Drugs
https://doi.org/10.1007/s40265-018-0874-x
THERAPY IN PRACTICE
Treatment of Tardive Dyskinesia: A General Overview with Focus
on the Vesicular Monoamine Transporter 2 Inhibitors
Nicki Niemann1 • Joseph Jankovic1
Ó Springer International Publishing AG, part of Springer Nature 2018
Abstract Tardive dyskinesia (TD) encompasses the spec-
trum of iatrogenic hyperkinetic movement disorders follow-
ing exposure to dopamine receptor-blocking agents (DRBAs).
Despite the advent of atypical or second- and third-generation
antipsychotics with a presumably lower risk of complications,
TD remains a persistent and challenging problem. Prevention
is the first step in mitigating the risk of TD, but early
recognition, gradual withdrawal of offending medications,
and appropriate treatment are also critical. As TD is often a
persistent and troublesome disorder, specific antidyskinetic
therapies are often needed for symptomatic relief. The
vesicular monoamine transporter 2 (VMAT2) inhibitors,
which include tetrabenazine, deutetrabenazine, and valbe-
nazine, are considered the treatment of choice for most
patients with TD. Deutetrabenazine—a deuterated version of
tetrabenazine—and valbenazine, the purified parent product
of one of the main tetrabenazine metabolites, are novel
VMAT2 inhibitors and the only drugs to receive approval
from the US FDA for the treatment of TD. VMAT2 inhibitors
deplete presynaptic dopamine and reduce involuntary move-
ments in many hyperkinetic movement disorders, particularly
TD, Huntington disease, and Tourette syndrome. The active
metabolites of the VMAT2 inhibitors have high affinity for
VMAT2 and minimal off-target binding. Compared with
tetrabenazine, deutetrabenazine and valbenazine have phar-
macokinetic advantages that translate into less frequent dos-
ing and better tolerability. However, no head-to-head studies
& Joseph Jankovic
josephj@bcm.edu;
http://www.jankovic.org
1
Parkinson’s Disease Center and Movement Disorders Clinic,
Department of Neurology, Baylor College of Medicine, 7200
Cambridge, Suite 9A, Houston, TX 77030, USA
have compared the various VMAT2 inhibitors. One of the
major advantages of VMAT2 inhibitors over DRBAs, which
are still being used by some clinicians in the treatment of
some hyperkinetic disorders, including TD, is that they are
not associated with the development of TD. We also briefly
discuss other treatment options for TD, including amantadine,
clonazepam, Gingko biloba, zolpidem, botulinum toxin, and
deep brain stimulation. Treatment of TD and other drug-
induced movement disorders must be individualized and
based on the severity, phenomenology, potential side effects,
and other factors discussed in this review.
Key Points
Tardive dyskinesia remains highly prevalent because
of the expanded use of ‘‘second-’’ and ‘‘third’’-
generation antipsychotics and other dopamine
receptor-blocking agents.
Prevention of tardive dyskinesia by judicious use of
these drugs and early diagnosis is essential in
lessening the impact of this iatrogenic disorder on
quality of life and in facilitating remission following
discontinuation of the offending agent.
Deutetrabenazine and valbenazine, two vesicular
monoamine transporter 2 inhibitors approved by the
US FDA, are the mainstay of treatment for tardive
dyskinesia.
In selected cases, other agents, such as botulinum
toxin for tardive dystonia, zolpidem for tardive
akathisia, amantadine for mild symptoms, or deep
brain stimulation for refractory symptoms, may also
be relevant treatment options.
 N. Niemann, J. Jankovic

