Tardive dyskinesia: Prevention, treatment, and prognosis

Official reprint from UpToDate® www.uptodate.com

©2022 UpToDate®

Tardive dyskinesia: Prevention, treatment, and

prognosis
Authors: Tsao-Wei Liang, MD, Daniel Tarsy, MD
Section Editors: Howard I Hurtig, MD, Stephen Marder, MD
Deputy Editor: April F Eichler, MD, MPH

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jun 2022. | This topic last updated: Jun 16, 2021.

INTRODUCTION

Tardive dyskinesia (TD) is a medication-induced hyperkinetic movement disorder

associated with the use of dopamine receptor-blocking agents, including first- and second-
generation antipsychotic drugs, metoclopramide, and prochlorperazine.

The most common manifestations of TD involve spontaneous movements of the mouth

and tongue, but the arms, legs, trunk, and respiratory muscles can also be affected. Less
commonly, the prominent feature is dystonia involving a focal area of the body such as the
neck. TD can be irreversible and lifelong, with major negative impacts on psychologic
health and quality of life.

TD is important to recognize, since early discontinuation of the offending drug offers the
best chance of recovery. However, in patients who require ongoing antipsychotic drug
therapy for management of psychiatric disorders, symptomatic therapies for TD can help
lessen movements, if only partially.

This topic will review the prevention and management of TD. Other aspects of TD are
discussed separately. (See "Tardive dyskinesia: Etiology, risk factors, clinical features, and
diagnosis".)

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Tardive dyskinesia: Prevention, treatment, and prognosis

PREVENTION

Prevention and early detection of TD are of paramount importance. The only certain
method of TD prevention is to avoid treatment with dopamine receptor-blocking agents.

Safe prescribing practices — When a dopamine receptor-blocking agent is deemed

necessary, prevention of TD begins at the time of prescription. Guidelines for prescribing
drugs to help decrease the risk of TD include the following [1-3]:

● Use dopamine receptor-blocking agents only when there is a clear indication for their
clinical use and safer effective alternatives are lacking.

• For antipsychotic drugs, continuous treatment beyond three to six months should
only be considered when the need for continuous treatment and potential harms
of nontreatment are deemed to be greater than the risks of TD and other
potential toxicities (mainly chronic psychotic illness).

• For metoclopramide, continuous use for longer than 12 weeks should be avoided.
The association between metoclopramide and TD is discussed in detail separately.
(See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis",
section on 'Metoclopramide'.)

● Prescribe the lowest effective dose and for the shortest duration necessary.

● Consider preferential use of second-generation antipsychotics over first-generation

antipsychotics to lessen risk of TD, especially in older patients, while acknowledging
that second-generation antipsychotics still carry risk. (See "Tardive dyskinesia:
Etiology, risk factors, clinical features, and diagnosis", section on 'Antipsychotic
drugs'.)

● Avoid acute drug-induced parkinsonism and akathisia, which are risk factors for
future TD, by dose reduction or use of a less potent agent. Drug-induced
parkinsonism may also mask signs of TD.

● Use particular care in older adults (50 years and older), patients with affective
disorder, patients with treatment-resistant schizophrenia, and females, as these
groups are at increased risk for TD (table 1).

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● Avoid chronic use of prophylactic anticholinergic drugs whenever possible, since they
do not prevent TD and may aggravate symptoms when they arise.

Informed consent and education — As an iatrogenic disorder, TD has medicolegal

implications [4]. Thus, it is important to inform patients of the risk of developing TD before
treating with antipsychotic drugs or metoclopramide, discuss treatment goals and
alternatives, and document discussion in the medical record.

Although there is no consensus, some experts also advocate obtaining written informed
consent from patients with decision-making capacity or from family members of patients
who are unable to consent.

Informed consent provides an opportunity to educate the patient and family members or
caregivers, so that they recognize abnormal movements should they occur.

