Abstract
The prevalence of depression in chronic obstructive pulmonary disease (COPD) is greater than in the general population, but the mechanism is unknown. Depression has been linked mechanistically to testosterone deficiency, and testosterone deficiency (hypogonadism) affects many men with COPD. Accordingly, we hypothesized that significant depressive symptoms would be associated with hypogonadism in men with COPD. The hypothesis was tested in a prospective cross-sectional investigation of 104 men (FEV1 = 43 ± 1% predicted (±SE)), 36 of whom had significant depressive symptoms (Geriatric Depression Scale score or GDS ≥ 11). Hypogonadism was present in 14 patients with GDS ≥ 11 (39%) and in 21 with GDS < 11 (31%; p = 0.41). The independent association between depressive symptoms and gonadal state was evaluated after adjusting for potential confounders: combined severity of lung disease and functional impairment (BODE-index), co-morbidities (Charlson co-morbidity-Index), age, active smoking, education, and marital status. After controlling for confounding variables, multivariable logistic-regression analysis revealed that only BODE-index (odds ratio 1.40; p = 0.003), lack of companion (2.73; p = 0.045) and younger age (0.93; p = 0.021) were independently associated with depressive symptoms. In a secondary analysis, patients were stratified into those with severe depressive symptoms (GDS ≥ 19) and those with mild depressive symptoms (GDS 11-18). Prevalence of hypogonadism was greater in first group than in the second (62% vs. 26%; p = 0.036). After controlling for confounders, however, gonadal state was not associated with severe depressive symptoms. Similarly, gonadal state was not associated with mood and motivation subscale scores of the GDS. In conclusion, presence of significant depressive symptoms was not associated with hypogonadism in men with COPD.
INTRODUCTION
The risk of developing depressive symptoms is greater in patients with chronic obstructive pulmonary disease (COPD) than in the general population (Citation1). In addition to personal suffering and mental anguish, depression in COPD is associated with more physical disability, greater difficulty in coping with the pulmonary disease, less success with smoking cessation, longer hospitalization during acute exacerbations and increased mortality (Citation2,3).
Patients with COPD are exposed to a number of bio-physiological, functional, social, and psychological processes that have been associated with increased risk of depression (Citation4) –particularly in genetically-predisposed individuals (Citation5). These include smoking, oxidative stress, vascular disease, decreased social contacts and physical and psychological stress (Citation2).
Although not universally established (6;7), clinical (8–10) and laboratory (11) observations suggest that low testosterone levels may be an additional mechanism. Testosterone activates the serotonergic system in the frontal cortex, cingulate cortex and hippocampus (11,12). Testosterone also inhibits monoamine oxidase-A, the enzyme that catabolizes intraneuronal norepinephrine and serotonin in the medial prefrontal cortex (Citation13) and decreases activity of the promoter for the corticotrophin-releasing hormone (Citation14). These observations have direct implications for the hypothesized causal connection between low testosterone levels and depression.
First, all cortical areas listed above are important in the modulation of mood (15,16). Second, growing experimental evidence supports the role of low norepinephrine and serotonin levels in the pathogenesis of depression (Citation4). Three, considerable evidence suggests that corticotrophin-releasing hormone and cortisol are involved in depression (Citation4). The last three considerations raise the possibility that low testosterone levels (hypogonadism) could magnify the effect of biochemical, psychophysiological and social factors on the risk of developing depression (Citation8). Considering the high prevalence of hypogonadism in men with COPD (Citation17), and given the alleged mechanistic link between testosterone and depression (11,12), it would appear biologically plausible to predict a link between depressive symptoms and gonadal state in men with COPD.
In this study, the presence of depressive symptoms was determined using the Geriatric Depression Scale (GDS) (18–20). In addition to identifying patients with depressive symptoms, the GDS scale can also be used to stratify patients into those with mild and those with severe depressive symptoms (18). Furthermore, the GDS can be used to identify separate clusters of symptoms such as mood symptoms (mood subscale) and motivation symptoms (motivational subscale) (Citation21).
The main objective of the study was to evaluate the relationship between hypogonadism and the presence of depressive symptoms in men with COPD. Specifically, we tested the primary hypothesis that hypogonadism would be associated with significant depressive symptoms in men with COPD. Two secondary analyses were also performed. One to explore the impact of the clinical characteristics (including gonadal state) on severity of depressive symptoms and another one to evaluate the impact of the clinical characteristics on mood and motivational subscale scores.
This is the first prospective cross-sectional investigation to directly explore the impact of gonadal state on depressive symptoms in men with COPD.
