Abstract: 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. 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.

Plain-language summary: 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.