Medication for the treatment of depression in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a term that mainly describes two lung conditions: chronic bronchitis and emphysema. The main symptoms of COPD include shortness of breath, persistent cough, wheezing, and/or frequent chest infections. There is no cure for COPD, but treatment can help slow the disease progress and relieve symptoms. Depression is very common in patients with COPD, but is often untreated. Studies show that untreated depression in patients with COPD can worsen quality of life, increase COPD exacerbations and hospital admissions, and make following a COPD treatment plan difficult. Treatment for depression can include antidepressant medication, psychological therapy, or both. However, evidence-based recommendations regarding antidepressant medication use specifically for patients with COPD are not currently available.

Why is this review important?

There is currently no clear overview of existing evidence showing whether antidepressants can effectively and safely reduce depressive symptoms in patients with COPD, therefore it was important to assess the existing experimental studies.

Who will be interested in this review?

Healthcare professionals, people with COPD and depression, researchers, and policymakers will be interested in the findings of this review.

What questions does this review aim to answer?

Our main aim was to assess whether pharmacological treatment (e.g. antidepressants) could effectively and safely treat COPD-related depression.

Which studies were included in the review?

This review included experimental studies called randomised controlled trials (studies in which participants are assigned to a treatment group based on a random method) that compared the effectiveness of pharmacological interventions (antidepressants) to placebo (inactive treatment in the same form as the active treatment, e.g. a pill). Study participants were adults diagnosed with COPD and depression.

What does the evidence from the review tell us?

We have identified only four studies worldwide that were eligible for inclusion in our review. This means limited evidence to support the use of antidepressants for the treatment of depression in patients with COPD. Only one study evaluated a tricyclic antidepressant, nortriptyline, finding that it reduced depressive symptoms when compared to a placebo. Three studies evaluated a newer generation class of antidepressants called selective serotonin reuptake inhibitors (SSRIs), finding no evidence for their effectiveness in improving depressive symptoms. Due to the limited evidence, we are unable to make definitive statements about the effectiveness but also safety of antidepressants when used for COPD-related depression. However, SSRIs may increase exercise capacity in patients with COPD.

Given that the current findings were based on only four small studies with evidence rated as of very low quality, it is important to interpret our results with caution.

What should happen next?

Insufficient evidence prevented us from making clear recommendations for doctors, other healthcare professionals, researchers, or policymakers. More studies with better methodological quality and a larger number of participants are needed.

Authors' conclusions: 

There is insufficient evidence to make definitive statements about the efficacy or safety of antidepressants for treating COPD-related depression. New RCTs are needed; with better methodological quality and more accurate reporting of the methods used. Moreover, longer-term follow-up data collection is needed, including outcomes such as adverse events, hospital utilisation and cost-effectiveness.

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Background: 

Studies report that up to 80% of individuals with chronic obstructive pulmonary disease (COPD) may struggle with symptoms of depression. However, this major comorbidity in COPD is rarely managed effectively. A number of recent studies indicate that left untreated, COPD-related depression is associated with worse quality of life, worse compliance with COPD treatment plan, increased exacerbations, hospital admissions, and healthcare costs when compared to individuals with COPD without depression. Regrettably, COPD practice guidelines do not provide conclusive treatment recommendations for the use of antidepressants in patients with COPD, and base their guidelines on findings from trials in the general population. This may be problematic, as there is an elevated risk of respiratory issues associated with antidepressant treatment and COPD. Evaluating effectiveness and safety of pharmacological interventions specifically for patients with COPD and depression was therefore paramount.

Objectives: 

To assess the effectiveness and safety of pharmacological interventions for the treatment of depression in patients with COPD.

Search strategy: 

The last search was performed on 26 November 2018. We initially searched the following databases via the Specialised Trials Registers of the Cochrane Airways and Common Mental Disorders Groups (to June 2016): MEDLINE, Embase, PsycINFO, CINAHL, AMED, and the Cochrane Library trials register (CENTRAL). Searches from June 2016 to November 2018 were performed directly on Ovid MEDLINE, Embase, PsycINFO and the Cochrane Library (Issue 11, 2018). We searched ClinicalTrials.gov, the ISRCTN registry, and the World Health Organization International Clinical Trials Registry Platform to 26 November 2018. We searched the grey literature databases to identify studies not indexed in major databases and the reference lists of studies initially identified for full-text screening.

