Tardive dyskinesia: Prevention and treatment

Author:
Daniel Tarsy, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
John F Dashe, MD, PhD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Sep 2017. | This topic last updated: Jul 24, 2017.

INTRODUCTION Tardive dyskinesia (TD) is a hyperkinetic movement disorder that

appears with a delayed onset, usually after prolonged use of dopamine receptor blocking
agents, mainly the antipsychotic drugs (also called neuroleptics) and the antiemetic
drug metoclopramide.

TD has numerous clinical manifestations that include chorea, athetosis, dystonia, akathisia,
stereotyped behaviors, and, rarely, tremor. The term "tardive" differentiates these dyskinesia
from acute dyskinesia, parkinsonism, and akathisia, which appear very soon after exposure
to antipsychotic drugs. TD is a clinical diagnosis, but tests may be performed to exclude
other causes of the patient's symptoms.

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

PREVENTION Prevention of TD and the early detection and treatment of potentially

reversible cases of TD are of paramount importance. The only certain method of TD
prevention is to avoid treatment with antipsychotic drugs and metoclopramide.

The use of antipsychotic drugs, particularly for longer than three months, requires
careful evaluation of indications, and risks and should be limited to situations where
there is no safer effective therapy.
Metoclopramide should not be used continuously for longer than 12 weeks.

As an iatrogenic disorder, TD has medicolegal implications [1]. Thus, it is important to inform

patients of the risk of developing TD before treating with antipsychotic drugs
or metoclopramide. Although there is no consensus, some experts also advocate obtaining
written informed consent from competent patients or from family members of patients who
are unable to consent. Once started on these medications, patients should be monitored
periodically for the development of TD.

Guidelines for antipsychotic drug treatment The American Psychiatric Association

Task Force report on TD lists specific indications for short- and long-term antipsychotic drug
treatment [2,3]. This is particularly important since TD is often irreversible despite cessation
of the offending drug. (See "Tardive dyskinesia: Clinical features and diagnosis", section on
'Clinical course'.)

The Task Force made the following recommendations:

Long-term use of antipsychotic drugs in neurosis, depression, anxiety, personality

disorder, and chronic pain states should be discouraged.
Even in schizophrenia or related chronic psychosis, efforts should be made to maintain
patients on the lowest effective dose of antipsychotic drugs while reexamining the need
for continued treatment at least every six months. After remission of a first acute
psychotic episode, the dose of antipsychotic drug should at least be decreased, and
probably best discontinued, within 6 to 12 months. Plans to continue treatment beyond
six months require discussion with the patient and family regarding the indication for
prolonged antipsychotic drug treatment and the risks of TD. (See "Pharmacotherapy for
schizophrenia: Side effect management".)
Particular care is indicated for patients age 50 and older, patients with affective
disorder, patients with treatment-resistant schizophrenia and negative symptoms, and
possibly women.
Since acute antipsychotic drug-induced parkinsonism and akathisia are an indicator of
the extent of D2 receptor blockade, these adverse effects should be avoided by dose
reduction or by use of a less potent agent. Drug-induced parkinsonism may also mask
signs of dyskinesia. It is prudent to use the smallest effective dose required to control an
individual patient's symptoms.
Except for prevention of acute dystonic reactions, chronic use of prophylactic
anticholinergic drugs should be discouraged since they do not prevent TD and can
aggravate the involuntary movements once they emerge.
Early antipsychotic drug withdrawal results in a better prognosis for recovery. Thus,
patients on antipsychotic drugs should be carefully monitored for signs of TD at regular
intervals with use of a standard dyskinesia rating scale such as the Abnormal
Involuntary Movement Scale (form 1), which is useful to heighten awareness of mild
manifestations of TD [4].
Where possible, antipsychotic drugs should be tapered and discontinued as soon as
the diagnosis of TD is made, although control of the patient's psychosis may ultimately
be the most critical factor in the use of the offending drug.

