Two FDA-approved medications, valbenazine and deutetrabenazine, are the primary treatments for tardive dyskinesia (TD). Both belong to a class called VMAT2 inhibitors, and both were approved in 2017, ending decades in which no drug had formal approval for the condition. Before these medications arrived, clinicians relied on off-label strategies with limited evidence. The treatment landscape has changed substantially, but it remains more complicated than simply prescribing a pill, because the underlying antipsychotic (or other dopamine-blocking drug) that caused TD often cannot be stopped.
How VMAT2 Inhibitors Reduce Involuntary Movements
Tardive dyskinesia involves repetitive, involuntary movements, most often around the face, tongue, and jaw, though limbs and trunk can be affected too. The leading theories about why it develops point to dopamine receptor hypersensitivity, damage to certain inhibitory brain circuits, and oxidative stress from long-term antipsychotic exposure.1PubMed. Tardive dyskinesia: pathophysiology and animal models2PubMed. Oxidative stress and tardive dyskinesia: pharmacogenetic evidence Each hypothesis has supporting and contradicting data, which partly explains why effective treatments took so long to develop.
VMAT2 inhibitors work by reducing the amount of dopamine available for release in the brain. They block a transporter protein that packages dopamine into tiny storage compartments inside nerve cells. With less dopamine loaded up and ready for release, the overactive dopamine signaling thought to drive TD gets dialed down, and involuntary movements decrease.3PubMed. Treatment of Tardive Dyskinesia: A General Overview with Focus on the Vesicular Monoamine Transporter 2 Inhibitors This mechanism is shared across all three VMAT2 inhibitors used in TD: valbenazine, deutetrabenazine, and the older drug tetrabenazine.
Valbenazine
Valbenazine (brand name Ingrezza) was the first drug to receive FDA approval specifically for TD. In its pivotal phase III trial, about 40% of people taking 80 mg per day achieved at least a 50% reduction in their involuntary movement scores, compared with roughly 9% on placebo. That translates to a number needed to treat of 4, which in clinical terms is a strong result.4PubMed. Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication A lower 40 mg dose also helped, though less dramatically, with a response rate around 26%.5PubMed Central. Efficacy of Valbenazine (NBI-98854) in Treating Subjects with Tardive Dyskinesia and Schizophrenia or Schizoaffective Disorder
Longer-term data are encouraging. After 48 weeks of open-label treatment, responder rates climbed further, reaching 50% at the 80 mg dose. But the data also reveal something important: when valbenazine was stopped during a washout period, movement scores drifted back toward baseline, meaning the drug controls TD rather than curing it.6PubMed Central. Efficacy of Valbenazine (NBI-98854) in Treating Subjects with Tardive Dyskinesia and Schizophrenia or Schizoaffective Disorder For most people, staying on the medication is necessary to maintain benefit.
Side effects with valbenazine are relatively mild. The main one to watch for is sleepiness. In pooled trial data, drowsiness and fatigue occurred in about 11% of people on valbenazine versus 4% on placebo. Discontinuation because of side effects was low, around 3%, not meaningfully different from placebo.7PubMed. Valbenazine for tardive dyskinesia: A systematic review of the efficacy and safety profile for this newly approved novel medication
Deutetrabenazine
Deutetrabenazine (brand name Austedo) was approved the same year as valbenazine. It is chemically related to the older drug tetrabenazine, but with a deuterium modification that slows its breakdown in the body, allowing for more stable blood levels and twice-daily dosing instead of three times daily. In a three-year open-label extension study, about two-thirds of patients achieved at least a 50% improvement in movement scores by the end of follow-up, with a mean score reduction of roughly 6.6 points on the standard rating scale.8PubMed Central. Long-Term Deutetrabenazine Treatment for Tardive Dyskinesia Is Associated With Sustained Benefits and Safety: A 3-Year, Open-Label Extension Study
Long-term safety looks reassuring. In an analysis covering over 330 patient-years of exposure, the rate of side effects was comparable to or lower than what was seen in the original trials, and the improvements held steady at about a year and a half of follow-up.9PubMed Central. Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia Deutetrabenazine does carry a boxed warning about depression and suicidality, a legacy of the tetrabenazine class, so clinicians monitor mood closely.
No large head-to-head trial has compared valbenazine directly against deutetrabenazine. Both clearly work better than placebo, both have manageable side-effect profiles, and both require ongoing use. The choice between them often comes down to insurance coverage, dosing convenience (once daily for valbenazine, twice daily for deutetrabenazine), and how a particular patient responds.
Why Stopping the Offending Drug Is Not Always Possible
The most intuitive first step for TD would be to simply stop the antipsychotic that caused it. Guidelines agree that reducing or withdrawing the offending medication is first-line management when clinically feasible.10PubMed Central. Treatment Recommendations for Tardive Dyskinesia In practice, though, this is often impossible. Many people with TD are taking antipsychotics to manage schizophrenia, bipolar disorder, or other serious psychiatric conditions. Stopping the antipsychotic risks psychotic relapse, hospitalization, or worse. TD also does not reliably resolve when the causative drug is removed, especially if it has been present for years. In some cases, movements even temporarily worsen when the antipsychotic dose is lowered, a phenomenon that can be alarming for patients and families.
