Alpha-1 antitrypsin deficiency (AATD) increases susceptibility to lung disorders such as emphysema and chronic obstructive pulmonary disease (COPD). Patients with AATD are known to develop lung disease at a significantly younger age compared with the general population. 

The typical pattern of lung disease onset includes the manifestation of respiratory symptoms such as cough, dyspnea, and wheezing in the third decade of life. The severity of these symptoms depend in part on whether there are additional risk factors such as smoking history or occupational exposure to mineral dust and fumes. 

The onset of respiratory illness typically means increased hospitalizations, polypharmacy, and a reduced quality of life. Shortness of breath and accompanying fatigue decreases patients’ ability to carry out activities of daily living, which can result in impaired social interactions. 

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It is no surprise that studies have demonstrated a link between lung disease and depression. Studies on patients with interstitial lung disease found that the prevalence of depression is significantly higher among patients with interstitial lung disease (14%-49%) compared with the general population. 

Read more about AATD etiology 

When assessing depression in a patient population, researchers have a number of depression assessment scales to choose from. Among the most commonly used are the Hospital Anxiety and Depression Scale and the Center for Epidemiologic Studies Depression Scale. These and other depression assessment scales help researchers to assess mental health from different angles to gain a fuller appreciation on how various mental health factors intersect. 

“Most likely, anxiety and depression emanate from a complex interaction of socio-economic status, environmental and genetic factors, physical disability and reduced social activities,” Yohannes writes in the Expert Review of Respiratory Medicine. 

The Psychological Burden of AATD 

To look at the specific impact of AATD on patient mental health, we can refer to a study conducted by Mobeen and colleagues published in the Journal of Chronic Obstructive Pulmonary Disease. They studied 840 patients with AATD who were on the UK ADAPT registry from 1996 to 2016. 

Mobeen and colleagues collected data regarding patient history of respiratory illness and lung function status. A history of depression or anxiety was assessed through medical records. The study comprised patients with AATD of all genotypes. 

The study revealed that depression and anxiety was associated with poorer lung function as measured in terms of forced expiratory volume in 1 second and St George’s Respiratory Questionnaire score. This was true for patients in both the PiZZ/PiZnull and the PiSZ cohorts. 

“The present study of AATD subjects is consistent with observations in non-deficient COPD that those with depression and/or anxiety exhibit a higher symptom burden and are likely to have more severe disease,” Mobeen et al write.

Their study highlights the significant psychological burden of AATD. It is important to note that only the impact of lung disease was assessed in this study, which excludes other comorbidities from AATD such as liver disease. It is likely that these and other comorbidities also contribute to feelings of depression and anxiety. 

“Increased feelings of panic, fear and hopelessness, in addition to dyspnea and fatigue, may amplify a cycle that modulates anxiety and depression,” the authors say. 

Possible Solutions 

It is therefore important that physicians treat mental health complaints with the same urgency as the physical manifestations of AATD. Primary care physicians should engage with psychiatric services at the first signs of depression and/or anxiety. 

Mobeen and colleagues report that this is already happening in more than one-half of the patients with AATD and psychiatric illness—around 61% in the PiZZ/PiZnull cohort and 72% in the PiSZ cohort. However, broaden the scope to include patients with other lung diseases and the figure drops significantly; a study found that less than 20% of patients with interstitial lung disease and mental illness were on antidepressant drug therapy. 

“Anxiety and depression are common in patients with interstitial lung disease, but frequently overlooked and un- or under-treated,” Yohannes writes. 

Read more about AATD treatment 

It is important to note that some scientists are skeptical that antidepressants are the best solution for mental illness in patients with AATD. The reasons for this are two-fold: first, antidepressants do not work for everyone and are known to worsen depression in some patients; second, antidepressants may interact with existing medications to produce yet-unknown adverse effects that may result in further physical impairment. 

In view of this, it may be better to focus on improving lung function parameters where there is still room to do so. In AATD, this means increasing exercise capacity and reducing dyspnea—studies have shown that patients who score better on breathlessness scores have a lower prevalence of depression and/or anxiety. Physicians can best pursue this approach while maintaining appropriate psychiatric monitoring in a multidisciplinary setting. 

Further research is needed to validate just how well pharmacological and nonpharmacological approaches work to improve depression and/or anxiety in patients with AATD. There is also room for psychological assessment tools to be further refined to fit the context of patients with AATD. 


Mobeen F, Edgar RG, Pye A, Stockley RA, Turner AM. Relationship between depression and anxiety, health status and lung function in patients with alpha-1 antitrypsin deficiencyCOPD. 2021;18(6):621-629. doi:10.1080/15412555.2021.1991904

Yohannes AM. Depression and anxiety in patients with interstitial lung diseaseExpert Rev Respir Med. 2020;14(9):859-862. doi:10.1080/17476348.2020.1776118

Tejwani V, Stoller JK. The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiencyTher Adv Chronic Dis. 2021;12_suppl:2040622321995691. Published 2021 Jul 29. doi:10.1177/2040622321995691