Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials

Aim: The aim of this study was to summarize the characteristics, efficacy, and safety of vesicular monoamine transporter- 2 (VMAT-2) inhibitors for treating tardive dyskinesia (TD). Materials and methods: We conducted a literature search in PubMed, Cochrane Database, and ClinicalTrials. gov, screening for systematic reviews, meta-analyses or double-blind, randomized, placebo-controlled trials (DBRPCTs) reporting efficacy or safety data of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. A random effects meta-analysis of efficacy and safety data from DBRPCTs was performed. Results: Two acute, 12-week DBRPCTs with deutetrabenazine 12-48 mg/day (n=413) and 4 acute, 4-6-week double-blind trials with valbenazine 12.5-100 mg/day (n=488) were meta-analyzable, without meta-analyzable, high-quality data for tetrabenazine. Regarding reduction in total Abnormal Involuntary Movement Scale (AIMS) scores (primary outcome), both deutetrabenazine (k=2, n=413, standardized mean difference [SMD]=-0.40, 95% confidence interval [CI]=-0.19, -0.62, p<0.001; weighted mean difference (WMD)=-1.44, 95% CI=-0.67, -2.19, p,<0.001) and valbenazine (k=4, n=421, SMD=-0.58, 95% CI=-0.26, -0.91, p < 0.001; WMD=-2.07, 95% CI=-1.08, -3.05, p, 0.001) significantly outperformed placebo. Results were confirmed regarding responder rates (>= 50% AIMS total score reduction; deutetrabenazine: riskratio [RR] = 2.13, 95% CI = 1.10, 4.12, p=0.024, number-needed-to-treat [NNT]= 7, 95% CI= 3, 333, p=0.046; valbenazine: RR=3.05, 95% CI=1.81, 5.11, p<0001, NNT=4, 95% CI=3, 6, p, 0.001). Less consistent results emerged from patient-rated global impression-based response (p=0.15) and clinical global impression for deutetrabenazine (p=0.088), and for clinical global impression change for valbenazine (p=0.67). In an open-label extension (OLE) study of deutetrabenazine (<= 54 weeks) and a dose-blinded valbenazine study (<=.48 weeks), responder rates increased over time. With valbenazine, discontinuation effects were studied, showing TD symptom recurrence towards baseline severity levels within 4 weeks after valbenazine withdrawal. No increased cumulative or specific adverse (AEs) events versus placebo (acute trials) in extension versus acute trial data were observed. Conclusion: The 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, are effective in treating TD, both acutely and long-term, without concerns about increased risk of depression or suicide in the TD population. No head-to-head comparison among VMAT-2 inhibitors and no high-quality, meta-analyzable data are available for tetrabenazine in patients with TD.