Tardive Syndromes REVIEW ARTICLE


By Joseph H. Friedman, MD, FAAN, FANA C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE


ABSTRACT VIDEO CONTENT
PURPOSE OF REVIEW: This
article reviews the history, nosology, clinical A V AI L A B L E O N L I N E

features, epidemiology, and treatment of tardive syndromes.

RECENT FINDINGS: Themajor advance in the field of tardive syndromes has

been the development and US Food and Drug Administration (FDA)
approval of two vesicular monoamine transporter type 2 inhibitors,
valbenazine and deutetrabenazine, for treating tardive syndromes. These
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medications are derivatives of tetrabenazine and reduce dyskinetic

movements by reducing dopamine stimulation. Treatment is not curative,
and the medications reduce, or “mask,” symptoms but presumably without
adding to the long-term risk of increased involuntary movements believed
to accrue from suppressive treatment with dopamine receptor–blocking
drugs. A confounding advance has been the accumulation of data finding
that second-generation antipsychotics, also known as atypical CITE AS:
CONTINUUM (MINNEAP MINN)
antipsychotics, may not be safer than first-generation antipsychotics in 2019;25(4, MOVEMENT DISORDERS):
causing tardive syndromes. The public health risk of tardive syndromes 1081–1098.
may actually have increased as some second-generation antipsychotics,
widely promoted to both doctors and patients, are increasingly used as Address correspondence to
Dr Joseph H. Friedman, 345
antidepressants. Blackstone Blvd, Butler Hospital,
Providence, RI 02906,
Joseph_Friedman@brown.edu.
SUMMARY: Tardive syndromes remain a public health risk. Second-generation
antipsychotics have not been proven to have less risk than first-generation RELATIONSHIP DISCLOSURE:
drugs in causing tardive syndromes and are nevertheless being used more Dr Friedman has received
honoraria from Cambridge
widely to treat depression, bipolar disease, and insomnia. Symptomatic University Press, MedLink, and
treatment for tardive syndromes is available, although expensive. Springer Press. He has received
research/grant support as site
investigator of clinical studies
for the Michael J. Fox
Foundation for Parkinson’s
INTRODUCTION Research and the National

T
Institutes of Health.
he first antipsychotic drug, chlorpromazine, was introduced in France
in 1952 and in the United States in 1954. Acute and subacute motor UNLABELED USE OF
side effects were recognized early, but the first report of a tardive PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
syndrome was first published in 1957.1,2 More cases came to light, and Dr Friedman discusses the
the condition, initially thought rare or nonexistent, was recognized as unlabeled/investigational use of
a significant problem.1,2 The term tardive dyskinesia, referring to the late onset, α-methyl-para-tyrosine,
botulinum toxin, clozapine,
was coined in 1964 and caught on.3 deep brain stimulation,
The reasons for doubting that a tardive syndrome was the result of a drug reserpine, and tetrabenazine for
the treatment of tardive
effect were much more understandable at the time than they seem in
syndromes.
retrospect. A wide spectrum of abnormal movements had been associated with
psychiatric disorders by psychiatrists of the early 20th century,4 raising the question
of whether the movements were part of the disease. In that era, little clarity for © 2019 American Academy
diagnoses existed, and a large percentage of people in psychiatric asylums had of Neurology.

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TARDIVE SYNDROMES

tertiary syphilis and other disorders, including forms of autism and other behavioral
disorders that could be associated with movement disorders.5 The second
observation was that the purported side effects, usually oral-buccal-lingual
dyskinesias, improved when the offending drug dose was increased and worsened
when the drug was decreased. These observations conflicted with canonical
thinking about drug side effects, which assumed that higher doses of a drug
that causes a side effect should result in more, not fewer, side effects. A third
observation was the variable nature of the movements, the variable time to
onset, and the lack of an apparent dose-effect relationship. It should be noted that
the relationship between drugs and tardive disorders rests on epidemiology, as
no mechanism has yet been elucidated (refer to the following section on
pathophysiology).

CLINICAL ASPECTS
The tardive syndromes may include overlapping signs, but there are often very
clear discriminating features that allow for distinct categorization. The signs,
symptoms, and nosology are important because treatments may be different for
each tardive syndrome.

Nosology
The term tardive dyskinesia is commonly used in two ways. It is often used
as an umbrella term to include all the tardive syndromes as well as the
most commonly recognized syndrome, oral-buccal-lingual dyskinesia. In this
article the term tardive syndrome6 will be used as the inclusive umbrella term,
and tardive dyskinesia will refer to the various choreoathetoid or stereotypic
movements, including oral-buccal-lingual dyskinesias. The American Psychiatric
Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) defines tardive dyskinesia as: “involuntary athetoid or
choreiform movements (lasting at least a few weeks)… developing in association
with the use of a neuroleptic medication for at least a few months. Symptoms
may develop after a shorter period of medication use in older persons.”7 It
is a modification of the definition from the Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), which
required continuous exposure to a neuroleptic for at least 3 months for those
younger than 60 years of age and continuous exposure for 1 month or more
for those older than 60 years of age, and the movement disorder needed
to develop either while the patient was on the drug or within 4 weeks of
stopping it. Rare cases caused by much shorter exposure have been described.8
The diagnoses of tardive dystonia and tardive akathisia are also listed in
the DSM-5.
Although some authors have embraced the idea that drugs that do not
block dopamine receptors may also cause clinical syndromes identical to a tardive
syndrome, this is uncertain.9 Almost all cases of tardive syndromes have occurred
in patients who developed symptoms after another psychoactive drug was added
to a dopamine receptor–blocking drug, in patients who had a history of dopamine
receptor–blocking drug use, or in patients whose history had not specifically
excluded exposure to dopamine receptor–blocking drugs. In many cases, the
movement disorder lasted only a brief time after the non–dopamine receptor–
blocking drug was discontinued and therefore did not meet clinical criteria for a
tardive syndrome. In a review of this topic, D’Abreu and colleagues9 asserted

