Tre a t m e n t o f Tard i v e

D ys kine s i a
Hassaan H. Bashir, MD, Joseph Jankovic, MD*

KEYWORDS
 Tardive dyskinesia  Tardive syndrome  VMAT2 inhibitors  Deutetrabenazine
 Valbenazine

KEY POINTS
 Tardive dyskinesia is a common movement disorder caused by treatment with antipsy-
chotics (‘neuroleptics’) and other dopamine receptor blocking agents.
 The judicious use of dopamine receptor blocking agents is key to the prevention of tardive
dyskinesia, reduction of disease burden, improvement in quality of life, and maintenance
of remission.
 Deutetrabenazine and valbenazine are vesicular monoamine transporter 2 inhibitors
approved by the FDA for the treatment of tardive dyskinesia, supported by high level ev-
idence from pivotal clinical trials.
 Although evidence is limited, other treatment options can be considered in those who
cannot tolerate or do not respond to vesicular monoamine transporter 2 inhibitors.
 Botulinum toxin or trihexyphenidyl can be considered for tardive dystonia and deep brain
stimulation or electroconvulsive therapy can be considered for disabling symptoms re-
fractory to other therapies.

INTRODUCTION AND OVERVIEW

The term, tardive dyskinesia (TD), originally was coined by Faurbye and colleagues1 in
their description of delayed-onset, persistent, rhythmic, stereotyped movements after
exposure to dopamine receptor blocking agents (DRBAs). Initial studies focused on
exposure to antipsychotics (or neuroleptics) but the DRBAs also include drugs used
in the treatment of nausea (antiemetics), gastroparesis (promotility agents), and cough
(antitussives). The original phenomenological descriptions focused on involuntary
movements involving chiefly face, mouth, and tongue (orobuccolingual [OBL]), later
classified as stereotypies; however, the phenomenology of TD gradually expanded
to include other motor and nonmotor features.2–4 This led to the concept of the
tardive syndrome (TS), an umbrella term representing the full spectrum of hyperkinetic

Department of Neurology, Baylor College of Medicine, Parkinson’s Disease Center and Move-
ment Disorders Clinic, 7200 Cambridge, 9th Floor, Suite 9A, Houston, TX 77030-4202, USA
* Corresponding author.
E-mail address: [email protected]

Neurol Clin - (2020) -–-

https://doi.org/10.1016/j.ncl.2020.01.004 neurologic.theclinics.com
0733-8619/20/ª 2020 Elsevier Inc. All rights reserved.
2 Bashir & Jankovic

and hypokinetic movement disorders that include stereotypy, dystonia, akathisia,

chorea, myoclonus, tics, tremor, parkinsonism, and gait disorders as well as ocular
deviations, respiratory dyskinesia, and various sensory symptoms.5,6 The use of the
term, extrapyramidal syndrome, particularly popular among psychiatrists, is now
strongly discouraged by experts for lack of clarity.7
The presentation of TS can vary from a mild, barely perceptible, orofacial movement
or a feeling of irritation or a burning sensation in the mouth or genital area to a disabling
and potentially even life-threatening condition that causes severe impairment in phys-
ical, mental, and social functioning.8 Among the most serious forms of TS is status
dystonicus as a complication of TD9,10 and neuroleptic malignant syndrome.11 TD
has been associated with higher mortality among psychiatric patients.12
Epidemiologic studies have shown that TD is a common problem, associated with
almost all DRBAs, except possibly clozapine.13 Early studies of TD estimated preva-
lence rates among patients exposed to DRBAs ranging from 24% to 56% with an
average closer to 20% to 30%.14–16 In the era of typical (first-generation) antipsy-
chotics, the risk of TD after exposure for 5 years was estimated to be 32%, 57% after
15 years and 68% after 25 years.17 At first, the arrival of atypical (second-generation or
third-generation) antipsychotics appeared to be associated with a lower risk of TD18
(13.1% vs 32.4%); however, later studies did not confirm these findings.19 The well-
known Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study, a large
randomized clinical trial comparing effectiveness of typical and atypical antipsy-
chotics in schizophrenia, failed to show decrease in TD with atypical antipsychotics.20
A recent meta-analysis comparing typical and atypical antipsychotics across 41
studies between 2000 and 2015, estimated a mean prevalence of 25.3% for all treat-
ment groups that was somewhat greater with typical antipsychotics (30%) versus
atypical (20%) although the significance of this difference could not be determined
because TD severity data were considered insufficient.21 Unfortunately, prescribing
rates for approved and off-label indications remain high and even may be increasing
worldwide.22 Antipsychotics are used frequently and inappropriately by physicians
and allied professionals as an off-label treatment of depression, anxiety, insomnia,
and other conditions.23,24 This concerning trend highlights the importance of educa-
tion about judicious use of antipsychotics.
Although the relationship of TD and antipsychotics is well established, drugs with
the potential to cause TD also include antiemetics (metoclopramide, prochlorperazine,
and promethazine), lithium, serotonin reuptake inhibitors (duloxetine and citalopram),
tricyclic antidepressants (amoxapine and amitriptyline), and calcium channel blockers
(cinnarizine and flunarizine).3 Except for the antiemetics that act by blocking dopamine
receptors, the other drugs appear to work through other mechanisms in causing TD.
Compared with antipsychotics, however, the evidence for these drugs causing TD
mostly are limited to case reports or case series.25 A recent review of the literature
found that rather than cause TD, both tricyclic antidepressants and selective serotonin
reuptake inhibitors may unmask or exacerbate TD from prior or concurrent use of
DRBAs, a possible priming effect.26
The exact cause of TD remains unknown although several theories have been pro-
posed.27 The mostly widely accepted theory is dopamine receptor supersensitivity,
whereby chronic blockade of dopamine receptors leads to receptor up-regulation
with subsequent postsynaptic supersensitivity. This theory is supported by the obser-
vation of reduction in TD when DRBA doses are increased and the exacerbation of TD
with abrupt withdrawal of DRBAs (including a severe, potentially life-threatening
variant known as withdrawal emergent dyskinesia).28–32 This theory, however, does
not explain the enduring symptoms of TD because the receptors would be expected
 Treatment of Tardive Dyskinesia 3

to eventually down-regulate after DRBA discontinuation. It also does not explain the
incidence of non-DRBAs causing TD. Alternatively, genetic factors, free radical dam-
age, and aberrant, maladaptive synaptic plasticity also have been implicated in the
pathophysiology of TD.27
Many risk factors have been identified for the development of TD.33 Broadly, these
are classified into modifiable and nonmodifiable factors. The modifiable include choice
of DRBA, higher cumulative antipsychotic dose, prior acute dystonic reaction, dia-
betes, smoking, and alcohol/substance abuse, among others. The nonmodifiable
include older age, female sex, white and African descent, intellectual disability,
mood disorders, and genetic differences in antipsychotic metabolism.27,33 An analysis
of 189,415 patients treated with antipsychotics found the following predictors for the
development of TD: age, diagnosis of schizophrenia, dosage of antipsychotic, and the
presence of bipolar and related disorders.34 Anticholinergics (eg, benztropine)
frequently are coprescribed with antipsychotics by psychiatrists in an effort to reduce
or prevent the onset of TD.35 This practice is not supported, however, by evidence and
even may precipitate or worsen TD.36,37
TD is an insidious, complex, and potentially devastating iatrogenic complication that
has an impact on a substantial proportion of vulnerable patients; 2017 was a crucial
year because it saw the approval of the first 2 medications to treat TD by the US
Food and Drug Administration (FDA),38 bringing renewed interest and much-needed
investment in educating physicians, especially psychiatrists, in the diagnosis and
treatment of TD. This article aims to provide the practicing neurologist with a succinct
review of the treatment options for TD, with emphasis on recent developments.