For patients who are developing signs of TD while receiving first generation (conventional)
antipsychotic drugs, but still require treatment for psychosis, it is now considered prudent to
switch to second generation (atypical) antipsychotic drugs that may be associated with a
lower risk for TD. However, there is no convincing evidence that altering the medication
regimen ameliorates the course of TD once symptoms have developed. (See 'Second
generation antipsychotic drugs' below.)

Discontinuation of metoclopramide treatment Metoclopramide is used primarily as an

antiemetic agent and/or as a prokinetic agent for the treatment of gastroparesis. It should be
stopped immediately if the diagnosis of TD is made, and alternative treatments of the
gastrointestinal symptoms should be used. As a preventive measure, metoclopramide should
not be used continuously for longer than 12 weeks.

The association of metoclopramide and TD is discussed in detail separately. (See "Tardive

dyskinesia: Etiology and epidemiology", section on 'Metoclopramide'.)

PHARMACOLOGIC TREATMENT Numerous studies have evaluated various

pharmacologic treatments of TD, but few therapies have produced more than slight to
moderate benefit in clinical practice [5]. Thus, prevention, early detection, and management
of potentially reversible cases are the cornerstones of modern treatment.

When clinically appropriate, pharmacologic interventions may be considered for patients who
are developing signs of TD. The two main strategies are:

Discontinuation of the offending drug

Switching from a first to a second generation antipsychotic drug

For patients with a diagnosis of TD, additional pharmacologic interventions include the
following:

Use of benzodiazepines, botulinum toxin injections, valbenazine, or tetrabenazine to

control symptoms of TD
Paradoxically, resuming treatment with antipsychotic drugs in order to suppress TD
(see 'Resumption of antipsychotic drugs' below)

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. 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 is more common among
chronic or institutionalized patients than in ambulatory patients, many of whom are in
psychiatric remission when TD appears.

Discontinuation of dopamine receptor blocking agent When feasible, immediate

tapering and discontinuation of the offending antipsychotic drug or metoclopramide is
recommended if TD becomes apparent [5]. Antipsychotic drug cessation (or dose reduction)
must be carefully considered because of the potential for relapse or worsening of psychotic
symptoms [6]. The dyskinesia may abate within several weeks of drug cessation, but
recurrence is possible if antipsychotic drug treatment is reintroduced.

The effectiveness of discontinuing the offending agent is not proven, since data are limited
and no randomized controlled clinical trials have studied complete cessation of antipsychotic
drugs for ameliorating TD [7,8]. A systematic review published in 2006 identified two trials
that evaluated antipsychotic dose reduction versus dose maintenance in a total of 17 patients
with TD [6]. Pooled data showed that dose reduction was associated with a trend toward a
clinically significant reduction in TD severity, but the findings just missed statistical
significance (relative risk 0.38, 95% CI 0.1-1.0).

New onset dyskinesias may occur during antipsychotic drug withdrawal. Such dyskinesias
often clear spontaneously over several weeks and do not require specific treatment. On the
other hand, more persistent dyskinesia may recur if antipsychotic drugs are resumed, which
should prompt the use of alternative pharmacologic management of the underlying
psychosis.

Some patients with bipolar disorder do not require persistent therapy with antipsychotic
drugs, as mood-stabilizing medications may adequately control the psychiatric symptoms.
However, temporary reintroduction of an antipsychotic drug may be necessary if the patient
has an acute exacerbation of psychotic symptoms. When a high-potency antipsychotic is
chosen, it should later be replaced by a second generation agent, preferably one with
demonstrated low risk for TD.

Second generation antipsychotic drugs Some reports suggest that the second
generation (atypical) antipsychotic drugs clozapine [9-12] and quetiapine [13-15] have
ameliorating effects on TD severity [16,17]. However, these observations may be due to
either masking effects of the drugs or, more likely, due to an antipsychotic drug "sparing"
effect, in which gradual improvement of TD occurs during treatment with weaker (second
generation) rather than more potent (first generation) dopamine blocking agents. Thus, it is
unclear if clozapine has definite antidyskinetic effects.

