• Justyna Pollok, Joep Em van Agteren, and Kristin V Carson-Chahhoud.
• Faculty of Health and Medical Sciences, The University of Adelaide, North Terrace, Adelaide, South Australia, Australia, 5005.
• Cochrane Db Syst Rev. 2018 Dec 19; 12: CD012346.

BackgroundStudies 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.ObjectivesTo assess the effectiveness and safety of pharmacological interventions for the treatment of depression in patients with COPD.Search MethodsThe 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and the reference lists of studies initially identified for full-text screening.Selection CriteriaAll published and unpublished randomised controlled trials (RCTs) comparing the efficacy of pharmacological interventions with no intervention, placebo or co-intervention in adults with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 AnalysisTwo 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 ResultsOf 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 placeboOnly one RCT (N = 30 participants) provided results for this comparison.Primary outcomesThe 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 outcomesThe 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 placeboThree RCTs (N = 171 participants) provided results for this comparison.Primary outcomesThe 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 outcomesThe 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.Authors' ConclusionsThere 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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