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that the non–dopamine receptor–blocking drug brought out a latent movement KEY POINTS
disorder induced via an unknown priming process induced by the dopamine
● The relationship between
receptor–blocking drugs.9,10 tardive dyskinesia and
antipsychotics took several
Phenomenology of Tardive Syndromes years to establish and was
Although the DSM-5 defines only choreoathetoid movements, dystonia, and initially thought to be rare.
akathisia as tardive, these as well as several other syndromes that can be included
● All definitions of tardive
in this category are discussed below.11 Note that this article uses the term tardive dyskinesia or tardive
dyskinesia to refer to the two most common tardive syndromes discussed first syndromes require at least
below, the choreoathetoid or stereotypic movement disorder, because their several weeks exposure to a
phenomenology and pharmacotherapy are very similar. drug preceding the
development of a new
movement disorder that
TARDIVE DYSKINESIA. Tardive dyskinesia is defined by the presence of persists for several weeks
choreoathetoid movements, which most commonly involve the tongue, lips, while on the drug, or off the
mouth, and jaw and cause chewing movements, tongue writhing (often with drug, and is not better
explained by an alternative
protrusion), lip puckering, and lip smacking, but may also cause choreic etiology.
and athetoid movements of the limbs or trunk (CASE 9-1 and CASE 9-2).
Respiratory changes may occur causing huffing, hyperventilation, or irregular
or loud breathing.

TARDIVE STEREOTYPY. Stereotypy is a term used to connote repeated voluntary

movements that are purposeless. Stereotypies are frequently present in people
with autism in the form of clapping or flapping, but the term is also used to
describe the frequent nonchoreic and nonathetoid movements seen as a tardive
syndrome in people who wring their hands, cross and uncross their legs, smile or
frown, and rock from side to side or forward and backward while denying any
sense of restlessness or distress (VIDEO 9-3, links.lww.com/CONT/A364).

TARDIVE AKATHISIA. Tardive akathisia exactly mimics acute akathisia, a sense of

uncomfortable restlessness that causes continuous voluntary movements to
relieve distress (CASE 9-3). Patients will rock in place while seated, shift weight,
pace, or march in place when standing, which may be more uncomfortable than
the psychosis itself. When minor, patients may have difficulty distinguishing this
feeling from anxiety and may perceive it as jitteriness. Some patients appear very
restless, squirming or rocking when sitting or swaying and marching in place
when standing, yet deny feeling restless. Since akathisia is defined by the
sensation of restlessness, this syndrome is defined as pseudoakathisia. These
patients often also have tardive stereotypy.

TARDIVE DYSTONIA. Dystonia is a sustained or transiently abnormal posture,

usually of a twisting nature. Tardive dystonia may be focal, restricted to a single
body part such as the neck or one limb; segmental, restricted to adjoining body
parts such as the neck, shoulder, and arm; or generalized, involving a larger part
of the body. It may be intermittent, as with jaw opening or jaw closing dystonia
or blepharospasm, or sustained, as usually seen in torticollis or spasmodic
dysphonia. Truncal hyperextension (opisthotonos) may rarely be seen
(VIDEO 9-6, links.lww.com/CONT/A367).

TARDIVE MYOCLONUS. Tardive myoclonus is a rare tardive disorder that more

commonly affects the arms than other body parts. Since some medications,

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TARDIVE SYNDROMES

CASE 9-1 A 77-year-old man presented for a neurologic evaluation for symptoms
of parkinsonism consisting of resting tremor, soft speech, slower
movements, and imbalance. He had been taking aripiprazole 5 mg/d for
3 years for bipolar disorder. It was the only neuroleptic he had ever taken.
A previous trial off aripiprazole had lasted only 2 weeks because of
worsened depression. His tremors had improved during that time.
His initial neurologic examination was normal aside from parkinsonism,
manifest by masked facial expression, resting tremor, bradykinesia,
and typical gait. He had a Unified Parkinson’s Disease Rating Scale,
part III, score of 36 and a Hoehn and Yahr stage of 2.5. His Abnormal
Involuntary Movement Scale (AIMS) score was 0. A dopamine transporter
scan was normal.
Aripiprazole was discontinued 11 days before his next follow-up
4 months later. Off his neuroleptic, his AIMS score was 4 but he was not
bothered by his symptoms.
Eight months later he returned for follow-up (VIDEO 9-1, links.lww.com/
CONT/A362). He and his wife reported that involuntary mouth
movements had worsened 1 month prior. The patient had continuous
chewing movements and tongue writhing. His jaw moved up and down
but also laterally. His lips appeared to not be involved but because of the
continuous tongue movements, it was difficult to be certain. The rest of
his face was not involved. He had stereotypic rubbing movements of his
fingers and dyskinetic movements of both legs, left greater than right.
The mouth movements were unlikely to be due to his being edentulous
because he was not rubbing his gums together and had the other
movements that are typical of oral, buccal, and lingual tardive dyskinesia.
His AIMS score was 13 with a severity rating of 4 (severe), and his Unified
Parkinson’s Disease Rating Scale motor score was 13.

COMMENT Several weeks after aripiprazole was stopped, this patient’s parkinsonism
improved but involuntary movements in his mouth developed. He was
edentulous, which may have contributed to the movements. The
emergence of a tardive syndrome when the offending drug is stopped is
not uncommon. When evaluating any patient on a neuroleptic, the
physician must evaluate both for parkinsonism and for a tardive syndrome.
Any patient on a neuroleptic is supposed to have an AIMS evaluation on a
regular basis, but the possibility of a tardive syndrome being masked by the
neuroleptic must always be kept in mind. It is also important to recognize
that second-generation antipsychotics may cause both parkinsonism and
tardive syndrome.
The patient was not treated for the movements because of medical and
psychiatric issues so the “natural history” of the disorder (ie, 19 months off
dopamine-blocking drugs) was evident, with improved parkinsonism and
minimal change in the tardive syndrome.