In a review of eight uncontrolled open studies published in 1991, the response of TD

to clozapine was variable and of uncertain significance [9]. However, in several later
uncontrolled studies, clozapine produced an apparent therapeutic effect [11,12]. It has
been particularly effective in some cases of severe tardive dystonia [9,11], possibly
related to its anticholinergic potency.
Quetiapine appears to have a low or even nonexistent tendency to cause TD [16], and
may alleviate TD [13-15]

Although the available data are limited and somewhat conflicting, we suggest changing to a
second generation antipsychotic drug in patients who are developing signs of TD if treatment
for psychosis remains critical [16]. In contrast to possible benefit in early TD, there is no
convincing evidence that altering the medication regimen is effective for ameliorating the
course of TD once symptoms have fully developed.

Clozapine is the preferred second generation agent in this setting, but requires frequent
blood testing, as discussed in the next section. Clozapine has weak affinity for dopamine
receptors whereas most of the other second generation antipsychotic drugs are potent D2
receptor blockers that carry the risk of causing or perpetuating TD. While quetiapine may be
capable of exerting clozapine-like therapeutic effects in TD, the evidence supporting its use
for ameliorating TD is limited. The risk of TD with second generation antipsychotic drugs is
reviewed elsewhere. (See "Tardive dyskinesia: Etiology and epidemiology", section on
'Second-generation antipsychotic drugs'.)

Clozapine dosing Clozapine titration begins with an initial dose of 25 mg daily. The dose
can be increased by 12.5 to 25 mg increments every one to two days, according to the
clinical response and as tolerated. The optimal dose for treating TD is uncertain, but
maintenance doses of 300 to 600 mg daily are usually required for antipsychotic efficacy.
Systemic side effects of clozapine are frequent and include potentially life-threatening
agranulocytosis, reported in 1 to 2 percent of patients during the first six months of treatment
and occurring less frequently thereafter. Other side effects include orthostatic hypotension,
weight gain, sedation, dizziness, vertigo, salivation, sweating, dry mouth, tachycardia,
syncope, nausea, and constipation. (See "Second-generation antipsychotic medications:
Pharmacology, administration, and side effects".)

Clozapine treatment requires weekly monitoring of the white blood cell count during the first
six months, biweekly monitoring for the next six months, followed by monitoring every four
weeks for the duration of treatment.

Benzodiazepines Because of evidence for gamma-aminobutyric acid (GABA) depletion

in some primate models of TD [18], GABA agonists have been tested in patients with TD with
modest success [19]. Benzodiazepines operate through a GABA mechanism, but evidence of
benefit in patients with TD is limited and inconclusive [20-22].

A systematic review published in 2006 identified three randomized trials that compared
benzodiazepines with placebo or no intervention [20]. The trials included a total of 56 patients
with schizophrenia or other chronic mental illnesses who had neuroleptic-induced TD. In two
trials with 30 patients, there was no significant difference between benzodiazepine treatment
and placebo for clinically important improvement, defined as a 50 percent improvement in
any validated scale for TD (relative risk 1.08, 95% CI 0.57-2.05). However, in one trial with 24
patients, benzodiazepine treatment resulted in a statistically significant improvement in
abnormal movement scores [20].

A fourth double-blind, randomized controlled trial [21] was not included in the meta-analysis
[20] because the data were only presented in graphs. In this trial, 19 patients with TD were
assigned to clonazepam (2 to 4.5 mg daily) or placebo [21]. At 12 weeks, clonazepam
reduced dyskinesia scores by 35 percent compared with placebo. The reduction in
dyskinesia scores was greater for patients with predominantly dystonic symptoms than for
those with predominantly choreoathetotic manifestations (41 and 26 percent, respectively).
Based upon the results of this trial, a guideline from the American Academy of Neurology
concluded that clonazepam is probably effective for decreasing TD symptoms short-term [8].
However, in five patients participating in an open study carried out immediately following the
double-blind study, the antidyskinetic effects disappeared after five to eight months [20].

