Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

all patients

1st line – consider withdrawal or modification of causative drug

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ACUTE
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1st line – 

consider withdrawal or modification of causative drug

Promptly identify the causative drug. This is usually an antipsychotic, but other dopamine receptor-blocking agents (e.g., metoclopramide) may also cause TD. Consult your local drug formulary for a full list of drugs that may cause TD. Patients may be taking multiple dopamine receptor-blocking agents and it may not be possible to identify which drug is the cause with any certainty.

For patients who can safely have the causative drug withdrawn, gradually reduce the dose and finally discontinue the drug (where possible).[11][12] TD symptoms may worsen as the dose is reduced.[11]

  • Explain to the patient that symptoms of TD may last for months to years after discontinuing the causative drug.[6][11]​​

  • Consider what alternative drugs are available to replace the withdrawn drug. In the long term, drugs that do not block dopamine receptors should be considered.

For patients who are unable to safely have the causative drug withdrawn, switch to a safer drug with lesser propensity to cause TD without causing other adverse effects and without compromising the treatment of the underlying primary disease.[11][12] For example:

  • Patients on typical (first-generation) antipsychotics (e.g., haloperidol) may be switched to atypical (second-generation) antipsychotics (e.g., quetiapine, clozapine), if not contraindicated[11]

  • Consider pimavanserin (if available) as the first-line treatment in patients with Parkinson's disease who experience psychosis[4][41]

  • Treat nausea/vomiting in patients with Parkinson's disease with an anti-emetic that does not block dopamine receptors (e.g., ondansetron), instead of dopamine receptor-blocking agents such as metoclopramide.[4]

As sudden discontinuation of dopamine receptor-blocking agents may lead to serious withdrawal symptoms, physicians who prescribe antipsychotics or anti-emetics should coordinate their efforts to select the most appropriate drugs and provide the optimum multidisciplinary care.[4]

There is not enough evidence to confirm whether maintaining the causative drug but at a reduced dose will ameliorate TD.[11][42]

2nd line – vesicular monoamine transporter type 2 (VMAT2) inhibitor

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2nd line – 

vesicular monoamine transporter type 2 (VMAT2) inhibitor

Prescribe a VMAT2 inhibitor depending on the patient's needs and preferences and after any modifications to the patient's antipsychotic therapy (or other causative drug).[12] The American Psychiatric Association recommends the use of VMAT2 inhibitors in patients who have moderate, severe, or disabling TD caused by antipsychotics.[6]

  • Three VMAT2 inhibitors are approved in the US for the treatment of TD in adults: tetrabenazine, deutetrabenazine, and valbenazine. However, deutetrabenazine and valbenazine may not be routinely available outside of the US.

  • Where available, give deutetrabenazine or valbenazine in preference to tetrabenazine.[6][11][12][43]

Deutetrabenazine, a deuterated version of tetrabenazine, has a relatively long half-life (9-10 hours), which allows a twice-daily dosing regimen. It also requires a lower dose compared with tetrabenazine to achieve equivalent clinical effect. Deutetrabenazine is approved in the US for the treatment of both TD and chorea in Huntington's disease based on the results of several pivotal trials.[44][45][46] Long term, deutetrabenazine provides clinically appreciable benefit and persistent reduction in Abnormal Involuntary Movement Scale (AIMS) score.[44] An extended-release formulation may be available in some locations, which facilitates a once-daily dosing regimen. It was demonstrated that the number needed to treat for >50% improvement in AIMS score at a therapeutic dose of deutetrabenazine versus placebo was 7, whereas the number needed to harm (for adverse effect-related discontinuation from trial) was 189.[47]

Valbenazine is the VMAT2 inhibitor with the longest half-life (15-22 hours). It is therefore prescribed as a once-daily dosing regimen. Its long-term efficacy was confirmed in the KINECT 3 study and it is approved in the US for the treatment of TD and chorea (in people with Huntington's disease).[48][49]

Tetrabenazine, the oldest of the three VMAT2 inhibitors, is approved in the US for the treatment of chorea associated with Huntington's disease. It may be approved for the treatment of TD in other countries. With a half-life of 5-12 hours, tetrabenazine typically needs to be administered three times daily. A systematic review found limited evidence for the use of tetrabenazine in treatment of TD and that it is associated with more adverse effects than valbenazine and deutetrabenazine.[11]

VMAT2 inhibitors may increase the risk of depression and suicidality (in patients with Huntington's disease). When considering prescribing VMAT2 inhibitors, these risks should be balanced against the clinical need for control of choreiform movement. They are contraindicated in patients who are actively suicidal or patients who have untreated/inadequately treated depression. Patients taking VMAT2 inhibitors should be closely monitored for the emergence or worsening of depression, suicidality, or unusual changes in behaviour.