Monitoring during treatment — All patients receiving long-term antipsychotic drugs or

metoclopramide should be regularly screened for the development of TD.

Screening for TD consists of direct observation. While the patient is sitting, the clinician
observes whether there are abnormal movements in the face, mouth, jaw, or extremities.
The tongue should be observed with the mouth held open. While standing or walking, the
patient is observed for abnormal movements of the trunk or limbs.

Clinicians may choose to use the Abnormal Involuntary Movement Scale (AIMS) for
documenting results of the examination (form 1). The AIMS includes both a standardized
examination and a system for rating abnormal movements.

INITIAL MANAGEMENT

All therapies for TD are symptomatic and only partially effective. Thus, early detection and
management of potentially reversible cases is imperative.

Discontinue offending agent, if possible — The offending drug should be discontinued

when TD first emerges, if possible (algorithm 1). TD is not always permanent, and the
earlier the drug is discontinued, the better chance for improvement or resolution of TD.
(See 'Prognosis' below.)

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Antipsychotic drug cessation (or dose reduction) must be carefully considered in the
context of the underlying psychiatric illness and the potential for relapse or worsening of
psychotic symptoms. Ongoing antipsychotic drug therapy is often necessary for patients
with schizophrenia or other severe psychotic illnesses. (See "Schizophrenia in adults:
Maintenance therapy and side effect management", section on 'Antipsychotic therapy'.)

When tapering a dopamine receptor-blocking agent, clinicians and patients should be

aware of the following [5,6]:

● The drug should be withdrawn slowly, over weeks to months depending on the
underlying condition and the duration of TD. Abrupt withdrawal may worsen or
precipitate TD.

● Dyskinesia may take several weeks to improve. In some cases, TD may take months
or years to remit and may never completely resolve.

● New-onset or worsened dyskinesia may occur during drug withdrawal (withdrawal-

emergent dyskinesia). Such dyskinesias often clear spontaneously over several weeks
and do not require specific treatment. In severe cases, the drug may need to be
reintroduced and more slowly tapered [7]. Alternatively, concurrent symptomatic
therapy for TD may be initiated in an attempt to facilitate the taper. (See 'Persistent,
moderate to severe TD' below.)

● TD may recur if a dopamine receptor-blocking agent is reintroduced. When possible,

a second-generation antipsychotic drug with a low risk of TD should be used in
preference to high-potency, first-generation drugs in patients with a history of TD
who require reintroduction of antipsychotic therapy.

The effectiveness of reducing or discontinuing the offending agent for ameliorating TD is

unproven and has not been well studied prospectively [8-10]. Studies primarily involve
patients with chronic psychiatric illness and longstanding TD. A 2018 systematic review
identified two trials that evaluated antipsychotic dose reduction versus dose maintenance
in a total of 17 patients with TD [9]. Pooled data showed that dose reduction was
associated with a trend toward a clinically important reduction in TD severity (relative risk
0.42, 95% CI 0.17-1.04).

Patients who require ongoing antipsychotic therapy

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Patients on a first-generation antipsychotic drug — Often when patients with severe

psychiatric disease develop TD on a first-generation antipsychotic drug, antipsychotic
therapy cannot be safely discontinued. For such patients, we suggest switching to a
second-generation antipsychotic drug with lower TD risk, whenever possible [11]. Such a
switch seldom worsens TD and may result in a reduction in TD severity, particularly for
early and mild symptoms.

For longstanding TD, clinicians and patients should be aware that improvement in
symptoms may take months or years, and in some cases there may be no observable
benefit. Therefore, the potential benefits of a switch may not exceed the risk of worsening
psychosis for longstanding TD.

There are no randomized trials comparing different second-generation antipsychotic drugs

in patients with TD caused by a first-generation antipsychotic drug. Risk of TD varies
among second-generation drugs, largely in relation to their potency as dopaminergic D2
receptor blockers. Clozapine, quetiapine, and iloperidone have weak affinity for dopamine
receptors, whereas most of the other second-generation antipsychotic drugs are more
potent D2 receptor blockers that carry relatively higher risk of causing or perpetuating TD.
(See "Tardive dyskinesia: Etiology, risk factors, clinical features, and diagnosis", section on
'Antipsychotic drugs'.)