1 Introduction hypo- or hyperkinetic movement caused by DRBAs, is best

avoided in favor of more descriptive terms, based on
specific predominant phenomenology [5, 13, 14]. The Di-
Tardive dyskinesia (TD), a term coined by Faurbye et al.
agnostic and Statistical Manual of Mental Disorders, Fifth
[1] in 1964, represents a group of delayed-onset (i.e.,
Edition (DSM-5) defines TD as ‘‘involuntary athetoid or
‘‘tardive’’), persistent iatrogenic movement disorders sec-
choreiform movements (lasting at least a few weeks)
ondary to exposure to dopamine receptor-blocking agents
generally of the tongue, lower face and jaw, and extremi-
(DRBAs). These drugs have also been referred to as
ties (but sometimes involving the pharyngeal, diaphrag-
‘‘neuroleptics’’, but we prefer the term DRBAs, which we
matic, or trunk muscles) developing in association with the
use in this review. TD is typically manifested by stereo-
use of a neuroleptic medication for at least a few months’’
typies (especially involving the oro-bucco-lingual [O-B-L]
[15]. However, this definition is not sufficiently broad to
muscles), dystonia, chorea, akathisia, myoclonus, tremor,
cover the phenomenological spectrum of tardive movement
or tics [2–5]. All DRBAs, including typical or first-gener-
disorders and does not include TS due to DRBAs that are
ation antipsychotics (FGAs), atypical or second-generation
not antipsychotics [4].
antipsychotics (SGAs), and third-generation antipsychotics
Although some patients have limited insight into their
(TGAs), and drugs used for gastrointestinal indications
condition (and thus may not be bothered by it) [16], TD is
(e.g., metoclopramide, prochlorperazine, and promet-
by no means a benign condition. Other than being
hazine), may potentially cause TD [3]. Although SGAs are
uncomfortable and socially embarrassing, TD can be
associated with a reduced risk of TD, their introduction has
associated with reduced quality of life [3], risk of bodily
had limited impact on the incidence of TD [6]. This is
injury (excoriation of the lips, increased tendency to fall),
partly because use has increased with expanded labeling
and even death (neuroleptic malignant syndrome, respira-
[7]. Many DRBAs are approved for treatment of not only
tory dyskinesias with life-threatening hypo- and hyper-
schizophrenia but also bipolar disorder, depressive epi-
ventilation from uncoordinated movements of the
sodes, or irritability in autistic disorder and are frequently
diaphragm and chest wall) [17].
used off-label (e.g., in the treatment of anxiety, insomnia,
Tardive parkinsonism is a controversial entity where
etc.) [8, 9]. TD remains a challenging disorder for the
parkinsonism persists long after the offending agent has
clinician to manage because of a lack of reliable predictors
been withdrawn [3], unlike drug-induced parkinsonism
to guide risk stratification, variable clinical presentation,
[18]. In a study of 20 patients who developed parkinsonism
and the continued need for DRBAs to control psychiatric or
while being treated with a variety of DRBAs, 123I-ioflu-
gastrointestinal symptoms.
pane single-photon emission computed tomography
The goal of this review is to provide an update on
(SPECT) revealed that 11 (55%) patients had evidence of
recognition and management of TD with a focus on
presynaptic nigrostriatal deficits, suggestive of underlying
vesicular monoamine transporter 2 (VMAT2) inhibitors,
idiopathic Parkinson’s disease [19]. It is therefore possible
especially deutetrabenazine and valbenazine, which
that some patients diagnosed with tardive parkinsonism
recently received US FDA approval for the treatment of
had idiopathic Parkinson’s disease that had been unmasked
TD. Non-FDA-approved drugs, for which the level of
by dopamine receptor blockade. Thus, a more definite
evidence is comparatively lower, are also briefly reviewed.
diagnosis of tardive parkinsonism may require neu-
roimaging demonstrating a lack of striatal dopaminergic
denervation.
2 Definitions and Clinical Phenomenology
Neuroleptic withdrawal-emergent syndrome refers to
dyskinesias (often choreiform), chiefly involving the limbs,
DRBA-related movement disorders include (1) drug-in-
body, and neck, that arise as a withdrawal phenomenon,
duced movement disorders, such as tremors, myoclonus,
occurring most often in children during fast tapering or
parkinsonism, acute dystonic reaction, acute akathisia, and
after abrupt discontinuation of DRBAs. It is always diag-
neuroleptic malignant syndrome, which generally resolve
nosed retrospectively, as it is self-limiting [20].
when the offending drug is discontinued and (2) tardive
The co-occurrence of multiple different phenomenolo-
syndrome (TS), which includes TD and other movement
gies, such as akathisia and stereotypic dyskinesias, in a
disorders, such as parkinsonism, gait disorders, with-
patient with a history of exposure to DRBAs generally
drawal-emergent syndrome, and a variety of sensory
increases the likelihood that the movement disorder rep-
symptoms that persist even when the offending DRBA is
resents TD. When TD is suspected based on presenting
discontinued [2–4, 10, 11]. The terms ‘‘extrapyramidal’’
phenomenology in the absence of history of treatment with
and extrapyramidal syndrome or ‘‘EPS’’, still used even in
DRBAs, it is critical that medical, hospital, and pharmacy
some recent reviews in psychiatric literature [12], for any
records are carefully reviewed for any evidence of prior
Tardive Dyskinesia
exposure to DRBAs. Other etiologies should also be con-
sidered, such as edentulous oral dyskinesias [21], other
drug-induced dyskinesias (including oral dyskinesias sec-
ondary to anticholinergic medications and levodopa-in-
duced dyskinesias) that resolve following drug
discontinuation [22, 23], Huntington disease [24, 25],
Wilson’s disease and other metabolic diseases [26], Tour-
ette syndrome [27], and immune-mediated chorea [28].
Some patients treated with DRBAs for their hyperkinetic
disorder, such as Huntington disease and Tourette syn-
drome, develop TD in addition to the underlying movement
disorder [29, 30].
3 Epidemiology and Risk Factors
Early studies of the risk of TD due to DRBA (specifically
antipsychotic drugs) exposure indicated overall prevalence
rates close to 30% [31–33]. The annual incidence rate of
TD is approximately 5% with FGAs, followed by a roughly
linear increase in incidence rates, at least during the initial
5 years of exposure [31, 34, 35]. However, in one study of
362 psychiatric outpatients followed for up to 25 years,
incidence rates were 32% after 5 years, 57% after 15 years,
and 68% after 25 years of exposure [34]. Elderly patients
appear to be at much higher risk of early-onset TD due to
exposure to FGAs, with 1-year incidence rates as high as
26% reported in prospective studies of patients with mean
age[65 years [36, 37]. In a review of the literature from
2004, annual rates of TD associated with SGAs were as
low as 0.8% in adults and 5.3% in patients aged[54 years
[38]. This suggests that the SGAs reduced the incidence of
TD compared with FGAs, particularly in elderly popula-
tions [39]. Coupled with lower rates of early parkinsonism
[40] and acute dystonic reactions with SGAs [41], these
findings helped fuel the expectation that the introduction of
SGAs would herald a vast reduction in rates of TD.
Several studies have examined the relative frequency of
TD related to FGAs versus SGAs. The annual incidence of
TD was found to be 5.5% with FGAs and 3.9% with SGAs
based on a systematic review of studies published between
2004 and 2008 [42]. The same study also found lower
prevalence rates of TD with SGAs (13.1%) compared to
FGAs (32.4%). However, the US-based CATIE (Clinical
Antipsychotic Trials of Intervention Effectiveness) [43]
and an intention-to-treat analysis of the UK-based
CUtLASS-1 (Cost Utility of the Latest Antipsychotics in
Schizophrenia Study Band 1) [44] did not demonstrate a
significant difference in TD rates between FGAs and
SGAs. Most recently, a meta-analysis of 41 studies yielded
TD prevalence rates of 20.7 and 30.0% with current use of
SGAs and FGAs, respectively [6]. However, because data
regarding TD severity were insufficient, the authors could
not determine whether the observed 9.3% difference in
prevalence rates translated into meaningful clinical sig-
nificance. As is evident from these studies, considerable
controversy still exists as to whether and how much SGAs
reduce the risk of TD. Although the preponderance of
evidence is that SGAs lower the risk of TD, there are many
reports of TD secondary to SGA use, including clozapine
[45] (in some cases with limited or no prior exposure to
DRBAs [46] and in others with prior exposure [47, 48]),
and the TGA aripiprazole [49].
The risk of TD in pediatric populations has been con-
sistently reported to be lower than in adult populations.
Studies of TD in children have yielded prevalence rates
ranging from 7.6 to 20.4% [50–54]. A systematic review
[42] reported the annual incidence rate at just 0.35% in
children. However, in a recent prospective study of 265
DRBA-naı̈ve or ‘‘quasi-naı̈ve’’ (less than 30 days of prior
DRBA exposure) children, 5.8% were found to meet cri-
teria for TD at 1-year follow-up after starting an SGA,
suggesting that the risk of TD in children may not be
significantly different from the risk in adults, although the
dropout rate was 59% [55].
Risk stratification in the era of SGA is difficult for
several reasons. Most studies of SGA are short term,
employ restrictive enrollment criteria (thus potentially
excluding the patients at highest risk of TD), include
patients with prior exposure to or current use of FGAs, and
often use haloperidol as the comparator or no comparator at
all [6, 17]. Further, earlier clinical trials of SGAs used
higher than recommended doses of haloperidol, thus
potentially exaggerating the initially perceived benefit of
SGAs [38, 56]. Aside from type of DRBA and older age,
other risk factors for the development of TD include
cumulative exposure to DRBAs (duration and dose)
[57, 58]. Paradoxically, repeated interruptions of DRBA
treatment (e.g., drug holidays) increase the risk of TD [59].
Classic TD (O-B-L stereotypy) tends to occur more fre-
quently in elderly women, whereas tardive dystonia is more
common in young men [4, 32, 60, 61]. Other risk factors
for TD include non-white race, mood disorders, diabetes
mellitus, intellectual disability, prior history of brain
injury, parkinsonism, and acute dystonic reactions
[3, 17, 62].
Although metoclopramide was the most common cause
of TD in patients followed in a movement disorders clinic
about 10 years ago, the rate of TD secondary to this drug
has substantially decreased, partly because of black box
warning and increased awareness about this adverse effect
among internists and gastroenterologists [63–65]. Meto-
clopramide has also been reported to cause classic TD in
children, even in an infant [53, 66].