MATERIALS AND METHODS
Patients
One hundred and four men with COPD were enrolled. Patients were recruited from the outpatient clinic of the Division of Pulmonary and Critical Care Medicine of the Edward Hines, Jr. Hospital. Inclusion criteria were as follows: age 55 years or older, chronic airway obstruction (post-bronchodilator forced expiratory volume in one second of 70% predicted or less, ratio of forced expiratory volume in one second to forced vital capacity of 70% or less) (Citation22), and stable clinical condition without an exacerbation during the preceding six weeks. Exclusion criteria included orchiectomy and current androgen and antiandrogen therapy. Patients with cirrhosis and alcoholism were excluded because these conditions can cause low testosterone concentrations. Appropriate institutional review board approved the study, and written consent was obtained.
Measurements
Demographic and clinical data
Demographic data were collected on enrolment in the study. Presence and severity of co-morbidities, including diagnosis of psychiatric disorders, were extracted from the patients’ medical records and patient self-report (Citation23).
Assessment of Depressive Symptoms
Presence of depressive symptoms was determined using the GDS developed by Yesavage et al (Citation18). In contrast to other screening tools, such as the Hamilton Depression Rating Scale (Citation24) and the Beck Depression Inventory (Citation25), somatic complaints are excluded from the GDS items, as they are considered to reflect concerns that are part of the normal aging process. The GDS score ranges from 0 (no depression) to 30 (severe depression) (18;19).
In addition to the assessment of depressive symptoms in general, the GDS allows stratification of patients into those with mild depressive symptoms (GDS 11-18) and those with severe depressive symptoms (GDS ≥ 19) (Citation18). Furthermore, the GDS allows also the identification and quantification of separate clusters of symptoms such as mood symptoms (mood subscale) and motivation symptoms (motivational subscale) (Citation21). The mood subscale, which consists of nine GDS items, reflects the presence of pessimistic outlook and sad mood. The motivational subscale consists of six items and identifies a loss of motivation or energy and difficulty in concentrating, making decisions, and problem solving (20;21).
BODE index
The multidimensional BODE index (Citation26), as modified by Martinez et al. (Citation27), was used to quantify the overall severity of lung disease and its impact on functional capacity. The four variables required for the calculation of the BODE index are: body mass index (B; kg/m2), degree of airflow obstruction (O; post-bronchodilator FEV1 percent predicted), level of functional dyspnea (D; Shortness of Breath Questionnaire) (Citation27) and exercise capacity (E; six-minute walking distance) (Citation26). The BODE index can range from 0 (best functional capacity) to 10 (worse functional capacity) (Citation26).
Charlson co-morbidity index
The Charlson co-morbidity index (Citation28) was used to determine the impact of co-morbid conditions on depressive symptoms. The relative risk of each co-morbid condition is assigned integer weights which added can give a score ranging from 0 to 33, with higher scores indicating more comorbid conditions (Citation28).
Pulmonary function tests
Lung volumes were measured by plethysmography and timed spirometry.
Blood samples
Morning blood samples were collected for measurement of free testosterone, total testosterone, and serum concentrations of luteinizing hormone. Free testosterone concentration was determined by equilibrium dialysis (Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA). For this technique, the intra- and inter-assay coefficients of variation are 5.4 and 6.2% (Citation29). Total testosterone concentration was determined by competitive immunoassay (Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA) in the first 53 patients –both intra- and inter-assay coefficients of variation equal to 4.7% (Citation29).
In the remaining 51 patients total testosterone concentration was determined by liquid chromatography tandem mass spectrometry (Quest Diagnostics, Nichols Institute, San Juan Capistrano, CA) –intra-assay coefficient of variation ranging from 9.1 to 10.8%, and inter-assay coefficient of variation ranging from 10.0 to 12.6% (Citation30). Because total testosterone concentrations with these two techniques are equivalent (Citation30), the concentrations of total testosterone obtained in the first group of patients were combined with concentrations of total testosterone measured in the second group of patients. Finally, two-site immunoassay was used to measure serum concentration of luteinizing hormone (Bayer Diagnostics, Tarrytown, NY) –intra-assay and inter-assay coefficients of variation 2.9% and 2.4% (Citation29).
Definition of hypogonadism
Hypogonadism was defined as the occurrence of free testosterone < 35 pg/ml for patients younger than 70 years, and free testosterone < 30 pg/ml for patients 70 years old and older (Citation30). These thresholds have been identified by assessing free testosterone concentrations in 264 ambulatory healthy men between the ages of 18-89 years who were taking no medication (Citation30).