Clozapine has been the preferred second-generation agent in the setting of TD, but it
requires frequent blood testing and carries a low but serious risk of bone marrow toxicity.
Supporting evidence consists largely of observational studies and secondary analyses of
randomized trials [12-18]. Quetiapine also carries relatively low risk and may have some
ameliorating effects on TD [19-21]. Administration of clozapine is reviewed separately. (See
"Guidelines for prescribing clozapine in schizophrenia".)

There are also data suggesting that other second-generation antipsychotic drugs,
including risperidone and olanzapine, may have some benefit on TD severity over
continued first-generation antipsychotic therapy, likely because they have relatively higher
D2 potency than clozapine or quetiapine [11,22-27]. In the only comparative trial with TD
as the primary outcome of interest, 60 patients with TD on a first-generation antipsychotic
were randomly assigned to risperidone or olanzapine after a three- to seven-day washout
period [25]. At 24 weeks, Abnormal Involuntary Movement Scale (AIMS) scores by blinded
raters improved over baseline in both groups (risperidone: -7.4 points, olanzapine: -6.2

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points).

The mechanism of benefit of clozapine or other second-generation drugs is likely primarily

an antipsychotic drug "sparing" effect, in which gradual improvement of TD occurs with
weaker dopamine-blocking effects. A direct antidyskinetic effect is less likely. With high
doses of antipsychotic drugs, TD may be masked by parkinsonism, but this practice is not
recommended [11].

Patients on a second-generation antipsychotic drug — When patients develop TD on a

second-generation antipsychotic drug with no prior exposure to dopamine receptor-
blocking agents, the indication and dose of the drug should be reviewed. In some cases, a
lower effective dose or an alternative class of drugs may be used.

If the patient requires ongoing therapy for psychiatric disease and the severity of TD is
bothersome, clinicians may consider a switch to clozapine, based on the data reviewed
above. (See 'Patients on a first-generation antipsychotic drug' above.)

Other patients may elect to stay on the same second-generation drug and try a
symptomatic therapy such as vesicular monoamine transporter type 2 (VMAT2) inhibitor if
movements are bothersome enough to require treatment. (See 'Persistent, moderate to
severe TD' below.)

Assess need for symptomatic therapy — For patients with ongoing symptoms despite an
optimized medical regimen, the need for drugs to control symptoms of TD should be
carefully assessed, since symptoms are often mild and not sufficiently bothersome to
require treatment and its associated side effects. Symptoms of TD can be stigmatizing,
however, even when mild, particularly the perioral and facial movements.

In some cases, family members are more disturbed by the involuntary movements than
the patient, who may be relatively unaware of their clinical manifestations. However, this
scenario is more common among chronic or institutionalized patients than in ambulatory
patients, many of whom are in psychiatric remission when TD appears.

PERSISTENT, MODERATE TO SEVERE TD

Overview of approach

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● For patients with persistent and bothersome TD, vesicular monoamine transporter
type 2 (VMAT2) inhibitors are the primary symptomatic therapy (algorithm 1).
Benzodiazepine therapy is sometimes helpful for mild symptoms but is unlikely to
help more severe TD. (See 'Vesicular monoamine transporter type 2 inhibitors' below
and 'Other drug treatments' below.)

● For the subset of patients with tardive dystonia (eg, cervical and truncal dystonia,
blepharospasm), botulinum toxin injections are a localized option that may spare the
need for systemic drug therapy (algorithm 1). (See 'Tardive dystonia' below.)

● Patients with refractory TD despite symptomatic therapies should be referred to a

movement disorder specialist for consideration of deep brain stimulation (DBS). (See
'Deep brain stimulation' below.)