4 Pathophysiology
Drugs with the potential to cause TD include all FGAs,
SGAs, and TGAs, antiemetics (metoclopramide, prochlor-
perazine, promethazine, clebopride, cisapride), anti-manic
agents (lithium), calcium channel blockers (cinnarizine,
flunarizine), and serotonin reuptake and serotonin nore-
pinephrine reuptake inhibitors (duloxetine, citalopram)
[2, 3].
Movements are regulated predominantly by two parallel
striato-pallidal pathways [67, 68]. The globus pallidus
interna (GPi) provides an inhibitory input to the thalamus.
Increased or decreased activity in the GPi thus inhibits or
facilitates, respectively, thalamo-cortical activity and
therefore movement. The GPi is chiefly regulated by the
‘‘direct’’ pathway, a single neuron pathway from the motor
striatum to the GPi, which is inhibitory and therefore
facilitates movement, and by the ‘‘indirect’’ pathway, a
three-neuron pathway from the motor striatum via the
globus pallidus externa (GPe) and subthalamic nucleus
(STN) to the GPi, which is excitatory and therefore inhibits
movement. Dopaminergic stimulation of these pathways
regulates (and facilitates) movements by exciting striatal
medium spiny neurons (MSNs) in the ‘‘direct’’ pathway
(expressing dopamine D1 receptors) and by inhibiting
those in the ‘‘indirect’’ pathway (expressing D2 receptors).
TD has been traditionally attributed to hypersensitivity
and upregulation of dopamine D2 receptors in the motor
striatum due to chronic iatrogenic dopamine receptor
blockade, although this theory does not explain why TD
persists after withdrawal of the offending agent [68]. In one
study, the dose of haloperidol correlated with the frequency
of vacuous chewing movements and extent of D2 receptor
occupancy in rats [69]. A study utilizing positron emission
tomography in human subjects with schizophrenia
demonstrated increased dopamine D2 receptor binding in
patients with a history of chronic DRBA exposure com-
pared with controls [70]. D2 receptor hypersensitivity may
enhance the inhibitory effect of dopamine in the ‘‘indirect’’
pathway and lead to hyperkinetic movement disorders.
Clinical evidence lends support to this theory. For instance,
increasing the dose of a DRBA will suppress involuntary
movements associated with TD, at least in the short-term,
whereas sudden withdrawal or dose reduction may pre-
cipitate or worsen TD [3]. Compared with FGAs, SGAs
(particularly clozapine and quetiapine) have lower D2
receptor affinity [71] and dissociate faster from the D2
receptors (as quickly as 12–24 h vs. several days) [72].
They also antagonize 5-HT2A/C receptors, which is asso-
ciated with reduced D2 antagonist binding in the motor
striatum relative to the nucleus accumbens, which may
translate into less risk of drug-induced parkinsonism
N. Niemann, J. Jankovic
without sacrificing the antipsychotic effect of the drug
[67, 68]. These effects may reduce the risk of TD due to
less D2 receptor upregulation [2]. Another theory proposes
that chronic dopamine receptor blockade leads to increased
metabolism of dopamine, with production of neurotoxic
free radicals resulting in nigrostriatal neurodegeneration
[73].
In addition to the dopaminergic and serotonergic sys-
tem, the GABAergic system may also play a role in the
pathophysiology of TD. For example, MSNs in the indirect
pathway receive feedforward inhibition from GABAergic
interneurons, which are thought to be damaged or dys-
functional (thus, promoting movement) in patients who
develop TD [74]. On the other hand, GABAergic drugs,
such as baclofen or benzodiazepines, have not been found
to produce consistent benefit in patients with TD [3].
Genetic factors may also play an important role in the
risk of TD. For instance, polymorphisms in several genes,
including those associated with drug metabolism;
dopaminergic, GABAergic, and serotonergic transmission;
neuronal functioning and connectivity; and oxidative
stress, have been implicated as susceptibility factors for TD
[75].
Synaptic plasticity is a dynamic process that allows
neurotransmission to be altered by prior experience [74].
This process is acutely impaired in the neocortex in
humans after administration of DRBAs and deranged in
several other hyperkinetic movement disorders (such as
Huntington disease and levodopa-induced dyskinesias) and
in patients with schizophrenia after multiple episodes of
psychosis compared with patients with schizophrenia with
first-time psychosis. Chronic dopamine receptor blockade
may thus lead to maladaptive synaptic plasticity associated
with an imbalance between the direct and indirect basal
ganglia pathway, resulting in the inability to unlearn
improper motor programs that are associated with abnor-
mal movements. This serves as a possible unifying theory
to explain why TD most often persists months and years
after withdrawal of DRBAs.
5 Rating the Severity of Tardive Dyskinesia (TD)
Although several TD rating scales exist, the Abnormal
Involuntary Movement Scale (AIMS), developed in the
1970s to evaluate abnormal movements related to TD
[76–78], is the most frequently used scale in studies eval-
uating treatments of TD [79]. The AIMS is a 12-item
clinician-administered rating scale that assesses the sever-
ity of abnormal movements in the face, neck, trunk, and
extremities (items 1–7); the severity, functional impact,
and patient awareness of their abnormal movements (items
Tardive Dyskinesia
8–10); and dental status and use of dentures (item 11–12),
which may be associated with edentulous dyskinesia [21]
and misdiagnosed as classic TD [77]. Items 1–10 are
scored along a 5-point scale (0 = none, 5 = severe),
whereas items 11–12 require yes/no answers. Experienced
raters generally have higher interrater reliability and record
more consistent scores over time [80]. Although the AIMS
has been used in most studies assessing response to phar-
macologic treatment of TD, another validated rating scale
is the St. Hans Rating Scale [81].
6 Prevention and Remission
Judicious use of DRBAs is the first step in preventing TD.
Unfortunately, SGAs are increasingly prescribed across all
age groups [82–84] and off-label uses have expanded to
include depressive disorder, a variety of behavioral prob-
lems, insomnia, anxiety, and head trauma [85]. Conversely,
prescriptions for metoclopramide, an antiemetic and gas-
trointestinal prokinetic agent with D2 receptor-blocking
properties, one of the most common cause of TD a few
years ago [63], have decreased since February 2009, when
the FDA issued a black box warning regarding the risk of
TD [86].
According to American Psychiatric Association guide-
lines, patients should be examined for signs of TD before
initiating DRBA therapy, at least biannually in patients
taking DRBAs, and upon changes in DRBA dose or agent
or observation of previously undetected movements [87].
Furthermore, patients should be clinically assessed for
abnormal involuntary movements if they are taking FGAs
every 6 months, or every 3 months if at increased risk; if
they are taking SGAs they should be assessed every
12 months, or every 6 months if at increased risk. Informed
consent when prescribing a DRBA is prudent practice and
may prevent legal consequences.
To mitigate the risk of TD, DRBAs with a lower risk of
TD should be preferentially used and at the lowest effective
dose for the shortest period of time with frequent critical
appraisal of the continued need for treatment. Patients who
are maintained chronically on DRBAs should frequently be
reassessed for early signs of TD. When TD is identified, it
is important to try and withdraw DRBAs in patients who
can tolerate it. DRBAs should be withdrawn slowly, as
sudden withdrawal may worsen or precipitate TD [3] and
worsen the underlying psychiatric disorder [88]. The SGAs
risperidone and olanzapine may be effective in suppressing
TD, but the American Academy of Neurology (AAN) 2013
guidelines cautioned against the use of SGAs in the treat-
ment of TD as they may themselves cause TD [89]. In
patients who require continued antipsychotic treatment,
clozapine and quetiapine (and possibly pimavanserin,
which has not yet been found effective outside of PD-
related psychosis [90]) may be considered, based on a
likely reduced risk of TD [3], although further studies are
needed to support this approach [89]. For patients requiring
treatment of nausea, antiemetics without dopamine recep-
tor-blocking activity should be considered first line.
Variable TD remission rates have been reported in the
literature. In a study of 49 psychiatric patients with TD, 36
were able to completely stop DRBAs. During follow-up
ranging from 1 to 59 months (mean * 40 weeks), 2% had
complete resolution of TD, whereas 20% were noted to
have significant improvement of symptoms [91]. In a large
cohort of 108 patients with TD and mean DRBA expo-
sure of * 4.8 years, the majority had been treated with
DRBAs for mood disorders or metoclopramide for gas-
trointestinal illness (94% non-psychotic indication) [92].
The inciting drug was completely withdrawn in all cases.
After a mean follow-up of 3.1 years, complete remission
was seen in 13% of patients, but only 2.8% were not
receiving symptomatic treatment. In contrast, remission
rates up to 62% have been reported in other studies where
patients continued treatment with DRBAs after developing
TD [93, 94], likely due to masking of symptoms secondary
to dopamine receptor blockade.
7 Treatment of TD
Figure 1 outlines a general approach to the treatment of
TD. Although, historically, many different drugs have been
used in the treatment of TD, as outlined in Fig. 1 and in the
text, the authors currently treat TD almost exclusively
using VMAT2 inhibitors because of their well-documented
efficacy, tolerability, safety, and their FDA approval.
Table 1 compares the clinical pharmacology of the
VMAT2 inhibitors, and Table 2 details a general outline
for the management of potential side effects related to
treatment with VMAT2 inhibitors. Evidence based guide-
lines regarding the treatment of TD have previously been
published [89, 95].
7.1 Drugs with High Level of Evidence for Use
in TD
7.1.1 Dopamine-Depleting Agents: The Vesicular
Monoamine Transporter 2 (VMAT2) Inhibitors
VMAT2 transports cytoplasmic monoamines, including
dopamine, histamine, norepinephrine, and serotonin, into
presynaptic vesicles by secondary active transportation
using the electrochemical proton gradient generated by the
vesicular membrane H?-ATPase [96]. Monoamines pre-
sent in the cytosol are degraded by monoamine oxidase.
 N. Niemann, J. Jankovic