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 A 64-year-old woman presented for a neurologic evaluation for CASE 9-2
involuntary mouth movements. She had been diagnosed with bipolar
disease 13 years earlier and had been treated with neuroleptic
medications for the last 10 years; she had been started on olanzapine but
switched to aripiprazole after a few months. She had required two
psychiatric hospitalizations in the preceding 5 years and had received
electroconvulsive therapy twice since in the last 3 years. Aripiprazole had
been stopped 2 years prior due to the development of involuntary mouth
and tongue movements recognized as tardive dyskinesia. After stopping
the aripiprazole, her movements worsened over the following year until
reaching a plateau. She frequently had sores on her tongue from its
rubbing her teeth. She stated that the movements also hurt her teeth and
that her mouth felt “like I chewed on some razor blades.” She noted that
her eyes closed involuntarily, but that this did not bother her because she
was blind from macular degeneration. When initially seen, she was taking
lithium 900 mg/d and oxybutynin 5 mg/d.
Her examination revealed moderately severe blepharospasm; oral,
buccal, and lingual dyskinesias; and possible torticollis (VIDEO 9-2, links.
lww.com/CONT/A363). She had no signs of parkinsonism. She did not
exhibit any other adventitious movements. She was treated with
tetrabenazine after consultation with the psychiatrist over the possibility
of worsening the depression. Oxybutynin was stopped due to concern
about anticholinergic action worsening mouth movements due to dryness
as well as to movement effects. She was started on tetrabenazine 12.5 mg
2 times daily and gradually titrated over 12 weeks to 50 mg 3 times daily.
Her tardive movements resolved, and she had no signs of parkinsonism.
However, 5 months later, on the same regimen, minimal signs of
parkinsonism emerged, and the tardive dyskinesia was not resolved.
Six months after this, her parkinsonism became severe, with prominent
tremor, slowness, and gait dysfunction, and tetrabenazine was reduced
to 37.5 mg 3 times a day.
Over the next year, parkinsonism remained a significant problem and
tardive dyskinesia recurred as her tetrabenazine was reduced. Trials of
deutetrabenazine 24 mg 2 times daily and then valbenazine 80 mg
allowed the parkinsonism to improve, but did not resolve. Her Abnormal
Involuntary Movement Scale (AIMS) score increased to 21. She opted to
try deep brain stimulation of globus pallidus internus.

This patient was treated with tetrabenazine before the drugs approved by COMMENT
the US Food and Drug Administration (FDA) were available. Tetrabenazine
was initially very helpful but required a high dose, which eventually caused
severe parkinsonism. As her parkinsonism lessened, with the reduction in
tetrabenazine then the trials of deutetrabenazine and valbenazine, her
tardive dyskinesia reemerged. Having failed all three drugs, she was
referred for globus pallidus internus deep brain stimulation.

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TARDIVE SYNDROMES

particularly clozapine, may cause asterixis, which is the “negative” form of

myoclonus, and may be difficult to clinically distinguish from myoclonus, other
potential causes should be excluded.

TARDIVE TICS. Vocal and motor tics may mimic Tourette syndrome. Unlike
Tourette syndrome, the syndrome of tardive tics is late in onset and develops
only after chronic exposure to dopamine receptor–blocking drugs. It is rare, and
at least one case with coprolalia has been reported (CASE 9-4).

TARDIVE TREMOR AND TARDIVE PARKINSONISM. The categories of tardive tremor

and tardive parkinsonism are contentious, as the duration of parkinsonian side
effects of the dopamine receptor–blocking drugs is highly variable and may
last for several years. Essential tremor may develop at any age, regardless of
medications. Improvement in parkinsonism or tremor with increased doses of the
dopamine receptor–blocking drugs needs to be observed to confirm this diagnosis.
These reports involve parkinsonian types of tremor (resting and postural).

CASE 9-3 A 45-year-old woman was intially referred for evaluation of severe
restlessness. She had been diagnosed with schizoaffective disorder at
age 30 and was treated with several first-generation antipsychotic drugs,
including haloperidol, chlorpromazine, thioridazine, and others. She
reported being extremely uncomfortable due to her restlessness and
could not keep from moving. She denied feeling anxious. She stated that
this had been present for about 4 years. It did not vary significantly during
the day, but resolved during sleep. She denied paresthesia or abnormal
sensations in her legs. Her husband did not report leg movements during
sleep. Although her antipsychotics had been altered during that time, her
movements had persisted. She had not improved with benztropine or
amantadine. She had no history of thyroid disease, substance abuse, or
medical problems. Her psychotic symptoms were controlled but she felt
helpless and depressed.
At the time of her initial neurologic evaluation, she was taking
haloperidol 2 mg/d and nortriptyline 100 mg/d. Other than the findings
shown in the video (VIDEO 9-4, links.lww.com/CONT/A365), her neurologic
examination was normal except for mild oral, buccal, and lingual
dyskinesias. She did not have parkinsonian signs.
She was diagnosed with akathisia. At the time of her initial evaluation,
the only drugs available to treat this were reserpine and α-methyl-para-
tyrosine. Tetrabenazine and its derivatives were not then available. It was
recommended that she be treated with clozapine once it became available
6 years later, which replaced her haloperidol. Her akathisia resolved
completely when the haloperidol was replaced by the clozapine, but the
dyskinetic mouth movements were unchanged.
VIDEO 9-5 (links.lww.com/CONT/A366) shows the same patient on
follow-up 33 years later. She has continuous writhing movements of her
tongue as well as continuous lip and jaw movements.

