Editors' note: Evaluating depression and suicidality in tetrabenazine users with Huntington disease

After a 2006 randomized clinical trial of 84 patients identified suicidality in 2 tetrabenazine (TBZ) users, the Food and Drug Administration issued a black box warning for this Huntington disease (HD) medication. Using the retrospective Enroll-HD database, Schultz et al. sought to clarify this relationship in a larger cohort. In keeping with the results of a prior observational study by Dorsey et al. (1,360 subjects), Schultz et al. observed no statistically significant increase in suicidality among TBZ users in the 4,091-patient cohort. In fact, this risk seemed to be attenuated by TBZ use after multivariable adjustment (p = 0.043). This finding has become the subject of much contention among HD specialists. Several groups highlight major concerns with the study's methodology—notably the selection bias introduced by nonrandomized treatment, confounding by treatment indication (whereby patients who were more depressed, and perhaps more likely to have suicidality, would be less likely to receive TBZ), and survival bias due to TBZ discontinuation in the retrospective treatment arm. Schultz et al. acknowledge the limitations of their retrospective design and confirm their findings that TBZ remains safe using a propensity score–matched analysis that accounted for prior depression. While these results may be promising for patients with HD, all investigators seem to agree that these results should be interpreted with caution.