Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Nov 1;29(6):603-609.
doi: 10.1097/MCP.0000000000001014. Epub 2023 Sep 1.

Neuropsychiatric adverse effects from CFTR modulators deserve a serious research effort

Michael B VanElzakker  1 , Emma M Tillman  2 , Lael M Yonker  1 , Eva-Maria Ratai  1 , Anna M Georgiopoulos  1
Affiliations
Review

Neuropsychiatric adverse effects from CFTR modulators deserve a serious research effort

Michael B VanElzakker et al. Curr Opin Pulm Med. .

Abstract

Purpose of review: This review highlights the problem of neuropsychiatric adverse effects (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI), current suboptimal mitigation approaches, a novel testable mechanistic hypothesis, and potential solutions requiring further research.

Recent findings: Studies show that a minority of persons with cystic fibrosis (PwCF) initiating cystic fibrosis transmembrane conductance regulator (CFTR) modulators experience neuropsychiatric AEs including worsening mood, cognition, anxiety, sleep, and suicidality. The GABA-A receptor is a ligand-gated chloride channel, and magnetic resonance spectroscopy neuroimaging studies have shown that reduced GABA expression in rostral anterior cingulate cortex is associated with anxiety and depression. Recent research details the impact of peripheral inflammation and the gut-brain axis on central neuroinflammation. Plasma ETI concentrations and sweat chloride have been evaluated in small studies of neuropsychiatric AEs but not validated to guide dose titration or correlated with pharmacogenomic variants or safety/efficacy.

Summary: Although ETI is well tolerated by most PwCF, some experience debilitating neuropsychiatric AEs. In some cases, these AEs may be driven by modulation of CFTR and chloride transport within the brain. Understanding biological mechanisms is a critical next step in identifying which PwCF are likely to experience AEs, and in developing evidence-based strategies to mitigate them, while retaining modulator efficacy.

PubMed Disclaimer

Conflict of interest statement

MBV reports grants from the National Institutes of Health; and service on the board of directors of PolyBio Research Foundation. EMT reports grants and travel reimbursement from the Cystic Fibrosis Foundation; grants from the National Institutes of Health; and personal fees from Snow Companies. LY reports grants from the Cystic Fibrosis Foundation and grants from the National Heart, Lung, and Blood Institute. EMR reports personal fees from Columbia University for a talk in 2022; personal fees from Imaging Endpoints; grants and travel reimbursement from the National Institutes of Health; grants from the National Science Foundation; and service on the advisory board of Brain Spec. AMG reports personal fees from the Belgian Cystic Fibrosis Foundation/King Baudouin Foundation; grants, personal fees, and travel reimbursement from Cystic Fibrosis Foundation; grants from the Dutch Cystic Fibrosis Foundation; travel reimbursement from the European Cystic Fibrosis Society; travel reimbursement from the French Cystic Fibrosis Society; personal fees from the Italian Cystic Fibrosis Research Foundation; grants from the National Heart, Lung, and Blood Institute; personal fees from Saudi Pediatric Pulmonology Association; grants and personal fees from Vertex Pharmaceuticals; and personal fees from Virginia Commonwealth University.

Figures

Box 1
Box 1
no caption available
FIGURE 1
FIGURE 1
The rostral anterior cingulate cortex (rACC) is an important structure in emotion regulation neurocircuitry. Several studies have shown that decreased GABA concentration in rACC is associated with neuropsychiatric symptoms such as anxiety and depression. ETI drug therapy may affect GABA function via chloride. Furthermore, rACC is dense with serotonin 2A receptors (5HT-2Ar), which are also involved in emotion regulation and directly modulated by ETI.
See this image and copyright information in PMC

References

    1. Griese M, Costa S, Linnemann RW, et al. Safety and efficacy of elexacaftor/tezacaftor/ivacaftor for 24 weeks or longer in people with cystic fibrosis and one or more F508del alleles: interim results of an open-label phase 3 clinical trial. Am J Respir Crit Care Med 2021; 203:381–385. - PMC - PubMed
    1. Ren CL, Morgan RL, Oermann C, et al. Cystic fibrosis foundation pulmonary guidelines. use of cystic fibrosis transmembrane conductance regulator modulator therapy in patients with cystic fibrosis. Ann Am Thorac Soc 2018; 15:271–280. - PubMed
    1. Fajac I, Daines C, Durieu I, et al. Nonrespiratory health-related quality of life in people with cystic fibrosis receiving elexacaftor/tezacaftor/ivacaftor. J Cyst Fibros 2023; 22:119–123. - PubMed

    2. These findings from 2 pivotal phase 3 trials of ETI demonstrate improvement in a range of CF-specific symptoms and functioning on the Cystic Fibrosis Questionnaire-Revised nonrespiratory domains.

    1. Cystic Fibrosis Foundation. Restore CFTR: Exploring Treatments for Rare and Nonsense Mutations. https://www.cff.org/research-clinical-trials/restore-cftr-exploring-trea... [Accessed 25 July 2023]
    1. Heo S, Young DC, Safirstein J, et al. Mental status changes during elexacaftor/tezacaftor /ivacaftor therapy. J Cyst Fibros 2022; 21:339–343. - PubMed

Publication types

MeSH terms