Selection criteria: 

All published and unpublished randomised controlled trials (RCTs) comparing the efficacy of pharmacological interventions with no intervention, placebo or co-intervention in adults with diagnosed COPD and depression were eligible for inclusion.

Data collection and analysis: 

Two review authors independently assessed articles identified by the search for eligibility. Our primary outcomes were change in depressive symptoms and adverse events. The secondary outcomes were: change in quality of life, change in dyspnoea, change in forced expiratory volume in one second (FEV1), change in exercise tolerance, change in hospital utilisation (length of stay and readmission rates), and cost-effectiveness. For continuous outcomes, we calculated the pooled mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI) as appropriate. For dichotomous outcomes, we calculated the pooled odds ratio (OR) and corresponding 95% CI using a random-effects model. We assessed the quality of evidence using the GRADE framework.

Main results: 

Of the 1125 records screened for eligibility, four RCTs (N = 201 participants), and one on-going study, met the inclusion criteria. Two classes of antidepressants were investigated in two separate comparisons with placebo: a tricyclic antidepressant (TCA) and selective serotonin reuptake inhibitors (SSRIs).

TCA versus placebo

Only one RCT (N = 30 participants) provided results for this comparison.

Primary outcomes

The TCA (nortriptyline) reduced depressive symptoms post-treatment compared to placebo (MD -10.20, 95% CI -16.75 to -3.65; P = 0.007; very low-quality evidence), as measured by the Hamilton Depression Rating Scale (HAM-D). Three participants withdrew from the trial due to adverse events related to the tested antidepressant (dry mouth, sedation, orthostatic hypotension).

Secondary outcomes

The overall results post-treatment indicated that nortriptyline was not effective in improving the quality of life of individuals with COPD, as measured by the Sickness Impact Profile (MD -2.80, 95% CI -11.02 to 5.42; P = 0.50; very low-quality evidence).

The results for the change in dyspnoea for the domains examined (e.g. dyspnoea scores for 'most day-to-day activities') post-treatment showed no improvement in the intervention group (MD 9.80, 95% CI -6.20 to 25.80; P = 0.23; very low-quality evidence).

No data were reported for change in FEV1, change in exercise tolerance, change in hospital utilisation, or cost-effectiveness. The TCA study provided short-term results, with the last follow-up data collection at 12 weeks.

The quality of the evidence for all the outcomes evaluated was very low due to a small sample size, imprecision, attrition, and selection and reporting bias.

SSRIs versus placebo

Three RCTs (N = 171 participants) provided results for this comparison.

Primary outcomes

The pooled results for two studies showed no difference for the change in depressive symptoms post-intervention (SMD 0.75, 95% CI -1.14 to 2.64; 148 participants; 2 studies; P = 0.44; very low-quality evidence). High heterogeneity was observed (I² = 95%), limiting the reliability of these findings.

While it was not possible to meta-analyse the total adverse events rates across the studies, it was possible to combine the results for two medication-specific adverse effects: nausea and dizziness. There were no significant post-treatment group differences for nausea (OR 2.32, 95% CI 0.66 to 8.12; 171 participants; 3 studies; P = 0.19; very low-quality evidence) or dizziness (OR 0.61, 95% CI 0.09 to 4.06; 143 participants; 2 studies; P = 0.61; very low-quality evidence).

Secondary outcomes

The pooled analysis of two trials reporting data for the change in quality of life did not show improvement post-treatment in the intervention group compared to placebo (SMD 1.17, 95% CI -0.80 to 3.15; 148 participants; 2 studies; P = 0.25; very low-quality evidence).

There was no difference between groups in change in FEV1 post-treatment (MD 0.01, 95% CI -0.03 to 0.05; 148 participants; 2 studies; P = 0.60; low-quality evidence). However, two trials reported improvement in exercise tolerance in the SSRI group versus the placebo group (MD 13.88, 95% CI 11.73 to 16.03; 148 participants; 2 studies; P < 0.001; very low-quality evidence).

The trials included in this comparison did not report data related to the change in dyspnoea, hospital utilisation rates, or cost-effectiveness.

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