Diseases of the lung are diverse in pathophysiology, course, and treatment, creating several challenges for the assessment and treatment of comorbid depression. The anxiety associated with shortness of breath—at times nearly indistinguishable from that of a panic—may be the most prominent psychiatric symptom in individuals with lung disease. However, depression of various degrees is also common (Fig. 16-1) and associated with significant morbidity and mortality. This chapter will first review the major classes of pulmonary diseases and the known epidemiology of depression in these groups. Subsequent sections will discuss over-arching pathophysiologic mechanisms, as well as the novel features of depression onset, progression, and treatment in this population.

Asthma, the chronic inflammation of airways characterized by smooth muscle hyper-reactivity, is common, and likely results from a combination of environmental and genetic factors. Worldwide, the prevalence of asthma has risen dramatically in recent years, especially among children and adolescents. In the United States, asthma prevalence increased from 7.3% in 2001 to 8.4% in 2010, making it one of the most common chronic diseases.¹ Exercise, infection, allergens, and other airborne irritants can all be associated with the onset of an asthma attack, which is typically marked by wheezing, dyspnea, chest discomfort, and coughing. Although there is no cure, there is effective treatment to prevent and treat acute asthmatic attacks. Depression has been reported in 15% to 50% of individuals with asthma.^2–4 Asthma has also been linked to suicidal thoughts, behaviors, and attempts, though the causal mechanisms remain poorly understood.⁵

Chronic obstructive pulmonary disease (COPD) involves the gradual, progressive narrowing of airways over time, but unlike asthma, these changes are not reversible. The associated tissue pathology may arise from cigarette smoke, other environmental exposures, and/or genetic disposition, such as in alpha-1 antitrypsin deficiency. Progression of COPD may slow sufficiently to allow psychological and social adjustment to the illness, though depression still arises in approximately 20% to 25% of cases, a rate higher than found in the general population.^6,7 One study of elderly patients with COPD found rates of clinical depression above 40%.⁸ Mood may also be acutely worsened by episodic complications of the disease, including infections, hospitalizations, and the need for supplemental oxygen. While depression does not directly correlate with pulmonary function (e.g., percent expected FEV₁), there is evidence that mood tends to worsen with advancing stages of disease.⁹

Cystic fibrosis (CF) arises from one of many autosomal recessive mutations in the CF transmembrane conductance regulator (CFTR) gene. As a consequence, sodium and chloride balance is disturbed across epithelial membranes, most critically in the lungs but also in the liver and pancreas. Diabetes, infertility, and gastrointestinal malabsorption with subsequent malnutrition are all typical complications of CF, though respiratory complications, arising from inflammation and infection, remain the most common cause of mortality. Depression prevalence ranges from approximately 11% to 17%, and is associated with poorer quality of life.^10,11 One center reported PHQ-9 scores in the clinically depressed range in 33% of CF patients, with 10% endorsing suicidal thoughts.¹²

Interstitial lung disease (ILD) can arise from environmental insults, autoimmune processes, or idiopathic mechanisms. Silicosis, systemic lupus erythematosis, rheumatoid arthritis, and drug adverse reactions are all examples of this group. Since the etiology varies, the course, severity, and prognosis in this group of diseases are variable and unpredictable, and when serious, may progress to pulmonary fibrosis. Sarcoidosis is a systemic inflammatory disease in which the lungs are the most commonly affected organ. Approximately half of patients develop permanent disease, with less than 15% progressing to pulmonary fibrosis. In idiopathic pulmonary fibrosis (IPF), the onset typically occurs after age 50, and the symptoms may progress suddenly and unpredictably. Transplantation may become an urgent consideration in severe cases of ILD, especially in those with IPF. Similar to COPD, depression prevalence in individuals with ILD is approximately 20% to 25%, and is significantly correlated with level of dyspnea and functional status.^13–15 Compared to matched controls, significant elevations in depression scores have been described in individuals with occupational silicosis.¹⁶

Sleep apnea (SA), marked by decreased or abnormal breathing during sleep, can arise from central or obstructive causes (OSA), with the latter accounting for the vast majority of cases. Surprisingly, many patients are unaware of their breathing difficulties and sleep disturbance. As a consequence, SA can occur for long periods without detection or treatment, gradually leading to cognitive impairment and changes in mood. The prevalence of depression in this population is estimated at 15% to 30%, with the severity of SA increasing the longitudinal risk of developing depression in multivariate models.¹⁷ Preliminary evidence also suggests that the combination of insomnia and major depression appears to increase the risk of having OSA compared to having either condition alone.¹⁸ Daytime fatigue is the symptom that is most predictive of depression, and may serve as a mediating factor in the relationship between sleep disorder and depressed mood in this population.¹⁹ It is important to note that disrupted sleep is common in pulmonary disease in general, even in the absence of OSA; a “negative” sleep study should not preclude further assessment and treatment of dyssomnia.