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TARDIVE PAIN. Tardive pain is rarely mentioned and is not strictly a
movement disorder; however, it has been described as the central symptom in
patients who also had a typical tardive movement syndrome and in whom
extensive testing for the pain was unrevealing.12 In patients with tardive pain,
the pain improves as the movement disorder improves. The pain has mostly
been described in the mouth and the pelvis. Unexplained pain in the absence
of a tardive movement syndrome should not be considered tardive in origin.
TABLE 9-1 lists the tardive syndromes.

APPROACH TO THE PATIENT

Several aspects need to be considered in evaluating patients with suspected
tardive syndromes. Most patients have chronic psychiatric disorders, primarily
schizophrenic disorders, or bipolar disease. Their histories may not be
reliable but must always be taken seriously and, when suspect, should be
confirmed with the treating physicians, other health care professionals, or
caregivers. The patient’s history of medication use over the previous year or

This patient’s movements reflect akathisia, an uncomfortable sense of COMMENT

restlessness, which forces people to move. By definition, akathisia reflects
a sensation of restlessness, which is not associated with stereotypies,
which are semivoluntary movements (ie, movements that occur with some
degree of volition, but without conscious thought). The movements are not
choreic jerks or athetoid serpentine or slow movements and were not
present during sleep. When mild, the signs and symptoms of akathisia can
be confused with anxiety. Unlike restless legs syndrome, there was no
diurnal variation. She had no thyroid abnormalities, and the problem had
been present for several years. There was no history to suggest drug
intoxication.
It is not clear why clozapine should have been helpful in this patient;
clozapine is thought to have no extrapyramidal side effects and would
have been assumed to have possibly made the akathisia worse, by
lessening the dopamine D2 blocking effect of the haloperidol. Akathisia
sometimes can occur as a persistent disorder, developing acutely but
persisting for long periods if the patient remains on the offending drug, but
little has been written about this. This is a possible explanation here;
however, the occurrence of the akathisia, in concert with the classic mouth
dyskinesias and the development of the akathisia after a long exposure,
suggests that a tardive explanation is likely.

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TARDIVE SYNDROMES

CASE 9-4 A 61-year-old woman with schizoaffective disorder was referred for
management of a movement disorder. She was unaware of her
movements, which her family noticed only within the past year. Once
pointed out to her, they did not bother or concern her. She did not
think that they attracted attention.
She had been treated with neuroleptics for 13 years, including
haloperidol, perphenazine, risperidone, aripiprazole, ziprasidone, and
brexpiprazole and was currently taking lurasidone. She liked being on
lurasidone because it controlled her auditory hallucinations and made
her feel better than she had on any of the other antipsychotics. She and
her family denied her having tics as a child and she had no family
history of tics or other movement disorders. She did not have
compulsive behaviors. Her identical twin had no tics or other
movement disorders. She had no history of other neurologic problems.
She was treated for hypertension, hypothyroidism, and increased
cholesterol. Her thyroid hormone levels had been therapeutic. Her
medications included lurasidone 40 mg/d.
Her neurologic examination showed mild parkinsonism, with mild facial
masking, a mildly stooped posture, and absent arm swing; her tics
manifested by sudden extension or flexion of either knee while sitting
VIDEO 9-7 (links.lww.com/CONT/A368), and she exhibited facial tics.

COMMENT This patient’s movements were tics. They primarily involved her legs, right
more than left. She also had facial tics, more commonly seen on the right,
affecting both the upper and lower face. It is unusual that she did not
perceive the movements, as most tics are associated with an urge to move.
Her lack of concern for attracting attention may reflect her social isolation,
her psychiatric disorder, or her personality. The standard approach to
treating the tardive tics would be replace her lurasidone with quetiapine
and then treat the tics with either valbenazine or deutetrabenazine. If the
quetiapine did not adequately control her psychotic symptoms, then
clozapine would be instituted. However, both drugs are associated with
weight gain, which was a major concern for this patient. She spontaneously
remarked how happy she had been on lurasidone, in contrast to the many
drugs she’s failed, and was very reluctant to change. In addition, she was
not aware of her movements, other than for being told about them, and did
not care about them. Since the natural history of these movements was
unknown, and may not worsen, the recommendation was to not alter
medications and simply follow her. Her movements, had they been
bothersome, could have been treated by adding valbenazine or
deutetrabenazine to her regimen of lurasidone.

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so is especially important as recent dose escalations or decreases may strongly
affect the severity of the movements, possibly masking them entirely.
The medication lists that patients carry with them sometimes do not include
neuroleptic medications that are injected every few weeks. Unless the
clinician is also taking responsibility for treating the patient’s psychiatric
disorder, it should generally be assumed that advice will need to be provided
to the patient’s psychiatrist, and that recommendations may not be followed.
What may be ideal for the movement disorder may not be ideal for the
psychiatric disorder.
Since most movement disorders vary significantly in relation to anxiety, do
not assume that marked changes in severity between how the patient appeared in
the waiting room versus the office reflects a “psychogenic” disorder, rather than
increased anxiety.

Recognition of a Tardive Syndrome

Early studies have demonstrated that tardive dyskinesia was frequently
overlooked by psychiatry residents.13,14 In one study involving 101 patients, 26%
of patients were identified as having tardive dyskinesia by faculty but only 11%
by residents.14 A previous smaller study revealed that psychiatry residents
missed 90% of tardive cases.13 While these studies were published 3 decades
ago, no further studies on this topic have been published. It is likely that the
common belief that second-generation antipsychotics have lowered the risk
of a tardive syndrome has translated into a decreased sensitivity to the problem.