Vesicular monoamine transporter type 2 inhibitors — VMAT2 inhibitors are the main

symptomatic drug therapy available for TD. In patients with moderate to severe or
disabling TD associated with antipsychotic therapy, VMAT2 inhibitors can be associated
with meaningful reductions in motor signs and symptoms [28-30].

They can be used with or without concurrent antipsychotic drug therapy. The drugs act
centrally to suppress TD by depleting dopamine storage in presynaptic vesicles.

Selecting an agent — Three VMAT2 inhibitors are in use. Tetrabenazine has been

available for decades and was approved by the US Food and Drug Administration (FDA) in
2008 for chorea in patients with Huntington disease, and two newer VMAT2 inhibitors,
valbenazine and deutetrabenazine, were FDA approved in 2017 for the treatment of TD.

The three drugs have not been compared directly, and regional availability and cost
influence agent selection in some cases. Valbenazine and deutetrabenazine are not
approved in Canada, for example. Assuming availability of all three, we generally prefer the
newer agents, based primarily on longer half-life and convenience.

The quality of the evidence for each of the three drugs is not uniform, but the overall
finding of benefit over placebo is consistent. For valbenazine and deutetrabenazine, the
available evidence consists of randomized trials with low risk of bias and good sample sizes
[28]. The duration of the randomized phase of the trials was relatively short, and as little as
four to six weeks in some studies. Long-term follow-up data are based primarily on open-

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label extension phases of the randomized trials. Data on tetrabenazine have a higher risk
of bias, smaller sample sizes, and inadequate blinding, yielding lower confidence; on the
other hand, tetrabenazine is associated with greater cumulative clinical experience than
the newer drugs.

Dosing and efficacy

Valbenazine

● Dosing – The recommended starting dose of valbenazine is 40 mg daily. The dose can
be increased as needed after one or more weeks to a maximum dose of 80 mg daily.
The maximum recommended dose is lower (40 mg/day) in patients taking strong
CYP2D6 inhibitors (eg, paroxetine, fluoxetine, bupropion) (table 2) or strong CYP3A4
inhibitors (table 3). Specific interactions may be determined using the Lexicomp drug
interactions tool (Lexi-Interact online) included in UpToDate.

● Efficacy – Valbenazine was approved for treatment of TD based on the six-week

KINECT-2 and KINECT-3 trials [31-34]. The larger KINECT-3 trial enrolled 225 patients
with schizophrenia, schizoaffective disorder, or a mood disorder and moderate or
severe TD [31]. Patients were randomly assigned to treatment with valbenazine 80
mg once daily, valbenazine 40 mg once daily, or placebo. By intention-to-treat
analysis, valbenazine reduced the mean Abnormal Involuntary Movement Scale
(AIMS) dyskinesia score, items 1 to 7 of the AIMS (form 1), from baseline to week 6 for
the 80 mg/day (-3.2) and 40 mg/day groups (-1.9) compared with placebo (-0.1).
Valbenazine treatment at both doses was generally well tolerated. Responses were
sustained in a 48-week open-label follow-up study, where there were no differences
in efficacy or tolerability for older (>50 years) versus younger patients [35,36].

Deutetrabenazine

● Dosing – The starting dose of deutetrabenazine is 6 mg twice daily. The dose can be
increased weekly in 6 mg/day increments depending on response and tolerability. In
a two-year open-label extension study, the mean daily maintenance dose was 38 mg
[37]. The maximum recommended dose is 36 mg/day in patients taking strong
CYP2D6 inhibitors (table 2) and 48 mg/day in all others. Specific interactions may be
determined using the Lexicomp drug interactions tool (Lexi-Interact online) included
in UpToDate.
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● Efficacy – In the 12-week ARM-TD trial of 117 patients with moderate to severe TD,
deutetrabenazine (titrated to a mean total daily dose of approximately 39 mg/day)
reduced the AIMS score from baseline compared with placebo (-3.0 versus -1.6) [38].
There was no difference between treatment groups on a clinical global impression
scale, although the trend favored deutetrabenazine. The larger 12-week AIM-TD trial
found improvements in AIMS scores compared with placebo for deutetrabenazine
titrated to a recommended dose of 36 mg/day (-3.3 versus -1.4) and 24 mg/day (-3.2
versus -1.4) but not 12 mg/day [39].