Differential diagnosis: Stop

No Yes
TD? anticholinergic
• Edentulous dyskinesias (unless tardive
• Drug-induced dyskinesias dystonia)
(e.g. levodopa)
• Hunngton disease and
other genec choreas • Reduce dose
Chronic
• Wilson’s disease and other No Yes • Consider
DRBA use
metabolic disorders Taper off necessary? clozapine,
• Touree syndrome slowly queapine, or
• Immune-mediated choreas possibly
pimavanserin
Persistent TD

Tardive Tardive Tardive Dose Comments

stereotypy dystonia akathisia (mg/day)
and/or chorea
Tetrabenazine 25-200 Monitor for akathisia,
X
depression, insomnia,
Deutetrabenazine 12-48 parkinsonism, sedation*
X
Valbenazine X 40-80
Deep brain Target: Experienced centers only
X (refractory) X
stimulation GPi
Botulinum toxin X X Variable 1st line for focal dystonia
Amantadine 100-300 Monitor for cognitive
X X X dysfunction and
hallucinations
Baclofen X 10-80 Monitor for sedation
Clonazepam 80-240 Monitor for sedation. May
X X
develop tolerance
Gingko biloba 0.25-4** Caution with use of
X X
(Egb-761) antiplatelets/anticoagulants
Propranolol 30-160 Monitor heart rate and blood
X X
pressure
Zolpidem X X 10-30 Monitor for sedation
Trihexyphenidyl 1-20 mg Monitor for sedation and
X
anticholinergic side effects
Fig. 1 Management of tardive dyskinesia. DRBA dopamine receptor- may be better tolerated than tetrabenazine. **240 mg/day used in
blocking agent, GPi globus pallidus interna, TD tardive dyskinesia, randomized controlled trial
VMAT2 vesicular monoamine transporter 2. *Similar side effects but

Inhibition of VMAT2 thus reduces presynaptic storage and
release of monoamines, particularly dopamine (Fig. 2
[97]). Whereas VMAT2 is present only in the central
nervous system, VMAT1 is present both centrally and
peripherally [98]. Reserpine, a nondiscriminatory VMAT1/
2 inhibitor previously used to treat hypertension and
hyperkinetic movement disorders, is therefore associated
with multiple peripheral side effects related to peripheral
VMAT1 inhibition, such as bronchospasm, nausea, vom-
iting, diarrhea, hypotension, itching, and nasal stuffiness
[99]. The selective VMAT2 inhibitors tetrabenazine,
deutetrabenazine, and valbenazine are less likely to be
Tardive Dyskinesia

Table 1 Vesicular monoamine transporter 2 inhibitors

Characteristic Tetrabenazine (XenazineÒ) Deutetrabenazine (AustedoÒ) Valbenazine (IngrezzaÒ)

FDA approval (year) TD (off-label), HD chorea (2008) TD (2017), HD chorea TD (2017)

Pivotal trials leading to FDA approval Not applicable ARM-TD, AIM-TD KINECT-2, KINECT-3
for TD
Mechanism of action Reversible inhibition of VMAT2 Reversible inhibition of Reversible inhibition of
VMAT2 VMAT2
Active metabolites Yes Yes Yes
Half-life (h) of active metabolites 5–7 9–10 15–22
Long-term efficacy and safety data * 20 *1 *1
(years)
Special considerations regarding None Take with fooda None
administration
Initial dose (mg/day) 12.5 6 40
Titration (mg/week) 12.5 6 40
Usual dose range (mg/day) 50–100 (maximum 200) divided 24–48c divided in two doses 40 or 80 as one dose
in three doses a dayb a day a day
CYP cytochrome P450, FDA US Federal Drug Administration, HD Huntington disease, TD tardive dyskinesia, VMAT2 vesicular monoamine
transporter 2
a
Increases the peak plasma concentration (Cmax) of the active metabolites
b
Consider CYP2D6 genotyping for doses[50 mg/day
c
In some cases, higher doses, up to 72 mg as used in some HD studies, may be required

Table 2 Practical management of side effects related to vesicular monoamine transporter 2 inhibitors
Side effect Management strategy

Medication Review co-administered medications, switch to alternative agents if interactions are found
interactionsa
Any side effect Consider dose reduction
Akathisia Clonidine, gabapentin, propranolol, zolpidem
Anxiety and Selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants,
depression mirtazapine
Insomnia Eszopiclone, zaleplon, zolpidem, trazodone, mirtazapine
Parkinsonism Amantadine, ropinirole, pramipexole, rotigotine, levodopa
Sedation Armodafinil, modafinil, methylphenidate, lisdexamfetamine
CYP cytochrome P450, VMAT2 vesicular monoamine transporter 2
a
Caution with concomitant use of CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, cinacalcet, mirabegron [may increase concentration of active
metabolites of all VMAT2 inhibitors]), CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, fluconazole, ketoconazole, verapamil, cimetidine
[may increase concentration of valbenazine and its metabolite, [?]-a-DHTBZ]), and QTc-prolonging agents (e.g., amitriptyline, citalopram,
escitalopram, quetiapine, venlafaxine, or CYP2D6 inhibitors by virtue of increasing VMAT2 inhibitor metabolites [all VMAT2 inhibitors])

associated with peripheral side effects, as they do not
inhibit peripheral VMAT1 and are therefore better toler-
ated. VMAT2 inhibitors have never been associated with
the development of TD. A single published report [100] is
difficult to accept as a case of tetrabenazine-induced TD
[99].
7.1.2 How Do VMAT2 Inhibitors Reduce Unwanted
Movements in TD?
As discussed in the pathophysiology section, the brain of a
patient with TD has been postulated to compensate for
chronic dopamine receptor blockade by upregulating and
raising the sensitivity of D2 receptors to dopamine (‘‘D2
receptor hypersensitivity’’), amongst other changes,
including alteration of synaptic plasticity. In effect,

