Do antidepressants work in patients with chronic obstructive pulmonary disease with comorbid depression?

Keywords::

• antidepressant drug therapy
• anxiety
• COPD
• depression
• SSRI
• TCA

Comorbid depression is common in patients with chronic obstructive pulmonary disease (COPD) and worsens health-related outcomes, for example, increases hospitalization and premature mortality [1]. One in five primary care COPD patients are likely to be diagnosed with moderate-to-severe depression before the COPD diagnosis and a new-onset diagnosis of depression after the diagnosis of COPD occurs at a rate of 16.2 per 1000 person-years [2]. A recent meta-analysis from our department identified a prevalence of major depression in patients with moderate-to-severe COPD in an outpatient setting of 40% [3]. Undiagnosed and untreated depression in patients with COPD is associated with increased risk for exacerbation and hospitalization [4], greater functional impairment and physical disability [5], social isolation, poor compliance with medical treatment and elevated risk of premature mortality [6]. The causes or the pathogenesis of depression in patients with COPD remains uncertain. This highlights the importance of exploring potential mechanisms that are related to depression in patients with COPD, including the role of systemic inflammation and biomarkers. Hanania and coworkers in a large cohort study of COPD patients demonstrated that depression was associated with female gender, with active smoking and with a history of cardiovascular disease [7].

Antidepressants are the cornerstone of the treatment of major depression both in primary and secondary care settings for patients with chronic diseases [8]. If they are effective, why are they not routinely offered to COPD patients with comorbid depression? A recent case-finding study [9] in the USA has reported less than a third of COPD patients with major depression have received appropriate treatment for their depression. The importance of screening COPD patients for depression is periodically paramount (especially after acute exacerbations and when changes occur in patients’ circumstances, e.g., loss of loved ones). This should be followed with appropriate treatment including referral of patients for specialist care. It is possible that physicians might be cautious, taking a ‘wait and see’ approach, which suggests that initially dealing with acute events of physical problems may aid to resolve the psychological problem without specific intervention [10]. In addition, COPD patients themselves are also more likely to refuse antidepressant drug therapy, possibly because of misconceptions of the disease (stigma associated with depression and/or a refusal to accept the diagnosis), a perception that antidepressants therapy is addictive, lack of interest and motivation, or hopelessness [11]. Therefore, it is important to educate healthcare professionals in how to explain the diagnosis and treatment of depression and in how to present the treatment plan in easily understandable language that is palatable to COPD patients.

Efficacy of tricyclic antidepressant treatment

Borson and colleagues examined the effectiveness of nortriptyline in depressed COPD patients (n = 30) in a randomized, double-blind placebo controlled trial for 12 weeks [12]. Their findings indicate that nortriptyline was effective in reducing depressive symptoms and anxiety and in increasing physical functioning. In a randomized controlled trial (n = 12), Light et al. investigated the efficacy of doxephine hydrochloride versus placebo in COPD patients with comorbid depression for 6 weeks [13]. Findings indicate that no significant improvement was observed between the groups in terms of exercise capacity, anxiety and depression scores. In a separate study, Strom et al. explored the benefits of protriptyline against placebo (n = 26), for 12 weeks [14]. The majority of the patients did not complete the trial because of the anticholinergic side effects. Unsurprisingly, no improvement was observed in depression or anxiety scores, dyspnea or quality of life for any of the groups. Thus, the literature on tricyclic antidepressant treatments (TCAs) in depression associated with COPD is inadequate and inconclusive. Given that TCAs are no longer first-line treatment for depression, it seems unlikely that further trials in this area will be conducted.

Efficacy of selective serotonin reuptake inhibitor treatment

The selective serotonin reuptake inhibitor treatments (SSRIs) have demonstrated greater safety and fewer side effects than TCAs for treatment of depression for patients with physical illness. Six studies have been identified that treated COPD patients with comorbid depression with SSRIs [15–19]. Three used a randomized, double-blind, placebo-controlled design. In two studies [15,16] fluoxetine (n = 51) and paroxetine (n = 15) were tolerated by patients after 6 and 12 weeks of therapy, respectively, and significant improvement was observed in the treatment groups in quality of life, dyspnea and fatigue. In another study (n = 28) of 6-weeks’ double-blinded therapy [17], paroxetine demonstrated no significant differences over placebo in quality-of-life or depression scores. This might be due to type II error and a short duration of intervention. The two uncontrolled studies (n = 6 and n = 7, respectively) [18,19] that examined efficacy of seretraline for 6 weeks revealed some improvements on daily activities, but numbers are too small for adequate statistical analysis. The third uncontrolled study was in our department [11]; we examined the efficacy of fluoxetine, in a single-blinded open trial study for 6 months (n = 57 elderly depressed COPD patients). Over two-thirds of our COPD patients declined fluoxetine therapy. Again, therefore, the level of evidence available to support the use of SSRIs for treatment of depression in patients with COPD is limited.