The effect of deutetrabenazine appears to be maintained over time, although follow-

up data beyond two years are not available. In an open-label extension study that
enrolled 343 patients who had completed the AIM-TD or ARM-TD trial, AIMS scores
remained stable over time with a mean treatment duration of approximately one
year, and no new safety concerns arose [37]. Limitations of the study included a
relatively high rate of attrition, with only 69 percent of patients available for efficacy
analysis by week 28.

Tetrabenazine

● Dosing – Tetrabenazine is initiated with 12.5 mg daily for one week and increased by
12.5 mg increments every few days, according to clinical response and as tolerated,
to a usual effective dose of 75 to 150 mg daily. Daily doses >37.5 mg should be
divided into three doses. The maximum recommended single and daily doses are
lower (25 and 50 mg, respectively) for patients taking strong CYP2D6 inhibitors (
table 2). Specific interactions may be determined using the Lexicomp drug
interactions tool (Lexi-Interact online) included in UpToDate.

● Efficacy – Efficacy data for tetrabenazine consist of several small, mostly open-label
trials in patients with TD [8]. In a double-blind, crossover trial with 24 patients,
tetrabenazine up to 150 mg daily produced marked reduction or disappearance of
dyskinesia in 70 percent of patients compared with no change for placebo [40]. An
open-label study in a small group of patients with chronic psychosis found that
tetrabenazine was less effective for TD than haloperidol [41]. Several open-label
studies have demonstrated improvement in TD with tetrabenazine in doses of up to
200 mg daily [42,43].

Adverse effects and precautions — All three VMAT2 inhibitors share common toxicities,
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most of which relate to their action to deplete dopamine at the synapse.

The most common side effects are somnolence and fatigue. Somnolence usually improves
with time and/or slower titration. Less common side effects, reported mainly in studies of
tetrabenazine, include akathisia, parkinsonism, depression, tremor, insomnia, confusion,
nausea, vomiting, hypotension, and dizziness. With long-term use, the most commonly
reported side effects are anxiety, somnolence, and depression [37].

Manufacturer labels carry a boxed warning on the risk of depression and suicidality.
Additional warnings include the potential for QT prolongation and neuroleptic malignant
syndrome.

Benzodiazepines — Prior to the availability of VMAT2 inhibitors, benzodiazepines were

commonly used for TD. Although evidence of efficacy is limited, our experience is that a
benzodiazepine such as clonazepam can be helpful to reduce both dyskinesia and
associated anxiety in patients with mild TD, at least in the short term. Patients with more
severe TD are less likely to benefit. Tolerance and loss of efficacy limit usefulness as a long-
term therapy [8].

● Dosing – Clonazepam is typically started at 0.5 mg daily and titrated by 0.5 mg

increments every five days according to response and as tolerated, up to a maximum
of 3 to 4 mg/day.

● Adverse effects – Side effects of benzodiazepines include sedation, confusion, ataxia,

and risk of falls, particularly in older adults. Central nervous system depressant
effects may be potentiated by barbiturates, hypnotics, anxiolytic, antipsychotic, and
antidepressant drugs.

● Efficacy – Evidence of benefit in patients with TD is limited and inconclusive [44,45]. A

systematic review identified four trials in a total of 75 patients with schizophrenia or
other chronic psychiatric illness that compared benzodiazepines with placebo,
inactive control, or no intervention [45]. In two trials with 32 patients, there was no
difference between benzodiazepine treatment and placebo for clinically important
improvement, defined as a ≥50 percent improvement in any validated scale for TD
(relative risk 1.12, 95% CI 0.60-2.09). A single trial in 21 patients found that more
patients taking clonazepam had clinically important improvement compared with
phenobarbital (60 versus 9 percent).
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Other drug treatments — Beyond VMAT2 inhibitors and benzodiazepines, there is

insufficient evidence to support routine use of any other drugs for TD, although many have
been studied.

