Tardive dyskinesia: Etiology and epidemiology

Author
Daniel Tarsy, MD
Section Editor Howard I Hurtig, MD
Deputy EditorJohn F Dashe, MD, PhD
Literature review current through: Jun 2014. | This topic last updated:
May 09, 2013.
INTRODUCTION Tardive dyskinesia (TD) is a hyperkinetic movement
disorder that appears with a delayed onset after prolonged use of dopamine
receptor blocking agents, mainly the antipsychotic drugs (also called
neuroleptics) and the antiemetic drug, metoclopramide [1,2].
TD has numerous clinical manifestations that include chorea, athetosis,
dystonia, akathisia, stereotyped behaviors, and rarely tremor. The term
"tardive" differentiates these dyskinesias from acute dyskinesia,
parkinsonism, and akathisia, which appear very soon after exposure to
antipsychotic drugs.
This topic will review the etiology and epidemiology of TD. Other aspects of
this condition are discussed separately. (See "Tardive dyskinesia: Clinical
features and diagnosis" and "Tardive dyskinesia: Prevention and treatment".)
ETIOLOGY Tardive dyskinesia (TD) is a unique complication of
antipsychotic drugs and metoclopramide; convincing cases have not
occurred after the chronic use of antidepressants or anti-anxiety medications
[1,2].
Pathophysiology The prolonged and often irreversible course of TD
suggests that structural cellular alterations in the brain are responsible for
the disorder. However, pathologic studies in laboratory animals and humans
have failed to demonstrate consistent findings following chronic exposure to
antipsychotic drugs [3].
The uniform capacity of antipsychotic drugs to block postsynaptic dopamine
receptors seems a likely mechanism for the development of both
antipsychotic drug-induced extrapyramidal reactions and TD. In animal
models, repeated treatment with antipsychotic drugs leads to dopamine
receptor supersensitivity [1,4]. In humans, there is evidence for upregulation
of striatal dopamine receptors following chronic antipsychotic drug exposure
[5], but correlation with clinical evidence of TD is uncertain. In addition,
dopamine supersensitivity in animal models is a universal and rapidly
appearing pharmacologic phenomenon that lasts for only several weeks.
This raises some doubt about its relevance to TD in humans, where it is
possible that more lasting structural changes in neurons or receptors may
have taken place.
An updated version of the dopamine hypothesis suggests that an imbalance

between D1 and D2 receptor-mediated effects in the basal ganglia may be

responsible for TD [6,7]. According to this theory, traditional antipsychotic
drugs preferentially block D2 receptors, resulting in excessive activity of D1mediated striatopallidal output, altered firing patterns in medial globus
pallidus, and eventual evolution of the clinical features of TD. This model
explains the low tendency of the second-generation antipsychotic clozapine
to cause TD, since clozapine produces relatively less D2 and relatively more
D1 blockade.
The development of TD may also involve changes in other basal ganglia
neuronal systems. TD could result from loss of striatal interneurons that
exert a feedback influence on nigrostriatal dopamine neurons and also form
part of an efferent output pathway from the basal ganglia. Such interneurons
may utilize gamma-aminobutyric acid (GABA), acetylcholine, or peptides as
their neurotransmitter.
Of these possibilities, the GABA hypothesis has been given the most
consideration. Chronic treatment of monkeys with antipsychotic drugs over a
period of several years has produced persistent dyskinesia and reduced
GABA and glutamic acid decarboxylase levels in several regions of the basal
ganglia [8]. An excitotoxic mechanism may account for this selective
destruction of a localized population of basal ganglia neurons [9]. According
to this hypothesis, chronic blockade of D2 receptors may lead to increased
release of glutamate within the striatum, thereby causing excitotoxic
destruction of striatopallidal GABA and peptide-containing neurons.
There are two potential mechanisms by which this might occur: First,
interference with the inhibitory action of dopamine on corticostriatal terminal
D2 receptors could cause excessive release of glutamate in the striatum,
leading to degeneration of striatopallidal GABA and peptide neurons;
second, blockade of nigrostriatal dopamine activity could, as in Parkinson
disease, lead to increased firing of glutamate-mediated subthalamic neurons
causing excitotoxic degeneration of globus pallidus neurons. A possible role
of free radicals generated by increased neuronal dopamine turnover caused
by antipsychotic drugs has also been considered [10]. The major flaw in this
hypothetical excitotoxic cascade is the lack of supporting pathologic
evidence from animal and human brain tissue.
EPIDEMIOLOGY Prevalence estimates of TD at a specific time have
several limitations when used to establish risks in different patient
populations or in those with different treatment exposures. Antipsychotic
drugs cause TD but can also mask its manifestations by their hypokinetic
effects [11]. The severity of TD often fluctuates with behavioral and
emotional arousal [12], and differences in population age, gender, treatment