Although evidence of efficacy is limited, we suggest the use of low doses of a

benzodiazepine, such as clonazepam, to reduce both dyskinesia and associated anxiety in
patients with mild TD. Patients with more severe manifestations of TD are less likely to show
a significant reduction in TD with benzodiazepine treatment.

Clonazepam dosing Clonazepam is initiated with 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. Previous benzodiazepine dependency may be a contraindication. Central nervous
system depressant effects may be potentiated by barbiturates, hypnotics, anxiolytic,
antipsychotic, or antidepressant drugs.
Botulinum toxin injections Evidence for the effectiveness of botulinum toxin for TD is
limited to 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 [23]. In another
retrospective study, botulinum toxin treatment was associated with similar improvement in
tardive cervical dystonia (n = 7) and idiopathic cervical dystonia (n = 156) [24].

We suggest botulinum toxin injections for patients with localized forms of debilitating tardive
dystonia, such as cervical dystonia, retrocollis, or blepharospasm [5]. 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.

Administration Botulinum toxin type A, onabotulinumtoxinA, is currently available in the

United States as Botox. The dose depends on site of injection. The most common forms of
TD treated with botulinum toxin are cervical dystonia and blepharospasm (involuntary forced
eye closure). Cervical dystonia requires highly individualized dosing, usually in the range of
150 units to start, increasing empirically to a maximum of 300 units according to individual
clinical response. Blepharospasm requires a total dose of approximately 25 units injected in
multiple sites in the orbicularis oculi muscles.

Botulinum toxin type B, rimabotulinumtoxinB, is available as Myobloc and may be given in

unit doses approximately 40 to 50 times higher than botulinum toxin type A, but only in the
event of failure to respond first to botulinum toxin type A.

Vesicular monamine transporter 2 inhibitors The vesicular monoamine transporter 2

(VMAT2) inhibitors may be useful therapeutic agents for TD. These agents act centrally by
depleting dopamine storage in presynaptic vesicles. Examples
include valbenazine, tetrabenazine, and deutetrabenazine.

Valbenazine Valbenazine is a selective VMAT2 inhibitor that may be effective for the
short-term treatment of TD, as demonstrated by the six-week, double-blind, KINECT 3 trial
[25]. The trial enrolled subjects with schizophrenia, schizoaffective disorder, or a mood
disorder and moderate or severe TD. Subjects were randomly to treatment with valbenazine
80 mg once daily, valbenazine 40 mg once daily, or placebo in a 1:1:1 ratio. By intention-to-
treat analysis (n = 225 participants), valbenazine reduced the mean Abnormal Involuntary
Movement Scale (AIMS) dyskinesia score, items 1 to 7 of the AIMS (form 1), from baseline to
week six 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.

Valbenazine was approved in April 2017 by the US Food and Drug Administration (FDA) for
marketing in the United States [26]. However, more data are needed to determine the long-
term efficacy and safety of valbenazine, and to learn whether it offers any advantage
over tetrabenazine.

Valbenazine dosing Valbenazine is started at 40 mg daily. After one week, the dose is
increased to 80 mg once daily. Potential adverse effects include somnolence and QT interval
prolongation. The drug should not be used in patients who have congenital or acquired long
QT syndrome.
Tetrabenazine Limited data from several old small trials suggest that tetrabenazine, a
VMAT2 inhibitor, is effective for the treatment of TD [8]. The range of findings is illustrated by
the following reports:

In a double-blind study with six patients, tetrabenazine 100 mg daily showed mild to
marked improvement in TD that was not greater than the effect of the active
control, diazepam [27].
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 [28].
An open-label study in a small group of patients with chronic psychosis found
that tetrabenazine was less effective for TD than haloperidol [29]. Several open-label
studies have demonstrated improvement in TD with tetrabenazine in doses of up to 200
mg daily [30,31].

Despite limited evidence of effectiveness, we suggest treatment with tetrabenazine (where

available) for patients with disturbing and intrusive TD, particularly those with tardive
dystonia.