Tardive Syndromes TABLE 9-1

Tardive Syndrome Characteristics

Tardive dyskinesia Choreoathetoid or stereotypic movements, which can affect any body part, but most
commonly the oral, buccal, lingual region

Tardive dystonia Dystonia, a sustained, involuntary muscle contraction, often writhing in nature, producing
an abnormal posture; this may cause torticollis, blepharospasm, jaw opening or closing
dystonia, or affect other body parts

Tardive akathisia An uncomfortable feeling of restlessness causing movements such as marching in place,
pacing, rocking in place while seated, and rubbing hands

Pseudoakathisia Overlaps with or may be considered stereotypy: patients are in constant motion as if
restless but deny the feeling of restlessness

Tardive stereotypy Repetitive, purposeless movements, such as rocking, crossing legs, rubbing hands when
not feeling restless

Tardive tics Usually motor and not vocal

Tardive tremor and tardive A debated syndrome since many authorities believe that cases reported as tardive tremor
parkinsonism or tardive parkinsonism really had essential tremor or idiopathic Parkinson disease.

Tardive pain A pain disorder associated with one of the above disorders that is not directly caused by
the movements themselves

Tardive myoclonus Myoclonic lightninglike jerk affecting isolated muscles causing an obvious limb or trunk
jerk or vocalization

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TARDIVE SYNDROMES

TABLE 9-2 Differential Diagnosis of Tardive Syndromesa

Tardive Dyskinesia
◆ Idiopathic oral facial dyskinesias of the elderly
◆ Stereotypic chewing in the edentulous
◆ Stereotypies in patients with autism
◆ Teeth, gum, tongue, mouth disorders (loose dentures)
◆ Chorea (inherited, metabolic, inflammatory, structural)
◆ Drug toxicity (eg, phenytoin, lithium)
◆ Levodopa-induced dyskinesias in a patient with Parkinson disease
◆ Psychogenic
◆ Tics
Tardive Stereotypies
◆ Behaviors unrelated to drugs
◆ Sensory neuropathies (“piano playing fingers”)
◆ Tactile hallucinations
◆ Anxiety
◆ Obsessive-compulsive disorder
◆ Tics
Tardive Akathisia
◆ Anxiety
◆ Drug withdrawal/drug intoxication
◆ Psychotic/other psychogenic internal stimuli
◆ Chorea
Tardive Dystonia
◆ Inherited or brain injury
◆ Peripheral injury
◆ Psychogenic
◆ Presenting feature of Parkinson disease or other neurodegenerative disorder
Tardive Myoclonus
◆ Tics
◆ Toxic or metabolic disorders
Tardive Tics
◆ Tourette syndrome

a
This table lists disorders that may be confused with the tardive syndromes.

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Self-Perception of Tardive Syndromes KEY POINT
It is commonly observed that patients with some tardive syndromes, particularly
● There are several
choreoathetosis and stereotypy, minimize or even fail to perceive their different tardive syndromes.
movements. While this is often believed to reflect the underlying psychiatric Dyskinesia and stereotypies
or cognitive disorder,15 much of this is likely due to the nature of the are very similar, while
movement disorder itself, as chorea is often underperceived by the patient, akathisia and dystonia are
very different. The others
regardless of the cause of the chorea or the patient’s cognitive and behavioral
are rare. Patients may have
capabilities.16,17 The mechanism for this agnosia is unknown but is hypothesized more than one syndrome. It
to reflect a “feed forward” process in which motor and sensory circuits are is important to note that
simultaneously stimulated.16 patients often have more
than one tardive syndrome.

Evaluation
The Abnormal Involuntary Movement Scale (AIMS) has become the standard
evaluation tool for tardive syndrome studies. The AIMS is focused on
choreoathetoid movements and stereotypies. It does not capture akathisia,
which is usually measured with the Barnes Akathisia Rating Scale.18 The
usual clinical research criteria for diagnosing tardive dyskinesia are the
Schooler-Kane19 criteria, which require scores of 2 (mild) or greater in at
least two body parts or one score of 3 (moderate) or greater in one body part,
while meeting the contemporary DSM-5 criteria for onset and duration.
TABLE 9-2 lists the differential diagnosis of the tardive syndromes.

Reversibility and Natural History

The natural history of tardive syndromes is not known. To determine natural
history, the clinician would need to stop the neuroleptic when a tardive
syndrome is identified, allowing for long-term follow-up; however, the vast
majority of patients taking these drugs require life-long neuroleptics. Since
these drugs generally mask the movement disorder, patients remaining on them
often have a syndrome masked by the same drug that caused the problem.
A 1982 meta-analysis of 285 treatment trials reported remission in 37% of
participants, but this remission percentage has not been borne out by more
recent studies.20 The largest chart review of patients with a tardive syndrome
who had stopped their dopamine receptor–blocking drugs involved 108 patients
who were followed for a mean duration of 3.1 years.21 Only 13.9% of participants
had complete resolution. Outcome was no better if patients had only taken
second-generation drugs. Younger age at onset, shorter duration of therapy, and
faster withdrawal appeared to improve outcomes. Most patients improved only
mildly. Other studies report conflicting results with stopping the neuroleptic,
with 11 of 12 patients improving in one report22 to 1 of 49 patients improving in
another.23 A 2018 Cochrane Review of 13 randomized controlled trials involving
771 subjects compared antipsychotic discontinuation versus continuing
antipsychotic treatment, or lowering dose or switching to an alternative
antipsychotic, and found only low-level evidence showing benefit to any
intervention.24 Fernandez and colleagues25 completed a 14-year follow-up of
patients in a long-term psychiatric hospital and found that in patients who
continued taking neuroleptics, the tardive syndrome improved, as measured
by AIMS assessments, but parkinsonism worsened. Medications were not
recorded, but the results suggest that tardive dyskinesia was likely masked,
not resolved.