This tension between psychiatric stability and movement-disorder treatment is the central challenge of TD management. VMAT2 inhibitors were developed precisely to fill this gap: they can be added on top of ongoing antipsychotic therapy without interfering with its psychiatric effects.
Switching Antipsychotics and the Role of Clozapine
For patients who can tolerate a change, switching from one antipsychotic to another with a lower TD risk is a reasonable strategy. Among antipsychotics, clozapine stands out. Multiple studies and a meta-analysis have found that switching to clozapine produces a measurable reduction in TD severity. The effect was especially pronounced in patients with moderate to severe movements.11The Journal of Clinical Psychiatry. Clozapine Monotherapy as a Treatment for Antipsychotic-Induced Tardive Dyskinesia: A Meta-Analysis In patients with mild TD, a switch to clozapine at least rarely worsened symptoms, and a trend toward improvement was observed.12PubMed. Clozapine and tardive dyskinesia in patients with schizophrenia: A systematic review
Clozapine is not a simple medication to use, however. It requires regular blood draws to monitor for a rare but serious drop in white blood cells, and it can cause weight gain, metabolic problems, and sedation. Because of these monitoring demands, it tends to be reserved for patients who have not responded to other antipsychotics, or in cases where TD is severe enough that the benefit of switching justifies the added burden.
Tetrabenazine and Off-Label Options
Before valbenazine and deutetrabenazine reached the market, clinicians sometimes turned to tetrabenazine, the original VMAT2 inhibitor. It works through the same basic mechanism and can substantially reduce involuntary movements. However, it has a heavier side-effect burden. In studies across all conditions it has been used for, sedation occurred in roughly a quarter to a third of patients, depression in around 8–15%, and parkinsonism (stiffness and slowness that mimics Parkinson’s disease) in 15–29%.13Psychiatry Research Case Reports. A patient with tardive dyskinesia treated with tetrabenazine: Case report Elderly patients are especially vulnerable to developing parkinsonism. These side effects often led to discontinuation, even when TD itself improved. Tetrabenazine was never FDA-approved for TD (its U.S. approval is for Huntington’s chorea), so its use in TD is entirely off-label.
A handful of other agents have shown some positive signals in small, early-phase trials, including amantadine, certain anticonvulsants like levetiracetam, clonazepam, propranolol, high-dose vitamin B6, and Ginkgo biloba extract.14PubMed Central. Tardive dyskinesia: therapeutic options for an increasingly common disorder None of these has robust enough evidence to be recommended routinely, and they are generally tried only when VMAT2 inhibitors are unavailable, unaffordable, or poorly tolerated.
Who Is Most at Risk for Developing TD
Understanding the risk factors helps put medication decisions in context. Some risk factors are fixed: older age, female sex, white or African descent, longer duration of psychiatric illness, and pre-existing brain damage or intellectual disability all raise TD risk. Among psychiatric diagnoses, mood disorders and cognitive symptoms appear to confer added vulnerability.15PubMed. Clinical risk factors for the development of tardive dyskinesia
Other risk factors are at least partially modifiable. Diabetes, smoking, and substance use are associated with higher TD rates. On the treatment side, higher antipsychotic doses, early parkinsonian side effects during treatment, use of anticholinergic medications alongside antipsychotics, and the type of antipsychotic all matter.16PubMed. Clinical risk factors for the development of tardive dyskinesia Recognizing these factors is important because they influence whether a clinician might choose a lower-risk antipsychotic upfront or monitor more closely.
Older Versus Newer Antipsychotics and TD Rates
The shift from first-generation antipsychotics (like haloperidol and chlorpromazine) to second-generation ones (like risperidone, olanzapine, and quetiapine) has meaningfully reduced TD incidence, though it hasn’t eliminated it. A meta-analysis of randomized trials found that the annual TD rate was about 6.5% with first-generation agents versus about 2.6% with second-generation ones, a risk roughly cut in half.17PubMed Central. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis That difference was not explained by the use of unusually high first-generation doses in the studies.
The gap is even more dramatic in older adults. One meta-analysis estimated TD incidence after one year of treatment at about 23% with first-generation drugs versus 7% with second-generation ones in older populations.18PubMed. Comparing the risk of tardive dyskinesia in older adults with first-generation and second-generation antipsychotics: a systematic review and meta-analysis By year three on first-generation antipsychotics, the cumulative incidence reached roughly 57%. These numbers explain why current guidelines strongly favor second-generation agents when antipsychotic treatment is necessary, especially in people over 65.
Even among second-generation drugs, TD risk is not zero. Annual rates around 1% in younger adults may sound small, but over years or decades of treatment they add up, and certain individual second-generation drugs carry different risk profiles from one another.19PubMed. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies This is why regular screening for early signs of TD remains important for anyone on long-term antipsychotic therapy, regardless of which agent they take.
