JoAnn Filipov, Mercer University College of Pharmacy
Tardive Dyskinesia is an involuntary movement disorder induced by continued exposure to dopamine receptor agents (DBRAs). It is associated with persistent, hindering physical conditions causing significant problems for psychiatric patients.  Second-generation (“atypical”) antipsychotics were thought have a decreased risk for tardive dyskinesia compared to first-generation antipsychotics, but current literature indicates the risk may be increased with both generations.  For management, the two main methods are: 1) reduce the antipsychotic dose or 2) discontinue the drug. However, literature suggests both may not be the best strategies as they may lead to suboptimal management of the psychiatric illness without resolving tardive dyskinesia. 
Vesicular monoamine transporter 2 (VMAT 2) inhibitors (e.g. tetrabenazine) have been used to treat movement-related symptoms of Huntington’s disease.  They regulate presynaptic packaging and dopamine release into the synapse. Due to this mechanism of action, it was proposed that VMAT2 inhibitors may be able to counterbalance involuntary movement side effects of antipsychotics.  Research sparked to develop valbenazine (Ingrezza Ò). Its exact mechanism of action is unknown; however, it is thought to reversibly inhibit VMAT2.  In 2017, the Food and Drug Administration approved valbenazine for the treatment of tardive dyskinesia in adults. Below summarizes the phase 3 trial of valbenazine. 
A phase 3 randomized, double–blind, placebo–controlled trial of valbenazine for tardive dyskinesia
|Design||Randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study; N=227|
|Objective||To further evaluate the efficacy, safety, and tolerability of valbenazine at fixed dosages in adults with tardive dyskinesia|
|Study Groups||Valbenazine 40 mg once-daily (n=72), valbenazine 80 mg once-daily (n=79), and placebo (n=75)|
– medically stable
– stable psychiatric status
– 18-85 years of age
– meet the following eligibility requirements: diagnosis of schizophrenia, schizoaffective disorder, or mood disorder according to DSM-IV criteria for greater than 3 months prior to screening
– a total score greater than or = to 50 on the Brief Psychiatric Rating Scale (BPRS) (all participants)
– a total score greater than or = to 70 on the Positive and Negative Syndrome Scale (PANSS) or a total score greater than or equal to 10 on the Calgary Depression Scale for Schizophrenia
– a total score of greater than or = to 10 on the Young Mania Rating Scale (YMRS) or a total score > 13 on the Montgomery-Asberg Depression Rating Scale (MADRS)
– any clinically significant unstable medical condition
– any comorbid involuntary movement disorder more prominent than tardive dyskinesia (i.e. parkinsonism, akathisia, truncal dystonia)
– a score greater than or = to 3 on two or more items of the Simpson-Angus Scale
– history of neuroleptic malignant syndrome
– significant risk of suicidal or violent behavior
Patients were randomly assigned in a 1:1:1 ratio to study groups. Investigators could reduce the dosage if necessary for tolerability. If on the 40mg/day dose, then patients were to stay at that dose, and the same if they were on the placebo. If patients were dosed on the 80mg/day, they were decreased to the 40mg/day.
Adverse effects were called untoward events that occurred or worsened in severity after first dose of the drug.
Three types of statistical analysis took place for the evaluation of the data. The safety population included everyone who was part of the randomization until the treatment, received minimum one dose of the drug, and had minimum one post-baseline safety assessment. The intent-to-treat population had everyone in the safety population who had at least one post-baseline AIMS assessment. The per-protocol population included all everyone in the intent-to-treat population who had an AIMS score and detectable plasma level of valbenazine at week 6. Based on these statistical analyses, the primary endpoint was analyzed in the intent-to-treat population using a mixed-effects model using baseline AIMS dyskinesia score as covariate; treatment group, psychiatric diagnosis, and study visit as fixed effect; subject as random effects; and treatment-by-week and baseline score-by-week as interaction terms. The statistical analyses also accounted for dependence within subjects across visits in the trial. Any changes in the AIMS dyskinesia scale were revealed by at least square means.
|Duration||October 2014 – September 2014|
|Primary Outcome Measure||A change from baseline to week 6 in the 80mg/day patient group compared to the placebo group on the Abnormal Involuntary Movement Scale (AIMS) dyskinesia score (1-7), which was assessed by AIMS video raters|
|Baseline Characteristics||Table 1. Baseline characteristics and concomitant use for participants in a trial of valbenazine for tardive dyskinesia
|Results||AIMS change in placebo vs. valbenazine 80 mg at week 6 (least squares mean)
AIMS change in placebo vs. valbenazine 40 mg at week 6 (least squares mean)
· Improvement of movement disorders at week 6 (placebo vs. valbenazine 80 mg vs. valbenazine 40 mg)
o Clinical Global Impression of Change scale (least squares mean): 3.2 vs. 2.9 vs. 2.8
§ score range: -3 (marked worsening) to +3 (marked improvement):
AIMS response ≥50% improvement from baseline at week 6:
**p< 0.001 *p=0.05
a Sudden death, possibly due to a cardiovascular event, in a 73 year-old-African American man; judged by the investigator as unlikely to be related to study group.
b Reported in greater than or equal to 2% of participants in the valbenazine total group (both dosage groups).
|Study Author Conclusions||The data indicate that once-daily valbenazine improved tardive dyskinesia who had underlying schizophrenia, schizoaffective disorder, or mood disorder. It showed to be relatively well-tolerated. They also revealed to keep a stable psychiatric status.|
For this article, the study had a high internal validity since it was a well-designed double-blind randomized trial. However, the duration of this study was only 6 weeks; therefore, long-term outcomes cannot be determined. A long-term, rollover study up to 72-weeks is currently ongoing. Although statistically significant outcomes were observed, the clinical significance cannot be determined as such criteria have not been well established with AIMS dyskinesia scores. However, when number needed to treat (NNT) and number needed to harm (NNH) are calculated, the outcomes showed that NNT for 80 mg is four and NNT for 40 mg is seven. The calculated NNH for 80 mg was 13 while it was -32 for 40 mg. The NNT and NNH suggest the benefits of valbenazine may outweigh the risk. The authors did not perform multivariable analyses; therefore, it is unclear if there are any significant confounders which may affect the outcomes. This may have been due to the small number of patients. Further analyses may provide information on which patients may benefit the most from valbenazine, or whether there are significant factors may differentiate responders from non-responders to valbenazine.
The study used two separate doses of valbenazine; however, the study was not designed to explore the effects of dose differences. Consequently, it cannot be determined if one dose is better than the other. Finally, without the long-term data, it is unknown if patients will experience remission after discontinuing valbenazine. Despite the limitations of the study, given the lack of effective management and the poor quality of life associated with tardive dyskinesia, valbenazine may be a viable option for patients with a history of least three months of antipsychotics who are suffering from tardive dyskinesia. Future studies on long-term safety and efficacy of valbenazine as well as whether the drug has an impact on quality of life may be of an interest.
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