Valbenazine may reduce abnormal involuntary movement up to 6 weeks in patients with schizophrenia/schizoaffective disorder or mood disorder and dopamine receptor blocker-induced tardive dyskinesia

EBM Focus - Volume 12, Issue 21

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Reference – KINECT 3 trial (Am J Psychiatry 2017 May 1;174(5):476) (level 2 [mid-level] evidence)

  • Tardive dyskinesia, a movement disorder characterized by involuntary and repetitive body movements, can develop after chronic exposure to dopamine receptor-blocking agents such as antipsychotics.
  • The efficacy of valbenazine, a vesicular monamine transporter 2 (VMAT2) inhibitor, to alleviate tardive dyskinesia signs was investigated in the KINECT 3 trial. This trial included 234 adults with schizophrenia, schizoaffective disorder, or mood disorder and dopamine receptor blocker-induced tardive dyskinesia. The patients were randomized to valbenazine 40 mg or 80 mg once daily vs. placebo for 6 weeks.
  • The mean improvement in the Abnormal Involuntary Movement Scale (AIMS) subscale score was 3.2 points with valbenazine 80 mg/day (p < 0.001 vs. placebo), 1.9 points with valbenazine 40 mg/day (p = 0.002 vs. placebo), and 0.1 points with placebo 80 mg. The clinical significance of these improvements in the AIMS subscale score are unclear.

Tardive dyskinesia is characterized by involuntary and repetitive body movements, often of the orofacial area, that can occur after chronic exposure to dopamine receptor-blocking agents (DRBA) such as antipsychotics, gastric motility agents, and antiemetics (Tremor Other Hyperkinet Mov (N Y) 2013;3:tre-03-161-4138-1). Limited evidence is available to guide management of this movement disorder and strategies include withdrawal of the causative medication (Cochrane Database Syst Rev 2006 Jan 25;(1):CD000459), switching to an atypical (second generation) antipsychotic (Int Clin Psychopharmacol 2005 Mar;20(2):79, J Clin Psychiatry 2010 Sep;71(9):1226), or off-label addition of tetrabenazine (Clin Ther 2012 Jul;34(7):1487) to decrease dopamine availability. Valbenazine, a vesicular monamine transporter 2 (VMAT2) inhibitor, has a mechanism of action similar to tetrabenazine, and is the first drug approved by the Food and Drug Administration to treat adults with tardive dyskinesia (FDA Press Release 2017). The efficacy of valbenazine was investigated in the KINECT 3 trial which included 234 adults with schizophrenia, schizoaffective disorder, or mood disorder and DRBA-induced tardive dyskinesia. The patients were randomized to valbenazine 40 mg or 80 mg once daily vs. placebo capsules for 6 weeks. The primary outcome was change in the total score of items 1-7 on the Abnormal Involuntary Movement Scale (AIMS) (range 0-28, with higher scores indicating more severe dyskinesia) between baseline and 6 weeks. Atypical antipsychotics were continued in 77% of patients and conventional antipsychotics in 17%. The range of AIMS subscale scores at baseline was 0-20 points with a mean of 10 points. The adjusted mean improvement in this score at six weeks was 3.2 points with valbenazine 80 mg/day (p < 0.001 vs. placebo), 1.9 points with valbenazine 40 mg/day (p = 0.002 vs. placebo) and 0.1 points with placebo. A ≥ 50% improvement in the AIMS subscale score between baseline and 6 weeks was observed in 40% with valbenazine 80 mg (p < 0.001 vs. placebo, NNT 3), 23.8% with valbenazine 40 mg (p = 0.02 vs. placebo, NNT 7), and 8.7% with placebo. However, the minimal clinically important difference for this scale has not been established (CADTH Common Drug Review). Also, there were no significant differences between the valbenazine and placebo groups in overall change in clinical impression assessed via mean Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) scores. The most common adverse effects with valbenazine (40 mg and 80 mg combined) were somnolence (in 5.3% with valbenazine vs. 3.9% with placebo), akathisia (agitation, restlessness) (in 3.3% with valbenazine vs. 1.3% with placebo), and dry mouth (in 3.3% with valbenazine vs. 1.3% with placebo) (statistical comparisons not reported). The KINECT 3 trial demonstrated a greater improvement in the AIMS subscale scores with valbenazine compared to placebo. The clinical significance of these improvements in score are unclear as the minimal clinically important difference for the AIMS score has not been determined. Moreover, no significant differences in the investigator-assessed overall clinical impression in change of tardive dyskinesia signs from baseline (CGI-TD score) were observed. Finally, the range of AIMS subscale scores at baseline (0-20 points) indicates that the proportion of patients with a ≥ 50% reduction in score may potentially include some patients with low scores at baseline and for whom a ≥ 50% reduction may not be clinically important. For now, this trial indicates that valbenazine may reduce abnormal involuntary movement up to 6 weeks in patients with tardive dyskinesia taking antipsychotics. The duration of this trial was short and evidence regarding long-term efficacy and safety in extension trials is pending. For more information, see the Tardive dyskinesia topic in DynaMed Plus. DynaMed users click here.


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