MANAGEMENT GOALS
 Recognizing TD and effectively utilize rating scales, such as the Abnormal Involun-
tary Movement Scale (AIMS) to determine severity and monitor treatment response
 Initiating therapy with the highest level of evidence to reduce the signs and symp-
toms of TD
 Reducing deficits in physical, mental, and social functioning that are either a
direct or indirect result of TD
 Minimize adverse effects (AEs) and the financial burden of treatment
 Emphasizing and promoting the judicious use of DRBAs
 Maintaining regular follow-up with frequent reassessments of the patient

GENERAL APPROACH

From the outset, the prevention of TD is of paramount importance. DRBAs should be

avoided whenever possible by choosing alternative medication with lower or no risk
of TD. If the use of a DRBA is necessary, then long-term treatment should be avoided
whenever possible. Frequent reassessments must be utilized to determine if ongoing
DRBA use is indicated and to remain vigilant for early symptoms and signs of TD.
When TD is identified, DRBAs should be withdrawn slowly in patients who can
tolerate it because abrupt withdrawal may worsen or precipitate TD (as well as the
underlying psychiatric disorder when present).29,39,40 Frequently, neurologists and
psychiatrists must work together to provide multidisciplinary care to balance the
risk of TD and management of underlying psychiatric illness. If patients require
continued treatment, then every effort should be made to switch to medication
with lower risk of TD. In the cases of antipsychotics, switching to clozapine or que-
tiapine may be considered because they have lower dopamine receptor affinity and
relatively low risk of TD.41,42 Pimavanserin, a nondopaminergic inverse serotonin
4 Bashir & Jankovic

agonist, is a novel antipsychotic approved for Parkinson disease psychosis43 that

also can be considered as an alternative, off-label treatment.44 In cases of anti-
emetics, those without dopamine receptor blocking activity should be considered
first line (eg, ondansetron and trimethobenzamide). Even when the offending agent
is withdrawn, remission rates may be as low as 13%.45 This combination of
increasing exposure rates and low remission rates highlights the need for effective
treatment of TD. It also has led to the increased use of off-label treatments. Despite
best efforts to minimize the risks of TD, a substantial proportion of patients will
develop TD and require pharmacologic and/or surgical treatment. Fig. 1 outlines a
general approach to treatment of TD.

1 st - 2nd-

Fig. 1. Treatment algorithm for TD. Levels of evidence according to AAN 4-tiered
scheme 5 level A (established as effective), level B (probably effective), level C (possibly
effective), and level U (data inadequate)55 (updated and modified).(Adapted from Bhidaya-
siri R, Jitkritsadakul O, Friedman JH, Fahn S. Updating the recommendations for treatment
of tardive syndromes: A systematic review of new evidence and practical treatment algo-
rithm. J Neurol Sci. 2018;389:67-75; with permission.)
 Treatment of Tardive Dyskinesia 5

PHARMACOLOGIC TREATMENTS
Vesicular Monoamine Transporter Type 2 Inhibitors
Although the pathogenesis of TD is not fully understood, the finding that increased
dopamine signaling plays an important role led to the pursuit of agents that could
modulate signaling without directly blocking receptors. The vesicular monoamine
transporters (VMATs) are transport proteins integrated into the synaptic vesicles of
presynaptic neurons and exist as 2 isoforms, VMAT1 and VMAT2.46 VMATs facilitate
the transport of cytoplasmic monoamines (dopamine, histamine, norepinephrine, and
serotonin) into presynaptic vesicles. In contrast to VMAT1, which is localized in both
the central and peripheral nervous system, VMAT2 is found only in central presynaptic
neurons.46,47 Inhibition of VMATs thus reduces presynaptic storage and release of
monoamines, particularly dopamine, which then are degraded by monoamine oxidase
in the cytoplasm, resulting in presynaptic dopamine depletion.13 Selective VMAT2 in-
hibition is preferred, because VMAT1 inhibitors, such as reserpine (a nonselective
VMAT inhibitor used to treat hypertension and hyperkinetic movement disorders),
are associated with multiple peripheral AEs such as bronchospasm, nausea, vomiting,
hypotension, and nasal stuffiness.47 Three selective VMAT2 inhibitors currently are
available for the treatment of TD: tetrabenazine (TBZ), deutetrabenazine (DTBZ),
and valbenazine (VBZ). Table 1 provides a summarized comparison of these
medications.

Tetrabenazine
TBZ originally was developed in the 1950s to treat psychosis and in 1971 it was
introduced in the United Kingdom for the treatment of hyperkinetic movement dis-
orders.48 It was not until 2008 that it was approved in the United States for the treat-
ment of Huntington chorea; however, it frequently is prescribed for off-label
indications, including TD.49
Kazamatsuri and colleagues50 reported the first clinical trial of TBZ in TD in 1972.
This prospective, single-blind study of 24 chronic psychiatric patients with TD at

Table 1
Comparison of vesicular monoamine transporter type 2 inhibitors

Tetrabenazine Deutetrabenazine Valbenazine

Characteristic (Xenazine) (Austedo) (Ingrezza)
Mechanism Reversible VMAT2 Reversible Reversible VMAT2 inhibitor
of action inhibitor VMAT2 inhibitor
US FDA HD chorea (2008) HD chorea (2017), TD (2017)
approval (y) TD (2017)
Pivotal trials TETRA-HD First-HD, AIM-TD, KINECT 2, KINECT 3
ARM-TD
Active Yes Yes Yes
metabolites
Half-life 5–7 h 9–10 h 15–22 h
Dose range 12.5–100 mg/d 6–48 mg/d 40–80 mg/d
(recommended)
Safety data >40 y >2 y >2 y
AE profile 1. Sedation 1. Sedation 1. Sedation
2. Parkinsonism 2. Insomnia 2. Headache
3. Depression (similar to placebo) 3. Fatigue

Abbreviation: HD, Huntington disease.