Protocol
Eligible patients who agreed to take part in the study underwent pulmonary function testing, functional assessment (including 6-minute walking distance) (Citation31), and collection of blood samples. Thereafter, patients completed the GDS (Citation18) questionnaire and the Shortness of Breath Questionnaire (Citation27). All patients were literate and none had any vision or manual dexterity impairment that restricted their ability to read and complete both self-administered (19,27) questionnaires without assistance. Patients were asked to complete the questionnaires independently (Citation32).
Data analysis
The Kolmogorow-Smirnov test was used to assess distribution of data. Normally distributed data are presented as mean ± standard error (SE). Non-normally distributed data are presented as median and interquartile ranges (IQR), and categorical variables are reported as proportions. Comparisons between patients experiencing significant depressive symptoms (GDS ≥ 11) and patients without such symptoms (GDS < 11) were performed using unpaired Students t-test for normally distributed continuous variables, differences in median using Mann-Whitney U-test for skewed continuous variables and differences in frequencies using Pearson Chi-square, as appropriate.
Multivariable logistic regression analysis was performed to evaluate the impact of the clinical characteristics of patients on the presence of significant depressive symptoms (i.e., GDS ≥ 11). The independent variables for the multivariable logistic regression analysis were: gonadal state, combined severity of lung disease and functional impairment (BODE index), active smoking, age, marital status (married/cohabitating), education (completed high school or above vs. less than high school), and Charlson co-morbidity-Index. Finally, 2 secondary analyses were also performed. In the first we explored the impact of the clinical characteristics (including gonadal state) in patients with severe depressive symptoms (GDS≥19) (Citation18). In the second, we evaluated the impact of the clinical characteristics on mood and motivational subscale scores (Citation21). Statistical analysis was performed using the Package for Social Sciences (version 18.0, SPSS, Chicago, IL). A value of p < 0.05 was considered significant.
RESULTS
Of 104 participants, 36 (35%) had significant depressive symptoms (GDS ≥ 11) ().Twenty-one patients –14 of 36 patients with GDS ≥ 11 (39%) and 7 of 68 (10%) patients with a GDS < 11 –carried a diagnosis of mood disorder (p = 0.029). Of the 21 patients with mood disorder, one had a diagnosis of bipolar disorder and all the rest had a diagnosis of major depressive disorder. Of the 14 patients with a GDS ≥ 11 and a diagnosis of mood disorder 9 were receiving medical treatment for depression. Of the 7 patients with a GDS < 11 and a diagnosis of depression, 3 were receiving medical treatment for depression.
Table 1 Characteristics of men with COPD who experienced significant depressive symptoms (Geriatric Depression Scale score ≥ 11) and without such symptoms (*)
Depressive symptoms and patients’ characteristics
The prevalence of hypogonadism (Citation30) was equivalent in patients with GDS scores in the depressed range and in patients with GDS scores below the depressed range (). BODE-index was worse in patients experiencing significant depressive symptoms than in patients without such symptoms (). More patients with high GDS were active smokers and were without a partner (no wife or a companion) than patients with low GDS ().
Of the four components of the BODE-index only the Shortness of Breath Questionnaire score was worse in patients with GDS ≥ 11 than in patients with GDS < 11: 68 ± 3 and 42 ± 3 (p < 0.0001). In contrast, FEV1 (42 ± 3% and 44 ± 2%, p = 0.421), body mass index (30 ± 1 kg/m2 and 29 ± 1 kg/m2; p = 0.552) and six-minute walking distance (345 ± 21 meters and 370 ± 13 meters, p = 0.276) were equivalent in the two groups.
Variables associated with increased risk for depressive symptoms
Multivariable logistic-regression analysis showed that greater BODE-index (odds-ratio 1.40; p = 0.003), lack of partner (odds-ratio 2.73; p = 0.045) and younger age (odds-ratio 0.93; p = 0.021) were independently associated with depressive symptoms after controlling for gonadal state, active smoking, Charlson and level of education ().
Table 2 Multivariable logistic analysis to determine relationship between significant depressive symptoms and patients’ characteristics
Mood and motivational subscale scores
As expected, the motivational subscale score (that reflects cognitive complaints such as difficulty with problem-solving, decision-making and concentration) and the mood subscale scores (that reflects more sadness and pessimistic outlook) were higher in patients with GDS ≥ 11 (3.8 ± 0.2 and 4.6 ± 0.4) than in patients with GDS < 11 (2.5 ± 0.1 and 0.6 ± 0.1; p < 0.00001). On multivariable regression analysis, BODE-index, and younger age independently associated with GDS mood score (p≤0.045). In contrast, none of the seven independent variables were associated with motivational subscale score.
