Chronic Obstructive Pulmonary Disease (COPD) Activity: Serotonin Transporter (SERT), Cytokines and Depression (CASCADE Study)

Depression is highly prevalent among patients with chronic obstructive pulmonary disease
(COPD) and is associated with adverse clinical outcomes. The overall goal of this proposal
is to examine the impact of inflammation and genetic risk factors on depression in patients
with severe COPD, and to assess the combined effects of inflammation, genetics, and
depression on changes in functional outcomes. There is increasing evidence that COPD is
associated with systemic inflammation that impacts other organ systems. High levels of
systemic inflammatory markers have also been linked to increased risk of depression in both
healthy and chronically ill populations. The neurotransmitter serotonin which is involved in
the pathophysiology of affective disorders is regulated by the serotonin transporter (SERT)
that controls reuptake of serotonin at brain synapses. Recent studies report that SERT
polymorphisms are associated with depression, suggesting that variants of this gene may be
important in determining whether patients with COPD will develop depression during the
course of their disease. The preliminary data linking SERT polymorphisms with depression and
data suggesting a relationship between inflammation, depression and COPD strongly argue for
a large scale prospective study to critically test these relationships. Therefore, the aims
of this prospective study of patients with moderate to very severe COPD are to: 1) Examine
the relationship between SERT polymorphisms with depression; 2) Examine the bi-directional
longitudinal relationship between markers of systemic inflammation (CRP, IL-1ra, IL-6,
IL-12, TNF-α, and IFN-γ) and depressive symptoms in COPD, and explore the role of
exacerbations and SERT genotype in this relationship; and 3) Determine the relationship of
depression, inflammation, and SERT genotype with decline in functional outcomes (six minute
walk test distance, physical activity measured with accelerometers, dyspnea severity, and
health related quality of life) in COPD over 2 years. Patients with COPD GOLD Stages II-IV
(n=350) will be recruited from two clinical sites over 30 months. Assessments at baseline,
year 1 and year 2 will include: blood samples for genotyping (5-HTTLPR, STin2 VNTR, and
rs25331) and cytokine assays (CRP, IL-1ra, IL-6, IL-12, TNF-α, and IFN-γ), spirometry,
assessment of depression, functional capacity (six minute walk test), performance (physical
activity derived from accelerometry), dyspnea, and health related quality of life (HRQL). We
will use advanced longitudinal statistical techniques, structural equations modeling and
latent growth models, to assess the dynamics of change in depression, inflammation, and
functional status as posited by our models as these processes unfold over time.

Inclusion Criteria:

- Diagnosis of COPD confirmed by the following: 1) FEV1/FVC < 70%; 2) Moderate to very
severe disease by GOLD criteria (FEV1 <65%); 2) Age > 40 years; and 3) A significant
history of current or past cigarette smoking (> 10 pack-years);

- Stable disease with no acute exacerbations of COPD in the past 4 weeks;

- Ability to speak, read and write English

Exclusion Criteria:

- Acute COPD exacerbation within the past 4 weeks (temp exclusion)

- Chronic obstructive lung disorders unrelated to COPD: asthma, bronchiectasis, cystic
fibrosis

- Idiopathic Pulmonary Fibrosis

- Congestive Heart Failure

- Chronic renal failure requiring dialysis

- Primary pulmonary vascular disease

- Chronic inflammatory, infectious or auto-immune disease, e.g. osteomyelitis, crohn's
disease or rheumatoid arthritis

- Chronic liver disease

- Metastatic cancer

- Chronic antibiotic use or ongoing infection

- Chronic oral prednisone use

- Moderate to severe dementia

- Severe primary mental illness, e.g. schizophrenia, bipolar disease, severe obsessive
compulsive disorder

- <2 years life expectancy

- History of fainting with spirometry