6 Bashir & Jankovic

Boston State Hospital began with a 4-week baseline period in which medications were
not changed (14 patients were taking DRBAs) followed by 4 weeks on placebo where
all DRBAs were discontinued; then, a 6-week treatment period with TBZ starting at
50 mg/d titrated to 100 mg/d to 150 mg/d. It ended with a 2-week TBZ washout period
on placebo. The primary outcome measure was mean frequency of dyskinetic move-
ments per minute as reported by a blinded rater; 8 patients (33%) had complete res-
olution of TD, 6 (25%) had marked improvement; another 6 had little or no change; and
4 patients did not complete the study (2 developed severe malaise, 1 withdrew due to
exacerbation of psychosis, and 1 was lost to follow-up).50 Compared with placebo,
TBZ was found to significantly reduce TD by 64%. Ondo and colleagues51 reported
a prospective, single-blind study of 20 patients with TD (mean duration 43.7 months)
who were videotaped before and after treatment with TBZ. One patient withdrew from
the study due to sedation. Videotapes were randomized and scored using the motor
subset of the AIMS by a blinded rater. The average improvement on the AIMS score
was 54.2% (from 17.9 to 8.2; P<.0001) after an average treatment period of 20.3 weeks
on a mean daily dose of 57.9 mg/d, 11 patients rated themselves as markedly
improved, 6 as moderately improved, and 2 as moderately improved.51
Two large, retrospective reports of TBZ in hyperkinetic movement disorders have
supported its beneficial role in TD.52,53 Combined, they report greater than 84% of
TD patients (a total of 242 patients) that rated their improvement as either moderate
or marked. These 2 studies also shed light on the most common AEs of TBZ, which
included sedation (25.0%–36.5%), parkinsonism (15.4%–28.5%), depression
(7.6%–15.0%), insomnia (4.9%–11.0%), anxiety (5.1%–10.3%), and akathisia
(7.6%–9.5%).52,53 Essentially, all TBZ-related AEs have been shown to be dose
related and decrease with dose reduction. They also can be managed with antide-
pressants, stimulants, and other pharmacologic strategies if patients otherwise
benefit from TBZ. Both the 2013 American Academy of Neurology (AAN) guideline
and a recently published systematic review gave TBZ a level C (possibly effective)
recommendation in the consideration of treatment of TD, based on lack of double-
blind, placebo-controlled studies.54,55
TBZ is quickly metabolized into a-dihydrotetrabenazine and b-dihydrotetrabenazine
(half-life 5–7 h) via hepatic isoenzyme CYP2D6. Because of its short half-life, TBZ typi-
cally is dosed 3 times a day.56 TBZ should be started at low doses (12.5–25 mg/d) with
careful titration (typical therapeutic dose, 50–75 mg/d) and monitoring for AEs. It is
recommended by the FDA that patients receiving more than 50 mg of TBZ per day
be genotyped for CYP2D6, but the various genotypes do not reliably predict the fre-
quency of AEs.56 With this need for frequent dosing and a side-effect profile restricting
its use, a strong interest grew in the development of novel VMAT2 inhibitors. Although
TBZ has been approved for the treatment of chorea associated with Huntington dis-
ease, it has not been approved for the treatment of TD.

Deutetrabenazine
DTBZ is a deuterated version of TBZ, incorporating 6 atoms of the naturally occurring
and nontoxic isotope deuterium or heavy hydrogen in its molecule.47 Deuterium-
carbon bonds are stronger than hydrogen-carbon bonds, thus more resistant to
metabolizing cytochrome P450 enzymes like CYP2D6.57 This provides significant
pharmacokinetic advantage (ie, longer half-life) over TBZ without altering target phar-
macology. DTBZ is dosed twice a day versus 3 times daily (half-life 9–10 h), with a
lower dose per administration to achieve similar clinical effect (6 mg of DTBZ is
approximately the equivalent of 12.5 mg TBZ).58 DTBZ first obtained FDA approval
for the treatment of Huntington chorea in April 2017 after the pivotal First-HD trial
 Treatment of Tardive Dyskinesia 7

demonstrated safety and efficacy.59,60 This was followed by approval for the treatment
of TD in August 2017 based on the results of 2 pivotal trials, Aim to Reduce Move-
ments in Tardive Dyskinesia (ARM-TD) and Addressing Involuntary Movements in Tar-
dive Dyskinesia (AIM-TD).61,62
ARM-TD was a phase 3, double-blind, multicenter trial of 177 patients with moder-
ate to severe TD (AIMS 6) that were randomized 1:1 to either placebo or DTBZ.61 Pa-
tients were allowed to continue DRBAs provided there was no recent change in
medications. The DTBZ group was started at 12 mg/d, with weekly titration of
6 mg/d until either adequate TD control was achieved, a significant AE occurred, or
the maximal allowable dose of 48 mg/d was reached. This was followed by a 6-
week maintenance period and 1-week washout. The primary endpoint was the change
in AIMS score from baseline to week 12 as assessed by 2 blinded video raters who
were movement disorder specialists. Secondary endpoints included treatment suc-
cess at week 12 on the Clinical Global Impression of Change (CGIC) and Patient
Global Impression of Change (PGIC). The mean daily dose was 38.8 mg at the end
of the study period. There was a mean 3.0-point reduction in AIMS score for DTBZ
versus 1.6 in the placebo group (P 5 .019), a treatment difference of 1.4. Although
the percentage of patients who achieved treatment success on the CGIC (48.2% vs
40.4%) and PGIC (42.9% vs 29.8%) favored DTBZ, these differences did not reach
statistical significance. Most common AEs for DTBZ versus placebo were somnolence
(13.8% vs 10.2%), insomnia (6.9% vs 1.7%), and akathisia (5.2% vs 0%). Discontin-
uation rates because of AEs were 1.7% versus 3.4%, respectively. Neither DTBZ nor
placebo group experienced any worsening in parkinsonism and rates of psychiatric
AEs were low: anxiety (3.4% vs 6.8%), depressed mood/depression (1.7% vs
1.7%), and suicidal ideation (0% vs 1.7%).
AIM-TD was a second-phase 3, double-blind, multicenter trial of 298 patients ran-
domized 1:1:1:1 to receive fixed doses of DTBZ 12 mg/d, 24 mg/d, 36 mg/d, or match-
ing placebo for 8 weeks after a 4-week titration period.62 The primary endpoint was
change in AIMS score from baseline to week 12 based on blinded video assessments.
From baseline to week 12, change in least squares mean AIMS score improved by
3.3 points in the DTBZ 36 mg/d group, 3.24 in the 24 mg/d group, and 2.1 points
in the 12 mg/d group, with a significant treatment difference of 1.9 points (P 5 .001),
1.8 points (P 5 .003), and 0.7 points (P 5 .217), respectively, compared with pla-
cebo.62 The investigators defined treatment success as “much improved” or “very
much improved” on the CGIC, which was accomplished in 49% of patients receiving
24 mg/d (P 5 .014) and 44% of those receiving 36 mg/d (P 5 .059) compared with
28% with 12 mg/d and 26% with placebo. There was no significant difference in
PGIC outcomes between DTBZ and placebo. The most common AE was headache
(5%). There were no other single AEs for DTBZ (all doses pooled) with incidence
greater than or equal to 5% or greater than that observed for placebo. Discontinuation
rates because of AEs were 4.1% for DTBZ (all doses pooled) versus 2.8% for placebo.
2 patients (1%) died, 1 each in the 24 mg/d and 36 mg/d groups; neither death was
deemed related to study drug.62
Pooling the data across both trials,63 the number needed to treat (NNT) for greater
than 50% reduction of the AIMS score at the therapeutic doses of DTBZ versus pla-
cebo was 7 (95% CI, 4–18). DTBZ was well tolerated, with low rates of AEs in both
ARM-TD and AIM-TD. AE-related discontinuation occurred among 3.6% of patients
randomized to DTBZ (at any dose) versus 3.1% for placebo, yielding a number needed
to harm of 189 (not significant). A recently published open-label extension study,
analyzing 331 patients treated for a mean of 352.9 days, confirmed safety outcomes
of both trials, demonstrating that DTBZ is well tolerated for long-term use in TD
8 Bashir & Jankovic

patients.64 DTBZ has received a level A (established as effective) recommendation for