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TARDIVE SYNDROMES

Unfortunately, the limited data suggest that there is no clear benefit to

stopping the offending drugs to allow “natural healing,” or that switching to
antipsychotics of lower potency will be beneficial long-term, although this is
done routinely.

PATHOPHYSIOLOGY
The pathophysiology of tardive syndrome is unknown. The most “popular” and
clearly the most heuristically appealing theory of tardive syndrome is the dopamine
receptor supersensitivity, or “up-regulation” theory.8,11,26 The hypothesis presumes
that, in some patients, long-term exposure to dopamine receptor–blocking drugs
causes an increase in D2 receptors or in their sensitivity. This is based largely on the
observation that dopamine receptor–blocking drugs or drugs that reduce dopamine
stimulation reduce the movements. The theory is further supported by rodent
studies showing that dopamine receptor–blocking drugs do cause receptor
hypersensitivity, but human studies have produced mixed results,27,28 and
long-term exposure of dopamine receptor–blocking drugs in rodents also do not
support this hypothesis. Alternative hypotheses include structural changes in the
synapse26,29 or the presynaptic dopamine-secreting neuron29 due to direct toxic
effects of the drugs, or indirectly via oxidative stress, genetic anomalies affecting
dopamine receptors, and alterations of RNA production affecting other
neurotransmitters induced by dopamine receptor–blocking drugs.
The synaptic plasticity hypothesis rests on the observation that synapses in the
human neocortex are altered by dopamine receptor–blocking drugs, as well as
in the striatum of rodents, and that abnormal plasticity is found in animal models
of hyperkinetic human disorders.26 The theory posits that the movements are
generated by abnormal signal processing.
Another hypothesis proposes that dopamine receptor–blocking drugs cause a loss
of dopamine-secreting cells in the substantia nigra, which, in turn, causes
“denervation supersensitivity and tardive dyskinesia.”30 However, data on loss of
neurons in the human substantia nigra in patients on chronic antipsychotics are
conflicting.31,32 An oxidative stress theory proposes an increase in hydrogen
peroxide and free radicals as a result of increased dopamine turnover resulting from
dopamine receptor blockade. Many human genetic studies reveal correlations
between tardive syndromes and a large number of dopamine, serotonin, and other
neurotransmitter receptors, suggesting the possibility that the genetics of a number
of different neuroreceptor subtypes may explain both the risk of developing a
syndrome and the type and severity of the disorder. Animal studies have revealed
changes in gene expression in the brains after chronic dopamine receptor–blocking
drug exposure, raising a question as to whether this may occur in humans as well.

EPIDEMIOLOGY
In American nursing homes, 20% of residents take antipsychotics. In addition,
some neuroleptics are also approved in the United States for treating depression
and are among the best-selling drugs in the country. As the elderly are at greatest
risk for the development of a tardive syndrome, having a fivefold greater risk
than younger patients,33 it is likely that many instances of tardive dyskinesia go
unnoticed in nursing homes.
The development of second-generation antipsychotics was thought to herald
the beginning of the end of tardive syndromes. Clozapine, the first “atypical”
antipsychotic, has not been linked to a tardive disorder except when there has

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been prior exposure to a dopamine receptor–blocking drug. Although the KEY POINT
impression persists that tardive syndromes are less common with second-
● While widely believed to
generation antipsychotics, the National Institutes of Health–supported CATIE represent dopamine
(Clinical Antipsychotic Trials of Intervention Effectiveness) trial upended that supersensitivity, the
conviction.34 The CATIE study, involving 1493 subjects seen at 57 sites, evaluated pathophysiology of tardive
subjects who were treated either with the first-generation antipsychotic, syndromes remains
unknown, and no
perphenazine, or one of the second-generation drugs (risperidone, olanzapine,
explanation explains the
ziprasidone, or quetiapine) found no differences in any extrapyramidal side variety of tardive
effects between subjects assigned to perphenazine versus any of three syndromes.
second-generation antipsychotics. Unfortunately, 74% of subjects did not
complete the 18 months of treatment that had been planned, confounding
interpretation. One meta-analysis of 31 randomized controlled trials involving
2230 subjects reported that, among the second-generation drugs, only clozapine
was safer.35 Another meta-analysis reported a 3.5-fold lower risk with second-
generation drugs,36 while a third reported a reduction in incidence from 5.5% to
3.9%31 and a change in point prevalence of 32.4% with first-generation drugs
to 13.1% with second-generation drugs. Conversely, a 30-month study found
no difference between tardive syndrome incidence with first-generation or
second-generation drugs.37 Before second-generation drugs were developed,
the risk of a tardive syndrome was thought to be 32% after 1 year, 57% after
15 years, and 68% after 25 years.38 A recent meta-analysis of 41 studies
involving 11,493 patients had a mean prevalence of 25.3%, with 20.7%
attributed to second-generation drugs and 30% with first generation.39
Why are there such conflicting results on tardive syndrome incidence and
prevalence? Inherent difficulties exist in interpreting any study of a tardive
syndrome while patients remain on drugs that both cause and mask the condition.
The vast majority of patients with a tardive syndrome are treated for primary
psychotic disorders, which are life-long. These patients therefore cannot stop
antipsychotic drugs, which, although they cause the problem, also mask it. Thus,
patients who harbor a tardive syndrome may have no adventitious movements
and will reveal their disorder only when their dopamine receptor blockade is
lessened. Some of these patients develop a tardive syndrome within days of
discontinuation, called withdrawal emergent dyskinesia, but most will have a
delayed onset as dopamine receptor–blocking drugs bind avidly to the dopamine
receptor while also being extremely lipid soluble, remaining in the brain for a very
long time. Thus, while their serum half-life is relatively short, the parkinsonian
side effects, which mask the tardive syndrome, may last several months. The
previously cited study on the natural history of tardive syndromes noted that
patients followed up after 14 years in a state psychiatric hospital had fewer rather
than more tardive disorders in association with a higher level of parkinsonism.25
Another caveat is a 2018 report indicating that almost all published cases of
purported tardive syndrome not caused by dopamine receptor–blocking drugs
had, at some point, been treated with a dopamine receptor–blocking drug, raising
the hypothesis that any exposure to a dopamine receptor–blocking drug may
produce a priming effect that increases the risk of a latent movement disorder
developing on drugs not known to cause a tardive syndrome.9

