Lack of Support for the Use of VMAT-2 Inhibitors for the Treatment of Tics in Tourette Syndrome.

Abstract

In the current issue of JAMA Network Open, Coffey et al1 report the results of Alternatives for Reducing Tics in Tourette syndrome (ARTISTS 2), a phase 3, randomized, double-blind, placebocontrolled, parallel-group, fixed-dose study of the reversible vesicular monoamine transporter 2 (VMAT-2) inhibitor deutetrabenazine for the treatment of Tourette syndrome. A total of 158 children and adolescents were enrolled across 52 sites in 10 countries. Participants were randomized to high-dose deutetrabenazine (up to 48 mg per day, adjusting for weight and cytochrome P450 2D6 status; n = 52), low-dose deutetrabenazine (up to 36 mg per day; n = 54), or placebo (n = 52). Clinically significant depression, a history of suicidal ideation within 2 years, or a prior suicidal attempt were criteria for study exclusion. The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Although a numeric improvement in the YGTSS-TTS favoring deutetrabenazine compared with placebo was observed at the end of the 4-week titration period, the difference was not significant at week 8 (least-squares mean difference, –0.8 points; 95% CI, –3.9 to 2.3 points; P = .60). Also, there were no significant differences between groups for key secondary end points. Depression was recorded in 4 participants (8%) in the high-dose group, 1 participant (2%) in the low-dose group, and in 0 participants in the placebo group. One participant in the high-dose group and 1 in the placebo group reported suicidal ideation during the study period. Among the more common treatment-emergent adverse events (TEAEs), somnolence was reported in 8 participants (15%) and fatigue in 5 participants (10%) in the high-dose group vs 1 participant (2%) and 0 participants, respectively, in the placebo group. Body weight increased by a mean of 2.2 kg in participants in the high-dose deutetrabenazine group compared with those in the placebo group. Neuroleptic drugs are well accepted to be the most efficacious medications to treat moderateto-severe tics in those with Tourette syndrome and other tic disorders. From a retrospective medical record review, Billnitzer and Jankovic2 reported that neuroleptic drugs provided moderate to marked benefit in 80.5% of 268 patients with Tourette syndrome. Neuroleptic drugs carry the risks of hyperglycemic metabolic complications, parkinsonism, and QTC prolongation. Although these and most other side effects can be regularly managed by lowering medication dosages or by switching to other neuroleptic medications, these agents carry appreciable risk for inducing tardive dyskinesia. Across 12 trials lasting at least 1 year (mean participant age, 39.7 years; n = 28 051; followed for 463 925 person-years), the annualized tardive dyskinesia incidence in the psychiatric population was 3.9% for second-generation and 5.5% for first-generation antipsychotic drugs.3 However, in distinction, in a 2011 literature review,4 only 20 potential cases of tardive dyskinesia in patients with Tourette syndrome were identified. Moreover, in only 2 of these cases, the reviewing authors considered there to be compelling evidence of tardive dyskinesia with persistence of symptoms upon neuroleptic withdrawal. Since this literature review, there do not appear to be any additional reported cases, including no identified cases in 2 large retrospective chart reviews totaling 789 patients with Tourette syndrome.2,4 Tetrabenazine was the first of 3 developed VMAT2 inhibitors, which nonselectively deplete monoamines, including dopamine, serotonin, norepinephrine, and histamine, from presynaptic nerve terminals. Tetrabenazine was approved by the US Food and Drug Administration in 2008 to treat chorea in adults with Huntington disease. More recently, deutetrabenazine was approved for + Related article