Treatment of Persistent Tardive Dyskinesia
For patients with moderate to severe or disabling persistent tardive dyskinesia, treat with a VMAT2 inhibitor (valbenazine or deutetrabenazine) as first-line pharmacotherapy. 1, 2
Initial Management Steps
Assess Severity and Consider Antipsychotic Modification
If clinically feasible, gradually withdraw the offending antipsychotic medication as this remains the primary intervention when the underlying psychiatric condition allows. 2, 3
If antipsychotic therapy must continue due to risk of psychiatric relapse, switch to an atypical antipsychotic with lower D2 receptor affinity, with clozapine having the lowest risk profile for movement disorders among all antipsychotics. 2
Quetiapine is another lower D2 affinity option, though it still carries some risk for causing or perpetuating movement disorders and has sedation/orthostatic hypotension concerns. 2
Consider gradual dose reduction of the current antipsychotic if positive symptoms are well-controlled. 2
Pharmacological Treatment for Persistent TD
VMAT2 Inhibitors (First-Line)
Both FDA-approved VMAT2 inhibitors demonstrate robust efficacy:
Valbenazine (INGREZZA): At 80 mg daily, demonstrated statistically significant improvement in AIMS dyskinesia total score compared to placebo in controlled trials, with effects appearing to reverse toward baseline after discontinuation. 4
Deutetrabenazine (AUSTEDO): At doses of 24-36 mg daily, showed statistically significant improvement of 3.2-3.3 units on AIMS total score compared to 1.4 units with placebo at Week 12. 5
The average effective dose of deutetrabenazine after titration was 38 mg per day in clinical trials. 5
Dosing Considerations
For CYP2D6 poor metabolizers, dosage reduction of valbenazine is required due to approximately 2-fold higher exposure to the active metabolite. 4
Deutetrabenazine is started at 6-12 mg per day and titrated upward in 6 mg increments at weekly intervals until satisfactory control is achieved, intolerable side effects occur, or maximal dose (48 mg/day) is reached. 5
Critical Pitfalls to Avoid
Do NOT Use Anticholinergic Medications
Anticholinergic medications (benztropine, trihexyphenidyl) are contraindicated for tardive dyskinesia and may actually worsen the condition. 1, 2, 6
Anticholinergics are indicated for acute dystonia and drug-induced parkinsonism, NOT tardive dyskinesia—this is a critical distinction. 1, 7
In elderly patients on typical antipsychotics, specifically avoid benztropine or trihexyphenidyl when extrapyramidal symptoms occur. 6
Antiparkinsonian drugs can precipitate toxic psychosis and intensify mental symptoms, particularly at treatment initiation or with dosage increases. 6
Alternative Antipsychotic Options
If Switching Antipsychotics
Clozapine is the preferred switch option if continued antipsychotic therapy is necessary, given its lowest risk profile for movement disorders. 2
Consider cariprazine or aripiprazole as alternatives, particularly if negative symptoms are prominent. 2
Perform gradual cross-titration informed by the half-life and receptor profile of each medication to minimize withdrawal dyskinesia. 2
Monitoring and Follow-Up
Use the Abnormal Involuntary Movement Scale (AIMS) to monitor treatment response, with regular assessments at least every 3-6 months. 2, 7
The AIMS dyskinesia total score (items 1-7) ranges from 0 to 28, with decreases indicating improvement. 5, 4
Following discontinuation of VMAT2 inhibitors, TD symptoms may return toward baseline, highlighting the need for continued treatment in most cases. 4
Evidence Quality Considerations
The recommendation for VMAT2 inhibitors is based on Level 1A evidence from the American Psychiatric Association guidelines 1, supported by FDA approval based on randomized controlled trials showing statistically significant improvements in AIMS scores for both valbenazine 4 and deutetrabenazine 5. The evidence for switching to atypical antipsychotics, particularly clozapine, is supported by multiple guideline societies 2 though based on lower-quality observational data. The contraindication of anticholinergics for TD is consistently emphasized across all major guidelines 1, 2, 6.