duration, and type and dose of antipsychotic drugs add complexity to the
ascertainment process [13].
Misclassification of spontaneous dyskinesia (ie, dyskinesia occurring
independent of antipsychotic drug treatment) may inflate prevalence
estimates of TD. Spontaneous orofacial dyskinesia are common in persons
older than age 65 even without exposure to antipsychotic drugs; pointprevalence estimates have ranged from 3 to 77 percent [14,15].
The incidence of new cases of TD appearing in a population during a
specified period of exposure is a better measure of risk than cross-sectional
estimates of prevalence at a particular observation point. However,
incidence data are much more difficult to acquire since they require repeated
observations over time.
The prevalence and incidence data for TD associated with first-generation
(conventional) antipsychotic drugs and second-generation antipsychotic
drugs are reviewed in the following sections.
FIRST-GENERATION ANTIPSYCHOTIC DRUGS When first described in
the 1960s, the frequency of TD was widely regarded to be low. This
misperception was due to a failure of patients with chronic psychosis to
complain of dyskinesia, and to the limited familiarity of movement disorders
among psychiatric clinicians [12,16]. By the late 1970s, it became apparent
that the prevalence of TD was substantial, ranging from 5 to 45 percent in
patients with psychiatric disorders [11,17].
An influential report from 1982 analyzed 56 studies involving nearly 35,000
patients treated with antipsychotic drugs and estimated the overall
prevalence of TD to be 20 percent [18,19]. In 19 studies involving 11,000
patients not exposed to antipsychotic drugs, the prevalence of spontaneous
dyskinesia was approximately 5 percent, suggesting a best-estimate,
corrected rate for antipsychotic drug-associated TD of about 15 percent (See
"First-generation antipsychotic medications: Pharmacology, administration,
and comparative side effects".).
Incidence of tardive dyskinesia Most prospective studies of patients
treated with conventional antipsychotics suggest the annual incidence of TD
is between 3 and 8 percent [19-22].

Beginning in 1977, the Hillside study enrolled 908 consecutive patients (19
to 40 years old) who were admitted to a single psychiatric hospital in New
York [20,21]. These patients were followed for up to 20 years, and monitored
for the presence of dyskinesia. Most subjects had only several months of

exposure to antipsychotic drugs at study entry. Psychiatric diagnoses

included schizophrenia, affective disorder, schizoaffective disorder, and other
conditions. Fifty-one patients (5.6 percent) met diagnostic criteria for TD at
initial evaluation or had a prior diagnosis of probable TD. All patients were
treated with conventional and predominantly high-potency antipsychotic
agents, such as haloperidol or fluphenazine.

The cumulative incidence of TD after antipsychotic drug exposure of 1, 5,

and 10 years was 5, 27 and 43 percent, respectively [23]
The cumulative incidence of persistent TD lasting for at least three months at
1, 5, and 10 years was 3, 20 and 34 percent, respectively [23]
These rates suggest an overall annual TD incidence of approximately 5
percent [23]. For TD persisting for at least three months, they suggest an
annual incidence of approximately 3 percent, and an early spontaneous
annual remission rate of approximately 2 percent.

The Yale study obtained similar results in 362 patients treated with
antipsychotic drugs, most of whom had chronic schizophrenia [24,25].
Although previous antipsychotic drug exposure (mean 8 years) was 14 times
longer than in the Hillside study, and age was greater (median 41 versus 30
years old), none was considered to have TD at study entry. For TD persisting
at least six months, the cumulative five-year incidence was 25 percent,
remarkably similar to the incidence of persistent TD in the Hillside study [19].
Incidence in the elderly Older patients appear to have a higher
incidence of TD than younger patients.

The Hillside group prospectively analyzed 261 patients older than 55 years
who were naive to antipsychotic drugs, of whom 63 percent had dementia
[26]. After beginning treatment with antipsychotic drugs, they were examined
quarterly for 2.2 years, during which time TD developed in 23 percent. TD
persisted for at least six months in two-thirds of those who developed TD.
Another prospective study followed 266 patients (mean age 65 years) with
psychiatric disorders but without dyskinesia at study entry who had relatively
brief prior exposure to antipsychotic drug treatment [27]. The cumulative
incidence of TD at one and three years was 26 and 60 percent.