● Amantadine – Amantadine may have some benefit for TD when used as adjunct
therapy with antipsychotic drugs [8], as suggested by the results of a short-term
crossover trial that randomly assigned 16 patients to amantadine (300 mg/day) or
placebo; both groups continued their regular antipsychotic drugs [46]. Dyskinesia
was reduced in patients taking amantadine.

● Ginkgo biloba extract – In a randomized controlled trial from China that included
157 patients with schizophrenia and TD, a standardized extract of Ginkgo biloba
leaves known as EGb-761 was effective in the treatment of TD [47]. At 12 weeks
compared with placebo, treatment with EGb-761 significantly decreased the
involuntary movement score.

● Others – A large variety of miscellaneous agents have been studied for treatment of
TD in case reports and open-label trials without convincing success, including vitamin
E, beta blockers, calcium channel blockers, serotonin antagonists, gamma-
aminobutyric acid (GABA) agonists, valproate, levetiracetam, buspirone, vitamin B6,
and lithium [8,48-55].

Deep brain stimulation — For patients who have permanent, disabling TD that is

unresponsive to pharmacologic treatment modalities, we suggest referral to a
multidisciplinary movement disorders clinic for consideration of DBS.

The basis for using DBS of the globus pallidus as a treatment for TD is the established
benefit of this procedure for treatment of levodopa-induced dyskinesia and idiopathic
dystonia. (See "Device-assisted and lesioning procedures for Parkinson disease" and
"Treatment of dystonia in children and adults", section on 'Surgical therapy'.)

More limited data in patients with refractory TD suggest that it is reasonable to pursue in
selected patients [8,11,29].

● Refractory TD – One of the larger prospective studies of DBS for TD included 19

patients with resolved or stabilized psychiatric disease who had severe TD refractory
to medical treatment [56]. All were treated with bilateral DBS of the internal part of

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the globus pallidus. At six months after surgical lead implantation, by double-blind
evaluation, the Extrapyramidal Symptoms Rating Scale (ESRS) score was significantly
lower with stimulation "on" compared with stimulation "off" (mean decrease 49
percent, range 9 to 84 percent). Among 14 patients with long-term (6 to 11 years)
follow-up, the improvement in ESRS scores with stimulation "on" was maintained
(mean decrease 60 percent, range 22 to 90 percent). Similar short-term and long-
term improvement was observed when outcome was assessed with the AIMS.

● Refractory tardive dystonia – In case reports and small series, patients with severe
forms of TD manifesting primarily as dystonia were successfully treated with DBS of
the globus pallidus or subthalamic nucleus [57-62]. These patients displayed various
combinations of orofacial, cervical, and truncal dyskinesia and dystonia that improved
dramatically within a relatively short period of time after surgery. One unblinded and
uncontrolled study of nine patients with refractory tardive dystonia found that benefit
of DBS persisted for longer than one year [62].

TARDIVE DYSTONIA

Tardive dystonia, although a less common form of TD than the classic orofacial dyskinesias,
is important to recognize because patients may be eligible for botulinum toxin injections,
which can spare the systemic side effects of oral therapies.

Botulinum toxin injections — We suggest botulinum toxin injections for patients with
localized forms of debilitating tardive dystonia, such as cervical dystonia, retrocollis,
oromandibular dystonia, and blepharospasm (algorithm 1) [5].

● Administration – The dose of botulinum toxin used depends on site of injection, the
serotype, and the formulation. The most common forms of TD treated with
botulinum toxin are cervical dystonia, oromandibular dystonia, and blepharospasm
(involuntary forced eye closure). Injections are repeated approximately every three
months. Adverse effects are excessive weakness of injected or neighboring muscles.
Botulinum toxin should generally not be used in patients with myasthenia gravis or
other neuromuscular conditions.

