Tardive Dyskinesia Research Review

Pharmacologic treatment of tardive dyskinesia: a meta-analysis and systematic review

Artukoglu, et al. J Clin Psychiatry. 2020; 81:19r12798.

Background
Tardive dyskinesia (TD) is a potentially debilitating condition. This study aimed to assess the efficacy of various available pharmacologic treatments for TD using published meta-analysis of clinical trials examining TD treatment.

Methods
PubMed was searched on December 12, 2017, for randomized, placebo-controlled trials examining the treatment of TD. Studies were included if they examined TD treatment as the primary outcome and were randomized and placebo-controlled trials. The effect size (standard mean difference) of improvement (compared with placebo) stratified by medication class is reported for each of the trials included in this systematic review. A meta-analysis was subsequently conducted.

Results
Vitamin E was associated with a significantly greater reduction in TD symptoms compared with placebo. There was significant evidence of publication bias in vitamin E studies. A shorter duration of treatment and lower dose of vitamin E was significantly associated with greater measured treatment benefit. Vitamin B₆ was associated with a significantly greater reduction in TD symptoms compared with placebo in 2 trials conducted by the same research group. VMAT2 inhibitors demonstrated significant benefit on TD symptoms compared with placebo. Amantadine was associated with a significantly greater score reduction compared with placebo. Calcium channel blockers were not associated with significantly greater score reduction compared with placebo.

Conclusions
Data from multiple trials suggests that VMAT2 inhibitors, vitamin E, vitamin B₆, and amantadine may be effective for the treatment of TD. Evidence of publication bias and a significant negative association of dose and duration of treatment with measured efficacy suggests that the benefits of vitamin E in TD may be overstated. Head-to-head trials are needed to compare the efficacy and cost-effectiveness of pharmacologic agents for TD.

Clinical Commentary (Sanjay Gupta, MD)
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies addressing the same scientific question. This method is often used to assess which interventions work. By combining multiple studies, the sample size can be significantly increased. Publication bias occurs in academic research when the outcome of a study determines whether it should be published or distributed.

Clinical Insights

• This study confirms that the 2 FDA-approved VMAT2 inhibitors valbenazine and deutetrabenazine are effective for the treatment of TD.
• Vitamin B₆ as a free radical scavenger was also noted to improve TD in 2 large double-blind studies conducted by the same research group. The first study had a high risk of bias, and the second study had a low risk of bias according to the Cochrane risk of bias tool. The details regarding randomization and maintaining the blind of the trial were unclear. This study needs replication. Vitamin B₆is not FDA approved for TD.
• Vitamin E—the most studied agent—was found to have a publication bias as noted by this meta-analysis. The quality of the studies has also been questioned by the authors of this meta-analysis. Hence, the efficacy findings of Vitamin E may be overstated.

Clinical Commentary (Joseph P. McEvoy, MD)
Before the availability of the VMAT2 inhibitors, healthcare professionals tried a wide range of medications to reduce the severity of TD. The few studies reported herein documented benefits in some patients from vitamin B₆ or amantadine, and many seasoned healthcare professionals believe, from their experiences, that these agents can be helpful.

Clinical Insights

• When new TD is noted, appropriate efforts should be undertaken to determine if continued treatment with a dopamine receptor–blocking agent is necessary.
• If treatment with a dopamine receptor–blocking agent is necessary, the dose should be adjusted to the lowest effective maintenance level.
• The patient and healthcare professional can reasonably consider brief (eg, 1 month) trials of vitamin B₆ and/or amantadine.
• If the TD does not improve (as will be true in most cases), the VMAT2 inhibitors remain available with a high likelihood to reduce TD severity without problems with tolerability.

Summary
In my opinion, we should be using valbenazine or deutetrabenazine (FDA approved) for the treatment of TD. The other agents studied do not have similar evidence of efficacy based on randomized, double-blind studies. It is hard to make a case for starting non-FDA–approved agents before FDA-approved agents have been tried.