Deep Brain Stimulation for Severe Cases
When medications fail or produce intolerable side effects, deep brain stimulation (DBS) is an option for severe, disabling TD. The procedure involves surgically implanting electrodes in a deep brain structure called the globus pallidus interna and delivering continuous electrical stimulation. Over the past two decades, multiple case series have reported that most patients experienced at least a 50% improvement in involuntary movement scores.20PubMed. Globus pallidus interna deep brain stimulation for tardive dyskinesia: case report and review of the literature
In a prospective trial of DBS for TD, movement scores dropped by about 56% at three months and the improvement held at six months, leading the investigators to conclude the trial early based on a pre-planned efficacy threshold. The results were confirmed in a blinded evaluation, and the benefit was maintained long-term, with follow-up data showing roughly a 60% reduction in overall movement scores years after surgery.21PubMed. Long-term efficacy and tolerability of bilateral pallidal stimulation to treat tardive dyskinesia22Archives of General Psychiatry. Bilateral Deep Brain Stimulation of the Globus Pallidus to Treat Tardive Dyskinesia All subscores, whether measuring facial movements, limb movements, or trunk involvement, improved.
DBS is brain surgery, with all the risks that entails: infection, bleeding, hardware complications, and the ongoing need for battery replacements and programming adjustments. It is reserved for people whose TD is severe enough to significantly impair daily functioning and who have not responded adequately to medication. Still, for those patients, the long-term results have been genuinely impressive.
Monitoring and the AIMS Scale
The standard tool for tracking TD severity is the Abnormal Involuntary Movement Scale, or AIMS. It rates involuntary movements across seven body regions — face, lips, jaw, tongue, upper extremities, lower extremities, and trunk — and is used both in clinical trials and in day-to-day practice. The total score across these items serves as the main outcome measure in treatment studies. A separate item on the scale, the clinician’s overall impression of severity, has also been validated as a practical shortcut for busy clinical settings.23CNS Spectrums. Using Item 8 of the Abnormal Involuntary Movement Scale (AIMS) to Assess Improvement in Patients with Tardive Dyskinesia
Regular AIMS assessments are recommended for anyone on long-term antipsychotic treatment, whether or not they currently show signs of TD. The American Psychiatric Association suggests screening at every visit for patients on first-generation antipsychotics and at least every six months for those on second-generation agents. Early detection matters because TD that is caught early and addressed with dose adjustments or medication changes is more likely to improve than TD that has been entrenched for years.
TD in Children and Adolescents
Most TD research and approved treatments focus on adults. Children and adolescents can develop TD from antipsychotic exposure, but the evidence base for treating them is thin. A systematic review found that, aside from dose reduction, discontinuation, or switching to a lower-risk antipsychotic, few interventions have strong evidence of working in younger patients. The best-supported pharmacological options remain VMAT2 inhibitors, but neither valbenazine nor deutetrabenazine is licensed for use in children.24PubMed. Tardive Dyskinesia with Antipsychotic Medication in Children and Adolescents: A Systematic Literature Review Small case reports have described clozapine helping TD in adolescents with schizophrenia, but these are isolated observations rather than clinical trial evidence.25Brain and Development. Clozapine for tardive dyskinesia in adolescents
The growing use of antipsychotics in pediatric populations for conditions beyond schizophrenia — including irritability in autism, behavioral problems, and mood disorders — makes this gap in evidence concerning. Clinicians treating children are essentially extrapolating from adult data, which is common in pediatric medicine but far from ideal for a condition whose trajectory and treatment response may differ by age.
The Oxidative Stress Angle
Beyond the well-known dopamine hypersensitivity theory, there is a body of research pointing to oxidative stress as a contributor to TD. Antipsychotic drugs appear capable of generating toxic free radicals in the brain, and animal studies have shown that this oxidative damage, combined with overactive glutamate signaling, can injure the striatum, a brain region central to movement control.26PubMed. Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats. Implications for tardive dyskinesia? Genetic studies in humans have identified variations in antioxidant-related genes that are associated with higher TD risk, lending some support to this idea.27PubMed. Oxidative stress and tardive dyskinesia: pharmacogenetic evidence
This line of research is what motivated trials of antioxidant supplements, including vitamin E and Ginkgo biloba extract, for TD prevention or treatment. Results have been mixed: some small trials reported modest benefits, but nothing strong enough to change practice. The oxidative stress hypothesis does, however, reinforce the idea that TD involves real structural damage to the brain rather than just a temporary chemical imbalance. That structural component likely explains why TD persists in many people even after the causative drug is stopped, and why early intervention is consistently associated with better outcomes.
Cost and Access
One practical barrier that deserves mention is cost. Valbenazine and deutetrabenazine are expensive brand-name medications, and insurance coverage can be inconsistent. An evidence review commissioned by the Institute for Clinical and Economic Review examined the value of both drugs when they first came to market.28JAMA Network (JAMA Internal Medicine). Effectiveness and Value of 2 Novel Treatments for Tardive Dyskinesia For patients whose insurance denies coverage or requires burdensome prior authorization, off-label tetrabenazine remains available and is generally less expensive, though its side-effect profile is harder to manage. Some patients end up navigating manufacturer assistance programs to afford the approved agents. This economic reality means that the “best” TD medication on paper is not always the one a given patient can actually access, and clinicians often factor cost into treatment planning.