Subgroup analysis
Out of 36 patients with a GDS ≥ 11, 23 patients had mild depressive symptoms (GDS 11-18) and 13 patients had severe depressive symptoms (GDS ≥ 19). In the sub-group with mild depressive symptoms the prevalence of hypogonadism was 26% and the corresponding value in the sub-group with severe depressive symptoms was 62% (p = 0.036). Despite the higher prevalence of hypogonadism in patients with severe depressive symptoms, on multivariable logistic-regression analysis gonadal state was not associated with severe depressive symptoms when controlling for BODE-index, partner, age, smoking, Charlson and level of education.
DISCUSSION
This is the first prospective cross-sectional study to directly explore the impact of hypogonadism on depressive symptoms (including mood and motivation) in men with COPD. The study has three major findings. First, testosterone deficiency –when corrected for confounding factors –was not associated with a higher prevalence of significant depressive symptoms. Second, the overall severity of lung disease with its impact on functional capacity (BODE-index), lack of partner and younger age were independently associated with the occurrence of significant depressive symptoms. Lastly, BODE-index and younger age were also independently associated with the occurrence of pessimistic outlook and sad mood (mood subscale).
Impact of hypogonadism on depressive symptoms
Contrary to our hypothesis, testosterone deficiency –when corrected for confounding factors –was not associated with a higher prevalence of significant depressive symptoms. There are at least two possible explanations for this finding. First, the attributed risk of depressive symptoms secondary to low testosterone level is small-to-none. Second, testosterone affects mood only in a genetically-determined subgroup.
Our hypothesis that hypogonadism would be associated with significant depressive symptoms in men with COPD was based on published laboratory studies (Citation11) and clinical observations conducted in patients who, for the most part, had no COPD (8,9). This association, however, has not been universally demonstrated (Citation7) and it cannot be supported or refuted epidemiologically. This because it remains unclear whether prevalence of hypogonadism in men with COPD is greater than in the general population (Citation17). (If low testosterone levels had a synergistic effect on depression in COPD a greater prevalence of hypogonadism paralleling the greater prevalence of depression in COPD would be expected.)
One way to reconcile our findings with studies supporting an association between low testosterone and depression (8,9,11) is the presence of genetic variability in the androgen-receptor gene (9,33). This gene has a highly polymorphic CAG trinucleotide repeat sequence, which results in a variable number of glutamines in the receptor's N-terminal (Citation33). A shorter CAG-repeat length increases the gene's expression –i.e., increased transactivation (Citation33). Results from the Massachusetts Male Aging Study (Citation9) and the CARDIA Male Hormone study (Citation33) suggest that the risk for depression is inversely proportional to the transactivation of the androgen receptor gene.
Non-testosterone factors and depressive symptoms
Factors (other than testosterone) that could play a role in determining depression in men with COPD include severity of lung disease, functional impairment, younger age, level of education, lack of companion, burden of co-morbidities, and smoking.
The possibility that severity of lung disease and greater functional impairment –as quantified by BODE-index –could predispose to depressive symptoms is supported by two findings. First, BODE-index was worse in patients experiencing depressive symptoms than in patients without such symptoms (). Second, BODE-index was independently associated with depressive symptoms () (including mood subscale scores). The independent association between depressive symptoms and BODE-index is supported by similar findings reported by Al-Shair et al. (Citation34).
Lack of companion was strongly associated with significant depressive symptoms (Tables and ). This finding is in agreement with previous reports of lower rates of depression in married people or those cohabitating than in people who never married or who are divorced, separated or widowed (35,36). Whether lower rates of depression in married people result from social factors, selection bias, or a combination of both remains to be determined (Citation37).
Patients with GDS ≥ 11 were younger than those with a GDS < 11: 66 ± 1 years and 71 ± 1 years; p < 0.001 (). Younger age was also independently associated with a GDS ≥ 11 (). Cohort effect, healthy survivor bias, unwillingness to report symptoms and belief that depressed mood is part of the unavoidable aging process may all contribute to association between younger age and significant depressive symptoms () (3,16,35).