These data suggest that the annual incidence of TD among older patients,
during continuous exposure to a variety of potent antipsychotic drugs, is
approximately 10 to 20 percent.
SECOND-GENERATION ANTIPSYCHOTIC DRUGS The introduction of
second-generation antipsychotic drugs, also known as atypical neuroleptics,
anticipated a lower risk of acute extrapyramidal reactions and TD because of
the weaker affinity of these drugs for blocking the dopamine receptor [13,2830]. The common term "atypical" emphasizes the relative freedom of
second-generation antipsychotic drugs from risks of acute extrapyramidal
reactions "typical" of older conventional antipsychotic drugs. (See "Secondgeneration antipsychotic medications: Pharmacology, administration, and
comparative side effects".)
Second-generation antipsychotic drugs approved for general clinical use in
the United States include aripiprazole, clozapine, olanzapine, quetiapine,
risperidone, and ziprasidone. It is commonly stated that these drugs have
lower risks of causing acute dystonia and parkinsonism than the
conventional antipsychotic drugs, and produce less cataleptic and other
motor-inhibitory effects in laboratory animals. However, evidence from large
prospective [31] and retrospective [32] studies comparing first and second
generation antipsychotic drugs indicate that any difference between these
medication classes in the incidence of acute extrapyramidal side effects may
be less than originally thought, or even negligible.
Pharmacologically, second-generation antipsychotic drugs are characterized
by relatively low affinity for, or rapid dissociation from, dopamine D2
receptors, thereby limiting antagonistic actions at these receptors [33,34]. In
addition, these agents often have potent antagonism at serotonin 5HT2A
receptors.
Nevertheless, some second-generation antipsychotic drugs, including
aripiprazole, ziprasidone, olanzapine and risperidone, particularly at
relatively high doses, have risks of acute extrapyramidal reactions that
overlap those of the conventional antipsychotic drugs of moderate or low
potency. In addition, all antipsychotic drugs appear to have some risk of
akathisia. Antipsychotic drugs have also been associated with rare instances
of neuroleptic malignant syndrome.
Risk of tardive dyskinesia among second-generation antipsychotic
drugs Among second-generation antipsychotic drugs, clozapine has an
unusually low risk for acute extrapyramidal reactions [35,36]. Reports of TD
attributable to clozapine have been rare and unconvincing [23,37].

In the prospective Hillside study, 28 patients with psychosis and an average

of six years of previous antipsychotic drug exposure at baseline, but no
definite preexisting TD, were treated with clozapine and followed for one
year [37]. Two patients (7.1 percent) developed TD that persisted for at least
five years. Although neither patient met criteria for definite TD at study entry,
both had evidence of some abnormal involuntary movements, raising
suspicion that the later dyskinesia was attributable to prior antipsychotic drug
use and not to clozapine [3]. In any case, clozapine treatment was
associated with a significantly lower cumulative incidence of TD when
compared with conventional antipsychotic drug treatment in another group of
patients from the same clinic [37].
Among patients never previously exposed to conventional antipsychotic
drugs, a review published in 2006 identified 13 reports of TD that developed
in patients treated exclusively with second-generation antipsychotic drugs
[23], including risperidone, olanzapine, and ziprasidone. Risperidone was
the drug used in 10 of these 13 cases.
The same study identified 39 reports of patients with previous exposure to
conventional antipsychotic drugs who developed new TD during long-term
treatment with second-generation antipsychotic drugs [23]. Risperidone,
which has been in clinical use longer than any second-generation
antipsychotic drug other than clozapine, was implicated in 22 of these 39 TD
cases (56 percent). The remaining drugs associated with TD were
olanzapine (n = 6), ziprasidone (n = 5), clozapine (n = 4), and quetiapine (n
= 2). Emergence of TD after withdrawal of previous conventional
antipsychotic drugs probably account for at least some of these cases.
Compared with risperidone, later introduction into the market and less
clinical use may account for the small numbers of TD cases associated with
other second-generation antipsychotic drugs such as quetiapine and
ziprasidone. However, this reasoning does not explain the rarity of TD cases
associated with clozapine, which has been in use for several decades.
Despite severe limitations, these case reports suggest that most secondgeneration antipsychotic drugs, other than clozapine, carry some risk for TD,
and that risperidone and perhaps olanzapine may have a greater risk of TD
than other second-generation antipsychotic drugs [23]. Nevertheless,
second-generation antipsychotic drugs vary markedly in their
neuropharmacologic properties and risks of acute extrapyramidal reactions,
making it unwise to assume that all are equivalent in risks for TD [34,36,38].
Is the rate of tardive dyskinesia declining? With increased use of
second-generation antipsychotic drugs, the prevalence of TD was expected
to decline, but data are conflicting.

Several studies published from 1996 to 2002 reported TD prevalence rates

of 16 to 43 percent [39-42], suggesting that risk of TD was similar to that
found in earlier studies with the use of conventional antipsychotic drugs.
However, these studies did not separate patients who received only secondgeneration antipsychotic drugs from those who received prior or concurrent
conventional antipsychotic drug treatment.
In contrast, a systematic review that evaluated four cross-sectional studies
published or presented from 2004 through 2007 found that the prevalence of
TD was significantly lower in adult patients taking second-generation
antipsychotic drugs than in those taking conventional antipsychotics (13
percent [95% CI 11.1-15.2] versus 32.4 percent [95% CI 29.0 to 35.9]) [43].
Furthermore, in 57 patients treated with second-generation antipsychotic
drugs who had no prior antipsychotic drug exposure, the prevalence of TD
was 5.3 percent.
SECOND- VERSUS FIRST-GENERATION ANTIPSYCHOTIC
DRUGS The risk of TD is probably lower with second-generation than
with conventional (first-generation) antipsychotic drugs. However, there is
mounting evidence that the incidence of TD associated with secondgeneration agents is higher than first reported. The following reports
illustrate this issue [43,44].

