AbstractIntroductionCystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI) significantly improves lung function but its effect on mental health and sleep remains poorly understood. We report on mental health, sleep, and respiratory health outcomes of adolescents with CF commenced on ETI therapy, and monitored the prevalence of neuropsychiatric issues through the coronavirus disease 2019 pandemic.MethodsWe conducted a prospective longitudinal study of 31 adolescents (aged 10–18 years) from July 2021 to October 2022. Data collected include demographics, Patient Health Questionnaire‐9 (PHQ‐9), General Anxiety Disorder‐7 (GAD‐7), Pediatric Daytime Sleepiness Scale (PDSS), Sleep Disturbance Scale for Children (SDSC) scores, and FEV1 percent predicted. Twenty of 31 adolescents had data before and after ETI initiation. Mean differences (MD) in mental health, sleep, and respiratory health pre‐ and post‐ETI therapy commencement were estimated using paired t‐tests. The prevalence and trajectories of anxiety, depression, and sleep disturbance were described between the ETI epochs, and over the pandemic period.ResultsFEV1 improved following ETI therapy commencement (MD, 95% confidence interval [CI]: 7.1% (4.7%–9.6%) whereas PHQ‐9, GAD‐7, PDSS, and SDSC scores did not change significantly. Ten percent of participants developed new‐onset anxiety/depression concerns and 10% developed new sleep concerns following ETI initiation.ConclusionThis is the first prospective longitudinal study of mental health and sleep changes after ETI commencement in adolescents with CF. Although respiratory outcomes improved, ETI did not improve anxiety, depression or sleep.