All patients had a history of cigarette smoking, and more than 40% of those with depressive symptoms were active smokers (). Despite the higher prevalence of active smoking in patients with depressive symptoms () and the reported association between smoking and depression (38;39) –particularly in men (Citation40) –active smoking was not independently associated with significant depressive symptoms (Tables ). In addition, active smoking did not discriminate between patients with and without sad mood or poor motivation. Several mechanisms could explain the absence of such associations. First, the relationship between smoking and depression is not causal but represents a common vulnerability to both smoking and depression (Citation41). Second, history of smoking is sufficient to cause (irreversible) white matter damage (Citation42). Such damage could in turn contribute to the development of depression (Citation16).
Scores of Charlson co-morbidity-Index in patients with or without significant depressive symptoms were equivalent (). The equivalent burden of co-morbidities in the two groups is surprising considering that depression has been reported to be more prevalent in patients with medical co-morbidities than in those without medical co-morbidities (Citation15). This finding raises the question of whether a unique synergism between COPD and perceived mood may be operative (43,44).
In persons younger than 54 years, lower socioeconomic status (less income, and low education) has been associated with increased prevalence of depression (Citation45). In the current investigation, however, there was no association between level of education and significant depressive symptoms (). Older age and selection bias (most veterans receive care in the Veterans Administration system have low income) (Citation46) may explain such discrepancy. This possibility is supported by an investigation of Borson et al. (Citation47) who reported that neither level of education nor income distinguished between depressed and non depressed veterans 60 years old or older.
Treatment of depressive symptoms and depression
The 35% prevalence of significant depressive symptoms in the current investigation is in keeping with the 26 to 40% prevalence of depression in COPD reported in epidemiological studies (3,43). Nearly 60% of patients with GDS ≥ 11 carried no diagnosis of mood disorder. This result suggests an under-recognition of depressive symptoms and depression in patients with COPD –a frequent finding in investigations focused on depression in this patient population (3,48–50).
Of the 14 patients with a GDS ≥ 11 carrying a diagnosis of mood disorder, 9 (64%) were receiving medical treatment for depressive symptoms and depression. This finding raises two considerations. First, the high prevalence of patients receiving medical treatment for depressive symptoms and depression compares favorably to the 6-to-25% prevalence of patients receiving treatment for depressive symptoms reported by other investigators (3,48,49). Second, two-thirds of patients receiving medical treatment for depressive symptoms and depression had residual depressive symptoms. The prevalence of residual depressive symptoms has been reported to range between 32% (Citation51) and 53% (Citation52). Whether depressed men with COPD are at higher risk of experiencing residual symptoms of depression following initiation of antidepressants remains to be determined.
CRITIQUE OF METHODS
The relationship between COPD and depression is likely bidirectional (Citation43). Depression that antedates COPD (early-onset depression) might serve as primary incentive to smoking (Citation43) –tobacco smoking may attenuate depressive symptoms through nicotine-induced activation of dopaminergic, noradrenergic and serotoninergic neural pathways and through compounds, other than nicotine, exerting potent inhibition of monoamine oxidase-A and B (Citation38). Alternatively, in genetically susceptible individuals (Citation5), the physical and psychological stresses accompanying COPD could increase the risk of depression (late-onset depression) (Citation43). The cross-sectional design of the investigation does not allow grouping of patients between those with early-onset depression and those with late-onset depression. Such grouping could be relevant if onset of depression had an impact on depression-associated increased morbidity and mortality in COPD (Citation2). To date, no such difference in outcome has been detected.
Testosterone levels can decrease during COPD exacerbations (Citation53), and hospitalization due to COPD exacerbations are longer in patients who are depressed that in those who are not depressed (2,3). By study design, patients were studied when stable, therefore, any association between depression, COPD exacerbations and testosterone levels are beyond the scope of the current investigation.
Only men with COPD were enrolled in the current study. The limitation of enrolling only men is, however, tempered by recent observations of Schneider et al. (Citation1). These investigators reported that risk of new-onset depression (and death after diagnosis of depression) in COPD tends to be higher in men than in women (Citation1). Whether menopause and hormone supplementation in women (10,54) with COPD could affect prevalence of mood disorders remains untested.
All patients in this study were veterans receiving care in a Veteran Administration hospital. The Veteran Administration patient population is known to have greater medical morbidity and socioeconomics stressors than a community based sample (Citation55). The prevalence of significant depressive symptoms in our patients, however, was similar to the prevalence of significant depressive symptoms reported in studies were most (Citation49) or all patients were not veterans (56,57). This observation suggests that our results may be applied other populations of men with COPD.