Fig. 2 Mechanism of action of VMAT2 inhibitors a VMAT2
sequesters dopamine in presynaptic vesicles. Upon fusion of the
vesicle with the membrane, dopamine is released into the synaptic
cleft to interact with postsynaptic dopamine receptors. b VMAT2
inhibitors block vesicular storage of dopamine. Instead, dopamine is
excessive stimulation of D2 receptors leads to excessive
inhibition of the indirect pathway, which serves to reduce
or stop movements, leading to relative dominance of the
direct pathway [68]. The sum of these changes are exces-
sive movements. At least three ways of addressing the
imbalance between the direct and indirect pathway exist:
1. Stopping the offending agent with the goal of allowing
the D2 receptor sensitivity to normalize and the brain
to unlearn the maladaptive motor programs associated
with TD, although this is rarely effective as discussed
in previous sections.
2. Raising the dose of the offending DRBA, or, if the
patient is not currently on a DRBA, starting a DRBA.
This would serve to further block the hypersensitive
D2 receptors with the hope of ‘‘normalizing’’ the
activity in the indirect pathway. However, as previ-
ously stated, such a course of action, while likely
reducing excessive movements in the short term, is
likely to cause other side effects (such as parkinson-
ism, sedation, and metabolic changes) and may
eventually worsen TD [101].
3. Reducing striatal dopamine using a VMAT2 inhibitor.
Rather than treating the disorder where the problem is,
i.e., at the postsynaptic D2 receptor, a VMAT2
inhibitor preferentially reduces the amount of dopa-
mine stored in presynaptic vesicles and thus the
amount of dopamine released into the synaptic cleft
N. Niemann, J. Jankovic
degraded by monoamine oxidase. In contrast, dopamine receptor-
blocking agents work post-synaptically by blocking membrane-bound
dopamine receptors. VMAT2 vesicular monoamine transporter 2.
Reproduced from Jankovic [97] with permission
[99]. In turn, this leads to less stimulation of hyper-
sensitive D2 receptors and therefore less inhibition of
the indirect pathway, which leads to a reduction of
movements [102]. Less dopamine will also be avail-
able to stimulate postsynaptic D1 receptors in the
direct pathway, which provides another mechanism of
action of VMAT2 inhibitors in TD. However, the
response to a specific dose of any of the VMAT2
inhibitors is likely to be variable, in part depending on
the amount of dopamine present in the presynaptic
terminal and the synaptic cleft, which could be altered
by dopamine-reuptake inhibitors and releasers, such as
amphetamines, and monoamine oxidase inhibitors or
concomitant use of a DRBA.
7.1.3 Tetrabenazine
Tetrabenazine was originally developed in the 1950–1960s
as a novel antipsychotic and antihypertensive agent. It was
approved in the UK in 1971 for the treatment of hyperki-
netic movement disorders, including TD [99]. It was
approved by the US FDA in 2008 for the treatment of
chorea associated with Huntington disease and is currently
being used off-label in the treatment of TD. At least 75% of
tetrabenazine is absorbed after oral ingestion, although it is
generally undetectable (doses of 12.5–50 mg) due to rapid
metabolism, mainly by carbonyl reductase [99], to positive
Tardive Dyskinesia
and negative (?/-) isomers of a- and b-dihydrotetra-
benazine (DHTBZ), which reach their peak plasma con-
centration (Cmax) within 1–1.5 h after each dose [103]. a-
and b-DHTBZ have VMAT2-binding affinities (Ki) of 3.1
and 20 nM, respectively, compared with 100 nM for
tetrabenazine [103, 104]. a- and b-DHTBZ subsequently
undergo conjugation with sulfate and glucuronide, medi-
ated by the cytochrome P450 (CYP) enzyme system,
mainly CYP2D6, prior to renal excretion (75% of each
dose). Tetrabenazine metabolites have limited or no off-
target binding at adrenergic, dopaminergic, and/or sero-
tonergic receptors, although the negative isomer of b-
DHTBZ has a Ki of 53 nM at the D2 receptor, which is of
unclear significance [105]. The half-lives of a- and b-
DHTBZ are 7 and 5 h, respectively [103]. Since poor
metabolizers of the active metabolites of tetrabenazine may
be at higher risk of treatment-associated side effects for a
given dose than intermediate, extended, and ultra-rapid
metabolizers, the FDA has recommended CYP2D6 geno-
typing for doses of tetrabenazine exceeding 50 mg/day
[106]. In a study of 127 patients with a range of hyperki-
netic movement disorders, 11 patients were categorized as
poor, 14 as intermediate, 100 as extensive, and two as
ultra-rapid metabolizers [106]. The titration period was
significantly longer for ultra-rapid metabolizers than for the
other groups (p\0.01), although there were no significant
differences in the total daily dose, treatment response, or
frequency of adverse events between the groups [106]. The
authors concluded, ‘‘these results do not support the need to
systematically genotype all patients prescribed more than
50 mg/day of tetrabenazine, and this recommendation
should be reconsidered’’. Of similar concern for all the
specific VMAT2 inhibitors (tetrabenazine, deutetra-
benazine, and valbenazine), studies have shown that co-
administration with strong CYP2D6 inhibitors (e.g.,
quinidine, paroxetine, fluoxetine) may significantly
increase the area under the curve (AUC), half-life, and
Cmax of the active metabolites, which may increase side
effects [103, 107, 108]. Other potential safety concerns for
these drugs as a group include the propensity for QTc-
prolongation, particularly in individuals with poor
CYP2D6 activity, in the presence of strong CYP2D6
inhibitors, or when co-administered with other agents that
have QTc-prolonging effects (e.g., DRBAs, moxifloxacin,
quinidine). As such, monitoring of the QTc-interval may be
warranted.
Most studies of tetrabenazine in TD have been relatively
small. A single-blind prospective study of tetrabenazine in
TD included 20 patients (15 female) who were assessed via
a randomized videotape protocol before and after treatment
[109]. One patient did not tolerate tetrabenazine because of
sedation and did not complete the study. The average
improvement on the AIMS was 54.2%, from 17.9 to 8.2
(p\0.001), after treatment with tetrabenazine for an
average of 20.3 weeks at a mean daily dose of tetra-
benazine 57.9 mg/day. All patients who completed the
study (95%) reported subjective improvement in symp-
toms, and 85% rated their improvement as moderate or
marked on a global response scale (GRS; where
1 = marked improvement, 4 = no change, 5 = worse).
The only other prospective and single-blind study included
24 chronic psychiatric patients with TD [110]. The study
consisted of a 4-week baseline period during which med-
ications were not altered (14 patients were taking DRBAs),
followed by 4 weeks on placebo during which all DRBAs
were withdrawn, then 6 weeks’ treatment with tetra-
benazine (starting at 50 mg/day with titration to
100–150 mg/day), and finally a 2-week tetrabenazine
washout period, during which patients were given placebo.
At the end of the tetrabenazine period, eight patients had
complete resolution of symptoms, six had marked
improvement, six had little or no change, and four patients
dropped out. The frequency of oral dyskinesias was
reduced by 64% in comparison with placebo.
In two large retrospective series including patients with
various hyperkinetic movement disorders treated with
tetrabenazine for up to 21.6 years,[84% of patients with
TD (total of 242 patients) rated their improvement as either
moderate or marked on a GRS [111, 112]. In these two
studies, the most common side effects of tetrabenazine (all
indications) 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%), all of which occurred in a dose-dependent
fashion. While there is a higher risk of depression while
being treated with tetrabenazine in patients with a pre-
existing history of depression, this symptom can be man-
aged by dose reduction or addition of an antidepressant
[113]. Tetrabenazine has received a level C recommenda-
tion and may be considered for treatment of TD according
to the AAN 2013 guideline [89] as well as in a recently
published systematic review [95].
Given the need for frequent dosing and the considerable
side effects associated with tetrabenazine, novel VMAT2
inhibitors have garnered significant interest in recent years,
and these are discussed in the subsequent sections.
7.1.4 Deutetrabenazine
Deutetrabenazine, a version of tetrabenazine containing
deuterium (also known as ‘‘heavy hydrogen’’: hydrogen
with one neutron rather than none) as two trideuter-
omethoxy groups in place of two methoxy groups, is a
novel and highly specific VMAT2 inhibitor [99]. Deuter-
ation does not alter the target pharmacology of a drug
[114]. At least 80% of deutetrabenazine is absorbed after