the treatment of TD.55

Valbenazine
The metabolites of TBZ possess several chiral centers that generate isomers with
different VMAT2 binding affinity.65 Once characterized, VBZ was developed as a pu-
rified parent drug of TBZ that metabolizes into an isomer of a-dihydrotetrabenazine
with a combined half-life of 15 hours to 22 hours.66 This allowed for a convenient
once-daily dosing. VBZ also was designed to metabolize slowly, minimizing high
peak plasma concentrations thereby improving tolerability.66 Its limited range of me-
tabolites reduces the likelihood of off-target effects that can occur with TBZ metabo-
lites.47,66 These pharmacokinetic and pharmacodynamic advantages made VBZ an
attractive agent for further study in TD.
KINECT 2 was a phase 2, 6-week, double-blind, placebo-controlled dose-titration
study that randomized 102 patients with moderate or severe TD to placebo or VBZ,
25 mg/d, with titration to a maximum of 75 mg/d; 76% of the VBZ group reached this
maximum allowed dose.67 The primary efficacy endpoint was change in AIMS from base-
line at week 6 scored by 2 blinded video raters. Secondary efficacy endpoint was CGIC.
At week 6, least squares mean AIMS scores were reduced by 2.6 points for the VBZ
group compared with 0.2 for placebo (P 5 .0005).67 CGIC and PGIC results also favored
VBZ versus placebo as a rating of “much improved” or “very much improved” occurred in
66.7% versus 15.9% (P<.0001) and 57.8% versus 31.8% (P 5 .001), respectively.
Treatment-emergent AE rates were 49% in the VBZ and 33% in the placebo subjects.
The most common AE (VBZ vs placebo) were fatigue and headache (9.8% vs 4.1%)
and constipation and urinary tract infection (3.9% vs 6.1%). These results supported
further study in a phase 3 trial.
KINECT 3 was a phase 3, randomized, double-blind, placebo-controlled trial of VBZ
in TD.68 It was designed similarly KINECT to 2. This 6-week study randomized 234 pa-
tients (of whom 86% received concomitant DRBAs) 1:1:1 to once-daily placebo or
VBZ (40 or 80 mg/d). Least squares mean AIMS scores improved by 1.9 points for
VBZ, 40 mg/d (P 5 .002); 3.2 for VBZ, 80 mg/d (P<.001); and only 0.1 for placebo.
In a pooled analysis of both trials, 36.5% of patients receiving VBZ (both doses) versus
12.4% receiving placebo had a greater than 50% reduction of AIMS scores, yielding
an NNT of 5 (95% CI, 3–7).69 The most common AEs reported (VBZ vs placebo) were
somnolence (5.4 vs 3.2%), headache (4.5 vs 3.2%), fatigue (4.0 vs 2.4%), dry mouth
(4.0 vs 0.8%), vomiting (3.0 vs 0%), and urinary tract infection (2.5 vs 4.8%).69 KINECT
3 did note that 4.2% of VBZ patients reported akathisia and suicidal ideation versus
1.3% and 5.3% in placebo, respectively.68 The 1-year KINECT 3 extension study of
198 patients supported long-term efficacy, safety, and tolerability of VBZ in TD.70
The recently published data from KINECT 4 (clinicaltrials.gov, NCT02405091), which
included 48 weeks of open-label treatment with VBZ followed by a 4-week washout,
demonstrated sustained and clinically meaningful improvement of TD, and VBZ gener-
ally was well tolerated without notable changes in the psychiatric status of patients.71
Based on these data, VBZ received FDA approval for the treatment of TD in April
2017. VBZ has a level A recommendation for the treatment of TD.55

Non–vesicular Monoamine Transporter Type 2 Pharmacologic Agents

Benzodiazepines
The g-aminobutyric acid (GABA)ergic system has been implicated in the pathophysi-
ology of TD.72 Benzodiazepines are allosteric GABAA agonists that hyperpolarize neu-
rons by increasing Cl influx and frequently are used in the treatment of TD.73
 Treatment of Tardive Dyskinesia 9

Clonazepam was evaluated in a 12-week, double-blind, randomized, crossover trial

of 19 chronically ill patients with TD taking DRBAs.74 Overall, a 37.1% reduction
(P<.001) in dyskinesia was noted from baseline after 12 weeks using the Maryland Psy-
chiatric Research Center movement disorders scale. Patients with dystonic symptoms
(n 5 6) showed greater benefit (41.5% reduction) than the remainder with choreoathe-
toid dyskinesia (n 5 13; 26.5% reduction).74 The investigators followed 5 patients for an
additional 9 months and noted they developed tolerance to clonazepam; however, an
antidyskinetic effect was recaptured after a 2-week drug holiday. Clonazepam has a
level B recommendation (probably effective) for the treatment of TD.55
Diazepam and alprazolam are shorter-acting benzodiazepines for which the
effectiveness in TD remains unclear. An open-label study of 21 patients with TD
demonstrated improvement in AIMS scores with diazepam.75 A 24-week, randomized,
placebo-controlled, crossover study of 13 patients using blinded rating did not find
improvement with diazepam.76 A small study comparing alprazolam, diazepam, and
placebo showed no benefit for TD.77 Alprazolam has not been studied in a randomized
trials; only case reports have been described.78

Ginkgo biloba
Ginkgo biloba extract (EGb-761) is obtained from the fan-shaped leaves and seeds of
the Ginkgo biloba tree (or maidenhair tree) and has antioxidative properties.79 It is
among the most sold medicinal plants in the world and commonly used in traditional
Chinese medicine. In a 12-week, double-blind, randomized, placebo-controlled trial of
157 patients with schizophrenia and TD, EGb-761 reduced AIMS scores by an average
of 2.13 (P<.001) compared with 0.1 for placebo80; 51.3% of patients in the EGb-761
group experienced greater than 30% reduction in AIMS score compared with just
5.1% of placebo (P<.001). Although additional studies are needed to confirm these
data, Gingko biloba has been given a level B recommendation for the treatment of TD.55

Amantadine
Amantadine, initially developed as an antiviral agent, is a noncompetitive N-methyl-D-
aspartate antagonist with antiglutamatergic properties, now commonly used in the
management of levodopa-induced dyskinesias.81 It was first reported to improve TD
in 1971 after 2 small case series.82,83 The investigators subsequently performed 2
double-blind, crossover studies of amantadine 100 mg 3 times and twice daily versus
matching placebo for 10 days (14 patients and 10 patients, respectively) that were
negative.84 More recently, 2 small studies evaluated amantadine in TD patients taking
DRBAs and noted positive results.85,86 Angus and colleagues85 reported a double-
blind, randomized, placebo-controlled, 7-week-per-arm, crossover trial of amanta-
dine initiated at 100 mg/d and titrated to 300 mg/d maintained for 3 weeks. The
mean AIMS score was significantly lower in the amantadine group than placebo
(7.312 vs 8.188; P<.05). Pappa and colleagues86 reported a double-blind, randomized,
placebo-controlled, 2-week-per-arm, crossover trial of amantadine up to 400 mg/d.
Patients receiving amantadine exhibited a reduced mean AIMS score (13.5–10.5;
P 5 .000) whereas the placebo group showed no reduction. These studies supported
the short-term use of amantadine; however, given the mixed results and small study
sizes, amantadine has a level C recommendation for the treatment of TD.55
Other Pharmacologic Treatments
There are several other oral agents for which there is insufficient evidence to support their
use in TD.54,55 These include cholinergic agents (eg, donepezil, physostigmine, choline,
and galantamine),87,88 anticholinergics (eg, benztropine),37 antioxidants other than
Ginkgo biloba (eg, vitamin B6 and vitamin E), baclofen, buspirone, eicosapentaenoic
10 Bashir & Jankovic

