The association between N-acetyl-L-cysteine and development of depression: A longitudinal cohort study in all patients with chronic obstructive pulmonary disease in Region Stockholm

BACKGROUND: Depression is a major cause of illness and sick leave and has a prevalence of 3,4% globally. Approximately 30-55% of patients suffering from depression do not respond to existing treatments. N-Acetyl-L-cysteine (NAC) is currently used as mucolytic agent and as antidote in paracetamol overdose. Lately, NAC has generated interest as neuroprotective agent. It is not known whether NAC can prevent depression. RESEARCH QUESTION: This study investigated whether higher consumption of NAC is associated with a lower risk of developing depression in patients with Chronic Obstructive Pulmonary Disease (COPD). STUDY DESIGN AND METHOD: The longitudinal cohort study included patients over 40 years old in Stockholm with COPD and/or chronic bronchitis diagnosis 2014-2016 without depression 2014-2019 (n = 16,875). Exposure consisted of defined daily doses (DDD) of NAC 2014-2019, and the outcome was occurrence of depression diagnosis 2020-2024. RESULT: Cox regression adjusted for age and sex revealed a hazard ratio for depression of 1.37 (95% CI 1.25-1.52) with low NAC exposure (41-875 DDD) and of 1.29 (95% CI 1.09-1.52) with high exposure (>875 DDD). The associations were somewhat attenuated when adjusted for hospital admissions and other COPD medications. CONCLUSION: Contrary to our hypothesis, our results show an increased hazard ratio of depression in patients treated with NAC. This most likely reflects the strong association, shown in other studies, between more severe COPD disease and an increased risk of depression. In this scenario, DDD of NAC acts as a proxy for disease severity.