oral ingestion, although it is generally undetectable due to
rapid metabolism, also by carbonyl reductase, to deuterated
a- and b-DHTBZ, which reach Cmax within 3–4 h after
each dose [107]. These metabolites are then further
metabolized by CYP2D6. More than 75% of each dose is
excreted renally. The half-life of the active metabolites is
9–10 h according to the prescribing information [107].
There is no significant difference in off-target binding or
VMAT2-binding affinity (Ki) for the deuterated than for
the non-deuterated forms of a- and b-DHTBZ (3.8 vs.
3.1 nM and 22 vs. 20 nM, respectively) [104]. By
strengthening the carbon–hydrogen bond, deuteration
slows metabolism of the active metabolites, resulting in
longer half-lives (from 4.8 to 8.6 h), larger AUC, and lower
Cmax than an identical dose of tetrabenazine, according to
Stamler et al. [115]. Food administration increases the Cmax
of the active metabolites deutetrabenazine (but not tetra-
benazine) by 50% [103, 107]. Clinically, the pharmacoki-
netic advantages of deutetrabenazine translate into less
frequent dosing (twice vs. three times daily) and lower dose
per drug administration (6 mg is roughly equivalent to
12.5 mg) than for tetrabenazine to achieve the same clin-
ical effect, which may translate into fewer adverse effects
due to lower peak plasma concentrations [99]. This may
further result in less need for CYP2D6 genotyping, if such
testing is pursued at all [106]. Potential safety concerns for
deutetrabenazine with respect to concomitant use of strong
CYP2D6 inhibitors and QTc-prolonging agents are other-
wise similar to those for tetrabenazine (see Sect. 7.1.3).
Deutetrabenazine received FDA approval for the treat-
ment of TD on 30 August 2017 based on two pivotal
double-blind, randomized, placebo-controlled trials: the
phase II/III trial ARM-TD (Aim to Reduce Movements in
TD) and the phase III trial AIM-TD (Addressing Involun-
tary Movements in TD) [107]. In both studies, patients
could continue use of DRBAs or antidepressants provided
there had been no recent change in these medications.
ARM-TD randomized 117 patients 1:1 to receive
deutetrabenazine or placebo starting at 12 mg daily (di-
vided in two doses) followed by titration with 6 mg/day/
week for up to 6 weeks until dyskinesia was controlled,
uncontrollable side effects occurred, or a maximum dose of
48 mg/day was reached [116]. This was followed by a
6-week maintenance period. The mean daily dose was
38.8 mg at the end of the study period. Deutetrabenazine
reduced least-squared (LS) mean AIMS scores by - 3.0
compared with - 1.6 for placebo (p = 0.019). Further,
there was a nonsignificant difference in the Clinical Global
Impression of Change (CGIC) and Patient Global Impres-
sion of Change (PGIC), both rated from 1 (very much
improved) to 7 (very much worse), in favor of deutetra-
benazine over placebo. AIM-TD randomized 298 patients
1:1:1:1 to receive either placebo or deutetrabenazine 12,
N. Niemann, J. Jankovic
24, or 36 mg daily (divided in two doses) for 8 weeks after
a 4-week titration period [117]. LS mean AIMS scores
improved by - 3.2 (p = 0.003) and - 3.3 (p = 0.001) in
the groups receiving 24 and 36 mg/day, respectively,
compared with - 1.4 for placebo. Improvement in AIMS
scores for the group receiving 12 mg/day were insignificant
(p = 0.217). Treatment success was defined as ‘‘much
improved’’ or ‘‘very much improved’’ on the CGIC and
was achieved in 49% of patients receiving 24 mg/day
(p = 0.014) and 44% of those receiving 36 mg/day
(p = 0.059) compared with 26% with placebo, whereas
there was no significant difference in outcome on the PGIC
of deutetrabenazine compared with placebo. In a pooled
analysis (not including patients receiving 12 mg/day) of
the results of both ARM-TD and AIM-TD, 30.0% of
patients receiving deutetrabenazine (vs. 14.8% for placebo)
had a[50% reduction of the AIMS score, equal to a
number needed to treat (NNT) of seven (95% confidence
interval [CI] 4–18) [118]. For CGIC and PGIC, the results
were 46.9% (vs. 33.0%) with an NNT of eight (95% CI
4–45) and 42.5% (vs. 30.4%) with an NNT of nine (95% CI
5–145), respectively, for a favorable outcome, i.e., out-
comes of ‘‘very much improved’’ (score 1) or ‘‘much
improved’’ (score 2). Deutetrabenazine was well-tolerated,
with low rates of side effects in both ARM-TD and AIM-
TD. In fact, the cumulative side effects of deutetrabenazine
versus placebo reported in both ARM-TD and AIM-TD
suggest minimal differences between the two groups in
terms of the frequency of reported side effects (sedation,
fatigue, diarrhea, dry mouth, anxiety, akathisia, and
depression), all of which occurred at a rate of B 4.3% in the
deutetrabenazine group [118]. Insomnia occurred in 6.9
versus 1.7% in ARM-TD but was not reported in AIM-TD
[116, 117]. Deutetrabenazine did not result in prolongation
of the QTc interval relative to placebo. A 159-week
extension study of ARM-TD and AIM-TD is currently
underway to assess safety, adverse effects, and efficacy
[119]. An interim analysis of this study at 54 weeks
showed that deutetrabenazine was well-tolerated long term,
with low rates of adverse effects [120]. Deutetrabenazine
has received a level A (established as effective) recom-
mendation for the treatment of TD [95].
A recent study demonstrated that overnight conversion
of tetrabenazine to deutetrabenazine followed by dose
titration to maximize efficacy is well-tolerated and asso-
ciated with improved motor outcome in patients with
chorea associated with Huntington disease [121].
Deutetrabenazine is also FDA approved for the treatment
of Huntington disease [122] and, based on positive pilot
data [123], is being investigated as a treatment for Tourette
syndrome.
Tardive Dyskinesia
7.1.5 Valbenazine
Valbenazine is the purified parent prodrug of the (?)-iso-
mer of a-DHTBZ [85, 124, 125]. Approximately 49% of
ingested valbenazine is absorbed following oral adminis-
tration [108]. Valbenazine is metabolized via two routes:
(1) hydrolysis of the valine ester leads to conversion to a-
DHTBZ, the primary VMAT2-inhibitor (Ki = 1–4.2 nM),
which is further metabolized by CYP2D6, and (2) mono-
oxidative metabolism of valbenazine by CYP3A4/5, which
generates the mono-oxy metabolite NBI-13611
(Ki = 160–220 nM), both of which have no off-target
binding [85, 105, 108, 126]. Cmax of valbenazine and a-
DHTBZ is reached 0.5–1 and 4–8 h, respectively, after
ingestion. Concomitant intake of fat significantly decreases
the Cmax (47%) and AUC (13%) of valbenazine, but the
Cmax and AUC of a-DHTBZ is unchanged. Valbenazine
itself has low affinity for VMAT2 (Ki = 110–190 nM).
The half-life of valbenazine and a-DHTBZ is 15–22 h.
These pharmacodynamic and -kinetic advantages allow for
once-daily dosing and potentially better tolerability com-
pared with tetrabenazine. Valbenazine metabolites pre-
dominantly undergo renal excretion (60%). Safety
concerns with regards to concomitant use of strong
CYP2D6 inhibitors or QTc-prolonging agents are other-
wise similar to those with tetrabenazine and deutetra-
benazine, with the additional warning that co-
administration of strong CYP3A4 inhibitors (e.g., keto-
conazole) may increase the Cmax and AUC of a-DHTBZ
and potentially increase the risk of clinically significant
side effects.
KINECT-2, a phase II, double blind, randomized, pla-
cebo-controlled dose-titration study, randomized 102
patients to placebo or valbenazine 25 mg/day with
biweekly increments of 25 mg up to 75 mg/day (76% of
patients reached the maximum dose) [126]. At week 6, LS
mean AIMS scores were reduced by - 2.6 for the valbe-
nazine group compared with - 0.2 for the placebo group
(p = 0.0005). Results on the CGI-TD and PGIC identified
as ‘‘much improved’’ or ‘‘very much improved’’ were also
significantly higher for valbenazine than for placebo (66.7
vs. 15.9%, p\0.0001, and 57.8 vs. 31.8%, p = 0.001,
respectively). Valbenazine received FDA approval for the
treatment of TD on 11 April 2017 [108] based largely on
the positive results of KINECT-3, a phase III, double-blind,
randomized, placebo-controlled trial [127]. In this study,
234 patients, of which 86% received concomitant DRBAs,
were randomized 1:1:1 to receive once-daily placebo or
valbenazine (40 or 80 mg) for 6 weeks. LS mean AIMS
scores improved by - 1.9 for valbenazine 40 mg/day
(p = 0.002) and - 3.2 for valbenazine 80 mg/day
(p\0.001) compared with - 0.1 for placebo. No signifi-
cant difference on CGI-TD scores were seen at 6 weeks for
valbenazine (40 or 80 mg/day) compared with placebo,
although further analyses in the per-protocol population
showed significant improvement for valbenazine (both
p = 0.011 for 40 and 80 mg/day) compared with placebo.
In a pooled analysis (all doses) of the results of KINECT-2
and -3, a total of 36.5% of patients in the valbenazine group
(vs. 12.4% for placebo) had a[50% reduction of AIMS
scores, yielding an NNT of five (95% CI 3–7) [128]. The
pooled results of patients achieving a favorable response
(i.e., score 1 or 2) on the CGI-TD was 40.4% for valbe-
nazine (vs. 18.6% for placebo), yielding an NNT of five
(95% CI 4–9). The most common side effects reported in
both studies (valbenazine 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%) [128]. In
KINECT-3, up to 4.2% of patients taking valbenazine
reported akathisia and suicidal ideation (vs. 1.3 and 5.3%,
respectively, for placebo) [127]. A recently published
pooled analysis of cardiovascular outcomes showed no
significant differences between the placebo and valbe-
nazine groups [129]. The 1-year KINECT-3 extension
study demonstrated long-term efficacy, safety, and tolera-
bility of valbenazine for the treatment of TD [130]. Val-
benazine has received a level A recommendation for the
treatment of TD [95].
Valbenazine is currently also being investigated in the
treatment of Tourette syndrome.
The role of VMAT2 inhibitors in the treatment of
hyperkinetic movement disorders is evolving. Their future
use may include other indications, including treatment of
self-injurious behaviors and possibly even as antipsy-
chotics. Indeed, tetrabenazine was initially developed as an
antipsychotic. Finally, the hypothesis that one of the
authors (JJ) proposed decades ago, that co-administration
of VMAT2 inhibitors with DRBAs may prevent or reduce
the risk of developing TD, should be tested in a prospective
longitudinal study.
7.2 Drugs with Lower Level of Evidence for Use
in TD
7.2.1 Amantadine
Amantadine is a non-competitive N-methyl-D-aspartate
(NMDA) antagonist with anti-glutamatergic properties
frequently used in the management of levodopa-induced
dyskinesias [23]. It was evaluated in the treatment of TD in
two small (16 and 22 patients) randomized placebo-con-
trolled trials. The studies demonstrated 15–22% (both
p\0.05) reduction of AIMS scores, supporting the short-
term use of amantadine in the treatment of TD when used
in conjunction with DRBAs [131, 132]. Amantadine has
 N. Niemann, J. Jankovic