acid, calcium channel blockers, acetazolamide, melatonin, zonisamide, and

propranolol.55
Trihexyphenidyl, an anticholinergic, showed improvement in TD from data of 2 retro-
spective studies using 10 mg/d to 32 mg/d in 3 of 8 patients89 and 6 mg/d to 12 mg/
d in 8 of 21 patients.90 This is consistent with the observation that anticholinergics are
useful in primary dystonia.91 The risk of cognitive AEs and worsening of OBL stereo-
typies, however, limit their use and it is generally discouraged in TD.92,93
Zolpidem, a nonbenzodiazepine hypnotic, has been reported to be effective for the
treatment of TD and tardive akathisia in a small series of 3 patients.94 Placebo-
controlled study is needed to further document effectiveness of zolpidem in TD.
Levetiracetam is an antiepileptic that targets synaptic vesicle glycoprotein 2A and
may modulate vesicle release.95 Two small open-label trials96,97 and a small random-
ized trial98 demonstrated reduced severity of TD. The latter was a 12-week, double-
blind study of 50 patients receiving levetiracetam (500–3000 mg/d) versus placebo.
AIMS scores declined 43.5% from baseline in the levetiracetam group compared
with 18.7% for placebo (P 5 .022); however, there was a high dropout rate because
of psychiatric disorientation, nonadherence, loss to follow-up, and unrelated
stressors.98 Although the results were somewhat promising, further studies have not
been done and levetiracetam has been given a has been given a level U (inadequate
evidence) recommendation for the treatment of TD.55
Lastly, although there is some evidence that initiating or switching to atypical anti-
psychotics can help reduce TD,99,100 based on the knowledge that all atypical antipsy-
chotics (with the possible exception of clozapine) can cause TD, both the 2013 AAN
guidelines and a recent systematic review do not recommend the use of these agents
to treat TD.54,55

DEEP BRAIN STIMULATION

Deep brain stimulation (DBS) is a well-recognized and widely used treatment option
for many movement disorders, including Parkinson disease, essential tremor, and
dystonia.101 DBS in TD typically is reserved for severe, disabling, medically refractory
cases (level C recommendation).55 A recent systematic review and metanalysis found
that the majority of DBS studies in TD to date are open-label case reports or part of
open-label case series of dystonia of various etiologies.102 All cases were related to
use of neuroleptics, except those of 2 patients, which were a result of metoclopramide
exposure.103,104 A majority of cases target bilateral posteroventral globus pallidus
internus (GPi), although a few cases of subthalamic nucleus DBS also have been suc-
cessfully reported with long-term follow-up.105,106 Across 51 cases of DBS in classical
TD, in which the outcome measure was change in AIMS score, the mean percentage
of AIMS score improvement was 62  15% after DBS surgery (median 58%; range
33%–90%).102 In cases of TD, the Burke-Fahn-Marsden (BFM) scale has been most
widely used. The BFM motor score improvement across 67 cases was 76  21% after
DBS (median 82%; range 7%–100%).102 The limitations of these data are the differ-
ences across case reports, including phenomenology, severity, clinical assessments,
frequency of follow-up, and the lack of prospective, controlled trial.

OTHER TREATMENT OPTIONS

Botulinum Toxin
Botulinum neurotoxin (BoNT) is derived from Clostridium bacteria and acts on presyn-
aptic vesicular release complex proteins to reduce neurotransmission.107 It has
emerged as one the most versatile therapeutic options in medicine. Within movement
 Treatment of Tardive Dyskinesia 11

disorders, BoNT type A (onabotulinumtoxinA) is approved for the treatment of bleph-

arospasm, craniocervical dystonia, and limb spasticity.107 There have been no
controlled trials studying the effects of BoNT in the treatment of TD. Several case re-
ports, case series, and open-label reports, however, have shown promising re-
sults.108–110 A majority of reports include patients with focal symptoms, such as
OBL stereotypies or TD that had failed other pharmacologic treatments. Slotema
and colleagues111 performed a single-blind (raters only) 33-week study of 12 patients
with orofacial TD receiving BoNT every 3 months for 3 treatments. Although there was
a nonsignificant (P 5 .15) reduction in TD severity overall, in the patients with no
change in their antipsychotic medication (ie, stable doses; n 5 8), the reduction was
significant (AIMS score 4.81–3.0; P 5 .035). After the study, 50% of the patients
preferred to continue treatment with BoNT. Notable limitations of BoNT in the treat-
ment of TD are the need for technical expertise (which can vary significantly between
injectors), need for reinjection, and the potential for perioral, lingual, or neck injections
to cause dysarthria and dysphagia. In the absence of controlled trials, BoNT currently
has a level U recommendation for the treatment of TD.55
Electroconvulsive Therapy
Electroconvulsive therapy (ECT) uses a small electric current to produce a generalized
cerebral seizure under general anesthesia, primarily used for the management of se-
vere, treatment-resistant psychiatric conditions.112 Multiple case reports have
described improvement of TD after ECT in patients treated for depression or schizo-
phrenia.113–115 Yasui-Furukori and colleagues116 reported a retrospective series of 18
patients receiving ECT that demonstrated a mean AIMS score improvement from
19.1  4.7 to 9.6  4.2. These findings contrast with reports (albeit quite dated) of
worsening TD,117 emergence of TD,118 or no change in TD119 with ECT. Overall, the
2013 AAN guidelines concluded that there is insufficient evidence (level U) for the ef-
ficacy of ECT in treating TD.54

SUMMARY

The aim of this review is to provide a summary of the current treatment options for TD
with emphasis on recent developments; 2017 was a pivotal year for TD with the
approval of 2 new drugs, VBZ and DTBZ, bringing with them renewed interest and
attention to the condition. The management of TD remains challenging, however,
given the heterogeneity of cases and limited treatment options. There are many impor-
tant areas of research specifically addressing those patients who remain refractory to
treatment despite recent developments. As discussed previously, many other agents
with different mechanisms and tolerance profiles have shown promise but need to be
studied in large, controlled, multicenter trials. In an era of precision medicine, better
understanding the pathophysiology and underlying genetics of TD will lead to new, tar-
geted treatments. The development of patient registries to provide long-term data will
be essential for such endeavors. Conceivably, the development of newer antipsy-
chotics that do not cause TD may reduce disease burden significantly. Physician ed-
ucation, however, regarding the judicious use of current DRBAs remains central to the
prevention and management of TD.

DISCLOSURE

Dr H.H. Bashir has nothing to disclose. Dr J. Jankovic has received research/training

funding from Allergan; CHDI Foundation; Dystonia Coalition; F. Hoffmann-La
Roche Ltd; Huntington Study Group; Medtronic Neuromodulation; Merz
12 Bashir & Jankovic

Pharmaceuticals; Michael J Fox Foundation for Parkinson Research; National Insti-

tutes of Health; Neurocrine Biosciences; Parkinson’s Foundation; Parkinson Study
Group; Revance Therapeutics, Inc; and Teva Pharmaceutical Industries. He has
served as a consultant/advisory board member for Abide; Aeon BioPharma; Nuvelu-
tion; Retrophin; and Teva Pharmaceutical Industries Ltd. He has served on editorial
boards of Expert Review of Neurotherapeutics; Journal of Parkinson’s Disease; Med-
link; Neurology in Clinical Practice; The Botulinum Journal; PeerJ; Therapeutic Ad-
vances in Neurologic Disorders; Neurotherapeutics; Tremor and Other Hyperkinetic
Movements; Toxins; and UpToDate. He has received royalties from Cambridge; Elsev-
ier; Future Science Group; Hodder Arnold; Medlink: Neurology; Lippincott Williams
and Wilkins; and Wiley-Blackwell.

