What are the treatment options for refractory tardive dyskinesia?

Treatment for Refractory Tardive Dyskinesia

For patients with moderate to severe or disabling tardive dyskinesia that has not responded to initial management strategies, treatment with a VMAT2 inhibitor (valbenazine or deutetrabenazine) is the recommended first-line pharmacotherapy. 1

Initial Management Steps Before VMAT2 Inhibitors

Before escalating to specific pharmacotherapy, attempt these foundational interventions:

• Gradually withdraw the offending antipsychotic medication if clinically feasible, as this remains the primary management strategy even in refractory cases 1, 2
• Switch to a second-generation antipsychotic with lower D2 affinity (such as clozapine or quetiapine) if discontinuation is not possible due to underlying psychiatric illness 3, 1
• Ensure regular monitoring using the Abnormal Involuntary Movement Scale (AIMS) every 3-6 months to objectively track progression and treatment response 1, 4

VMAT2 Inhibitors: First-Line Pharmacotherapy

When tardive dyskinesia persists despite the above measures, VMAT2 inhibitors are the treatment of choice:

Valbenazine (FDA-Approved)

• Starting dose: 40 mg once daily, with option to increase to 80 mg once daily after one week based on tolerability and response 5
• Mechanism: Reduces presynaptic dopamine by inhibiting VMAT2, leading to decreased abnormal involuntary movements 6, 7
• Efficacy: Demonstrated statistically significant improvement in AIMS dyskinesia total score at Week 6 compared to placebo, with the 80 mg dose showing superior efficacy 5
• Advantages: Once-daily dosing and rapid onset of effect within 2 weeks of treatment initiation 8
• Dosage adjustment for CYP2D6 poor metabolizers: Reduce dose due to 2-fold higher drug exposure 5

Deutetrabenazine (FDA-Approved)

• Starting dose: 12 mg per day, titrated upward in 6 mg increments at weekly intervals until satisfactory control is achieved, intolerable side effects occur, or maximum dose of 48 mg per day is reached 9
• Efficacy: Demonstrated statistically significant improvement of 3.2-3.3 units on AIMS total score at Week 12 compared to 1.4 units with placebo 9
• Average effective dose: 38-40 mg per day after titration 9
• Pharmacokinetic advantages over tetrabenazine: Deuterated formulation allows less frequent dosing and better tolerability 7

Critical Medications to AVOID

Do NOT use anticholinergic medications (benztropine, trihexyphenidyl) for tardive dyskinesia, as they are indicated for acute dystonia and parkinsonism, not TD, and may actually worsen involuntary movements 1, 10

Common Pitfall to Avoid

• Distinguish between drug-induced parkinsonism and tardive dyskinesia before prescribing anticholinergics, as anticholinergics may benefit parkinsonism but will worsen TD 10
• Anticholinergics can precipitate toxic psychosis in patients with mental disorders on neuroleptics, particularly at treatment initiation or with dosage increases 10

Alternative and Adjunctive Options

If VMAT2 inhibitors are unavailable, not tolerated, or provide insufficient benefit, consider:

• Amantadine, clonazepam, Ginkgo biloba, or zolpidem as alternative pharmacologic options, though evidence is limited compared to VMAT2 inhibitors 7
• Botulinum toxin injections for focal or segmental TD affecting specific body regions 7
• Deep brain stimulation for severe, treatment-refractory cases where all pharmacologic options have failed 7

Monitoring Treatment Response

• Use AIMS examination at baseline and regularly during treatment to objectively measure improvement 4
• Expect improvement within 2 weeks for valbenazine and 4-8 weeks for deutetrabenazine based on titration schedules 8, 9
• Continue long-term monitoring as TD symptoms may return toward baseline following discontinuation of VMAT2 inhibitors 5

Special Considerations

• Up to 50% of youth receiving neuroleptics may experience some form of tardive dyskinesia, emphasizing the importance of prevention and early intervention 1, 2
• The concern over TD should not outweigh potential benefits of antipsychotics for patients who genuinely need these medications for serious mental illness 1, 2
• VMAT2 inhibitors have the major advantage of not causing TD themselves, unlike dopamine receptor blocking agents 7