Clinical implications
The role of testosterone supplementation for treatment of depression remains unclear (Citation58). It has been suggested that testosterone supplements might be beneficial in men who exhibit low-to-borderline testosterone levels and a partial response to conventional antidepressants (Citation58). The value of testosterone treatment in older men with COPD remains to be demonstrated (Citation17). The issue is more than a theoretical concern: long-term testosterone supplementation can cause side effects, including increased risk of cardiovascular adverse events (Citation59), polycythemia, sleep apnea, and prostatic hypertrophy (Citation17).
Long-term effects of testosterone supplementation on risk of prostate cancer remains unknown (Citation17). Our study was not intended to investigate whether testosterone replacement improves mood in men with COPD and low testosterone levels; nevertheless, our findings do not support use of such therapy if the goal is solely to lessen depressive symptoms. This finding complements our previous investigations (29,60) that could not support testosterone administration to hypogonadal men with COPD if the sole goal was to improve respiratory and limb muscle function, exercise capacity, respiratory symptoms or general health.
In summary, the mechanisms responsible for depression in COPD remain unclear. The cross-sectional data in this investigation do not support an association between depressive symptoms and low testosterone. In contrast, depressive symptoms were associated with severity of lung disease and COPD-associated functional impairment (BODE-index), lack of partner and younger age. The results in this investigation raise the additional possibility that combined severity of lung disease and functional impairment (BODE-index) and younger age heighten the risk for increased sadness and helplessness. In conclusion, in this prospective cross-sectional study, hypogonadism was not associated with significant depressive symptoms in men with COPD.
DECLARATION OF INTEREST
Declaration Of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
ACKNOWLEDGMENTS
The authors gratefully thank Dr. James M. Sinacore (Department of Preventive Medicine & Epidemiology, Loyola University, Maywood, IL) for his statistical advice and to all the veterans who took part to this project.
REFERENCES
- Schneider C, Jick SS, Bothner U, Meier CR. COPD and the risk of depression. Chest 2010; 137:341–347.
- Maurer J, Rebbapragada V, Borson S, Goldstein R, Kunik ME, Yohannes AM, Hanania NA. Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest 2008; 134:43S-56S.
- Hanania NA, Mullerova H, Locantore NW, Vestbo J, Watkins ML, Wouters EF, Rennard SI, Sharafkhaneh A. Determinants of depression in the ECLIPSE COPD Cohort. Am J Respir Crit Care Med 2011; 183:604–611. Epub 2010 Oct.
- Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008; 358:55–68.
- Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301:386–389.
- Amiaz R, Seidman SN. Testosterone and depression in men. Curr Opin Endocrinol Diabetes Obes 2008; 15:278–283.
- Araujo AB, Durante R, Feldman HA, Goldstein I, McKinlay JB. The relationship between depressive symptoms and male erectile dysfunction: Cross-sectional results from the Massachusetts Male Aging Study. Psychosom Med 1998; 60:458–465.
- Joshi D, van Schoor NM, de Ronde W, Schaap LA, Comijs HC, Beekman AT, Lips P. Low free testosterone levels are associated with prevalence and incidence of depressive Symptoms in older men. Clin Endocrinol (Oxf) 2010; 72:232–240.
- Seidman SN, Araujo AB, Roose SP, McKinlay JB. Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol Psychiatry 2001; 50:371-376.
- Morsink LF, Vogelzangs N, Nicklas BJ, Beekman AT, Satterfield S, Rubin SM, Yaffe K, Simonsick E, Newman AB, Kritchevsky SB, Penninx BW. Associations between sex steroid hormone levels and depressive symptoms in elderly men and women: results from the Health ABC study. Psychoneuroendocrinology 2007; 32:874–883.
- Fink G, Sumner B, Rosie R, Wilson H, McQueen J. Androgen actions on central serotonin neurotransmission: relevance for mood, mental state and memory. Behav Brain Res 1999; 105:53–68.
- Summers CH, Larson ET, Ronan PJ, Hofmann PM, Emerson AJ, Renner KJ. Serotonergic responses to corticosterone and testosterone in the limbic system. Gen Comp Endocrinol 2000; 117:151–159.
- Meyers B, D'Agostino A, Walker J, Kritzer MF. Gonadectomy and hormone replacement exert region- and enzyme isoform-specific effects on monoamine oxidase and catechol-O-methyltransferase activity in prefrontal cortex and neostriatum of adult male rats. Neuroscience 2010; 165:850–862.
