Mental Health Safety Signals with CFTR Modulators: Pharmacovigilance Data Warrant Structured Monitoring, Not Alarm

Diane A Merino, Samuel D Cohen, Nouha Ben Othman, et al.

Summary: This study analyzed spontaneous adverse-event reports from the French Pharmacovigilance Database (116 cases) and VigiBase (3,407 cases) to characterize psychiatric adverse events associated with CFTR modulators (CFTRms), primarily elexacaftor/tezacaftor/ivacaftor (ETI), reported between 2012 and 2024. Sleep disorders predominated in children, while mood and suicidality-related reports were more common in adolescents. Disproportionality analysis using Reporting Odds Ratio showed that mental health disorders were over-represented with CFTRms — particularly ETI — compared with other drugs in VigiBase, with signals somewhat stronger in pediatric patients. Completed suicides were not reported; six suicide attempts were identified in the French database.

Why it matters: ETI has dramatically improved lung function and survival in CF, but its near-universal uptake means that even rare adverse effects carry population-level importance. Mental health concerns have been raised anecdotally and in earlier case series; this analysis is among the more systematic pharmacovigilance efforts to date and adds age-stratified signal detection. If a genuine causal relationship exists, it has direct implications for monitoring protocols, prescribing guidance, and patient and family counseling — especially in pediatric populations where neurodevelopmental vulnerability may amplify risk.

Expert perspective: The methodology is appropriate for pharmacovigilance hypothesis generation: disproportionality analysis using ROR is a recognized signal-detection tool, and adherence to STROBE and READUS-PV guidelines is a positive indicator of rigor. However, the fundamental limitations of spontaneous reporting databases must be kept in view. These systems are subject to notoriety bias — clinicians are more likely to report psychiatric events for a drug already under scrutiny — as well as underreporting of routine events, absence of a true denominator, and complete inability to adjust for confounders, including the well-documented burden of anxiety and depression intrinsic to living with CF. The dramatic improvement in physical health that ETI produces may itself unmask pre-existing psychological distress, alter sleep architecture, or shift patients' attention toward previously suppressed mental health symptoms. The signal with ETI but not other combination therapies is intriguing, though the comparison is complicated by vastly different numbers of exposed patients and reporting periods. The pediatric-versus-adult stratification adds value, but sample sizes in subgroups limit precision. The median time to onset of 60 days is clinically useful if confirmed prospectively. Reassuringly, completed suicides were absent and suicidal behavior was infrequent overall. This is useful hypothesis-generating evidence that appropriately calls for prospective, controlled observational studies with validated psychiatric endpoints, baseline assessments, and CF-specific comparator populations — not a reason to alter prescribing, but a reasonable basis for structured clinical monitoring.

Relevance: Cystic Fibrosis

Source: https://pubmed.ncbi.nlm.nih.gov/42707002/

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