Pulmonary hypertension is characterized by elevation of blood pressure in the vasculature of the lung. It can represent a primary disease process, or arise as a complication of cardiac, vascular, or pulmonary dysfunction. Idiopathic and familial variants are relatively rare compared to pulmonary hypertension arising from scleroderma, rheumatoid arthritis, or systemic lupus erythematosus. Pulmonary causes include COPD, ILD, and SA, though the latter tends to have a relatively minimal effect. Among patients with pulmonary arterial hypertension (PAH), depressive symptoms as measured by PHQ-8 have been suggestive of major depressive disorder in 15% of cases, with 40% of individuals reporting symptoms in the mild to moderate range.²⁰

The possibility that pulmonary disease and depression share an underlying pathophysiology remains intriguing, though relatively unexplored (Box 16-1). There is increasing recognition of an “inflammatory type” of depression, marked by elevations in pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF)-α, ultimately leading to oxidative and nitrosative stress as well as disrupted serotonin metabolism in the brain.

Although cytokines and these other stressors can produce a depressed phenotype, inflammation is not necessarily observed in all cases of depression. This discrepancy may in part depend on the timing of the measurement of inflammatory markers in relation to the onset of mood symptoms. Interestingly, COPD is also associated with systemic, as well as localized, inflammation in many but not all cases.²¹ There is increasing focus on understanding these inflammatory factors as they are somewhat distinct among lung diseases, and can guide more effective treatment.²²

Depression may represent a cause or effect of the variation in inflammatory factors. One of the few studies to link these phenomena revealed that asthmatics with moderate-to-severe depression had significantly higher levels of serum and sputum TNF-α, as well as lower levels of the anti-inflammatory cytokine IFN-γ, when compared to matched nondepressed asthmatics as well as healthy controls.²³ In a study of patients with COPD, elevated serum levels of TNF-α were correlated with more severe depressive symptoms.²⁴ In a larger COPD cohort, however, physiologic measures of inflammation were not associated with the incidence of depression.²⁵ Inflammation also plays a prominent role in the pathophysiology of CF and ILDs, but specific links with mood disorders have not been elucidated.

Other shared mechanisms may exist. Vitamin D deficiency represents a common complication of CF, and is a theoretical risk factor for developing depression. Although studies examining the relationship between vitamin D level and mood have been generally mixed, one cross-sectional study of children with CF did find an association between lower serum vitamin D levels and higher depression scores.²⁶ Larger, longitudinal studies are necessary to confirm this finding, though proactive monitoring of vitamin D levels and supplementation are nonetheless reasonable recommendations in this population. While the precise mechanism linking vitamin D to depression is not well understood, high-dose supplementation in CF patients does appear to reduce levels of IL-6 and TNF-α, though other factors, including IL-1, are not changed significantly.²⁷

Although sleep dysfunction is observed in SA as well as depression, the precise physiologic relationship linking the diseases remains unknown. One study of middle-aged men found lower serum testosterone levels, and significantly higher depression scores, in patients with OSA when compared to matched controls.²⁸ Another growing theory suggests that oxidative stress may mediate the relationship. Increased production of superoxide radicals, along with decreased serum nitrate and nitrite levels, represents an indicator of systemic oxidative stress. The overall level of oxidative stress appears to be positively correlated with the degree of sleep fragmentation, nocturnal hypoxemia, daytime fatigue, and depressive symptoms.²⁹ Oxidative stress also activates inflammatory pathways, providing a theoretical explanation for why SA can lead to cardiac and metabolic diseases, as well as mood and cognitive disorders.

Notably, environmental stress and associated exposures can lead to comorbid pulmonary disease and mood disorders. The most dramatic instances of this phenomenon include experienced acts of war and terrorism, such as the attacks on the World Trade Center in 2001. In the years following September 11, upper and lower respiratory conditions arising from exposure to dust and smoke, primarily asthma, occurred in approximately 20% to 30% of police and civilian responders.³⁰ While epidemiologic studies have found a PTSD prevalence of approximately 10% in this population, probable depression was also found in a significant 9% to 10% of individuals near the attacks.^31,32 As a consequence, screening for depression, as well as PTSD symptoms, is critical in patients presenting with pulmonary sequelae from occupational or traumatic exposures.

In pulmonary illness, the clinical presentation of depression potentially has several distinctive features (Fig. 16-2). Comorbid anxiety, especially around dyspnea or hypoxia, is relatively prevalent, with panic attacks closely resembling acute exacerbations of asthma or COPD (Box 16-2).³³ Because anxiety is such a prominent and dramatic symptom, it may mask underlying depression and other psychiatric comorbidities. Fatigue is a common symptom in both chronic lung disease and depression, though is certainly not specific to either. Thus, careful screening for negative or depressive thoughts (hopelessness, helplessness, and self-blaming) can be more informative than relying on neurovegetative or somatic indicators of depression.

For patients with chronic lung disease, especially COPD or ILD, any history of smoking, regardless of duration or known causality, can lead to specific feelings of guilt. Similarly, the inability to quit smoking as the disease progresses can engender self-blame and hopelessness. Encouragement, reassurance, and aggressive interventions to promote smoking cessation may address these concerns. It is important to note that the presence of depression predicts a lower rate of success at quitting smoking, underscoring the need for proactive screening and treatment of mood symptoms.³⁴

Given the extensive overlap of mood, sleep, and lung function, insomnia may serve as a heralding symptom of depression. Patients with subjective sleep disturbance and daytime fatigue should be evaluated for depression, keeping in mind that the primary pulmonary illness coexists. Sleep studies should be considered in patients with any refractory sleep disturbance, especially if they experience daytime fatigue.