RISK FACTORS
Most reports on risk factors for tardive syndromes have not been confirmed.
Older age as a risk factor has the most support. In cohorts of older versus

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TARDIVE SYNDROMES

younger patients exposed to neuroleptics for the same period of time, the older
patients are more likely to develop a tardive syndrome. Other cited factors are
not so reliable. Presumed racial differences may be explained by different
prescribing and diagnosing patterns. African Americans are thought to have a
higher risk than white Americans, but this is confounded by the observation that
African Americans generally received higher doses of antipsychotics, and racial
distinctions may not be scientifically accurate. It could also be argued that this
higher dosing might actually mask the syndrome, reducing the perceived risk. A
history of early-onset extrapyramidal side effects such as acute dystonic
reactions, akathisia, or parkinsonism has been suggested but not confirmed as
risk factors for later onset of a tardive syndrome. Brain damage has also been
suggested as a risk factor, but this is a difficult risk factor to quantify. The
presence of an affective disorder has been proposed to increase the risk. Female
gender, duration of antipsychotic use, dose of the antipsychotic, dementia,
diabetes mellitus, HIV infection, intellectual disability, brain damage, and
anticholinergic use all have soft support for being risk factors.40

TREATMENT
Anticholinergic drugs were commonly used when neuroleptics were initiated
to reduce the acute extrapyramidal side effects, particularly acute dystonic
reactions, and they were effective for this purpose. They were also commonly
used to treat parkinsonian side effects, with much less clear benefit. This
common use was expanded so that they have frequently been used to treat
tardive syndromes, particularly dyskinetic ones, although no evidence
supports their utility, and it is likely that they worsen the tardive syndromes,
as anticholinergic drugs worsen choreic movements in general; additionally,
for patients with oral, buccal, lingual movements, the dry mouth caused by
anticholinergics increases the discomfort and the movements themselves.
Only two treatments approved by the US Food and Drug Administration
(FDA) exist for tardive syndromes: valbenazine and deutetrabenazine, both
of which are tetrabenazine-related drugs. They are similar to the previous
standard therapies, reserpine, tetrabenazine, and α-methyl-para-tyrosine,
in that they reduce dopamine stimulation. They, like tetrabenazine, are
selective vesicular monoamine transporter inhibitors type 2, which reduce the
incorporation of dopamine (as well as histamine, serotonin, and norepinephrine)
into vesicles, hence reducing dopamine stimulation. Deutetrabenazine has a
deuterated hydrogen atom, while valbenazine is a prodrug of the most active isomer
of tetrabenazine, both of which have significantly longer serum half-lives than
tetrabenazine, leading to a more sustained pharmacokinetic profile, possibly
explaining their much reduced side effects, avoiding depression and parkinsonism41
in particular. Unfortunately, these two drugs cost between $65,000 and $100,000
each year.
Four Class I trials of both drugs41 have shown significant reductions in
AIMS scores, the primary outcome variable, and no depression or parkinsonism
within the 6 to 12 week study and open-label extensions. The studies did not
distinguish the various types of tardive syndromes, however. The drugs
probably are more effective for dyskinesias, stereotypies, and akathisia than
dystonia or myoclonus. Interestingly, patients were less impressed by their
improvement than the blinded raters. These drugs have not been compared head
to head either with each other or with the older remedies.

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 Tardive dystonia should be considered separately from the other tardive KEY POINTS
disorders, which all share a similar response to pharmacotherapy. No approved
● Tardive syndromes
treatment exists for tardive dystonia, but numerous reports and series support remain a major problem
the use of botulinum toxin for focal dystonia, particularly blepharospasm and for patients treated with
torticollis, and deep brain stimulation of the globus pallidus internus in severe dopamine receptor–
cases.41 Both of these interventions are nonspecific interventions for dystonia blocking drugs. While there
are data to suggest that
regardless of cause. In addition, there are several reports of clozapine being
second-generation
helpful specifically for tardive dystonia, treating both the psychosis and the antipsychotics are less likely
movement disorder, when used at the dose required to control psychosis, which is to cause a tardive syndrome
generally in the 300 mg/d to 900 mg/d range. Whether the benefit was due to than first-generation
antipsychotics, these data
stopping the prior neuroleptic or specifically due to the effect of clozapine
are not convincing, and the
is uncertain. largest study performed to
The underlying question in treating a tardive syndrome is what to do about answer this question did not
the antipsychotic medication. Where the dopamine receptor–blocking drug find a difference.
is being used as an antidepressant or for nausea or gastroparesis, the answer is to
● Deutetrabenazine and
try alternatives that do not block dopamine receptors, if at all possible. Both valbenazine are approved
doctors and patients are appropriately reluctant to use electroconvulsive therapy, treatments for tardive
but this is often very helpful in treating depression refractory to medications, syndromes, and probably
allowing patients to be kept in remission on doses of antidepressants that had work best for nondystonic
disorders. Replacing the
previously not been helpful. Electroconvulsive therapy has been widely reported neuroleptic with clozapine
to improve mobility in patients with Parkinson disease, but its effect on choreic at a dose to treat the
disorders, dystonia, and tardive syndromes is uncertain. psychosis may be very
In the more common case of a tardive syndrome occurring in a patient who helpful, especially for
dystonic syndromes.
requires an antipsychotic, the usual recommendation is to switch to either clozapine
or quetiapine. These two drugs rarely, if ever, cause extrapyramidal disorders. This ● Botulinum toxin is likely to
comes as close as possible to drug withdrawal, hence the term “passive healing,” in be helpful for all focal
which the tardive syndrome hopefully reverses when the dopamine receptor– dystonias, including tardive
blocking drug is stopped. This is often not possible as patients may have failed dystonias. Deep brain
stimulation, with globus
these drugs. In such cases, the usual recommendation is to switch to aripiprazole. pallidus internus as the
However, it is unclear if this strategy is at all useful.42,43 target, may be helpful for
When the disorder is bothersome, either deutetrabenazine or valbenazine is dystonic or choreoathetoid
used,41 with a slow upward titration. No data imply the superiority of either drug. tardive disorders.
Valbenazine is given once daily and deutetrabenazine twice daily. Valbenazine
has only two strengths, while deutetrabenazine can be titrated over several
dosages. Since occasional cases will remit, attempts at slow reduction of doses
should be considered.
Three double-blind trials of gingko biloba, used as a presumed antioxidative
agent, have been conducted. There were 299 subjects reported in the three
12-week trials comparing antipsychotic plus gingko biloba versus antipsychotic
with placebo, reporting a benefit in the AIMS similar to that reported with the
tetrabenazinelike drugs, but the follow-up was limited.42 While many drugs have
been considered promising for treating tardive syndromes, most have fallen by
the wayside. Of the current crop, amantadine is of interest since it has been
approved for treating levodopa-induced dyskinesias in Parkinson disease, a
phenomenologically similar syndrome to tardive dyskinesia, and is a useful drug
for treating neuroleptic-induced parkinsonism, thus offering the possibility of
treating both disorders, which are commonly both present. Only one small
crossover trial has been published. Drugs thought to have possible utility to treat
tardive syndromes include tetrabenazine, clonazepam, gingko biloba, and
amantadine.41 A small number of reports support the use of botulinum toxin for

