VMAT2 inhibitors for tardive dyskinesia: Ingrezza and Austedo state of practice

Background

Tardive dyskinesia affects roughly 20 to 30 percent of patients on long-term first-generation antipsychotic exposure and 15 to 20 percent on second-generation drugs. See our tardive dyskinesia side effect page. Older treatments (benztropine, propranolol, botulinum toxin) had limited efficacy and were symptomatic only.

VMAT2 inhibitors block the transport of dopamine into synaptic vesicles, reducing dopamine release and thereby modulating the dopamine supersensitivity that drives TD.

The three VMAT2 inhibitors

Valbenazine (Ingrezza):

• FDA-approved April 2017
• Once daily 40 mg to 80 mg
• Titrate to 80 mg after 1 week
• Take with or without food
• 40 mg for CYP3A4 inhibitors, CYP2D6 poor metabolizers
• Half-life 15 to 22 hours

Deutetrabenazine (Austedo, Austedo XR):

• FDA-approved August 2017
• Original Austedo: 6 mg BID starting, titrate weekly to maximum 24 mg BID
• Austedo XR: 48 mg once daily maximum
• Take with food
• Longer half-life than original tetrabenazine due to deuteration
• Dose-adjust for CYP2D6 poor metabolizers or with strong CYP2D6 inhibitors

Tetrabenazine (Xenazine):

• FDA-approved 2008 for Huntington's chorea
• Used off-label for TD before valbenazine/deutetrabenazine approvals
• Short half-life (4 hours) requiring TID dosing
• Higher rates of depression, suicidality, sedation, and parkinsonism
• Now largely superseded by valbenazine and deutetrabenazine

Trial data

Valbenazine: KINECT trials (KINECT 3 and 4) showed statistically significant reduction in Abnormal Involuntary Movement Scale (AIMS) scores at 6 weeks. Response rates of 40 to 50 percent for 50 percent AIMS reduction.

Deutetrabenazine: AIM-TD trial showed similar efficacy. ARM-TD trial data.

Tolerability

Common adverse events (both drugs):

• Somnolence
• Fatigue
• Restlessness (uncommon; from partial D2 modulation)
• Dry mouth
• Insomnia

Concerning but rare:

• Depression (VMAT2 inhibitors carry class-wide depression warning; smaller effect than older tetrabenazine)
• QT prolongation (mild)
• Parkinsonism (rare at therapeutic doses)

Discontinuation rates were modest (5 to 10 percent) in trials.

Practical considerations

Cost: Very high. Ingrezza list around $8,000 per month. Austedo similar. Manufacturer assistance programs important for eligible patients. Insurance PA required.

When to start: For patients with tardive dyskinesia causing distress or functional impact. Milder asymptomatic TD may not require treatment.

Continued antipsychotic: TD patients often need to continue their antipsychotic. VMAT2 inhibitor treats the TD; drug switching to a lower-TD-risk drug (see antipsychotics with lowest EPS) may be considered but is separate.

Ideal complement: switching to clozapine (which has lowest TD risk) plus VMAT2 inhibitor for existing TD gives best outcomes in some patients.

Common questions

Is Ingrezza better than Austedo? Similar efficacy. Once-daily Ingrezza dosing is more convenient than twice-daily original Austedo. Austedo XR now offers once-daily too. Cost and insurance coverage often drive choice.

Do VMAT2 inhibitors cure TD? No. They reduce movements while taken. Discontinuation typically leads to return of movements over weeks. Long-term use is standard.

Can VMAT2 inhibitors cause depression? Class warning applies. Older tetrabenazine had significant depression and suicidality. Newer agents have lower rates but the warning persists. Baseline mood assessment appropriate.

Should I switch my antipsychotic if I develop TD? Consider yes. Switching to a lower-TD-risk drug (clozapine, aripiprazole, Cobenfy) can reduce further exposure to the offending mechanism. Combined with VMAT2 inhibitor is often optimal.

Are there cheaper alternatives? Tetrabenazine (Xenazine) is older and less expensive but has more side effects. Some patients tolerate it well. Non-drug interventions (drug reduction, mouth guard for orofacial dyskinesia) have limited effect.

Do VMAT2 inhibitors work for Huntington's chorea? Yes. Tetrabenazine, valbenazine (KINECT-HD trial), and deutetrabenazine all have Huntington's applications. Deutetrabenazine has specific FDA indication for Huntington's chorea.

Can they be used long-term? Yes, extension data supports safe multi-year use. Effectiveness maintained.

What about pregnancy and VMAT2 inhibitors? Not well studied. Risk-benefit conversation for individual patients. Reversible drug options (drug switching, dose reduction) may be preferred where possible.

Sources

• Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484.
• 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;4(8):595-604.
• Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study. Neurology. 2017;88(21):2003-2010.
• Ingrezza (valbenazine) prescribing information. Neurocrine Biosciences; approved April 2017.
• Austedo (deutetrabenazine) prescribing information. Teva Pharmaceuticals; approved August 2017.