REFERENCES

1. Faurbye A, Rasch PJ, Petersen PB, et al. Neurological symptoms in pharmaco-

therapy of psychoses. Acta Psychiatr Scand 1964;40(1):10–27.
2. Uhrbrand L, Faurbye A. Reversible and irreversible dyskinesia after treatment
with perphenazine, chlorpromazine, reserpine and electroconvulsive therapy.
Psychopharmacologia 1960;1(5):408–18.
3. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to
treatment. Tremor Other Hyperkinet Mov (N Y) 2013;3:1–11.
4. Macaluso M, Flynn A, Preskorn SH. Tardive dyskinesia: a historical perspective.
J Psychiatr Pract 2017;23(2):121–9.
5. Savitt D, Jankovic J. Tardive syndromes. J Neurol Sci 2018;389:35–42.
6. Frei K, Truong DD, Fahn S, et al. The nosology of tardive syndromes. J Neurol
Sci 2018;389:10–6.
7. Obeso JA. The Movement Disorders journal 2016 and onward. Mov Disord
2016;31(1):1–2.
8. McEvoy J, Carroll B, Gandhi S, et al. Effect of tardive dyskinesia on quality of life:
patient-reported symptom severity is associated with deficits in physical,
mental, and social functioning (P4.077). Neurology 2018;90(15 Supplement):
P4.077.
9. Kovacs N, Balas I, Janszky J, et al. Status dystonicus in tardive dystonia suc-
cessfully treated by bilateral deep brain stimulation. Clin Neurol Neurosurg
2011;113(9):808–9.
10. Rohani M, Munhoz RP, Shahidi G, et al. Fatal status dystonicus in tardive dysto-
nia due to depletion of deep brain stimulation’s pulse generator. Brain Stimul
2017;10(1):160–1.
11. Pileggi DJ, Cook AM. Neuroleptic malignant syndrome. Ann Pharmacother
2016;50(11):973–81.
12. Ballesteros J, González-Pinto A, Bulbena A. Tardive dyskinesia associated with
higher mortality in psychiatric patients: results of a meta-analysis of seven inde-
pendent studies. J Clin Psychopharmacol 2000;20(2):188–94.
13. Niemann N, Jankovic J. Treatment of tardive dyskinesia: a general overview with
focus on the vesicular monoamine transporter 2 inhibitors. Drugs 2018;78(5):
525–41.
14. Tepper SJ, Haas JF. Prevalence of tardive dyskinesia. J Clin Psychiatry 1979;
40(12):508–16.
15. Kane JM, Woerner M, Lieberman J. Tardive dyskinesia: prevalence, incidence,
and risk factors. J Clin Psychopharmacol 1988;8(4 Suppl):52S–6S.
 Treatment of Tardive Dyskinesia 13

16. Gardos G, Casey DE, Cole JO, et al. Ten-year outcome of tardive dyskinesia.
Am J Psychiatry 1994;151(6):836–41.
17. Glazer WM, Morgenstern H, Doucette JT. Predicting the long-term risk of tardive
dyskinesia in outpatients maintained on neuroleptic medications. J Clin Psychi-
atry 1993;54(4):133–9.
18. Correll CU, Schenk EM. Tardive dyskinesia and new antipsychotics. Curr Opin
Psychiatry 2008;21(2):151–6.
19. Woods SW, Morgenstern H, Saksa JR, et al. Incidence of tardive dyskinesia with
atypical versus conventional antipsychotic medications: a prospective cohort
study. J Clin Psychiatry 2010;71(4):463–74.
20. Miller DD, Caroff SN, Davis SM, et al. Extrapyramidal side-effects of antipsy-
chotics in a randomised trial. Br J Psychiatry 2008;193(4):279–88.
21. Carbon M, Kane JM, Leucht S, et al. Tardive dyskinesia risk with first- and
second-generation antipsychotics in comparative randomized controlled trials:
a meta-analysis. World Psychiatry 2018;17(3):330–40.
22. Hálfdánarson Ó, Zoëga H, Aagaard L, et al. International trends in antipsychotic
use: a study in 16 countries, 2005-2014. Eur Neuropsychopharmacol 2017;
27(10):1064–76.
23. Domino ME, Swartz MS. Who are the new users of antipsychotic medications?
Psychiatr Serv 2008;59(5):507–14.
24. Mulder R, Hamilton A, Irwin L, et al. Treating depression with adjunctive antipsy-
chotics. Bipolar Disord 2018;20(Suppl 2):17–24.
25. D’Abreu A, Akbar U, Friedman JH. Tardive dyskinesia: epidemiology. J Neurol
Sci 2018;389:17–20.
26. D’Abreu A, Friedman JH. Tardive dyskinesia-like syndrome due to drugs that do
not block dopamine receptors: rare or non-existent: literature review. Tremor
Other Hyperkinet Mov (N Y) 2018;8:570.
27. Frei K. Tardive dyskinesia: who gets it and why. Parkinsonism Relat Disord 2019;
59:151–4.
28. Lo Y-C, Peng Y-C. Amisulpride withdrawal dyskinesia: a case report. Ann Gen
Psychiatry 2017;16:25.
29. Thomson AM, Wallace J, Kobylecki C. Tardive dyskinesia after drug withdrawal
in two older adults: clinical features, complications and management. Geriatr
Gerontol Int 2019;19(6):563–4.
30. Pugin D, Bally J, Horvath J, et al. Life-threatening neuroleptic withdrawal emer-
gent syndrome resembling status dystonicus. Parkinsonism Relat Disord 2017;
35:96–7.
31. Cerovecki A, Musil R, Klimke A, et al. Withdrawal symptoms and rebound syn-
dromes associated with switching and discontinuing atypical antipsychotics:
theoretical background and practical recommendations. CNS Drugs 2013;
27(7):545–72.
32. Mejia NI, Jankovic J. Tardive dyskinesia and withdrawal emergent syndrome in
children. Expert Rev Neurother 2010;10(6):893–901.
33. Solmi M, Pigato G, Kane JM, et al. Clinical risk factors for the development of
tardive dyskinesia. J Neurol Sci 2018;389:21–7.
34. Patterson-Lomba O, Ayyagari R, Carroll B. 62 predictors of tardive dyskinesia in
psychiatric patients taking concomitant antipsychotics. CNS Spectr 2019;24(1):
207–8.
35. Wijegunaratne H, Qazi H, Koola MM. Chronic and bedtime use of benztropine
with antipsychotics: is it necessary? Schizophr Res 2014;153(1–3):248–9.
14 Bashir & Jankovic