A systematic review published in 2004 analyzed 11 studies of at least one

year duration that examined second-generation antipsychotic drug treatment
[44]. The studies included a total of 2769 subjects (average age 45 years);
schizophrenia was the diagnosis in 82 percent. The following observations
were reported:

Across all 11 studies, the mean annual incidence of TD associated with

second-generation antipsychotic drugs was 2.1 percent.
In three studies that directly compared treatment using a second-generation
antipsychotic drug with a conventional antipsychotic (haloperidol) in young
and middle-aged adults (mean age 39 years, range 18 to 65), the mean
annual incidence of TD was approximately five- to six-fold lower with
second-generation antipsychotic drugs than with haloperidol (<1 percent
versus 5.4 percent).

A later systematic review from the same investigators identified antipsychotic

drug treatment studies of at least one year duration published or presented
from 2004 to 2007 [43]. Included were 12 studies with over 28,000 patients
(mean age 40 years; dementia was the diagnosis in 92 percent) that
reported TD incidence rates. The following observations were noted:

Across all studies and age groups, the annual incidence rate of TD was
significantly lower with second-generation antipsychotic drugs than with
conventional antipsychotic drugs (4.0 percent [95% CI 3.6-4.3] versus 5.5
percent [95% CI 5.1-6.1]).
In six studies directly comparing second-generation antipsychotic drug
treatment with conventional antipsychotics, there were 12,924 patients
(mean age 51 years, range 25 to 83). The annual incidence rate of TD was
again significantly lower with second-generation antipsychotic drugs than
with conventional antipsychotic drugs (4.2 percent [95% CI 3.8-4.5] versus
5.5 percent [95% CI 5.0-6.1]).

Thus, the earlier systematic review suggested that second-generation

antipsychotic treatment reduced the risk of TD by up to six-fold compared
with conventional agents [44], while the later review suggests that the risk
reduction is much less [43]. However, these data are not definitive for the
following reasons:

Most findings are based primarily on short-term studies not designed to

address TD risk.
Few of the studies included specific neurologic assessments.
The studies included very few patients not previously exposed to
conventional antipsychotic drugs that may also contribute to TD risk.
In the earlier systematic review, the three studies with a comparator used
haloperidol, a high-potency conventional antipsychotic drug, sometimes
given in relatively high doses [44]. The later systematic review covering 2004
to 2007 included several studies that used moderately dosed, mid-potency
conventional antipsychotics [43]. Furthermore, most patients in the earlier
systematic review had schizophrenia, while most in the later review had
dementia.
A majority of the included studies in the 2004 to 2007 review used
nonstandard definitions of TD [43].

Interpretation of such findings is further complicated by spontaneous

remission of TD over time and by suppression of dyskinetic symptoms by
antipsychotic drug treatment, even with second-generation agents [25,4547], possibly resulting in a misleadingly low incidence of TD. However, since
several prospective studies excluded patients with dyskinesia at baseline,
suppression of TD is unlikely to entirely account for the lower rates of new
TD cases observed during treatment with second-generation antipsychotic
drugs [44].
Conclusion While the risk of TD is probably lower with most secondgeneration antipsychotic drugs than with high-potency conventional
antipsychotic drugs, the risk with second-generation agents is not
necessarily lower than that associated with low-potency conventional
antipsychotic drugs taken at moderate doses [38]. TD still occurs with
second-generation agents other than clozapine, possibly most often with
risperidone or olanzapine [23].
Further studies of patients never treated with first-generation antipsychotic
drugs and exposed to only a single second-generation antipsychotic drug
are necessary to establish and quantify any hypothesized decline in the
incidence of TD in association with use of particular drugs.
METOCLOPRAMIDE Metoclopramide is a dopamine receptor antagonist
that blocks both D1 and D2 receptors in the central nervous system. When
given in higher doses, it also blocks serotonin receptors.
Metoclopramide is used primarily as an antiemetic agent, and/or as a
prokinetic agent for the treatment of gastroparesis. It is approved in the US
by the FDA for short-term therapy (12 weeks) of gastroesophageal reflux,
and for treatment of diabetic gastroparesis (8 weeks). However,
gastroparesis is a chronic condition, and some patients have been exposed
to long-term metoclopramide use.
Accumulating evidence, mainly retrospective, suggests that chronic
metoclopramide use is a major cause of TD in adults [2,48-51]. However, the
precise incidence and prevalence of metoclopramide-induced TD is unclear.

In a case-control study, patients treated with metoclopramide had a higher

risk of developing TD than controls, but the finding did not achieve statistical
significance (relative risk [RR] 1.67, 95% CI 0.93-2.97) [2]. Metoclopramide
treatment was associated with a significantly increased risk of drug-induced
parkinsonism (RR 4.0, 95% CI 1.5-10.5) [2].
In a study that included 10 patients treated with metoclopramide who

developed TD, the average duration of metoclopramide exposure before TD

onset was approximately one year [50].
In some referral centers, metoclopramide has replaced haloperidol as the
medication most commonly associated with TD [51].
RISK FACTORS FOR TD Older age is the most robust risk factor for TD.