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 level of 75 to 150 mg daily. Daily doses >37.5 mg should be divided into three
doses. Potential adverse effects include parkinsonism, sedation, fatigue, depression, anxiety,
akathisia, tremor, insomnia, confusion, nausea, vomiting, hypotension, and dizziness.

Deutetrabenazine Deutetrabenazine, the deuterated form of tetrabenazine, also may be

effective for treating TD. 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)
[32]. However, there was no difference between treatment groups on a clinical global
impression scale, although the trend favored deutetrabenazine. Further study is needed to
establish the long-term efficacy of this agent for TD and its utility compared
with valbenazine and tetrabenazine.

Anticholinergic drugs Trihexyphenidyl, benztropine, and other anticholinergics are

usually ineffective or may even exacerbate choreiform dyskinesias but are sometimes helpful
in ameliorating tardive dystonia. This is consistent with the observation that anticholinergics
often exacerbate any of the choreiform disorders but may be useful in primary dystonia.

Retrospective studies have shown improvement in tardive dystonia

following trihexyphenidyl (10 to 32 mg daily) in three of eight patients [30] and with
trihexyphenidyl (6 to 12 mg daily) in 8 of 21 patients [33].

We suggest trihexyphenidyl for patients with severe and more widespread tardive dystonia
that is refractory to other interventions, such as botulinum toxin injection, which is indicated in
relatively localized dystonia. We recommend not using trihexyphenidyl to treat TD unless
accompanied by severe tardive dystonia. Similarly, we suggest tetrabenazine for more
generalized tardive dystonia when localized use of botulinum toxin is not practical.
Trihexyphenidyl dosing Trihexyphenidyl is 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, pupil 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.

Gingko 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 [34]. At 12 weeks compared with placebo,
treatment with EGb-761 significantly decreased the involuntary movement score.

Resumption of antipsychotic drugs As a last resort, it may be necessary to resume

treatment with a first or second generation antipsychotic drug in order to suppress TD in
some patients with permanent and disabling or life-threatening TD that is treatment-resistant,
even in the absence of active psychosis.

Data supporting this approach are equivocal, since both short- and long-term studies of
conventional antipsychotic drugs have produced mixed results [35]. However, there is some
evidence that treatment with second generation antipsychotic drugs may be associated with
amelioration of TD. (See 'Second generation antipsychotic drugs' above.)

Fortunately, continued antipsychotic drug exposure does not appear to worsen the severity of
TD once it becomes established or chronic [36,37].

Cholinergic agents Because of the reciprocal relationship between dopamine and

acetylcholine in basal ganglia, it had been predicted that cholinergic drugs might ameliorate
TD. In available trials, treatment with galantamine, choline, lecithin, deanol, and other
cholinergic medications has been ineffective [8,38].

Vitamin E Vitamin E has been used for the treatment of TD based upon the hypothesis
that this antioxidant may reverse a possible toxic effect of free radicals produced during
chronic administration of antipsychotic drugs [39].

Clinical trials of vitamin E in relatively small numbers of patients with TD have produced
conflicting results [8,40-45]. However, in a systematic review published in 2011 that included
six placebo-controlled trials with 256 patients, vitamin E treatment was not beneficial for a
clinically relevant improvement in TD (relative risk 0.95, 95% CI 0.89-1.02) [46]. Vitamin E
was given in doses of 600 to 1600 units daily for up to 20 weeks in most of these trials.

Other drug treatments Amantadine may have some benefit for TD when used as adjunct
therapy with antipsychotic drugs [8], as suggested by the results of short-term crossover trial
that randomly assigned 16 patients to amantadine (300 mg/d) or placebo; both groups
continued their regular antipsychotic drugs [47]. Dyskinesia was significantly reduced in
patients taking amantadine.