36. Miller DD, McEvoy JP, Davis SM, et al. Clinical correlates of tardive dyskinesia in
schizophrenia: baseline data from the CATIE schizophrenia trial. Schizophr Res
2005;80(1):33–43.
37. Bergman H, Soares-Weiser K. Anticholinergic medication for antipsychotic-
induced tardive dyskinesia. Cochrane Database Syst Rev 2018;(1):CD000204.
38. Hauser RA, Truong D. Tardive dyskinesia: out of the shadows. J Neurol Sci 2018;
389:1–3.
39. Vijayakumar D, Jankovic J. Drug-induced dyskinesia, part 2: treatment of tar-
dive dyskinesia. Drugs 2016;76(7):779–87.
40. Viguera AC, Baldessarini RJ, Hegarty JD, et al. Clinical risk following abrupt and
gradual withdrawal of maintenance neuroleptic treatment. Arch Gen Psychiatry
1997;54(1):49–55.
41. Mentzel TQ, van der Snoek R, Lieverse R, et al. Clozapine monotherapy as a
treatment for antipsychotic-induced tardive dyskinesia: a meta-analysis. J Clin
Psychiatry 2018;79(6).
42. Ricciardi L, Pringsheim T, Barnes TRE, et al. Treatment recommendations for tar-
dive dyskinesia. Can J Psychiatry 2019;64(6):388–99.
43. Hawkins T, Berman BD. Pimavanserin: a novel therapeutic option for Parkinson
disease psychosis. Neurol Clin Pract 2017;7(2):157–62.
44. Nasrallah HA, Fedora R, Morton R. Successful treatment of clozapine-
nonresponsive refractory hallucinations and delusions with pimavanserin, a se-
rotonin 5HT-2A receptor inverse agonist. Schizophr Res 2019;208:217–20.
45. Zutshi D, Cloud LJ, Factor SA. Tardive syndromes are rarely reversible after dis-
continuing dopamine receptor blocking agents: experience from a university-
based movement disorder clinic. Tremor Other Hyperkinet Mov (N Y) 2014;
4:266.
46. Yaffe D, Forrest LR, Schuldiner S. The ins and outs of vesicular monoamine
transporters. J Gen Physiol 2018;150(5):671–82.
47. Jankovic J. Dopamine depleters in the treatment of hyperkinetic movement dis-
orders. Expert Opin Pharmacother 2016;17(18):2461–70.
48. Chen JJ, Ondo WG, Dashtipour K, et al. Tetrabenazine for the treatment of hy-
perkinetic movement disorders: a review of the literature. Clin Ther 2012;34(7):
1487–504.
49. Niemann N, Jankovic J. Real-world experience with VMAT2 inhibitors. Clin Neu-
ropharmacol 2019;42(2):37–41.
50. Kazamatsuri H, Chien C, Cole JO. Treatment of tardive dyskinesia. I. Clinical ef-
ficacy of a dopamine-depleting agent, tetrabenazine. Arch Gen Psychiatry
1972;27(1):95–9.
51. Ondo WG, Hanna PA, Jankovic J. Tetrabenazine treatment for tardive dyski-
nesia: assessment by randomized videotape protocol. Am J Psychiatry 1999;
156(8):1279–81.
52. Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic move-
ment disorders. Neurology 1997;48(2):358–62.
53. Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the
treatment of hyperkinetic movement disorders. Mov Disord 2007;22(2):193–7.
54. Bhidayasiri R, Fahn S, Weiner WJ, et al. Evidence-based guideline: treatment of
tardive syndromes: report of the Guideline Development Subcommittee of the
American Academy of Neurology. Neurology 2013;81(5):463–9.
55. Bhidayasiri R, Jitkritsadakul O, Friedman JH, et al. Updating the recommenda-
tions for treatment of tardive syndromes: a systematic review of new evidence
and practical treatment algorithm. J Neurol Sci 2018;389:67–75.
 Treatment of Tardive Dyskinesia 15

56. Mehanna R, Hunter C, Davidson A, et al. Analysis of CYP2D6 genotype and

response to tetrabenazine. Mov Disord 2013;28(2):210–5.
57. Mullard A. Deuterated drugs draw heavier backing. Nat Rev Drug Discov 2016;
15(4):219–21.
58. Teva Pharmaceuticals USA Inc. AUSTEDO (deutetrabenazine): US prescribing
information. Available at: http://www.fda.gov.2017. Accessed July 1, 2019.
59. Huntington Study Group, Frank S, Testa CM, Stamler D, et al. Effect of deutetra-
benazine on chorea among patients with huntington disease: a randomized clin-
ical trial. JAMA 2016;316(1):40–50.
60. Bashir H, Jankovic J. Deutetrabenazine for the treatment of Huntington’s chorea.
Expert Rev Neurother 2018;18(8):625–31.
61. Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deu-
tetrabenazine for tardive dyskinesia: the ARM-TD study. Neurology 2017;88(21):
2003–10.
62. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of
involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-
blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry 2017;
4(8):595–604.
63. Citrome L. Deutetrabenazine for tardive dyskinesia: a systematic review of the
efficacy and safety profile for this newly approved novel medication-What is
the number needed to treat, number needed to harm and likelihood to be
helped or harmed? Int J Clin Pract 2017;71(11). https://doi.org/10.1111/ijcp.
13030.
64. Fernandez HH, Stamler D, Davis MD, et al. Long-term safety and efficacy of
deutetrabenazine for the treatment of tardive dyskinesia. J Neurol Neurosurg
Psychiatry 2019;90(12):1317–23.
65. Yao Z, Wei X, Wu X, et al. Preparation and evaluation of tetrabenazine enantio-
mers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors.
Eur J Med Chem 2011;46(5):1841–8.
66. Müller T. Valbenazine granted breakthrough drug status for treating tardive
dyskinesia. Expert Opin Investig Drugs 2015;24(6):737–42.
67. O’Brien CF, Jimenez R, Hauser RA, et al. NBI-98854, a selective monoamine
transport inhibitor for the treatment of tardive dyskinesia: a randomized,
double-blind, placebo-controlled study. Mov Disord 2015;30(12):1681–7.
68. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized,
double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia.
Am J Psychiatry 2017;174(5):476–84.
69. Citrome L. Valbenazine for tardive dyskinesia: a systematic review of the effi-
cacy and safety profile for this newly approved novel medication-What is the
number needed to treat, number needed to harm and likelihood to be helped
or harmed? Int J Clin Pract 2017;71(7). https://doi.org/10.1111/ijcp.12964.
70. Factor SA, Remington G, Comella CL, et al. The effects of valbenazine in partic-
ipants with tardive dyskinesia: results of the 1-year KINECT 3 extension study.
J Clin Psychiatry 2017;78(9):1344–50.
71. Lindenmayer J-P, Marder SR, Singer C, et al. 77 long-term valbenazine treat-
ment in patients with schizophrenia/schizoaffective disorder or mood disorder
and tardive dyskinesia. CNS Spectr 2019;24(1):214–5.
72. Teo JT, Edwards MJ, Bhatia K. Tardive dyskinesia is caused by maladaptive
synaptic plasticity: a hypothesis. Mov Disord 2012;27(10):1205–15.
73. Lin C-C, Ondo WG. Non-VMAT2 inhibitor treatments for the treatment of tardive
dyskinesia. J Neurol Sci 2018;389:48–54.
16 Bashir & Jankovic