One study found that the incidence of new cases of TD for patients exposed
to conventional antipsychotic drugs was three to five times greater in
patients above age 50 than in younger patients [20]. In addition, the
prevalence of TD was five to six times greater in patients older than age 65
when compared with younger patients.
In two systematic reviews evaluating second-generation antipsychotic drugs,
the incidence of TD was very low in studies involving children, higher in
studies involving predominantly middle-aged adults, and highest in studies
involving older adults [43,44].
Rates of spontaneous TD remission decrease with increasing age [18,52].
Other factors that have been tentatively associated with greater prevalence
of TD include female sex, brain damage, dementia, major affective disorder,
diabetes, longer duration of antipsychotic drug exposure, use of
anticholinergic-antiparkinson drugs, and a history of previous acute
extrapyramidal reactions to antipsychotic drugs. Most of these associations
are based on prevalence rather than incidence studies. Thus, their role as
risk factors for TD is not firmly established.
Drug exposure by dose is particularly difficult to evaluate as a potential risk
factor. Dosing may be an important risk factor in elderly patients [26], but
several retrospective studies have reported little difference in TD prevalence
between moderate and high doses of conventional antipsychotic drugs, or
between the daily equivalent of 300 and 3000 mg of chlorpromazine [11].
The risk of TD may already be maximal at chlorpromazine-equivalent doses
of approximately 300 mg daily, which is in the mid-range of typical
antipsychotic doses [38].
In a prospective study, 57 patients with first-episode psychotic disorders and
no evidence of TD at baseline were treated with low-dose haloperidol (mean
1.7 mg daily) [53]. At 12 months, dyskinesia developed in seven (12.3
percent). Although there was no control group, the incidence of apparent TD
was similar to that in other prospective studies of TD incidence involving
treatment with conventional antipsychotic drugs at standard doses.

In a prospective study of 9000 patients with schizophrenia, the presence of

extrapyramidal symptoms (dystonia, akathisia, or parkinsonism) at baseline
predicted an increased risk for the development of TD over one year of
treatment with several different antipsychotics (hazard ratio 2.0, 95% CI 1.62.6) [54]. In the prospective Hillside studies, patients with a history of severe,
early extrapyramidal reactions to antipsychotic drugs developed TD more
frequently than those without early extrapyramidal reactions [20,26].
However, the high rates of acute extrapyramidal reactions may have
reflected use of more potent antipsychotic drugs at relatively high doses.
Among older patients, a history of electroconvulsive treatment was a
predictor of TD [26]. Female sex and African-American ethnicity were also
identified as risk factors for TD [21,24-26].
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Basics topics (see "Patient information: Tardive dyskinesia (The Basics)")

SUMMARY

Tardive dyskinesia (TD) is a unique complication of antipsychotic drugs and

metoclopramide. (See 'Etiology' above.)
The ability of antipsychotic drugs to block postsynaptic dopamine receptors
is a potential mechanism for the development of TD. An updated version of
the dopamine hypothesis suggests that an imbalance between D1 and D2
receptor-mediated effects in the basal ganglia may be responsible for TD.
(See 'Pathophysiology' above.)

In patients treated with conventional (first-generation) antipsychotic drugs,

the annual incidence of TD is approximately 3 and 8 percent overall, and
approximately 10 to 20 percent in those older than 55 years. (See 'Firstgeneration antipsychotic drugs' above.)
Among second-generation antipsychotic drugs, also known as atypical
neuroleptics, clozapine has a very low risk for TD or acute extrapyramidal
reactions. (See 'Second-generation antipsychotic drugs' above.)
With increased use of second-generation antipsychotic drugs, the
prevalence of TD was expected to decline, but data are conflicting. (See 'Is
the rate of tardive dyskinesia declining?' above.)
The risk of TD is probably lower with most second-generation antipsychotic
drugs than with high-potency conventional antipsychotic drugs.
Nevertheless, it is not certain whether most second-generation antipsychotic
drugs have a lower risk in comparison to low-potency conventional
antipsychotic drugs taken at moderate doses. (See 'Second- versus firstgeneration antipsychotic drugs' above.)
Accumulating evidence, mainly retrospective, suggests that chronic
metoclopramide use is a major cause of TD in adults. (See 'Metoclopramide'
above.)
Older age is the most robust risk factor for TD. (See 'Risk factors for TD'
above.)
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Tardive dyskinesia: Clinical features and diagnosis

Author Daniel Tarsy, MD Section Editor Howard I Hurtig, MD
Deputy Editor John F Dashe, MD, PhD
Literature review current through: Jun 2014. | This topic last updated:
Nov 20, 2013.
INTRODUCTION Tardive dyskinesia (TD) is a hyperkinetic movement
disorder that appears with a delayed onset 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.
The clinical features and diagnosis of TD will be reviewed here. Other

aspects of TD are discussed separately. (See "Tardive dyskinesia: Etiology

and epidemiology" and "Tardive dyskinesia: Prevention and treatment".)
CLINICAL FEATURES Manifestations of tardive dyskinesia (TD) can
include a variable mixture of orofacial dyskinesia, athetosis, dystonia,
chorea, tics, and facial grimacing. The symptoms involve the mouth, tongue,
face, trunk, or extremities. Tardive tremor has been rarely described [1,2].
Oral, facial, and lingual dyskinesia are especially conspicuous in elderly
patients. These may include:

Protruding and twisting movements of the tongue

Pouting, puckering, or smacking movements of the lips
Retraction of the corners of the mouth
Bulging of the cheeks
Chewing movements
Blepharospasm
Tongue movements are insidious in onset and at first may be limited to
subtle back and forth or lateral movements. In other patients, tic-like facial
movements or increased blink frequency are initial manifestations.
Dyskinesia of the limbs also occur, such as:

Twisting, spreading, and "piano-playing" finger movements

Tapping foot movements
Dystonic extensor postures of the toes
Limb involvement is often more severe in younger individuals in whom
dystonic postures and ballistic movements may occur.
Dyskinesia of the neck and trunk may include the following:

Retrocollis
Torticollis
Axial dystonia
Shoulder shrugging
Rocking and swaying movements
Rotatory or thrusting hip movements

Respiratory dyskinesia may produce tachypnea, irregular breathing rhythms,

and grunting noises that are commonly misinterpreted as primary respiratory
problems.
Severe orofacial dyskinesia is highly disfiguring and may greatly interfere
with speech, eating, swallowing, or breathing, while truncal dystonia can be
extremely distressing and interfere with gait and mobility.
TD is much less common in children than in adults. The manifestations of TD
in children have been called "withdrawal emergent symptoms" because they
usually occur when antipsychotic drugs are discontinued.
Cognitively intact and psychiatrically stable patients are usually very aware
of mild and early manifestations of TD. In contrast, failure to complain of TD
symptoms often occurs in patients with little insight who are chronically
institutionalized or psychotic.
Subtypes of tardive dyskinesia A number of TD variants or subtypes
have been described based on the type of involuntary movements that
predominate in these conditions [3,4].

Tardive dystonia refers to TD in which more sustained dystonic

manifestations such as retrocollis, opisthotonus, shoulder dystonia,
hyperextension of the arms or legs, blepharospasm, and jaw dystonia
predominate [5]. Tardive dystonia occurs more frequently in patients younger
than age 40; it may have a lower spontaneous remission rate than TD.
Tardive akathisia refers to late-appearing motor restlessness. It differs from
acute akathisia by the presence of dyskinesia and absence of subjective
motor restlessness [6].
Tardive tics, tardive myoclonus, tardive stereotypy, tardive tremor, and
tardive oral pain syndromes have also been described [3], but these are rare
and often difficult to distinguish from other manifestations of TD or from
effects of the patient's underlying psychosis. Many of these additional
manifestations were well described in early reports of TD. They typically
coexist with the more common manifestations. They illustrate the notion that
TD encompasses a variety of motor manifestations without delineating a
specific movement disorder [7].
TD has also been classified based upon symptom duration or chronologic
appearance and remission. In this scheme, subtypes include transient TD,
withdrawal emergent TD, and persistent TD [8].

Transient TD is limited to a relatively brief period of time during the course of

treatment with antipsychotic drugs followed by spontaneous resolution
Withdrawal emergent TD has been used to describe dyskinesia in pediatric
patients that occurs transiently, immediately following the discontinuation of
antipsychotic drugs
Persistent TD refers to long-lasting or permanent TD
Clinical course The onset of TD is insidious and typically occurs while
the patient is receiving an antipsychotic drug. TD may appear as early as
one to six months following antipsychotic drug exposure. In the initial
literature, it was believed that TD occurred only after two or more years of
antipsychotic treatment.
It is common for TD to first appear after a reduction in dose, after switching
to a less potent antipsychotic drug, or following discontinuation of an
antipsychotic drug. This "unmasking" effect is due to the hypokinetic effects
of antipsychotic drugs that frequently cause a delay in the recognition of TD.
Withdrawal dyskinesia usually resolves within several weeks of antipsychotic
drug discontinuation, but is likely to be a precursor of more persistent forms
of TD.
Although once considered a persistent or permanent condition, TD is often
reversible [9]. In initial studies, remission rates of persistent TD were only 5
to 40 percent, but early identification of TD in younger outpatient populations
is associated with remission in 50 to 90 percent of patients. Remission of TD
usually occurs within several months after antipsychotic drug withdrawal, but
may occur as late as one to three years [10].
The prognosis of TD in patients who require continued antipsychotic drug
treatment is unknown. In most cases, TD either remains unchanged, or is
suppressed by the hypokinetic effects of the antipsychotic drug when used
at a higher dose [11,12].
DIAGNOSIS The diagnosis of TD is based upon the presence of
dyskinetic or dystonic involuntary movements, a history of at least one
month of antipsychotic drug treatment, and the exclusion of other causes of
abnormal movements.
It is important to identify TD as early as possible since, as noted in the
preceding section, the potential for remission appears to be related to the
duration of symptoms before discontinuation of the antipsychotic drug.
Differential diagnosis Although the diagnosis of TD is usually

