Global burden of insomnia medication-associated suicidality, 1967–2024: A disproportionality analysis of the global pharmacovigilance database

Background: While insomnia is recognized as a risk factor for suicidality, the potential influence of insomnia medications on this risk requires further investigation. Methods: We utilized the global pharmacovigilance database, to detect pharmacovigilance signal of insomnia medication-related suicidality from 1967 to 2024. The analysis included benzodiazepines, Z-drugs, antidepressants, first-generation H1 antagonists, and dual orexin receptor antagonists for insomnia medications. Multivariable logistic regression models were used to calculate the reporting odds ratio (ROR) and 95 % confidence interval (CI) of suicidality for each medication class, adjusting for age, sex, and reporting region, with melatonin and its receptor agonist as the reference. Results: We identified 13,899 reports of suicidality associated with insomnia medications. Benzodiazepines (ROR, 1.78 [95 % CI, 1.62–1.97]), Z-drugs (1.52 [1.40–1.66]), antidepressants (2.08 [1.88–2.31]), and first-generation H1 antagonists (1.59 [1.45–1.73]) showed stronger signal of suicidality compared to melatonin and its receptor agonist. In contrast, dual orexin receptor antagonists (ROR, 0.36 [0.31–0.42]) exhibited a lower signal risk. The melatonin receptor agonist ramelteon (ROR, 0.29 [0.21–0.39]) showed a weaker signal than melatonin. Similarly, dual orexin receptor antagonists suvorexant (ROR, 0.31 [0.26–0.37]), daridorexant (0.20 [0.14–0.29]), and lemborexant (0.24 [0.11–0.51]) significantly lowered the signal risk of suicidality compared to melatonin. Conclusions: Although this disproportionality analysis did not permit causal interpretation, our study highlights significant variations in suicidality signal risk among insomnia medications, with benzodiazepines, Z-drugs, antidepressants, and first-generation H1 antagonists posing stronger signal, and dual orexin receptor antagonists presenting a weaker signal. Given the limitations of pharmacovigilance data, further studies are needed to confirm these findings and guide safer prescribing practices, particularly for individuals at high risk of suicidality.