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TARDIVE SYNDROMES

focal tardive dystonias, and deep brain stimulation, generally targeting the
globus pallidus internus segment, for uncontrolled dyskinesias and dystonia.

CONCLUSION
Tardive dyskinesia reduces quality of life and remains a major public health
issue.44 Second-generation antipsychotics have not been shown to decrease the
risk of tardive syndromes, and their increasing use for nonpsychotic indications
is likely to increase the prevalence. Our understanding of tardive syndrome
pathophysiology is not significantly better than it was decades ago. Two bright
spots have been the emergence of effective and safe symptomatic treatment for
tardive syndrome and the possibility that antipsychotic drugs that do not involve
dopamine are being developed.45 Meanwhile, there is a continued need for
vigilance in our use of dopamine receptor–blocking drugs and a need for
better treatments.

VIDEO LEGENDS
VIDEO 9-1 VIDEO 9-5
Tardive dyskinesia and stereotypy. Video Classic tardive dyskinesia. Video shows a
shows the 78-year-old man discussed in CASE 9-1 78-year-old woman with symptoms of classic
exhibiting involuntary mouth movements indicative tardive dyskinesia, involving oral, buccal, and lingual
of tardive dyskinesia and stereotypy. Exposure to a movements. She is the same patient discussed in
second-generation antipsychotic drug at usual CASE 9-3, 33 years later. She has continuous writhing
doses may result in tardive syndromes in a patient movements of her tongue as well as continuous lip
with no risk factors other than age. and jaw movements.
http://links.lww.com/CONT/A362 http://links.lww.com/CONT/A366
© 2019 American Academy of Neurology. © 2019 American Academy of Neurology.

VIDEO 9-2 VIDEO 9-6

Tardive dyskinesia and tardive dystonia. Mild, segmental tardive dystonia with
Video shows the 64-year-old woman discussed in associated tachypnea. Video shows a
CASE 9-2 exhibiting continuous chewing movements, 70-year-old man with mild, segmental tardive
lip puckering, blepharospasm, and left leg dystonia exhibiting irregular contractions of the
stereotypies indicative of tardive dyskinesia and corners of his mouth, asymptomatic tachypnea,
tardive dystonia. Her posture reveals moderate and a masked facial expression. The mouth
torticollis, with her head rotated to her right and the movements are dystonic in nature, and he has no
right shoulder mildly elevated. The patient’s other signs of a tardive syndrome. He had been
movement disorder is generalized, involving face, treated with chlorpromazine, risperidone, and
neck, and trunk. other antipsychotics for several decades. His
http://links.lww.com/CONT/A363 movements developed when risperidone was
© 2019 American Academy of Neurology. changed to quetiapine. At the time of this video,
the patient was taking risperidone 0.5 mg twice
daily and tetrabenazine 12.5 mg twice daily.
VIDEO 9-3
http://links.lww.com/CONT/A367
Leg stereotypies or dystonia. Video shows the
legs of a 95-year-old woman exhibiting bilateral leg © 2019 American Academy of Neurology.
movements that may be classified as stereotypies or
dystonia. The patient also exhibits tachypneic breathing, VIDEO 9-7
which is a symptom of the tardive syndrome. Tardive tics. Video shows the 61-year-old
http://links.lww.com/CONT/A364 woman described in CASE 9-4 exhibiting tardive tics
© 2019 American Academy of Neurology. primarily involving her legs, right more than left.
Tardive tics are uncommon, and these are
VIDEO 9-4 particularly unusual in that the patient is unaware of
Tardive akathisia. Video shows the 45-year-old them and is not bothered by them.
woman described in CASE 9-3 with tardive akathisia http://links.lww.com/CONT/A368
exhibiting severe restlessness. The patient also has © 2019 American Academy of Neurology.
oral, buccal, and lingual dyskinesias (not shown).
http://links.lww.com/CONT/A365
© 2019 American Academy of Neurology.

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