straightforward, clinicians should consider other important causes of

involuntary movements, such as Wilson disease or Huntington disease, in
patients being treated with antipsychotic drugs for a psychiatric disorder. A
comprehensive, methodical drug history is an essential part of the diagnostic
evaluation. (See "Wilson disease: Diagnostic tests" and "Huntington disease:
Clinical features and diagnosis".)
Advanced Huntington disease is readily identified clinically by the positive
family history, marked gait abnormality, and dementia. Early-stage
Huntington disease can be harder to differentiate from TD because
involuntary choreiform movements may be the only manifestation, and may
be mild.
TD must be distinguished from the stereotypies and psychotic mannerisms
associated with chronic schizophrenia [13], autism, and severe mental
retardation. Stereotypies in schizophrenia are usually less rhythmic, more
stereotyped, and more complex in appearance than the simpler, repetitive,
and often rhythmic involuntary movements associated with TD. Unlike TD,
choreoathetosis and dystonia are absent. (See "Schizophrenia: Clinical
manifestations, course, assessment, and diagnosis" and "Autism spectrum
disorder: Clinical features", section on 'Stereotyped behaviors'.)
TD should also be distinguished from other antipsychotic drug-induced
extrapyramidal syndromes that often coexist. (See "First-generation
antipsychotic medications: Pharmacology, administration, and comparative
side effects", section on 'Side effects' and "Second-generation antipsychotic
medications: Pharmacology, administration, and comparative side effects",
section on 'Side effects'.)

Akathisia occurs both early and late in antipsychotic drug treatment and, in
the case of tardive akathisia, may persist after cessation of such treatment
[6]. Akathisia is a subjective feeling of motor restlessness accompanied by
inability to sit or stand still. Manifestations may include repeated leg
crossing, weight shifting, or stepping in place. When akathisic movements of
the legs occur late in antipsychotic drug treatment and are associated with
dyskinesia elsewhere in the body, they are referred to as tardive akathisia
and should be considered a manifestation of TD.
Acute dyskinesia typically occurs immediately after introduction of an
antipsychotic drug, but may resemble TD. Acute dyskinesia can sometimes
occur late in treatment after switching to a more potent antipsychotic drug, or
can occur episodically during treatment with long-acting injectable
fluphenazine esters.
With rare exception [1,2], tremor is an uncommon manifestation of TD.

Tremor is nearly always a reversible sign, usually associated with rigidity and
akinesia, due to drug-induced parkinsonism. Rabbit syndrome is a rare
perioral tremor that also may occur late in antipsychotic treatment, but, like
other tremors, remits with discontinuation of antipsychotic drugs.
Spontaneous orofacial dyskinesia often occurs in elderly people. The mean
prevalence of dyskinesia among patients treated with antipsychotic drugs
has been estimated at 20 percent, compared with a mean prevalence of 5
percent in untreated patients [14]. This indicates that a significant
background level of spontaneous dyskinesia is present in the general
population, especially in the elderly. Spontaneous oral dyskinesia in the
elderly is often associated with edentulism and dementia.
Meige syndrome is an idiopathic cranial dystonia with onset in middle age
manifested by blepharospasm and oromandibular dystonia. Meige
syndrome, blepharospasm, and oromandibular dystonia are all
phenotypically indistinguishable from orofacial TD. Thus, differentiating these
conditions from TD depends on an adequate drug history.
In a young person, tardive dystonia involving axial or cervical muscles
should be differentiated from primary torsion dystonia, which has a slowly
progressive course and is not related to antipsychotic drug exposure.
Tourette syndrome is easily identified by a history of fluctuating motor and
vocal tics since childhood. (See "Tourette syndrome".)
Other, less common possibilities in the differential diagnosis of TD include
the following:

Facial grimacing and choreoathetosis associated with chronic liver disease

Chorea or dystonia with antiphospholipid antibody syndrome
Chorea due to hyperthyroidism or hypoparathyroidism
Rheumatic or lupus chorea
Acute drug intoxications with levodopa, amphetamines, anticholinergic
drugs, certain calcium channel blockers with dopamine receptor blocking
effects (eg, flunarizine and cinnarizine, which are unavailable in the United
States), antidepressants, and anticonvulsants
Basal ganglia calcification and structural disorders of the basal ganglia
INFORMATION FOR PATIENTS UpToDate offers two types of patient
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Basics topics (see "Patient information: Tardive dyskinesia (The Basics)")

SUMMARY

Manifestations of tardive dyskinesia (TD) can include a variable mixture of

orofacial dyskinesia, athetosis, dystonia, chorea, tics, and facial grimacing.
The symptoms involve the mouth, tongue, face, trunk, or extremities. Tardive
tremor has also been rarely described. (See 'Clinical features' above.)
A number of TD variants or subtypes have been described based on the
type of involuntary movements that predominate in these conditions,
including the following:

Tardive dystonia
Tardive akathisia
Tardive tics
Tardive myoclonus
Tardive stereotypy
Tardive tremor
Tardive oral pain syndromes
(See 'Subtypes of tardive dyskinesia' above.)

