Depression and Chronic Obstructive Pulmonary Disease: Treatment Trials

Chronic obstructive pulmonary disease (COPD) affects over 16 million people in the United States and is a major cause of disability and death worldwide. Its prevalence and mortality are increasing disproportionately among the elderly, women, African-Americans, persons of lower socioeconomic status, and the populations of developing countries in which tobacco is aggressively marketed. In contrast to other major chronic diseases such as heart disease and cancer, medical treatments for COPD have not made decisive inroads into its morbidity or death rates over the last 20 years, resulting in continuing efforts to reduce disability in patients with established disease. Depression is a source of increased disability in COPD, and, as in other chronically ill patient populations, is often unrecognized and untreated in the primary and specialty care sectors. Nearly half of all patients experience some depressive symptoms and at least one-fifth have had one or more major depressive episodes, frequently of long duration. Evidence from randomized controlled trials supports the thesis that patients with mild depression improve with multidisciplinary rehabilitation, whereas patients with major depression may require specific pharmacotherapy to achieve significant improvement in mood disorder and day-to-day function. In addition to its impact on disability, depression may contribute indirectly to the etiology and progression of COPD through its relationship to addictive smoking. Mood disorder in adolescence and early adulthood contributes to early smoking and failure to quit, even after the onset of respiratory disease in later life. Patients with a history of major depression are more likely to fail in smoking cessation programs and to develop a major depressive episode when they do stop. This relationship calls for psychiatrically informed intervention models to improve long-term abstinence rates. The functional impairments associated with COPD are themselves potential promoters of depressive morbidity and chronicity, acting through complex causal pathways. Progressive hypoxia due to respiratory insufficiency leads to structural brain changes and neurocognitive deficits that impair day-to-day function and reduce adaptive potential; and oxygen therapy, as now practiced, offers minimal neurocognitive and mood benefits to most patients. Limited data from studies of experimental hypoxia in animals suggest that relatively mild lack of oxygen impairs the function and plasticity of critical neurotransmitter systems implicated in both cognition and mood, although current practice standards withhold oxygen therapy until late in the course of disease when the damaging effects of hypoxia on the brain have become well established. Neuropsychiatric approaches to the prevention, delay, and treatment of brain dysfunction should be a primary objective of research to improve patient outcomes. A comprehensive relational model that links pulmonary disease, hypoxia, neurocognitive impairment, and structural brain disease with depression provides a useful framework for the design of such studies. The near-term research agenda should include three components: (1) practical methods for improving physician and patient recognition of depression and neurocognitive impairment as targets for intervention; (2) additional trials of standard antidepressant treatment approaches for both major and minor depression; and (3) tests of the hypothesis that late-onset depression in patients with COPD is a marker for the presence of neurocognitive deficits and structural brain changes. The long-range research agenda must aim at preventive interventions designed to forestall brain deterioration. Controlled clinical trials of supplemental oxygen in patients with mild hypoxia and minimal cognitive deficits are needed to determine whether early treatment can reverse or moderate decline, reduce the incidence and chronicity of depression, and improve response to antidepressant treatment. Novel neuroprotective therapies such as antioxidant supplementation and modulation of monoaminergic neurotransmission, coupled with overall improvements in long-term respiratory disease management that minimize episodes of increased systemic oxidative stress, should be considered for multisite trials designed to define optimal treatment and prevention.