74. Thaker GK, Nguyen JA, Strauss ME, et al. Clonazepam treatment of tardive
dyskinesia: a practical GABAmimetic strategy. Am J Psychiatry 1990;147(4):
445–51.
75. Singh MM, Becker RE, Pitman RK, et al. Diazepam-induced changes in tardive
dyskinesia: suggestions for a new conceptual model. Biol Psychiatry 1982;
17(6):729–42.
76. Weber SS, Dufresne RL, Becker RE, et al. Diazepam in tardive dyskinesia. Drug
Intell Clin Pharm 1983;17(7–8):523–7.
77. Csernansky JG, Tacke U, Rusen D, et al. The effect of benzodiazepines on tar-
dive dyskinesia symptoms. J Clin Psychopharmacol 1988;8(2):154–5.
78. Jordan HW, Williams BC. Tardive dyskinesia successfully treated with alprazo-
lam. J Natl Med Assoc 1990;82(9):673–5.
79. Singh B, Kaur P, Gopichand, et al. Biology and chemistry of Ginkgo biloba. Fi-
toterapia 2008;79(6):401–18.
80. Zhang W-F, Tan Y-L, Zhang X-Y, et al. Extract of Ginkgo biloba treatment for tar-
dive dyskinesia in schizophrenia: a randomized, double-blind, placebo-
controlled trial. J Clin Psychiatry 2011;72(5):615–21.
81. Vijayakumar D, Jankovic J. Drug-induced dyskinesia, part 1: treatment of
levodopa-induced dyskinesia. Drugs 2016;76(7):759–77.
82. Vale S, Espejel MA. Amantadine for dyskinesia tarda. N Engl J Med 1971;
284(12):673.
83. Decker BL, Davis JM, Jonowsky DS, et al. Amantadine hydrochloride treatment
of tardive dyskinesia. N Engl J Med 1971;285(15):860. Available at: http://www.
ncbi.nlm.nih.gov/pubmed/5570853.
84. Janowsky DS, El-Yousef MK, Davis JM, et al. Effects of amantadine on tardive
dyskinesia and pseudo-parkinsonism. N Engl J Med 1972;286(14):785.
85. Angus S, Sugars J, Boltezar R, et al. A controlled trial of amantadine hydrochlo-
ride and neuroleptics in the treatment of tardive dyskinesia. J Clin Psychophar-
macol 1997;17(2):88–91.
86. Pappa S, Tsouli S, Apostolou G, et al. Effects of amantadine on tardive dyski-
nesia: a randomized, double-blind, placebo-controlled study. Clin Neurophar-
macol 2010;33(6):271–5.
87. Tammenmaa IA, Sailas E, McGrath JJ, et al. Systematic review of cholinergic
drugs for neuroleptic-induced tardive dyskinesia: a meta-analysis of random-
ized controlled trials. Prog Neuropsychopharmacol Biol Psychiatry 2004;28(7):
1099–107.
88. Tammenmaa-Aho I, Asher R, Soares-Weiser K, et al. Cholinergic medication for
antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev
2018;(3):CD000207.
89. Kang UJ, Burke RE, Fahn S. Natural history and treatment of tardive dystonia.
Mov Disord 1986;1(3):193–208.
90. Suzuki T, Hori T, Baba A, et al. Effectiveness of anticholinergics and neuroleptic
dose reduction on neuroleptic-induced pleurothotonus (the Pisa syndrome).
J Clin Psychopharmacol 1999;19(3):277–80.
91. Burke RE, Fahn S, Marsden CD. Torsion dystonia: a double-blind, prospective
trial of high-dosage trihexyphenidyl. Neurology 1986;36(2):160–4.
92. Desmarais JE, Beauclair L, Annable L, et al. Effects of discontinuing anticholin-
ergic treatment on movement disorders, cognition and psychopathology in pa-
tients with schizophrenia. Ther Adv Psychopharmacol 2014;4(6):257–67.
 Treatment of Tardive Dyskinesia 17

93. Vinogradov S, Fisher M, Warm H, et al. The cognitive cost of anticholinergic

burden: decreased response to cognitive training in schizophrenia. Am J Psy-
chiatry 2009;166(9):1055–62.
94. Waln O, Jankovic J. Zolpidem improves tardive dyskinesia and akathisia. Mov
Disord 2013;28(12):1748–9.
95. Abou-Khalil BW. Antiepileptic drugs. Continuum (Minneap Minn) 2016;22(1
Epilepsy):132–56.
96. Konitsiotis S, Pappa S, Mantas C, et al. Levetiracetam in tardive dyskinesia: an
open label study. Mov Disord 2006;21(8):1219–21.
97. Bona JR. Treatment of neuroleptic-induced tardive dyskinesia with levetirace-
tam: a case series. J Clin Psychopharmacol 2006;26(2):215–6.
98. Woods SW, Saksa JR, Baker CB, et al. Effects of levetiracetam on tardive dyski-
nesia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry
2008;69(4):546–54.
99. Grover S, Hazari N, Kate N, et al. Management of tardive syndromes with cloza-
pine: a case series. Asian J Psychiatr 2014;8:111–4.
100. Chan H-Y, Chiang S-C, Chang C-J, et al. A randomized controlled trial of risper-
idone and olanzapine for schizophrenic patients with neuroleptic-induced tar-
dive dyskinesia. J Clin Psychiatry 2010;71(9):1226–33.
101. Lozano AM, Lipsman N, Bergman H, et al. Deep brain stimulation: current chal-
lenges and future directions. Nat Rev Neurol 2019;15(3):148–60.
102. Macerollo A, Deuschl G. Deep brain stimulation for tardive syndromes: system-
atic review and meta-analysis. J Neurol Sci 2018;389:55–60.
103. Pouclet-Courtemanche H, Rouaud T, Thobois S, et al. Long-term efficacy and
tolerability of bilateral pallidal stimulation to treat tardive dyskinesia. Neurology
2016;86(7):651–9.
104. Gruber D, Trottenberg T, Kivi A, et al. Long-term effects of pallidal deep brain
stimulation in tardive dystonia. Neurology 2009;73(1):53–8.
105. Meng D-W, Liu H-G, Yang A-C, et al. Long-term effects of subthalamic nucleus
deep brain stimulation in tardive dystonia. Chin Med J (Engl) 2016;129(10):
1257–8.
106. Deng Z-D, Li D-Y, Zhang C-C, et al. Long-term follow-up of bilateral subthalamic
deep brain stimulation for refractory tardive dystonia. Parkinsonism Relat Disord
2017;41:58–65.
107. Jankovic J. Botulinum toxin: state of the art. Mov Disord 2017;32(8):1131–8.
108. Hennings JMH, Krause E, Bötzel K, et al. Successful treatment of tardive lingual
dystonia with botulinum toxin: case report and review of the literature. Prog Neu-
ropsychopharmacol Biol Psychiatry 2008;32(5):1167–71.
109. Kasravi N, Jog MS. Botulinum toxin in the treatment of lingual movement disor-
ders. Mov Disord 2009;24(15):2199–202.
110. Jankovic J. An update on new and unique uses of botulinum toxin in movement
disorders. Toxicon 2018;147:84–8.
111. Slotema CW, van Harten PN, Bruggeman R, et al. Botulinum toxin in the treat-
ment of orofacial tardive dyskinesia: a single blind study. Prog Neuropsycho-
pharmacol Biol Psychiatry 2008;32(2):507–9.
112. Weiner RD, Reti IM. Key updates in the clinical application of electroconvulsive
therapy. Int Rev Psychiatry 2017;29(2):54–62.
113. Chacko RC, Root L. ECT and tardive dyskinesia: two cases and a review. J Clin
Psychiatry 1983;44(7):265–6.
18 Bashir & Jankovic

114. Nobuhara K, Matsuda S, Okugawa G, et al. Successful electroconvulsive treat-

ment of depression associated with a marked reduction in the symptoms of tar-
dive dyskinesia. J ECT 2004;20(4):262–3.
115. Peng L-Y, Lee Y, Lin P-Y. Electroconvulsive therapy for a patient with persistent
tardive dyskinesia. J ECT 2013;29(3):e52–4.
116. Yasui-Furukori N, Nakamura K, Katagai H, et al. The effects of electroconvulsive
therapy on tardive dystonia or dyskinesia induced by psychotropic medication:
a retrospective study. Neuropsychiatr Dis Treat 2014;10:1209.
117. Holcomb HH, Sternberg DE, Heninger GR. Effects of electroconvulsive therapy
on mood, parkinsonism, and tardive dyskinesia in a depressed patient: ECT and
dopamine systems. Biol Psychiatry 1983;18(8):865–73.
118. Roth SD, Mukherjee S, Sackeim HA. Electroconvulsive therapy in a patient with
mania, parkinsonism, and tardive dyskinesia. Convuls Ther 1988;4(1):92–7.
119. Asnis GM, Leopold MA. A single-blind study of ECT in patients with tardive
dyskinesia. Am J Psychiatry 1978;135(10):1235–7.