The onset of TD is insidious and typically occurs while the patient is

receiving an antipsychotic drug. In addition, it is common for TD to first
appear after a reduction in dose, after switching to a less potent

antipsychotic drug, or following discontinuation of an antipsychotic drug.

(See 'Clinical course' above.)
Although once considered a persistent or permanent condition, TD is often
reversible. (See 'Clinical course' above.)
The diagnosis of TD is based on the presence of dyskinetic or dystonic
involuntary movements, a history of at least one month of antipsychotic drug
treatment, and the exclusion of other causes of abnormal movements. (See
'Diagnosis' above.)
TD should be distinguished from other extrapyramidal syndromes, including:

Wilson disease
Huntington disease
Akathisia
Acute dyskinesia
Stereotypies associated with chronic schizophrenia, autism, and severe
mental retardation
Spontaneous orofacial dyskinesia
Meige syndrome
Blepharospasm
Oromandibular dystonia
(See 'Differential diagnosis' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
Tardive dyskinesia: Prevention and treatment
Author Daniel Tarsy, MD
Section Editor Howard I Hurtig, MD
Deputy Editor John F Dashe, MD, PhD
Disclosures: Daniel Tarsy, MD Nothing to disclose. Howard I Hurtig, MD Nothing to

Literature review current through: Jun 2014. | This topic last updated:
Oct 03, 2013.
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 tardive dyskinesia (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 (AIMS), which is useful to
heighten awareness of mild manifestations of TD [4]. The AIMS is available
at www.cqaimh.org/pdf/tool_aims.pdf.
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 and switching from first to second
generation antipsychotic drugs
For patients with a diagnosis of TD, additional pharmacologic interventions
include the following:

Use of benzodiazepines, botulinum toxin injections, tetrabenazine, or

anticholinergic drugs 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 lifethreatening 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 comparative side effects", section on
'Clozapine'.)
Clozapine treatment requires weekly monitoring of the white blood cell count
during the first six months, biweekly monitoring for the next six months, then
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 tardive dyskinesia 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.
Tetrabenazine Drugs that deplete dopamine storage in presynaptic
vesicles, such as tetrabenazine or reserpine, may be the most effective
therapeutic agents for TD, and particularly for tardive dystonia.
Limited data suggest that tetrabenazine is useful 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 [25].
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 [26].
An open-label study in a small group of patients with chronic psychosis
found that tetrabenazine was less effective for TD than haloperidol [27].
Several open-label studies have demonstrated improvement in TD with
tetrabenazine in doses of up to 200 mg daily [28,29].
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.
Potential adverse effects include parkinsonism, sedation, fatigue,
depression, anxiety, akathisia, tremor, insomnia, confusion, nausea,

vomiting, hypotension, and dizziness.

Anticholinergic drugs Trihexyphenidyl or benztropine are usually
ineffective or may even exacerbate dyskinesia but are sometimes helpful in
tardive dystonia. This is consistent with observations that anticholinergics
may be useful in primary dystonia but often exacerbate choreiform disorders.
Retrospective studies have shown improvement in tardive dystonia following
trihexyphenidyl (10 to 32 mg daily) in three of eight patients [28] and with
trihexyphenidyl (6 to 12 mg daily) in 8 of 21 patients [30].
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 [31]. 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

[32]. 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 [33,34].
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 [8,35].
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
[36].
Clinical trials of vitamin E in relatively small numbers of patients with TD
have produced conflicting results [8,37-42]. However, in a systematic review
published in 2001 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) [43]. 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 [44]. 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 [7,8,45]. Levetiracetam, an antiepileptic
agent with therapeutic effects in levodopa-induced dyskinesia, reduced the
severity of TD in two small open-label trials [46,47] and a small randomized
trial [48] that was limited by a high dropout rate [8].
Experimental GABA agonists, such as progabide, muscimol, and
tetrahydroisoxazolopyridinol (THIP) or gamma-vinyl-GABA, a GABAtransaminase inhibitor that elevates brain GABA levels, have been studied in

relatively few clinical trials with mixed results [49], 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 involved 10 patients
with resolved or stabilized psychiatric disease who had severe TD refractory
to medical treatment [50]. All were treated with bilateral DBS of the internal
part of the globus pallidus. At six months after surgical lead implantation,
using double-blind evaluation of stimulation on or off, the Extrapyramidal
Symptoms Rating Scale score was significantly lower with stimulation-on
compared with stimulation-off (mean decrease, 50 percent; range, 30 to 66
percent).
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 [51-56]. 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 [56].
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.
INFORMATION FOR PATIENTS 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 grade
reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces 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 information: Tardive dyskinesia (The Basics)")

SUMMARY AND RECOMMENDATIONS

The only certain method of 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
tetrabenazine (Grade 2C). (See 'Tetrabenazine' above and 'Tetrabenazine
dosing' 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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