The efficacy of antidepressant drugs for treatment of depression in patients with COPD has not been rigorously tested in randomized controlled trials. Findings from the current literature are greatly limited by methodological weaknesses including low sample size, sample heterogeneity and variation in the diagnostic tools used to measure and to monitor the treatment of depression. In addition, which specific SSRIs may be appropriate to treat depression in patients with COPD requires further investigation.

Where do we go from here?

There is some evidence to suggest that depressed elderly COPD patients are most likely to refuse antidepressant drug therapy for the reasons discussed above. These issues are important for the patients and family/caregivers and have to be handled in a balanced manner in order to demystify patients’ perceptions and enable effective patient engagement with the treatment plan.

There is evidence to suggest that the collaborative care model (CCM) is beneficial for the treatment of depression in primary care settings for patients with chronic diseases [20]. The CCM has been shown to improve quality of life and reduce healthcare utilization for patients with variety chronic diseases complicated by depression.

The CCM is designed to address the barriers to care for depressed COPD patients. The intervention is aimed to put the patient ‘at the center’ in order to engage in the self-management programme. CCM is administered by trained care managers who work collaboratively with each patient around the patient’s treatment plan. The care managers will identify barriers to adherence specific to each patient and, through education and support, help promote adherence to antidepressants drug therapy. The care managers engage with the patient on a regular basis either face-to-face or by phone. Currently, however, there is no research evidence to suggest that CCM is effective in the treatment of depression for patients with COPD (specifically). Therefore, well-controlled randomized controls trials are needed.

Cognitive–behavioral therapy (CBT) is defined as therapy that focuses on the clients’ patterns of thoughts and behaviors that induce a depressed mood [21]. CBT can be performed either in a group or an individual patient setting, and usually requires multiple ‘sessions’ to recognize and modify thoughts and behaviors in order to reduce symptoms of depression. A recent randomized controlled trial by Kunik and coworkers explored whether eight 1-h sessions of group CBT therapy was superior to eight sessions of COPD education (45 min lectures/15 min discussion) in patients with COPD with comorbid depression [22]. Their findings indicate that education and CBT are equally effective in improving depression and anxiety in both short-term (8 weeks) and long-term (12 months) follow-up. This raises the important issue of whether CBT (or indeed education) should be offered on its own or with other adjunct modalities (e.g., antidepressant drug therapy) for severe depression. It is also worth exploring further the number of people who responded to CBT or to education to the level of ‘remission’.

There is strong evidence to suggest that pulmonary rehabilitation (PR) is effective in improving quality of life and exercise capacity in COPD patients [1]. A recent systematic review also showed that PR is beneficial in reducing anxiety and depressive symptoms, but the long-term benefit is unknown [23]. Alexopoulos and colleagues examined the additional benefits of intensive inpatient PR (2 weeks) plus antidepressant drug therapy (with low-dose escitalopram) for patients admitted with acute exacerbations of COPD [24]. Their findings indicate the combination of intervention is beneficial in reducing both depressive symptoms and physical disability [24]. de Godoy and de Godoy explored the efficacy of 12 weeks PR with an additional 12 psychotherapy sessions (vs PR alone in the form of 24 sessions of physical exercise, 24 sessions of physiotherapy and three educational sessions) on anxiety and depression in patients with COPD [25]. Their findings showed that PR with psychotherapy was more effective in the short term in ameliorating depressive and anxiety symptoms than PR alone. However, the long-term benefit of this PR programme is unknown.

Clinical & research implication

The high prevalence and untreated depression in patients with COPD will have deleterious effects on patients’ quality of life and increases healthcare utilization (burden). Patients with COPD with moderate-to-severe depression require further examination by a psychologist or psychiatrist. Those with severe depression, where appropriate, should be offered antidepressant drug therapy. However, care managers (healthcare professionals) should support COPD patients receiving antidepressant drug therapy in order to promote understanding of the disease and adherence to the treatment programme. Simply offering an antidepressant drug is not adequate. Further research studies are required to investigate the efficacy of antidepressant drug therapy with larger sample sizes, with long-term treatment follow-up to improve the psychological well-being of COPD patients.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.