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Pharmacological interventions
Vesicular monoamine transporter type 2 inhibition can lead to effective and tolerable management of tardive dyskinesia
  1. Leslie Citrome
  1. Correspondence to Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY 10595, USA; citrome{at}cnsconsultant.com

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Commentary on: Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017 Aug;4(8):595–604.

What is already known on this topic  

Tardive dyskinesia (TD), characterised by involuntary movements of the tongue, lips, face, trunk and extremities, is thought to be a generally irreversible consequence of the use of dopamine receptor blocking agents and is not rare. The introduction of second-generation antipsychotics has not  eliminated TD. Vesicular monoamine transporter type 2 (VMAT2) inhibition has been known to reduce TD, as observed with tetrabenazine, but tetrabenazine has been relatively complex to use because of its short half-life and sensitivity to CYP2D6 metabolism.1 Deutetrabenazine is related to tetrabenazine in that deuterium is substituted for hydrogen at the key sites of primary metabolism, altering the pharmacokinetics of drug metabolism by slowing it down.

Methods of the study

In this randomised, double-blind, placebo-controlled study,2 participants were patients 18–80 years old with TD in the USA and Europe. A total of 639 participants were assessed for eligibility; 341 were ineligible, and 298 were randomised. Interventions were deutetrabenazine at a dosage of 12, 24 or 36 mg or placebo, daily, for 12 weeks. The primary outcome measure was change in the Abnormal Involuntary Movement Scale (AIMS) dyskinesia total score, from baseline to week 12, as assessed centrally by raters who were movement disorder specialists. Videos were recorded and submitted to the central raters with concealment of visit number, site and date of recording. Other outcomes included AIMS response (≥50% improvement from baseline) and assessments of tolerability. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one postbaseline rating; n=222) and 293 patients comprised the safety population.

What this paper adds

  • From baseline to week 12, the AIMS score improved by –3.3 points (SE 0.42) in the deutetrabenazine 36 mg/day group, –3.2 points (0.45) in the 24 mg/day group and –2·1 points (0.42) in the 12 mg/day group, versus –1·4 points (0.41) in the placebo group.

  • The fixed dose design provides evidence that a modest dose of deutetrabenazine 24 mg/day can be efficacious, an observation that could not be made from a prior, smaller, flexible-dose study where the average dose achieved was 38.8 mg/day.3

  • The overall tolerability of deutetrabenazine, as observed by rates of discontinuation because of an adverse event, appears favourable; percentages of patients discontinuing because of an adverse event were 4% for deutetrabenazine (all doses) vs 3% for placebo.

  • The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 (51%)), 24 mg/day group (n=32/73 (44%)) and 12 mg/day group (n=36/74 (49%)) and those in the placebo group (n=34/72 (47%)).

  • Two patients died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor.

Limitations

  • It is unknown what prior attempts were made to manage TD in the individual participants.

  • Because TD is usually enduring, treatment may be indefinite; this study is limited to 12 weeks.

What next in research

  • Independent studies of longer term continuation therapy, as well as assessing the effect of discontinuation after such use.

  • A head-to-head comparison of deutetrabenazine with valbenazine,4 another efficacious and well-tolerated VMAT2 inhibitor, would be helpful to discern if there are any clinically relevant differences in therapeutic response, or safety and tolerability.

Do these results change your practices and why?

Probably yes. Deutetrabenazine is worth considering. The percentage of participants who achieved a response, as defined by ≥50% decrease from baseline on the AIMS dyskinesia score, was 34% of deutetrabenazine-treated patients receiving 12 mg or 18 mg twice daily, compared with 12% for those treated with placebo, resulting in a number needed to treat of 5. This is a clinically relevant effect size, particularly when coupled with the estimate of the number needed to harm for the outcome of discontinuation because of an adverse event of 100.

References

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Footnotes

  • Competing interests No external funding or writing assistance was used in the production of this commentary. In the past 12 months, Leslie Citrome has served as a consultant to: Acadia, Alkermes, Allergan, Intra-Cellular Therapeutics, Janssen, Lundbeck, Merck, Neurocrine, Noven, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva and Vanda. In the past 12 months, Leslie Citrome has served as a speaker for: Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva and Vanda. Other disclosures: stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago; and royalties: Wiley (Editor-in-Chief, International Journal of Clinical Practice), UpToDate (reviewer) and Springer Healthcare (book).

  • Patient consent Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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