- Bao AM, Fischer DF, Wu YH, Hol EM, Balesar R, Unmehopa UA, Zhou JN, Swaab DF. A direct androgenic involvement in the expression of human corticotropin-releasing hormone. Mol Psychiatry 2006; 11:567–576.
- Alexopoulos GS. Depression in the elderly. Lancet 2005; 365:1961–1970.
- Alexopoulos GS, Kelly RE Jr. Research advances in geriatric depression. World Psychiatry 2009; 8:140–149.
- Laghi F, Adiguzel N, Tobin MJ. Endocrinological derangements in COPD. Eur Respir J 2009; 34:975–996.
- Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO. Development and validation of a geriatric depression screening scale: A preliminary report. J Psychiatr Res 1982; 17:37–49.
- Stiles PG, McGarraham JE. The Geriatric Depression Scale: a comprehensive review. J Clinl Geropsychol 1998; 4:89–110.
- Nebes RD, Vora IJ, Meltzer CC, Fukui MB, Williams RL, Kamboh MI, Saxton J, Houck PR, DeKosky ST, Reynolds CF III. Relationship of deep white matter hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression. Am J Psych 2001; 158:878–884.
- Sheikh JI, Yesavage JA, Brooks JO III, Friedman L, Gratzinger P, Hill RD, Zadeik A, Crook T. Proposed factor structure of the Geriatric Depression Scale. Int Psychogeriatr 1991; 3:23–28.
- National Heart, Lung, and Blood Institute & World Health Organization. 2008 update. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. www.goldcopd.com. 2011.
- Collins EG, Langbein WE, Fehr L, O'Connell S, Jelinek C, Hagarty E, Edwards L, Reda D, Tobin MJ, Laghi F. Can ventilation-feedback training augment exercise tolerance in patients with chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2008; 177:844–852.
- Hamilton M. A rating scale in depression. J Neurol Neurosurg Psychiat 1960; 23:56–62.
- Beck AT, Steer RA. Internal consistencies of the original and revised Beck Depression Inventory. J Clin Psychol 1984; 40:1365–1367.
- Celli BR, Cote CG, Marin JM, Casanova C, Montes DO, Mendez RA, Pinto PV, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:1005–1012.
- Martinez FJ, Foster G, Curtis JL, Criner G, Weinmann G, Fishman A, DeCamp MM, Benditt J, Sciurba F, Make B, Mohsenifar Z, Diaz P, Hoffman E, Wise R. Predictors of mortality in patients with emphysema and severe airflow obstruction. Am J Respir Crit Care Med 2006; 173:1326–1334.
- Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic co-morbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373–383.
- Laghi F, Antonescu-Turcu A, Collins E, Segal J, Tobin DE, Jubran A, Tobin MJ. Hypogonadism in men with chronic obstructive pulmonary disease: prevalence and quality of life. Am J Respir Crit Care Med 2005; 171:728–733.
- Salameh WA, Redor-Goldman MM, Clarke NJ, Reitz RE, Caulfield MP. Validation of a total testosterone assay using high-turbulence liquid chromatography tandem mass spectrometry: Total and free testosterone reference ranges. Steroids 2010; 75:169–175.
- ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166:111–117.
- Norris JT, Gallagher D, Wilson A, Winograd CH. Assessment of depression in geriatric medical outpatients: the validity of two screening measures. J Am Geriatr Soc 1987; 35:989–995.
- Colangelo LA, Sharp L, Kopp P, Scholtens D, Chiu BC, Liu K, Gapstur SM. Total testosterone, androgen receptor polymorphism, and depressive symptoms in young black and white men: the CARDIA Male Hormone Study. Psychoneuroendocrinology 2007; 32:951–958.
- Al shair K, Dockry R, Mallia-Milanes B, Kolsum U, Singh D, Vestbo J. Depression and its relationship with poor exercise capacity, BODE index and muscle wasting in COPD. Respir Med 2009; 103:1572–1579.
- Byers AL, Yaffe K, Covinsky KE, Friedman MB, Bruce ML. High occurrence of mood and anxiety disorders among older adults: The National Co-morbidity Survey Replication. Arch Gen Psychiatry 2010; 67:489–496.
- Council on Scientific Affairs. The etiologic features of depression in adults. American Medical Association. Arch Fam Med 1993; 2:76–83.
- Kessler RC, Essex M. Marital status and depression: the role of coping resources. Soc Forces 1982; 61:484–507.
- Wiesbeck GA, Kuhl HC, Yaldizli O, Wurst FM. Tobacco smoking and depression–results from the WHO/ISBRA study. Neuropsychobiology 2008; 57:26–31.
