questions/time for evaluation	-21 items -2 past weeks	-30 items (long version) -15 items (short version) -current/past week	-20 items [112] (and other versions) -1 past week	-14 items (7-anxiety-related, 7-depression-related)
Are evaluated	patients with somatic, affective, cognitive and vegetative symptoms	normal community-dwelling elderly and elders hospitalized for depression	patients with positive/negative effect, somatic problems, evaluating their activity level	psychiatric and medical patients, including cancer, traumatic brain injury, cardiac, stroke, intellectual disabilities, epilepsy, chronic obstructive pulmonary disease, etc., ages 16–65 years
Scale	*a 4-point scale: 0-means not at all 3-extreme form of each symptom	*a scale – «yes or no»	*a 4-point scale: 0-rarely(<1/day) 1-some/little of the time (1-2 days) 2-occasionally or a moderate amount of time (3-4 days) 3-most or all of the time (5-7 days)	*a 4 point Likert scale, ranging from 0-3
Score interpretation	*minimal range= 0-13 *mild depression= 14-19 *moderate depression= 20-28 *severe depression= 29-63	*long form: 0-9-normal, 10-19-mild depression, 20-30-severe depression *short form: >5-suggestive for depression and >10-highly likely depression	Easily hand scored. The items should be summed to obtain a total score.	*0-7-normal *8-10-mild *11-15-moderate *>=16-severe
Time to administer/complete	*self-administration= 5-10 min. *oral administration= 15 min.	*long version – 5-10 min. *short version – 2-5 min.	10 minutes	<=5 min. (1-2 min.)
Response format	0-3 rating scale	«yes» or «no»	4 point Likert scale	*0-3 rating scale
Sensitivity to change	*5-point difference=minimally important clinical difference *10-19points =moderate difference *>20 points =large difference [113]	*the short form shows the sensitivity of 81.3% *the long form shows the sensitivity of 77.4%	*ranges of 13-21 have been provided for detecting of 80-90% reliable change.	*sensitivity = 56-100 %
Restrictions/ limitations	Overlapping symptoms between other medical conditions and depression, cost and reading level	It is valid in younger samples. In needs caution when used with cognitively impaired individuals and severely cognitively impaired individuals	Response format can be difficult in original 20-item instrument, and is a contributing reason for the development of shorter versions	It is better to compare HADS to other measures of depression
Ease to use	time to complete – 5-15 min.	self-administered questionnaire	Time to interpret <10 min. Easily self-administered/ administered by interviewer.	self-administered questionnaire

9. Impact of COPD Medication on Depression and Vice Versa

Managing anxiety and depression in COPD need a multidisciplinary approach. COPD progression impact mental health and targeted strategies such as smoking cessation [114], influenza vaccination [115], oxygen therapy [116], pharmacological interventions [117], surgical procedures for select patients [118], structured exercise programs to condition peripheral muscles[119], and self-management strategies [120] becomes more pronounced.

While COPD medications help relieve symptoms, corticosteroids especially in asthma-COPD overlap [121,122], such as depression, psychosis, mania, anxiety, and delirium [123]. The use of corticosteroids is strongly associated with psychiatric and neurological side effects, with reported rates of depression (40.5%), mania (27.8%), psychosis (13.9%), and delirium (10.1%) [124]. A case study documented severe mania induced by the combined use of prednisone and clarithromycin [125].

Although rare, such effects require careful monitoring. Another study assessed the impact of long-acting beta-agonists (LABAs) and theophylline on suicidal ideation, finding no significant link with LABAs but an increased risk with theophylline, underscoring the need for psychological risk assessment. [126]. Beta-2 adrenergic agonists, such as albuterol, indacaterol, and salmeterol, are known to cause dose-dependent prolongation of the QT interval and potassium depletion. Similarly, serotonin reuptake inhibitors (e.g., escitalopram, citalopram, fluoxetine) and tricyclic antidepressants (e.g., nortriptyline, doxepin) also have the potential to prolong the QT interval. When used together, these medications may increase the risk of ventricular arrhythmias, including torsade de pointes, and could elevate the risk of sudden death[127]. Pulmonary rehabilitation (PR) is a key COPD treatment approved by the American Thoracic Society and the European Respiratory Society [128]. It benefits patients with moderate-to-severe disease, functional limitations, and stable conditions without severe comorbidities [129]. PR improve independence, quality of life, and symptom control [130]. Beyond respiratory benefits, it also reduce depression and cognitive decline [131]. According to its effectiveness, PR should be included in treatment plans for all COPD stages [132,133].

Even with the high prevalence of depression in people with COPD and the impact on quality of life, research on its management remains limited [134]. With the pressing need for effective treatment options, it is essential to consider factors such as the risk of respiratory depression, potential side effects, and possible drug interactions when prescribing antidepressants [135].

Selective serotonin reuptake inhibitors (SSRIs) are considered the first-line treatment for depression in COPD patients, but they inhibit cytochrome P450 enzymes [136], which play a crucial role in the oxidative metabolism of therapeutic substances [137]. The initiation or use of SSRIs, SNRIs, and tricyclic antidepressants (TCAs), whether individually or in combination, has been significantly associated with an elevated risk of pneumonia [138].Particular attention is needed when prescribing tricyclic antidepressants (TCAs) and mirtazapine to COPD patients with hypercapnia [139,140]. Likewise, benzodiazepines can induce respiratory depression, posing a significant risk for COPD patients who retain CO₂ [141]. Frequently, bupropion, a dopaminergic agent, is prescribed for smoking cessation. However, data suggest that dopamine agonists may impair ventilatory responses to hypoxemia and hypercapnia by inhibiting carotid-body chemoreception through dopamine-mediated mechanisms[142]. Medication tolerance should be assessed over 1–3 weeks, with psychiatric referral for suicidal behavior or severe psychiatric comorbidities [143].

10. Future Perspective

Despite the impact of depression on COPD prognosis, clinical guidance on its management is limited. Future research should integrate mental health into COPD management, with regular screening for depression. Long-term efficacy of treatment needs to be assessed in large studies, including personalized pharmacological approaches with fewer side effects. By addressing these gaps, a more comprehensive and patient-centered approach to COPD care can be developed, ultimately improving both physical and mental health outcomes.

11. Conclusions

COPD is a severe and disabling condition with significant complications, one of the most troubling being comorbid depression. While there is substantial evidence supporting the connection between COPD and depression, the exact pathogenetic mechanisms are still not fully understood, and a universal treatment that works for most patients has not yet been established. Although current therapies help many individuals, they still need refinement and further development to enhance their effectiveness. Significant improvements in patient care and global health outcomes can only be achieved by advancing our understanding and treatment of both COPD and depression.