Dosing is individualized according to the form of dystonia, target muscles, and brand
and serotype of toxin used. For cervical dystonia, 150 units of onabotulinumtoxinA
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(Botox) is a general starting dose that can be increased as needed and tolerated to
300 to 400 units. Blepharospasm often requires a lower dose of onabotulinumtoxinA,
with typical doses varying between 25 to 75 units in both orbicularis oculi and
associated facial muscles.

IncobotulinumtoxinA (Xeomin) and abobotulinumtoxinA (Dysport) are alternative

formulations of botulinum toxin type A, approved for cervical and other forms of
dystonia. It is important to note that dosing of incobotulinumtoxinA is similar to
onabotulinumtoxinA (but not equivalent), while abobotulinumtoxinA requires a
larger-unit dose (approximately three to five times higher).

For patients who do not respond or become refractory to a type A toxin,

rimabotulinumtoxinB (Myobloc) can be used. Although it is customary to use
rimabotulinumtoxinB as an alternative to type A toxins, it is also possible to use this
as the first toxin in a treatment-naive patient. RimabotulinumtoxinB is typically
administered in unit doses approximately 40 to 50 times higher than
onabotulinumtoxinA or incobotulinumtoxinA.

● Efficacy – Evidence for the effectiveness of botulinum toxin for TD consists of

retrospective case series and case reports [8]. In one multicenter study, botulinum
toxin produced marked or moderate improvement in 29 of 34 patients with relatively
localized TD manifesting as cervical dystonia or blepharospasm in most cases [63]. In
another retrospective study, botulinum toxin treatment was associated with similar
improvement in tardive cervical dystonia (n = 7) and idiopathic cervical dystonia (n =
156) [64].

Nonfocal or refractory dystonia — For patients with more widespread tardive dystonia

that is not amenable to botulinum toxin injections, or for whom injections are not
acceptable or practical, vesicular monoamine transporter type 2 (VMAT2) inhibitors are the
main symptomatic therapy. DBS may also be an option in selected patients, as reviewed
above. (See 'Vesicular monoamine transporter type 2 inhibitors' above and 'Deep brain
stimulation' above.)

Anticholinergic drugs (eg, trihexyphenidyl, benztropine) are one additional option for
refractory tardive dystonia. Although they are usually ineffective in patients with TD or may
even exacerbate choreiform dyskinesias, they are sometimes helpful in ameliorating
tardive dystonia. This is consistent with the observation that anticholinergics often
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exacerbate other choreiform disorders but may be useful in primary dystonia. (See
"Treatment of dystonia in children and adults".)

Retrospective studies have shown improvement in tardive dystonia following

trihexyphenidyl (10 to 32 mg daily) in three of eight patients [42] and with trihexyphenidyl
(6 to 12 mg daily) in 8 of 21 patients [65].

When used for tardive dystonia, trihexyphenidyl can be initiated at 1 mg twice daily and
titrated to a total dose of 4 to 6 mg daily as tolerated.

Narrow-angle glaucoma, confusion, and dementia are contraindications to the use of

trihexyphenidyl. The possibility of exacerbating underlying psychosis is a particular
concern in patients with TD. Trihexyphenidyl should be used with caution in people over
60, and in patients with benign prostatic hypertrophy or obstructive gastrointestinal
disorders. Other anticholinergic side effects include dry mouth, blurred vision,
constipation, urinary hesitancy or retention, tachycardia, pupillary dilatation, and increased
intraocular pressure. Patients may develop tolerance to these effects with continued low-
dose treatment. Additional side effects of trihexyphenidyl include dizziness, confusion,
memory impairment, nausea, vomiting, and anxiety.