VMAT2 inhibitors are metabolised by hepatic isoenzyme CYP2D6. It may be recommended that patients taking these drugs, particularly in higher doses, should be genotyped for CYP2D6. This is not a practical or cost-effective approach, however, and is rarely employed in medical practice.[50] Review drug-drug interactions if patients are on other drugs; coadministration of certain drugs may need to be avoided or a dose adjustment may be necessary.

Deutetrabenazine and tetrabenazine are contraindicated in patients with hepatic impairment. Valbenazine may be used with caution in patients with hepatic impairment (a dose reduction may be necessary).

Primary options

deutetrabenazine: 6 mg orally (immediate-release) twice daily initially, increase gradually according to response, maximum 48 mg/day (36 mg/day in poor CYP2D6 metabolisers); 12 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 48 mg/day (36 mg/day in poor CYP2D6 metabolisers)

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OR

valbenazine: 40 mg orally once daily for 1 week, followed by 80 mg once daily, adjust dose according to response, maximum 80 mg/day (40 mg/day in poor CYP2D6 metabolisers)

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OR

tetrabenazine: 12.5 mg orally twice or three times daily initially, increase gradually according to response, maximum 200 mg/day (50 mg/day in poor CYP2D6 metabolisers)

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3rd line – benzodiazepine

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3rd line – 

benzodiazepine

In patients with severe TD symptoms or symptoms that impact the patient, consider a benzodiazepine if VMAT2 inhibitors are unavailable or not tolerated.[4][43] However, the data regarding the efficacy of benzodiazepines are not robust.[51] Systematic reviews discourage the use of benzodiazepines as a treatment for TD, due to there being little evidence to support their use and given the adverse effects in patients with mental health disorders.[11][51]

Primary options

clonazepam: consult specialist for guidance on dose

4th line – amantadine

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4th line – 

amantadine

Consider amantadine if other treatments are unavailable or not tolerated.[11][43] However, the data regarding the efficacy of amantadine are not robust.[11] A systematic review classified two randomised crossover trials of amantadine for the treatment of TD, one with low risk of bias and the other with high risk of bias.[11] Although the magnitude of improvement was small in both of these trials, there was statistically significant improvement compared with placebo.[52][53]

Primary options

amantadine: consult specialist for guidance on dose

5th line – chemodenervation

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5th line – 

chemodenervation

Although there are no controlled trials for chemodenervation using botulinum toxin for the treatment of TD, several case reports and open-label studies have reported improvement when botulinum toxin is injected by experienced injectors into the target muscles that are involuntarily contracting.[54][55][56] Botulinum toxin injections are considered for patients who do not improve with pharmacotherapy at a tolerable dose. This may be particularly useful in patients with tardive dystonia.[4]

Possible adverse effects when injected into oromandibular muscles include dysarthria and dysphagia, which are usually minimised when botulinum toxin is injected by movement disorder neurologists experienced in administering these injections. As there are no controlled trials, there is insufficient evidence to support or refute chemodenervation using botulinum toxin to treat TD.[4][54][55]

6th line – deep brain stimulation

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6th line – 

deep brain stimulation

Deep brain stimulation of bilateral globus pallidus interna may be considered in patients with TD that is refractory to pharmacotherapy or chemodenervation with botulinum toxin, and where TD symptoms are severe and distressing and any psychiatric condition is stabilised.[4][11]​ In a systematic review (117 patients; 4 with classic TD and the others with tardive dystonia), there was 62 ± 15% improvement in Abnormal Involuntary Movement Scale (AIMS) score after a mean follow-up of 25.6 ± 26.2 months.[57]​ Other reviews deem that there is either insufficient evidence or that deep brain stimulation of bilateral globus pallidus interna is possibly effective.[11][43]​

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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