Drug Eases Tardive Dyskinesia Linked to Antipsychotic Use

Megan Brooks

July 05, 2017

Deutetrabenazine (Austedo, Teva Pharmaceuticals) significantly reduced abnormal involuntary movements in patients with tardive dyskinesia (TD) caused by antipsychotic medications and was generally well tolerated in a phase 3 study.

Fixed doses of 24 mg/day and 36 mg/day were both effective, suggesting that dosing regimens "could be individualized and tailored for patients on the basis of dyskinesia control and tolerability," the study team says.

Results of the Addressing Involuntary Movements in Tardive Dyskinesa (AIM-TD) study were published online June 28 in Lancet Psychiatry.

Significant Unmet Need

TD resulting from exposure to dopamine receptor antagonists may be managed by lowering the dose or discontinuing the causative drug. "There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses," write Karen E. Anderson, Research Division, Department of Psychiatry, Georgetown University, in Washington, DC, and colleagues. Deutetrabenazine may be one option.

Vesicular monoamine transporter–2 (VMAT-2) is responsible for the storage and release of dopamine from synaptic vesicles in the brain. The US Food and Drug Administration (FDA) approved the first VMAT-2 inhibitor, tetrabenazine (Xenazine, Prestwick Pharmaceuticals), for treatment of chorea associated with Huntington's disease.

However, the high peak concentrations and plasma fluctuations of tetrabenazine cause problems with tolerability that restrict its use, Dr Anderson and colleagues point out.

Deutetrabenazine is a deuterated form of tetrabenazine that does not break down as fast or have the same peaks in concentration, thereby enabling less frequent dosing and perhaps greater tolerability.

Deutetrabenazine is already approved in the United States for Huntington's chorea, and this summer the FDA will evaluate it for TD. In April, the FDA approved the VMAT-2 inhibitor valbenazine (Ingrezza, Neurocrine Biosciences) for TD.

In the AIM-TD study, 298 patients with TD were randomly assigned to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or placebo; 293 patients made up the safety population. The primary efficacy sample comprised 222 patients with a protocol-specified baseline total score of 6 or more on the Abnormal Involuntary Movement Scale (AIMS).

Compared with a change of -1.4 points in the placebo group, the least-squares mean AIMS score improved by -3.3 points in the deutetrabenazine 36 mg/day group, by -3.2 points in the 24 mg/day group, and by -2.1 points in the 12 mg/day group, with treatment differences of -1.9 points, -1.8 points, and -0.7 points, respectively, vs -1.4 points in the placebo group.

The proportion of patients who showed an improvement of 50% or more in AIMS total score was significantly greater in the deutetrabenazine 24 mg/day (35%; odds ratio [OR], 3.96, 95% confidence interval [CI], 1.46 - 10.72; P - .005) and 36 mg/day (33%; OR, 3.80, 95% CI, 40 - 10.36; P = .007) groups than in the placebo group (12%).

Patients who received deutetrabenazine 24 or 36 mg/day also had "meaningful improvements" on scores on the Clinical Global Impression of Change Scale compared with those who received placebo, "indicating that overall improvements were recognized clinically by the site investigators," the authors write. "This findings are promising given the stigmatizing social aspect of the outwardly visible involuntary movements that define this disorder."

The frequency of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (51%), the 24 mg/day group (44%), the 12 mg/day group (49%), and the placebo group (47%).

In the deutetrabenazine groups, serious adverse events were reported in four (5%) patients who took 36 mg/day, six (8%) who took 24 mg/day, and two (3%) patients who were given 12 mg/day, compared with four (6%) patients given placebo.

Rates of psychiatric adverse events were similar across all groups. Rates of depression, depressed mood, and suicidal ideation were low in the deutrabenazine groups and did not show a dose-response relationship, the investigators report.

Three (1%) patients had suicidal ideation, one each in the deutetrabenazine 24 and 36 mg/day groups. These two events were deemed unrelated to treatment. The other report of suicidal ideation occurred on day 2 in a patient taking deutetrabenazine 24 mg/day. It was deemed possibly related to the drug.

Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigators or sponsor.

Key Questions Remain

In a comment published with the study, Christoph Correll, MD, and Maren Carbon, MD, of Zucker Hillside Hospital, Psychiatry Research, Northwell Health, in Glen Oaks, New York, praise the investigators for this well-designed and well-conducted study.

"When tardive dyskinesia develops and stopping of the dopamine receptor antagonist, dose reduction, or switch to a lower-risk dopamine receptor antagonist is not feasible or ineffective, the only currently available, evidence-based treatments are deutetrabenazine or valbenazine.

"Importantly, in the short-term trials, depression, suicidality, and interference with the efficacy of dopamine receptor antagonists was not a clinical problem with these two drugs," write Dr Correll and Dr Carbon.

The recent success of VMAT-2 inhibitors raises several questions, they add. These include the following:

  • What differentiates patient subgroups regarding severity, persistence, and clinical effect of TD and their likelihood of response to VMAT-2 inhibitors?

  • Can VMAT-2 inhibitors prevent progression from early or subsyndromal signs to full or more severe dyskinesia?

  • What is the time course of TD in patients with and without long-term treatment with dopamine receptor antagonists who are receiving VMAT-2 inhibitors?

  • What predicts successful discontinuation of VMAT-2 inhibitors after resolution of tardive dyskinesia?

"Availability of two new-generation VMAT-2 inhibitors that effectively reduce the severity of tardive dyskinesia will hopefully stimulate research to answer these and related questions, as well as provide benefit to patients," conclude Dr Correll and Dr Carbon.

The study was funded by Teva Pharmaceuticals. Several study authors and the authors of the comment have financial relationships with Teva Pharmaceuticals and other pharmaceutical companies. The original articles contain listings of all relevant financial relationships.

Lancet Psychiatry. Published online June 28, 2017. Abstract, Comment


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