Reply to Piehler et al.: Depression Symptoms in Patients with Cystic Fibrosis Fluctuate at Baseline and Improve with Elexacaftor/Tezacaftor/Ivacaftor Therapy

From the Authors:

It is pleasing to read that Piehler and colleagues agree with our conclusion that there remains a small subgroup of patients with cystic fibrosis (CF) whose depression symptoms worsen after elexacaftor/tezacaftor/ivacaftor (ETI) initiation and require follow-up. Their study is one of seven cited by Ramsey and colleagues (1), as well as us (2), that evidence this view. Although they make some valid points about variability between time points, Piehler and colleagues acknowledge that their findings are tempered by there being no contemporary control group, unlike the study by Blackwelter and colleagues (3), which shows that patients who had low scores on the Patient Health Questionnaire-9 (PHQ-9) at baseline increased their scores after commencing ETI more than the control group did.

What is of real clinical importance is the tracking of those who score in the moderate and severe ranges of the PHQ-9. Numbers may be small, but it is vital to understand these presentations, particularly after the initiation of ETI. At this time, there remain more questions than answers. Piehler and colleagues speculate about decreases in PHQ-9 scores but only focus on the potential benefits of ETI, particularly of the effects of ivacaftor and its metabolites on the central nervous system activity profile and on sleep (4). However, there are other equally plausible influencing variables (e.g., antidepressant medications, psychotherapy, changes in pandemic lockdown restrictions, or extraneous socioeconomic changes). All are worthy of further exploration in larger studies.

The hugely transformative gains in health and quality of life for people with CF after the initiation of ETI might intuitively lead to the anticipation of improvements in psychological symptoms and mental health, and for many, there will be. However, all of us in the CF community need to really listen to people with CF and their families, ask important questions about how their lives are changing, and keep one eye on what is known and the other on what is not. For now, let’s all agree to monitor the subgroup of patients with worsening of depression symptoms after ETI initiation and support them.