Table 3 Active phase II or III trials for treatment of tardive dyskinesiaa

Study Status; Phase n Design Intervention Outcome
duration

NCT03254186 Recruiting; II/III 15 Randomized, Propranolol Primary: change in AIMS score. Secondary: Change in
Sep 2017– crossover, hydrochloride CGI-S and CGI-I score
Feb 2019 blinded, PC 20 mg QID vs.
PL
NCT03176771 Recruiting; II/III 240 Multicenter, (1) 40 or Primary: change in AIMS score
Jun 2017– randomized, 80 mg/day MT-
Jul 2019 blinded, PC 5199b vs. PL
(2) Extension
study: 40 or
80 mg MT-
5199
NCT01804920 Not II/III 16 Randomized, D-serine (up to Primary: change in AIMS score
recruiting; blinded 4 g/day) vs. PL
Mar 2013–
Jan 2018
NCT02198794 Not III 343 Open-label SD-809c Primary: long-term incidence of AE, SAE, drug-related
(RIM-TD) recruiting; extension AE, AE leading to drug withdrawal. Secondary:
Oct 2014– study change in AIMS score, QOL, PGIC, proportion of
Sep 2019 responders
AE adverse effect, AIMS Abnormal Involuntary Movement Scale, CGI-I Clinical Global Impression of Improvement, CGI-S Clinical Global
Impression of Severity, PC placebo-controlled, PGIC Patient Global Impression of Change, PL placebo, QID four times daily, QOL quality of
life, SAE serious adverse effect
a
From http://www.clinicaltrials.gov using search terms ‘‘tardive dyskinesia,’’ ‘‘not yet recruiting,’’ ‘‘recruiting,’’ ‘‘active, not recruiting,’’ ‘‘phase
2, 3’’
b
MT-5199 = valbenazine
c
SD-809 = deutetrabenazine