A large variety of miscellaneous agents have been studied for treatment of TD in case
reports and open-label trials without convincing success, including beta blockers, calcium
channel blockers, serotonin antagonists, buspirone, vitamin B6,
and lithium [7,8,48,49]. Levetiracetam, an antiepileptic agent with therapeutic effects in
levodopa-induced dyskinesia, reduced the severity of TD in two small open-label trials
[50,51] and a small randomized trial [52] that was limited by a high dropout rate [8].

Experimental GABA agonists, such as progabide, muscimol, and

tetrahydroisoxazolopyridinol (THIP) or gamma-vinyl-GABA, a GABA-transaminase inhibitor
that elevates brain GABA levels, have been studied in relatively few clinical trials with mixed
results [53], while valproate and baclofen have not shown significant promise.

DEEP BRAIN STIMULATION The basis for using deep brain stimulation (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.

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 [54]. All
were treated with bilateral DBS of the internal part of 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 Abnormal
Involuntary Movement Scale (AIMS).

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
[55-60]. 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 [60].

For patients who have permanent, disabling TD that is unresponsive to pharmacologic

treatment modalities, we suggest DBS in the globus pallidus when it can be performed at
centers with expertise in this technique.

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Here are the patient education articles that are relevant to this topic. We encourage you to
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Basics topics (see "Patient education: Tardive dyskinesia (The Basics)")

SUMMARY AND RECOMMENDATIONS

The only certain method of tardive dyskinesia (TD) prevention is to avoid treatment
with antipsychotic drugs or metoclopramide. 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. (See 'Prevention' above.)
The need for TD treatment should be carefully assessed, since symptoms are often
mild and not sufficiently disturbing to require treatment. (See 'Pharmacologic
treatment' above.)
For patients who develop dyskinesia during treatment with a dopamine receptor
blocking agent (ie, antipsychotic drug or metoclopramide), we recommend immediate
discontinuation of the offending medication if feasible. However, antipsychotic drug
cessation or dose reduction must be carefully considered because of the potential for
relapse or worsening of psychotic symptoms. (See 'Discontinuation of dopamine
receptor blocking agent'above.)
For patients who are developing signs of TD but still require treatment for psychosis,
we suggest using a second generation antipsychotic drug rather than a first generation
agent (Grade 2C). Clozapine is the preferred second generation agent, but requires
frequent blood testing because there is a 1 to 2 percent risk of
agranulocytosis. Quetiapine in low doses is an alternative second generation agent.
(See 'Second generation antipsychotic drugs'above and 'Clozapine dosing' above.)
For patients with relatively mild TD and associated anxiety, we suggest the use of low
doses of a benzodiazepine (Grade 2C). Our preferred agent is clonazepam.
(See 'Benzodiazepines' above and 'Clonazepam dosing'above.)
For patients with localized forms of severe tardive dystonia, such as cervical dystonia,
retrocollis, or blepharospasm, we suggest treatment with botulinum toxin injections
(Grade 2C). (See 'Botulinum toxin injections' above.)
For patients who have disturbing and intrusive TD or tardive dystonia not amenable to
treatment with botulinum toxin, we suggest treatment
with valbenazine or tetrabenazine (Grade 2C). (See 'Valbenazine' above
and 'Tetrabenazine' above.)
Anticholinergic drugs are usually ineffective or may even exacerbate dyskinesia but
are sometimes helpful in tardive dystonia. For patients with severe debilitating tardive
dystonia that is refractory to the interventions above, we suggest treatment
with trihexyphenidyl (where available) (Grade 2C). (See 'Anticholinergic drugs' above
and 'Trihexyphenidyl dosing' above.)
 For patients with permanent, disabling TD that is treatment-resistant, we suggest TD
suppression by resuming treatment with a first or second generation antipsychotic drug
(Grade 2C). (See 'Resumption of antipsychotic drugs'above.)
For patients who have permanent, disabling TD that is unresponsive to pharmacologic
treatment modalities, we suggest deep brain stimulation in the globus pallidus when it
can be performed at centers with expertise in this technique (Grade 2C). (See 'Deep
brain stimulation' above.)
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