- Gudmundsson G, Gislason T, Janson C, Lindberg E, Suppli UC, Brondum E, Nieminen MM, Aine T, Hallin R, Bakke P. Depression, anxiety and health status after hospitalisation for COPD: a multicentre study in the Nordic countries. Respir Med 2006; 100:87–93.
- Wang Y, Browne DC, Storr CL, Wagner FA. Gender and the tobacco-depression relationship: a sample of African American college students at a Historically Black College or University (HBCU). Addict Behav 2005; 30:1437–1441.
- Kendler KS, Neale MC, MacLean CJ, Heath AC, Eaves LJ, Kessler RC. Smoking and major depression. A causal analysis. Arch Gen Psych 1993; 50:36–43.
- Longstreth WT, Jr., Manolio TA, Arnold A, Burke GL, Bryan N, Jungreis CA, Enright PL, O'Leary D, Fried L. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. Stroke 1996; 27:1274–1282.
- Norwood R, Balkissoon R. Current perspectives on management of co-morbid depression in COPD. COPD 2005; 2:185–193.
- Arne M, Janson C, Janson S, Boman G, Lindqvist U, Berne C, Emtner M. Physical activity and quality of life in subjects with chronic disease: chronic obstructive pulmonary disease compared with rheumatoid arthritis and diabetes mellitus. Scand J Prim Health Care 2009; 27:141–147.
- Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Co-morbidity Survey. Arch Gen Psychiatry 1994; 51:8–19.
- Payne SM, Lee A, Clark JA, Rogers WH, Miller DR, Skinner KM, Ren XS, Kazis LE. Utilization of medical services by Veterans Health Study (VHS) respondents. J Ambul Care Manage 2005; 28:125–140.
- Borson S, Barnes RA, Kukull WA, Okimoto JT, Veith RC, Inui TS, Carter W, Raskind MA. Symptomatic depression in elderly medical outpatients. I. Prevalence, demography, and health service utilization. J Am Geriatr Soc 1986; 34:341–347.
- Lacasse Y, Rousseau L, Maltais F. Prevalence of depressive symptoms and depression in patients with severe oxygen-dependent chronic obstructive pulmonary disease. J Cardiopulm Rehabil 2001; 21:80–86.
- Fan VS, Ramsey SD, Giardino ND, Make BJ, Emery CF, Diaz PT, Benditt JO, Mosenifar Z, McKenna R Jr., Curtis JL, Fishman AP, Martinez FJ. Sex, depression, and risk of hospitalization and mortality in chronic obstructive pulmonary disease. Arch Intern Med 2007; 167:2345–2353.
- Hynninen MJ, Bjerke N, Pallesen S, Bakke PS, Nordhus IH. A randomized controlled trial of cognitive behavioral therapy for anxiety and depression in COPD. Respir Med 2010; 104:986–994.
- Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med 1995; 25:1171–1180.
- Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psych 2006; 163:28–40.
- Karadag F, Ozcan H, Karul AB, Yilmaz M, Cildag O. Sex hormone alterations and systemic inflammation in chronic obstructive pulmonary disease. Int J Clin Pract 2009; 63:275–281.
- Frye CA, Walf AA. Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites. Physiol Behav 2009; 97:266–269.
- Kazis LE, Miller DR, Clark J, Skinner K, Lee A, Rogers W, Spiro A, III, Payne S, Fincke G, Selim A, Linzer M. Health-related quality of life in patients served by the Department of Veterans Affairs: results from the Veterans Health Study. Arch Intern Med 1998; 158:626–632.
- Wagena EJ, Arrindell WA, Wouters EF, van Schayck CP. Are patients with COPD psychologically distressed? Eur Respir J 2005; 26:242–248.
- Yohannes AM, Baldwin RC, Connolly MJ. Depression and anxiety in elderly outpatients with chronic obstructive pulmonary disease: prevalence, and validation of the BASDEC screening questionnaire. Int J Geriatr Psychiatry 2000; 15:1090-1096.
- Kanayama G, Amiaz R, Seidman S, Pope HG Jr. Testosterone supplementation for depressed men: current research and suggested treatment guidelines. Exp Clin Psychopharmacol 2007; 15:529–538.
- Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S. Adverse events associated with testosterone administration. N Engl J Med 2010; 363:109–122.
- Laghi F, Langbein WE, Antonescu-Turcu A, Jubran A, Bammert C, Tobin MJ. Respiratory and skeletal muscles in hypogonadal men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 171:598- 605.