received a level C (possibly effective) recommendation for
the treatment of TD [95]
7.2.2 Clonazepam
Clonazepam, a GABAA agonist (benzodiazepine), was
evaluated in a 12-week double-blind, randomized, cross-
over trial that included 19 patients with TD [133]. An
overall 37% (p\0.001) decrease in the Maryland Psychi-
atric Research Center Movement Disorders Scale was seen
at 12 weeks. Tolerance developed within 3–9 months, so
clonazepam is therefore recommended only for short-term
(\3 months) treatment of TD. Clonazepam has received a
level B (probably effective) recommendation for the
treatment of TD [95].
7.2.3 Gingko Biloba
A Gingko biloba extract (EGb-761) with antioxidative
properties has been found to be beneficial in the treatment
of patients with schizophrenia with TD [134]. In a double-
blind, randomized, placebo-controlled trial of 157 patients
with TD, treatment with EGb-761 reduced AIMS scores by
an average of - 2.13 (p\0.0001) compared with ?0.1 for
placebo, whereas 51.3% of patients in the EGb-761 group
experienced a[30% (p\0.001) reduction in AIMS scores
compared with 5.1% of patients in the placebo group [135].
Interestingly, a polymorphism in the gene for brain-derived
neurotrophic factor (Val/Val genotype) seems to predict a
favorable response to EGb-761 [136]. Gingko biloba has
received a level B recommendation for the treatment of TD
[95].
7.3 Other Drugs with Minimal or No Evidence
for Use in TD
Several oral agents either have minimal benefit, insufficient
evidence to support or refute their use, or evidence to
support not using them as treatment for TD. These medi-
cations include acetazolamide, anticholinergics (e.g., ben-
ztropine), cholinergics (e.g., donepezil), antioxidants,
buspirone, calcium channel blockers, eicosapentaenoic
acid, levetiracetam, melatonin, pyridoxine, propranolol,
thiamine and other vitamins, and other prescription and
non-prescription treatments [3, 89, 95]. Although anti-
cholinergics may be useful in tardive dystonia, their routine
use in the treatment of so-called extrapyramidal symptoms
should be discouraged because of cognitive side effects
[137, 138] and worsening of O-B-L stereotypies [139].
Zolpidem was reported to be effective for the treatment of
Tardive Dyskinesia
TD and tardive akathisia in a small series of three patients,
although further studies are needed [140].
8 Other Treatment Options
8.1 Botulinum Toxin
Although no controlled trials have evaluated botulinum
toxin in the treatment of TD, several small reports describe
improvement of involuntary tongue movements, O-B-L
stereotypies, pain, and craniocervical dystonia
[2, 3, 141, 142]. Given the absence of controlled trials,
botulinum toxin currently has a level U (insufficient evi-
dence) recommentation for the treatment of TS [95].
8.2 Deep Brain Stimulation
Deep brain stimulation (DBS) of the GPi is reserved for
medically refractory and severely disabling TD (level C
recommendation) [95]. More than 70 cases of DBS tar-
geting the GPi for TD have been reported in the literature
as case reports and case series, in many instances demon-
strating[50% long-term improvement of symptoms on
standardized rating scales [143]. Two case reports have
also reported improvement of tardive dystonia following
treatment with STN DBS [144, 145]. Given the lack of
controlled studies, as well as the invasive nature of the
treatment, DBS cannot be recommended for routine use in
the treatment of TD.
8.3 Electroconvulsive Therapy
Finally, a few case reports and retrospective series report
improvement of TD with electroconvulsive therapy,
although no firm conclusions can be made based on those
reports [144–148].
Table 3 provides a list of active phase II/III studies.
9 Conclusion
Contrary to expectations, TD has not vanished despite the
introduction of SGAs and TGAs, which are marketed as
having a lower risk of TD than FGAs, although this
remains a contentious topic. Instead, changing prescription
practices and increased off-label prescription of these drugs
have placed more patients than ever at risk of this poten-
tially dangerous and disabling condition. Although signif-
icant insights have been gained into the pathophysiology of
TD, much is yet unknown, and there are significant gaps in
our understanding of risk stratification and optimal man-
agement. Prevention by judicious use of DRBAs is
mandatory. Whenever possible, DRBAs should be slowly
withdrawn or switched to an alternative with less or no risk
of TD. When TD does occur, VMAT2 inhibitors, a class of
drugs that now include two FDA-approved medications
(deutetrabenazine and valbenazine) for which evidence of
long-term efficacy and safety exists, are the mainstay of
treatment, including in the setting of concomitant DRBA
exposure. In milder cases, use of amantadine, clonazepam,
or Gingko biloba may also be considered. Finally, DBS
should be reserved for severe, refractory cases, whereas the
main indication for botulinum toxin, anticholinergics, and
muscle relaxants is dystonia, although the evidence is
scarce.
Author contributions NN contributed to the conception, design,
organization, and execution of the study and the writing of the first
and subsequent drafts. JJ contributed to the conception, design,
organization, and execution of the study, to review and critique, and
to writing of the second and subsequent drafts.
Funding No sources of funding were used to conduct this study or
prepare this manuscript.
Compliance with Ethical Standards
Conflict of interest Nicki Niemann has no conflicts of interest that
are directly relevant to the content of this study. Dr. Jankovic has
received research and/or training grants from Adamas Pharmaceuti-
cals, Inc.; Allergan, Inc.; Biotie Therapies; CHDI Foundation; Civi-
tas/Acorda Therapeutics; Dystonia Coalition; Dystonia Medical
Research Foundation; F. Hoffmann-La Roche Ltd; Huntington Study
Group; Kyowa Haako Kirin Pharma, Inc.; Medtronic Neuromodula-
tion; Merz Pharmaceuticals; Michael J. Fox Foundation for Parkinson
Research; National Institutes of Health; Neurocrine Biosciences;
NeuroDerm Ltd; Parkinson’s Foundation; Nuvelution; Parkinson
Study Group; Pfizer Inc.; Prothena Biosciences Inc.; Psyadon Phar-
maceuticals, Inc.; Revance Therapeutics, Inc.; Sangamo BioSciences,
Inc.; St. Jude Medical; and Teva Pharmaceutical Industries Ltd. Dr.
Jankovic has served as a consultant or as an advisory committee
member for Adamas Pharmaceuticals, Inc.; Allergan, Inc.; Merz
Pharmaceuticals; Pfizer Inc.; Prothena Biosciences; Revance Thera-
peutics, Inc.; and Teva Pharmaceutical Industries Ltd. Dr. Jankovic
has also received royalties or other payments from Cambridge;
Elsevier; Future Science Group; Hodder Arnold; Medlink: Neurol-
ogy; Lippincott Williams and Wilkins; and Wiley-Blackwell.
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