Elexacaftor/Tezacaftor/Ivacaftor impact on anxiety symptoms in cystic fibrosis: a systematic review

Introduction: Cystic fibrosis (CF) is a life-threatening, multisystem autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) [1]. The introduction of CFTR modulators has significantly transformed disease management and improved life expectancy in individuals with CF, particularly with the advent of the triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) [2]. Despite these advances, mental health symptoms, including anxiety and depression, remain highly prevalent in CF and are associated with poorer clinical outcomes, including reduced lung function, increased hospitalizations, and decreased quality of life [3]. However, the impact of ETI therapy on anxiety outcomes remains incompletely understood.

Aims: This systematic review aims to evaluate the impact of ETI therapy on anxiety outcomes in individuals with CF, integrating evidence from both validated psychometric assessments and adverse event (AE) reports, and to critically examine the variability in findings across different methodological approaches.

Methods: A systematic literature search was conducted from inception through March 21, 2026, using PubMed, Embase, and Scopus, in accordance with PRISMA guidelines [4]. Eligible studies included randomized controlled trials, prospective and retrospective observational studies, and large registry-based analyses reporting anxiety outcomes in CF patients treated with ETI. Studies were included if they assessed anxiety either as a reported AE or through validated psychometric scales, mostly the Generalized Anxiety Disorder 7-item scale (GAD-7). A qualitative synthesis was performed due to heterogeneity in study designs, outcome measures, and follow-up durations.

Results: Out of 397 identified records, 20 studies met inclusion criteria and were categorized into: (i) studies reporting anxiety as an AE of ETI therapy (n = 9), and (ii) studies assessing anxiety symptom progression using psychometric scales (n = 11). Studies reporting anxiety as an AE consistently showed low frequencies of anxiety-related events, generally ranging between approximately 1% and 3% across observational cohorts. Pharmacovigilance analyses identified a signal of anxiety-related events; however, these data were limited by the absence of reliable incidence estimates. In contrast, scale-based studies predominantly demonstrated overall stability of anxiety symptoms during follow-up, with two studies reporting statistically significant global improvements. Notably, improvements in respiratory outcomes, including ppFEV1 and CFQ-R scores, were consistently observed across studies, but were not systematically associated with parallel improvements in anxiety symptoms. Taken together, these findings suggest a divergence between population-level stability in anxiety scores and the occurrence of anxiety-related AEs in a subset of patients.

Conclusions: ETI therapy does not appear to be associated with a consistent worsening of anxiety at the population level and may be linked to stable or modestly improved anxiety outcomes in many individuals with CF. However, anxiety-related AEs may occur in a clinically relevant minority of patients, particularly in vulnerable subgroups, underscoring the importance of routine mental health monitoring in CF care. Future research should prioritize longitudinal designs and the integration of biological and psychosocial variables to better characterize the impact of CFTR modulator therapies on mental health.

References

1-Elborn, J. S., 2016. Cystic fibrosis. The Lancet 388 (10059), 2519–2531. 10.1016/S0140-6736(16)00576-6 2-Burgel, P. R., et al., 2024. Multisystemic Effects of Elexacaftor–Tezacaftor–Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease. Ann. Am. Thorac. Soc. 21 (7), 1053–1064. https://doi.org/10.1513/AnnalsATS.202312-1065OC 3-Yohannes, A. M., et al., 2012. Relationship between anxiety, depression, and quality of life in adult patients with cystic fibrosis. Respir. Care 57 (4), 550–556. https://doi.org/10.4187/respcare.01328 4-Page, M.J., et al., 2021. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med 18(3). https://doi.org/10.1371/journal.pmed.1003583