PROGNOSIS

Although once considered a persistent or permanent condition, TD is often reversible. In

historical studies, remission rates of persistent TD were only 5 to 40 percent, but early
identification of TD in younger outpatient populations has been associated with remission
in 50 to 90 percent of patients [66]. Remission of TD usually occurs within several months
after withdrawal of the offending agent, but may occur as late as in one to three years [67].

Prognosis of TD in patients who require continued antipsychotic drug treatment is not well
established, but fortunately, continued antipsychotic drug exposure does not appear to
worsen the severity of TD once it becomes established or chronic [68,69]. In most cases, TD
either remains unchanged or is suppressed by the hypokinetic effects of an antipsychotic
drug.

INFORMATION FOR PATIENTS

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UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
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about a given condition. These articles are best for patients who want a general overview
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are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Tardive dyskinesia (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Definition – Tardive dyskinesia (TD) is a medication-induced hyperkinetic movement

disorder that can be disabling and irreversible. All dopamine receptor-blocking
agents have the potential to cause TD. The most commonly implicated drugs are
antipsychotics and metoclopramide. (See 'Introduction' above.)

● Prevention – The only certain way to prevent TD is to avoid chronic administration.

The use of antipsychotic drugs should be limited to situations where there is no
alternative effective therapy. Metoclopramide should not be used continuously for
longer than 12 weeks. Particular caution is required in high-risk groups (table 1). (See
'Prevention' above.)

• Patients receiving long-term antipsychotic drugs or metoclopramide should be

regularly screened for the development of TD (form 1). (See 'Monitoring during
treatment' above.)

• If dyskinesia develops during treatment with a dopamine receptor-blocking agent,

the offending drug should be discontinued, whenever possible (algorithm 1).
Dyskinesias may worsen transiently during withdrawal and may take weeks to
months to improve. (See 'Discontinue offending agent, if possible' above.)

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Tardive dyskinesia: Prevention, treatment, and prognosis

• For most patients who develop TD on a first-generation antipsychotic but still

require antipsychotic therapy, we suggest switching to a second-generation
antipsychotic drug (Grade 2C). Such a switch seldom worsens TD and may result
in a reduction in TD severity, particularly for early and mild symptoms. (See
'Patients on a first-generation antipsychotic drug' above.)

• For patients who develop TD on a second-generation antipsychotic drug that

cannot be discontinued, options include lowering the dose, when possible,
switching to clozapine, and using symptomatic therapy to suppress TD. (See
'Patients on a second-generation antipsychotic drug' above.)

● Symptomatic therapy – Mild TD may not be sufficiently bothersome to require

treatment and its associated side effects. For patients with moderate to severe TD,
vesicular monoamine transporter type 2 (VMAT2) inhibitors and botulinum toxin
injections are the main symptomatic therapies (algorithm 1). (See 'Overview of
approach' above.)

• For patients with ongoing moderate to severe TD, we suggest treatment with a
VMAT2 inhibitor (valbenazine, deutetrabenazine, or tetrabenazine) (Grade 2B).
Benzodiazepines are sometimes helpful for mild symptoms but are unlikely to
help more severe TD. (See 'Vesicular monoamine transporter type 2 inhibitors'
above.)

The three VMAT2 inhibitors have not been compared directly, and regional
availability and cost may vary. When available, we generally prefer the newer
agents (valbenazine and deutetrabenazine), based primarily on longer half-life
and convenience.

• For the subset of patients with focal tardive dystonia (eg, cervical dystonia), we
suggest botulinum toxin injections (Grade 2C). VMAT2 inhibitors and
anticholinergic drugs are an alternative if botulinum toxin is not effective or
practical. (See 'Botulinum toxin injections' above.)

● Refractory dyskinesia – Patients with permanent, disabling TD may be candidates

for surgical therapy with deep brain stimulation (DBS) and should be referred to a
multidisciplinary movement disorder center for consideration. (See 'Deep brain
stimulation' above.)
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Tardive dyskinesia: Prevention, treatment, and prognosis
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